Conditions: Immune Thrombocytopenic Purpura (ITP)
Keywords: Immune thrombocytopenic purpura Healthy subjects M254 Intravenous immunoglobulin (IVIg)
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 50
Healthy volunteers: yes

Brief summary:
The purpose of this study is to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of M254 after administration of a single ascending dose and repeat doses in healthy volunteers and immune thrombocytopenic purpura (ITP) patients. The pharmacodynamics of the drug will be measured as platelet response in patients with ITP.

Detailed description:
The Part A of the study is currently not accepting healthy volunteers as the recruitment for the part A has completed.

Arms:
arm 1: Healthy volunteers will receive a single ascending dose of M254 or placebo arm 2: Immune thrombocytopenic purpura (ITP) patients will receive a single ascending dose of M254 followed by IVIg arm 3: ITP patients will receive a single dose of M254 or IVIg, followed by a single dose of the other drug approximately 28 days later arm 4: ITP patients will receive repeated doses of M254

Interventions: intervention 1: Biological: M254 intervention 2: Placebo intervention 3: Intravenous immunoglobulin (IVIg)
Intervention descriptions: intervention 1: M254 administered as intravenous infusion intervention 2: Placebo administered as intravenous infusion intervention 3: IVIg administered as intravenous infusion

Protocol document:
Prot_000.pdf: 
Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
Momenta Confidential Information  
 
Page 1 of 127 
 
 
TITLE PAGE 
Protocol Title: 
A 4-part Phase 1/2 study to evaluate the safety, tolerability, 
pharmacokinetics, and pharmacodynamics of M254 in healthy 
volunteers and in patients with immune thrombocytopenic 
purpura  
Protocol Number: 
MOM-M254-001 
Compound Number: 
M254 
Study Phase: 
Phase 1/2 
Short Title: 
Safety and tolerability of M254 in healthy volunteers and 
immune thrombocytopenic purpura (ITP) patients 
Sponsor  
Sponsor 
Name 
Momenta Pharmaceuticals, Inc. 
Legal 
Registered 
Address 
301 Binney Street 
Cambridge, MA 02142, USA 
Regulatory Agency 
Identifier Number(s) 
NCT: 03866577 
EudraCT: 2018-003534‐32 
Protocol Date: 
Document Version 
Date 
v 8 Global  
 28 April 2020 
This study will be conducted, recorded, and reported in accordance with the Protocol and in 
compliance with the principles of Good Clinical Practice (GCP). These are stated in 
“Guidance for Good Clinical Practice,” International Council for Harmonisation (ICH) of 
Technical Requirements for Registration of Pharmaceuticals for Human Use, the Declaration 
of Helsinki, and any other applicable regulatory requirements. 
CONFIDENTIALITY NOTICE 
The information contained in this protocol and all other information relevant to M254 are the 
confidential and proprietary information of Momenta Pharmaceuticals, Inc., and except as 
may be required by federal, state or local laws or regulation, may not be disclosed to others 
without prior written permission of Momenta Pharmaceuticals, Inc. 
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Protocol: MOM-M254-001 
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Investigator Protocol Agreement 
Study Title: 
A 4-part Phase 1/2 study to evaluate the safety, tolerability, 
pharmacokinetics, and pharmacodynamics of M254 in healthy 
volunteers and in patients with immune thrombocytopenic purpura 
Study Number: 
MOM-M254-001 
Version: 
8 Global  
Date: 
28 April 2020 
 
I will provide access to the study protocol and access to all study-related information to the 
study personnel at my site who are involved with this protocol. I will discuss with them this 
material and the material in the Investigator’s Brochure to ensure that they are fully informed 
about the investigational drug and understand the protocol. All documents will be kept in the 
strictest confidence. 
I confirm that my core staff and I have carefully read and understand this protocol. I agree to 
conduct this study according to the attached protocol. I also agree to conduct this study in 
compliance with Good Clinical Practice (GCP) and all applicable national and local laws and 
regulations, as well as with the requirements of the appropriate Institutional Review Board or 
independent Ethics Committee (IRB/EC) and any other institutional requirements. These are 
stated in “Guidance for Good Clinical Practice,” International Council for Harmonisation 
(ICH) guideline E6(R2) of Technical Requirements for Registration of Pharmaceuticals for 
Human Use, the Declaration of Helsinki, and any other applicable regulatory requirements. 
No changes will be made to the study protocol without prior written approval of the Sponsor 
and the IRB/EC. 
I have read, understand, and agree to abide by all conditions and instructions contained in 
this protocol. 
 
Principal Investigator’s Signature 
 
Date 
 
Name (print): 
 
 
Clinical Site/Institution: 
 
 
 
 
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Protocol: MOM-M254-001 
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Table of Contents 
1 
PROTOCOL SUMMARY .................................................................................................8 
1.1 
Synopsis ...................................................................................................................8 
1.2 
Schedule of Activities ............................................................................................20 
2 
INTRODUCTION ...........................................................................................................36 
2.1 
Study Rationale ......................................................................................................36 
2.2 
Background ............................................................................................................37 
2.2.1 
Disease Background.....................................................................................37 
2.2.2 
Background of Investigational Product, M254 ............................................38 
2.2.3 
Background of Study Product, 
 IVIg ............................................38 
2.3 
Benefit/Risk Assessment .......................................................................................38 
3 
OBJECTIVES AND ENDPOINTS .................................................................................39 
3.1 
Part A (Netherlands only) ......................................................................................39 
3.2 
Part B (USA sites included) ...................................................................................40 
3.3 
Part C (USA sites included) ...................................................................................41 
3.4 
Part D (USA sites included) ...................................................................................42 
3.5 
Hypothesis..............................................................................................................42 
4 
STUDY DESIGN.............................................................................................................42 
4.1 
Overall Design .......................................................................................................42 
4.1.1 
Part A (Netherlands only) ............................................................................43 
4.1.2 
Part B (USA sites included) .........................................................................44 
4.1.3 
Part C (including sites within the USA) ......................................................45 
4.1.4 
Part D (USA sites included) .........................................................................46 
4.1.5 
Study Duration for Participants ...................................................................46 
4.1.6 
Number of Participants ................................................................................46 
4.1.7 
Replacement of Participants ........................................................................47 
4.1.8 
Number of Sites ...........................................................................................47 
4.2 
Scientific Rationale for Study Design....................................................................47 
4.3 
Justification for Dose .............................................................................................47 
4.3.1 
Justification for M254 Dose.........................................................................47 
4.3.2 
Justification for IVIg Dose...........................................................................48 
4.4 
End of Study ..........................................................................................................48 
4.4.1 
End of Study Definition ...............................................................................48 
4.5 
Patient Input on Study Design ...............................................................................48 
5 
STUDY POPULATION ..................................................................................................48 
5.1 
Eligibility Criteria for Healthy Volunteers (Netherlands only) .............................49 
5.1.1 
Inclusion Criteria for Healthy Volunteers....................................................49 
C
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5.1.2 
Exclusion Criteria for Healthy Volunteers ..................................................50 
5.2 
Eligibility Criteria for ITP Patients ........................................................................51 
5.2.1 
Inclusion Criteria for ITP Patients (USA sites included).............................51 
5.2.2 
Exclusion Criteria for ITP Patients (USA sites included) ...........................52 
5.3 
Screen Failures .......................................................................................................53 
6 
STUDY INTERVENTION ..............................................................................................54 
6.1 
Study Intervention(s) Administered .......................................................................54 
6.1.1 
Investigational Products ...............................................................................54 
6.1.2 
Non-investigational Products .......................................................................55 
6.2 
Preparation/Handling/Storage/Accountability .......................................................55 
6.2.1 
Study Drug Packaging and Storage .............................................................55 
6.2.2 
Study Drug Accountability ..........................................................................56 
6.3 
Measures to Minimize Bias: Randomization and Blinding ...................................56 
6.4 
Study Intervention Compliance .............................................................................56 
6.5 
Concomitant Therapy.............................................................................................56 
6.6 
Dose-Cohort Study Escalation Rules .....................................................................57 
6.7 
Stopping Rules .......................................................................................................58 
6.7.1 
Dose-Cohort Study Stopping Rules .............................................................58 
6.7.2 
Dose Limiting Toxicities .............................................................................58 
6.7.3 
Rules for Dosing Adjustments, Withholding or Restarting, Permanent 
Discontinuation ............................................................................................58 
6.7.4 
Study Stopping Rules ...................................................................................59 
6.8 
Intervention After the End of the Study .................................................................59 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................................59 
7.1 
Discontinuation of Study Intervention ...................................................................59 
7.2 
Discontinuation/Withdrawal From the Study ........................................................60 
7.3 
Lost to Follow-up ...................................................................................................61 
8 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................62 
8.1 
General Study Periods............................................................................................62 
8.1.1 
Screening, Enrollment, and/or Randomization ............................................62 
8.1.2 
Treatment Period ..........................................................................................62 
8.1.3 
Follow-up .....................................................................................................63 
8.2 
Efficacy Assessments.............................................................................................63 
8.3 
Safety Assessments ................................................................................................63 
8.3.1 
Adverse Events ............................................................................................63 
8.3.2 
Vital Signs ....................................................................................................64 
8.3.3 
12-Lead ECG ...............................................................................................64 
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8.3.4 
Physical Examinations .................................................................................64 
8.3.5 
Infusion Reaction Evaluation .......................................................................65 
8.3.6 
Clinical Safety Laboratory Assessments .....................................................66 
8.3.7 
Pregnancy Screen .........................................................................................66 
8.4 
Adverse Events and Serious Adverse Events ........................................................66 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information ........66 
8.4.2 
Method of Detecting AEs and SAEs ...........................................................67 
8.4.3 
Follow-up of AEs and SAEs ........................................................................67 
8.4.4 
Regulatory Reporting Requirements for SAEs ............................................67 
8.4.5 
Pregnancy .....................................................................................................68 
8.5 
Treatment of Overdose ..........................................................................................68 
8.6 
Pharmacokinetics ...................................................................................................68 
8.7 
Pharmacodynamics ................................................................................................69 
8.8 
Exploratory Biomarkers and Anti-drug Antibodies ...............................................69 
8.9 
Health Economics/Medical Resource Utilization and Health Economics .............69 
9 
STATISTICAL CONSIDERATIONS.............................................................................70 
9.1 
Sample Size Determination....................................................................................70 
9.2 
Populations for Analyses .......................................................................................70 
9.3 
Statistical Analyses ................................................................................................70 
9.3.1 
Efficacy Analyses ........................................................................................71 
9.3.2 
Safety Analyses ............................................................................................72 
9.3.3 
Other Analyses .............................................................................................72 
9.4 
Interim Analyses ....................................................................................................72 
9.5 
Handling of Missing Data ......................................................................................72 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ..73 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ................73 
10.1.1 
Regulatory and Ethical Considerations ........................................................73 
10.1.2 
Financial Disclosure.....................................................................................74 
10.1.3 
Informed Consent Process ...........................................................................74 
10.1.4 
Data Protection.............................................................................................75 
10.1.5 
Committees Structure...................................................................................75 
10.1.6 
Dissemination of Clinical Study Data..........................................................75 
10.1.7 
Data Quality Assurance ...............................................................................76 
10.1.8 
Source Documents .......................................................................................76 
10.1.9 
Study and Site Closure .................................................................................77 
10.1.10 Publication Policy ........................................................................................77 
10.2 
Appendix 2: Clinical Laboratory Tests ..................................................................78 
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10.3 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ...................................................................81 
10.3.1 
Definition of AE ..........................................................................................81 
10.3.2 
Definition of SAE ........................................................................................82 
10.3.3 
Recording and Follow-up of AE and/or SAE ..............................................83 
10.3.4 
Reporting of SAEs .......................................................................................85 
10.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information ............................................................................................................86 
10.5 
Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments and 
Study Intervention Rechallenge Guidelines...........................................................91 
10.6 
Appendix 6: ITP-BAT ...........................................................................................93 
10.7 
Appendix 7: Abbreviations ..................................................................................121 
11 REFERENCES ..............................................................................................................125 
  
List of Tables 
Table 1-1.  
Part A Schedule of Activities (Netherlands only) ......................................20 
Table 1-2. 
Part B Schedule of Activities (USA sites included) ..................................23 
Table 1-3. 
Part C Schedule of Activities (USA sites included) ..................................27 
Table 1-4.  
Part D Schedule of Activities (USA sites included) ..................................31 
Table 6-1. 
M254 and IVIg Infusion Rate ....................................................................55 
Table 10-1. 
Protocol-required Laboratory Assessments Parts A and B ........................79 
Table 10-2. 
Protocol-required Laboratory Assessments Part C and Part D ..................80 
 
List of Figures 
Figure 1-1.  
Overall Schematic of 4-part Study Design Versus Timing .......................12 
Figure 1-2. 
Part A Study Schema .................................................................................14 
Figure 1-3. 
Part B Study Schema .................................................................................16 
Figure 1-4. 
Part C Study Schema .................................................................................17 
Figure 1-5. 
Part D Study Schema .................................................................................18 
 
 
 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: A 4-part Phase 1/2 study to evaluate the safety, tolerability, 
pharmacokinetics, and pharmacodynamics of M254 in healthy volunteers and in patients with 
immune thrombocytopenic purpura. This study was opened in Europe in 2018 (EudraCT: 
2018-003534‐32) as a 4-part study. Part A enrolled 25 healthy volunteers at a single site in 
the Netherlands and has been completed. This study will open in the United States (US) as a 
3-part study with Parts B, C, and D; no subjects in the USA will be enrolled in Part A. 
Short Title: Safety and tolerability of M254 in healthy volunteers and immune 
thrombocytopenic purpura (ITP) patients 
Rationale: 
Alterations in endogenous immunoglobulin G (IgG) sialylation have been reported to be 
associated with treatment response in inflammatory/autoimmune diseases [1, 4]. M254 is a 
hypersialylated immunoglobulin engineered from commercially available intravenous 
immunoglobulin (IVIg; 
). M254 has demonstrated increased anti-inflammatory 
activity over IVIg in several animal models, including collagen antibody-induced arthritis 
and pemphigoid skin blistering [23], K/BxN – sera-induced arthritis model and an immune 
thrombocytopenia (previously called immune thrombocytopenic purpura; ITP) mouse model 
[23]. These findings support the clinical development of M254 for ITP and (antibody-
induced) inflammatory diseases.  
Intravenous immunoglobulin has been used for the treatment of a variety of acute and 
chronic autoimmune and systemic inflammatory diseases for decades [1, 3, 15, 13]. At the 
current maximal dosing regimens, only partial and transient responses are obtained in many 
clinical instances [3, 15]. In addition, the long infusion times (4 to 6 hours) associated with 
the high volume of IVIg treatment consume significant resources at infusion centers [6] and 
negatively affect patient-reported outcomes, such as convenience and quality of life [9]. 
M254 is expected to be many fold more potent compared to commercially available IVIg 
based on preclinical pharmacological experiments. This may lead to reduced infusion time 
for patients compared to commercially available IVIg. Hypersialylation may increase IVIg-
related anti-inflammatory and immune-modulating activities. 
Intravenous immunoglobulin is an approved therapy for the treatment of ITP with prompt 
increases in platelet counts as early as a day after treatment with peak platelet response 
occurring within 2 to 7 days. This known treatment effect with easily measurable 
pharmacodynamics (PD) endpoint of increasing platelet count makes ITP patients a suitable 
population for investigation of M254. The present 4-part (each part will be initiated 
sequentially), first in-human study will be conducted first in healthy subjects and 
subsequently in ITP patients to evaluate the safety, tolerability, pharmacokinetics (PK), and 
PD platelet response of M254 administered as single followed by multiple intravenous (IV) 
doses. 
C
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Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
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• To assess PD of repeated intravenous 
doses of M254 in ITP patients 
• Platelet response after repeated M254 
administration 
 
Hypothesis: 
No formal hypothesis testing will be used. 
Overall Design: 
This is a Phase 1/2, study investigating single and repeated administration of M254 in a 
4-part study. The overall design of each part (A, B, C, and D) is summarized below 
(Figure 1-1). A Scientific Review Committee (SRC) will review safety data as described in 
each of the parts below. Adverse events (AEs) will be graded using the Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0. For all healthy volunteers 
and patients with ITP, a 28-day duration of safety monitoring following dosing of either 
M254 or IVIg has been selected based on nonclinical comparability of PK between M254 
and IVIg, and clinical observations with IVIg where platelets return to ≤15% above baseline 
within 28 days.  
For Parts B, C, and D of the study, during the follow-up period, participants may have 
laboratory assessments, vital signs, electrocardiogram (ECG), and PK samples assessed at 
home or another location mutually agreed with the site, but can be seen by the study staff if 
complications arise or for participant comfort. 
Figure 1-1.  
Overall Schematic of 4-part Study Design Versus Timing 
 
 
Part A (Netherlands only) 
Part A is a single-ascending-dose, randomized, double-blinded sponsor unblind, safety, 
tolerability, and PK assessment of M254 or placebo in 6 cohorts of healthy volunteers. 
Planned doses include 3, 10, 30, 60, 120, and 250 mg/kg. In Cohort 1, 5 subjects will be 
enrolled with 3:2 (active:placebo) randomization. In all other cohorts, subjects will be 
randomized 3:1 (active:placebo) with total of 4 subjects in each cohort. There will be 
approximately 25 subjects in Part A. Up to 2 additional cohorts may be added based on 
Part A
Part B
Part C
Part D
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Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
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findings in prior cohorts. Additional dosing cohorts may be added on the recommendation of 
the SRC.  
Following screening to confirm eligibility to participate, subjects will be randomized to 
receive M254 or placebo. Please refer to Section 4.3.1 and Figure 1-2 for dosing details. 
At the first dose level (3 mg/kg), a sentinel group of 2 subjects (1 M254, 1 placebo) will be 
dosed and closely monitored for 48 hours before dosing the remainder of the cohort (2 M254, 
1 placebo). The subjects in this sentinel group will be closely observed by the Investigator for 
any safety signals for the first 48 hours following drug administration. The general 
tolerability of the study drug will be monitored during this time and the ECG recordings and 
vital signs data will be reviewed. In addition, any reported AEs will be considered by the 
Investigator. If the safety and tolerability results of the first 48 hours following dosing for the 
initial subjects are acceptable to the Investigator, the other subjects in Cohort 1 of Part A may 
be dosed. There will be no additional sentinel groups in the study beyond this cohort 
(Cohort 1 Part A). 
Safety assessments will be conducted out to Day 28 post M254 dosing. The SRC will review 
all available safety data after each cohort has completed at least 10 days of assessments after 
the single dose of M254. Dose escalation will only proceed after the recommendation of the 
SRC.  
The SRC will review all safety data for all subjects in Part A out to Day 28.  
Cohorts in Part B may start before the completion of Part A; however, prior to initiation of 
any cohort in Part B, either the same or a higher dose level will have been given in Part A 
and have a positive recommendation by the SRC, with the exception of doses greater than 
250 mg/kg. 
Dose escalation and continuation to the next study part may only occur when the SRC has 
given a positive recommendation and the Ethical Committee has given a statement of no 
objection, as per local requirement (where required). 
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Protocol: MOM-M254-001 
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Figure 1-2. 
Part A Study Schema 
Day
1
Screening (N = 25) a
Day
28
N = 5b;
Subjects randomized 3:2
3 mg/kg M254:placebo
Day
14
N = 4;
Subjects randomized 3:1
10 mg/kg M254:placebo
N = 4;
Subjects randomized 3:1
30 mg/kg M254:placebo
N = 4;
Subjects randomized 3:1
60 mg/kg M254:placebo
N = 4;
Subjects randomized 3:1
120 mg/kg M254:placebo
N = 4;
Subjects randomized 3:1
250 mg/kg M254:placebo
 
Note: Arrows represent dose escalation; Safety will be assessed prior to dose escalation.  
a 
Up to 2 additional cohorts may be added based on findings in prior cohorts.  
b 
In Cohort 1, dosing will be initially limited to a sentinel group (1 active, 1 placebo) that will be monitored 
for at least 48 hours before the remainder of the cohort is dosed. 
 
Part B (USA sites included) 
Initiation of any cohort in Part B will only proceed on the recommendation of the SRC after 
safety data from Part A Cohort 4 at the 60-mg/kg dose level has been reviewed and 
confirmed by SRC. 
Part B is a single-ascending-dose, fixed-sequence, open-label part to assess safety, 
tolerability, PK, and PD of M254 followed by 1000 mg/kg IVIg in 4 cohorts of 2 ITP 
patients per cohort. Planned doses include 60, 120, 250, and 500 mg/kg. Up to 2 additional 
cohorts may be added based on findings in prior cohorts to better understand the safety of 
M254 and/or to better understand the efficacy to assist with dose selection for Part C. The 
maximum dose for Part B will not exceed 500 mg/kg (the no-observed-adverse-event-level 
[NOAEL] of 1000 mg/kg was determined in the toxicology study in cynomolgus monkeys). 
Additional patients may be added to dosing cohorts, including prior dose level cohorts, on the 
recommendation of the SRC.  
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Following screening to confirm eligibility to participate, patients will be dosed with M254. 
Please refer to Section 4.3.1 and Figure 1-3 for dosing details. There will be a 14-day safety 
monitoring period between enrollment of the first and second patients in the 500 mg/kg 
cohort. 
Safety and platelet assessments will be conducted initially out to Day 28 post M254 
administration. Patients will receive a fixed dose of IVIg at 1000 mg/kg on Day 29 if the 
patients’ platelet count returns to ≤15% above baseline level. Patients whose platelets have 
not returned to ≤15% above baseline dosing level by Day 28 will have platelet 
determinations weekly until platelets return to ≤15% above baseline, up to 56 days postdose. 
If these conditions are not met by Day 57, IVIg will be administered, as long as the patients’ 
platelets have returned to <50 × 109/L. If the platelets have not returned to ≤15% above 
baseline and are >50 × 109/L, the patient will complete Follow-Up assessments and be 
discharged from Part B. After dosing with IVIg, safety and the other assessments listed in the 
Schedule of Activities will be conducted for 28 days following IVIg administration.  
The SRC will review all safety data for all patients in Part B up to at least 28 days following 
M254 administration for the last patient. Initiation of Part C will only proceed on the 
recommendation of the SRC. Dose escalation and continuation to the next study part may 
only occur when the SRC has given a positive recommendation and the Ethical Committee 
has given a statement of no objection, as per local requirement (where required). 
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Figure 1-3. 
Part B Study Schema 
 
Note: Arrows represent dose escalation; Safety will be assessed prior to dose escalation. 
IVIg = Intravenous immunoglobulin; NOAEL = no-observed-adverse-event-level. 
a 
Up to 2 additional cohorts may be added based on findings in prior cohorts. Additional patients may be 
added to cohorts, including prior dose level cohorts. Maximum dose will not exceed 500 mg/kg (a NOAEL 
of 1000 mg/kg determined in the toxicology study in cynomolgus monkeys). 
b 
All patients will receive a dose of IVIg (1000 mg/kg) at approximately Day 29. 
 
Part C (USA sites included) 
Part C consists of 2 randomized, unblinded crossover cohorts, to assess safety and PD of a 
single dose of M254 compared to a single dose of IVIg in ITP patients. The dose of M254 for 
each of these 2 cohorts will be determined after analysis of the data from Part A and Part B. 
Each cohort consists of 10 patients with 2 arms in each cohort consisting of 5 patients in each 
arm, for an overall total of 20 patients in Part C. 
Following screening to confirm eligibility to participate, in crossover Cohort 1 or Cohort 2, 
5 patients in each cohort will be randomized to M254 by IV administration and 5 patients 
will be randomized to 1000 mg/kg IVIg. Please refer to Section 4.3.1 and Figure 1-4 for 
dosing details. 
Safety and platelet assessments will be conducted initially out to Day 28 post M254 or IVIg 
administration. Patients will receive 1 dose of either M254 or IVIg, depending on their 
assigned arm within the cohort on Day 29 if the patients’ platelet count returns to ≤15% 
above baseline level. Patients whose platelets have not returned to ≤15% above baseline 
dosing level by Day 28 will have platelet determinations weekly until platelets return to 
≤15% above baseline up to 56 days post the first M254 or IVIg administration. Patients who 
do not meet this criteria will receive the second administration of M254 or IVIg, as long as 
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Protocol: MOM-M254-001 
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the platelets have returned to <50 × 109/L. If the platelets have not returned to ≤15% above 
baseline and are ≥50 × 109/L, the patient will complete Follow-Up assessments on or around 
Day 57 post first infusion and be discharged from Part C; and the patient may be replaced. 
After patients are crossed over to M254 or IVIg, they are followed for an additional 28 days 
with safety and platelet assessments or until platelet counts return to ≤15% above their 
baseline level following similar rules to the first dose in Part C. 
The SRC will review all safety data from both crossover cohorts in Part C; however the 
initiation of Part D will proceed after the SRC reviews all safety data from Cohort 1 and the 
recommendation is to proceed with Part D. Dose escalation and continuation to the next 
study part may only occur when the SRC has given a positive recommendation and the 
Ethical Committee has given a statement of no objection, as per local requirement (where 
required). 
Figure 1-4. 
Part C Study Schema  
Day
1
Screening (N = 20)
Day
29a
Day
57
IVIg (1000 mg/kg)
M254 (TBD)
Cohort 1 (N = 10)
M254 (TBD)
IVIg (1000 mg/kg)
Arm 1 (N = 5)
Arm 2 (N = 5)
IVIg (1000 mg/kg)
M254 (TBD)
Cohort 2 (N = 10)
M254 (TBD)
IVIg (1000 mg/kg)
Arm 1 (N = 5)
Arm 2 (N = 5)
 
 
IVIg = Intravenous immunoglobulin; TBD = to be determined. 
a 
Patients will be followed for 28 days or until their platelet counts have returned to ≤15% above baseline 
levels and then crossed to the second period. Patients will again be dosed and followed for an additional 
28 days with safety and platelet assessments. 
 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
Momenta Confidential Information  
 
Page 18 of 127 
 
Part D (USA sites included) 
Part D is a repeated, fixed-dose, open-label study of M254. Any patients who participate in 
Parts B or C are allowed to participate in Part D if they meet the eligibility criteria during 
screening for Part D. Part D may have up to 2 dose levels with up to approximately 15 to 
34 ITP patients in total. The initial dose level for Part D will be less than or equal to the 
maximum tolerated dose, and it will be selected based on review of Part B data and available 
data from Part C. Following completion of Part C, the dose for new patients in Part D may be 
revised (the dose level will not be modified for patients who have already received at least 
1 dose). Patients who have participated in Part B or C may be allowed to participate in 
Part D, prior to completion of randomization in Part C. New patients not in Part B or C may 
participate in Part D following complete randomization in Part C. The dose levels of M254 
for Part D will be determined after analysis of available data from Part A, Part B, and Part C. 
Following screening to confirm eligibility to participate (including rescreening patients who 
participated in Part B or C), M254 naïve patients will receive 4 doses of M254, and patients 
from Part B or C will receive 3 doses of M254 every 14 days. Patients in Part C may roll 
over into Part D by including any data after the last dose of IVIg or M254 in Part C for 
assessment of screening in Part D as long as those data are within the screening window 
specified. Please refer to Section 4.3.1 and Figure 1-5 for dosing details. 
During Part D, if the patient’s platelet count has not returned to ≤100 × 109/L, their platelet 
count will be monitored weekly until platelets return to ≤100 × 109/L. If these conditions are 
not met, M254 will not be administered further. Patients will be followed for safety 
assessments and platelet counts up to at least 28 days post their last dose of M254. Safety 
will be reviewed by the SRC quarterly (or more often as required). 
Figure 1-5. 
Part D Study Schema 
Day
1
Screening = Na
ITP Subjects M254 naïve:  M254b Q2W (4 doses)
Day
71
ITP Subjects from Part B or C:  M254b Q2W (3 doses)
Day
15
Day
29
Day
43
Day
1
Day
57
Day
15
Day
29
 
ITP = Immune Thrombocytopenia; Q2W = every 2 weeks. 
Note: Days with tick marks before the timeline break (before Day 71 or Day 57) indicate dosing days. 
a 
Patients may either be new to the study (M254 naïve) or have previously received M254 in Part B or C. 
This part will include up to approximately 15 to 34 patients. 
b 
Dose of M254 to be ≤500 mg/kg (dose to be confirmed based on review of Parts A, B, and C and not to 
exceed the maximum dose tolerated in the prior study parts to date). 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
Momenta Confidential Information  
 
Page 19 of 127 
 
 
Number of Participants: 
In Part A (Netherlands only), approximately 25 healthy volunteers will be included, 
18 subjects will receive M254 and 7 will receive placebo. In Part B, up to approximately 
20 patients will receive 1 dose of M254 and 1 dose of IVIg (2 each in 4 planned cohorts; 
2 each in 2 optional cohorts; and 8 in optional expansions of existing cohorts or the optional 
cohorts). In Part C, 20 patients will receive 1 dose of M254 and 1 dose of IVIg. In Part D, up 
to approximately 15 to 34 patients will receive repeated doses of M254. Patients from Part B 
and C can continue to Part D. In total for Parts B, C, and D, there will be up to 74 patients 
who will receive at least 1 dose of M254 or IVIg. 
Intervention Groups and Duration: 
The total duration of study participation for each cohort in Part A (Netherlands only) will be 
up to 8 weeks; up to 4 weeks for screening and 4 weeks observation and follow-up. The total 
duration of participation in Parts B and C will be 12 to 20 weeks: up to 4 weeks for screening 
and 4 to 8 weeks for M254 period and 4 to 8 weeks for IVIg period based on platelet 
measurements returning to baseline as described above. The total duration of study 
participation in Part D will be 12 to 14 weeks: 4 weeks for screening and 8 (patients from 
Parts B or C) or 10 (M254-naïve patients) weeks observation and follow-up. 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version: 8 Global 28 April 2020   
 
MOMENTA CONFIDENTIAL INFORMATION 
20  
1.2 
Schedule of Activities 
Table 1-1.  
Part A Schedule of Activities (Netherlands only) 
 
Day 
-28 to 
-2 
-1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
2 
3 
4 
5 
8 
±1 
10n 
±1 
12n 
±1 
15 
±1 
18n 
±1 
22 
±1 
29 
±2 
Procedurea 
Hour 
Screening 
Pre-infusion 
Infusion 
Post-infusion 
Follow-up 
-- 
0 
0 
0 
(end of 
infusion)  
0.08 
(5 min) 0.25 
0.5 
1 
2 
4 
8 
12 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Unit Admit 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant 
Medicationse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Assessmente 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteriab 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
Xp 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xp 
Drug Screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Height and Body Mass 
Index 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsc 
X 
X 
X 
X o 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
X 
12-lead ECG 
X 
X 
 
X o 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
X 
Safety Labsf 
Xf 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
X 
 
 
X 
 
X 
X 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version: 8 Global 28 April 2020   
 
MOMENTA CONFIDENTIAL INFORMATION 
21  
Table 1-1.  
Part A Schedule of Activities (Netherlands only) 
 
Day 
-28 to 
-2 
-1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
2 
3 
4 
5 
8 
±1 
10n 
±1 
12n 
±1 
15 
±1 
18n 
±1 
22 
±1 
29 
±2 
Procedurea 
Hour 
Screening 
Pre-infusion 
Infusion 
Post-infusion 
Follow-up 
-- 
0 
0 
0 
(end of 
infusion)  
0.08 
(5 min) 0.25 
0.5 
1 
2 
4 
8 
12 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Serology: HBsAg, 
anti-HCV, anti-HIV 1 
and 2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total IgGh 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
 
 
X 
 
X 
X 
Blood Samples for 
PKh, i  
 
 
X q 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
X 
Blood Samples for 
Biomarkers 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Urinalysis 
X 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
X 
 
 
X 
 
X 
X 
Pregnancy Testg 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Telemetry (set on 
alarm)d 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M254 IV Infusionj 
 
 
X 
(start) 
Xk 
(end) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infusion Reactionl 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Unit Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Discharge from Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
AE = adverse event; ECG = electrocardiogram; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; IgG = immunoglobulin G; 
IV = intravenous; PK = pharmacokinetics. 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version: 8 Global 28 April 2020   
 
MOMENTA CONFIDENTIAL INFORMATION 
22  
a 
Procedures should occur in the order presented above from top to bottom if more than 1 procedure occurs at the same nominal time Urine sampling or anything with a specific 
footnote may be done out of order. 
c 
Inclusion/exclusion criteria does not need to be redone for subsequent dose of IVIg, but follow other pre-infusion assessments. 
d 
Vital signs includes tympanic body temperature, supine (after 5 minutes) blood pressure, pulse rate, and respiratory rate. Vital signs will be assessed every 30 minutes during 
an infusion with a window +3 minutes. For infusions <35 minutes, vital signs assessments may occur just after starting the infusion and just prior to the end of the infusion. 
Refer to Footnote O for exception. 
e 
Telemetry should start at or before beginning of infusion and stop at or after end of infusion. 
f 
Concomitant Medications and AEs will be assessed throughout the infusion and the study. Subjects will be queried and observed for AEs daily during the confinement period, 
then at each subsequent clinic visit. 
g 
Safety labs will include complete blood count (CBC), hematology, serum chemistry, coagulation, and coagulation screening lab (at screening only) (see Table 10-1). 
h 
Women of childbearing potential, only. Urine test on Day -1; serum test during Screening and on Day 29. 
i 
Samples should be analyzed in a blinded fashion in Part A – see Part A lab manual for additional details.  
j 
Samples drawn 15 minutes after in supine position at in-house visits. For ambulatory visits, samples drawn 15 minutes after sitting. 
k 
Duration of infusion is based on dosing instructions (details provided in the pharmacy manual). Patients will be required to drink 2 glasses of liquid in the morning before the 
start of infusion. Just before infusion, patients will be provided the opportunity to urinate. 
l 
If infusion duration is <20 minutes, end of infusion activities may be scheduled as logistically feasible with the PK sample drawn from 1 minute before the end of infusion to 
2 minutes after the end of infusion. For infusion durations ≥20 minutes, activities should occur in the order of the table (top to bottom) unless a footnote indicates otherwise. 
m 
Subjects will assessed for 2 types of infusion reactions: 1) cutaneous infusion reaction 2) systemic reactions. For either types of infusion reactions and AE must be recorded. 
In the event of systemic reactions, a sample of blood will be drawn to measure histamine, anaphylatoxin (C5a), IgE, and tryptase and will be compared with the baseline 
sample drawn prior to the first dose of study drug. 
n 
Discharge from study after final study period unless further follow-up of open AEs is deemed necessary by the Investigator. 
o 
Follow-up may be conducted by telephone for these visits 
p 
ECG and vital signs assessments required at the end of the infusion may be initiated 15 minutes prior to the end of infusion  
q 
These should be conducted as abbreviated physical exams 
r 
PK sample is required prior to the start of infusion (on the day of the infusion). 
 
 
 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version: 8 Global 28 April 2020   
 
MOMENTA CONFIDENTIAL INFORMATION 
23  
Table 1-2. 
Part B Schedule of Activities (USA sites included) 
(Schedule of Activities below is repeated when the patient receives their second infusion, which will be IVIg) 
 
Day 
-28 
to -2 
-1 n 
1 n 
1 
1 
1 
1 
1 
2 
3b 
4b 
5b 
8±1b 
10 
±3 
12 
±3b 
15 
±3b 
18 
±3b 
22 
±3b 
29 
±3n 
Procedurea 
Hour 
Screening 
Pre-infusion 
Infusion 
Post-infusion 
Follow-up 
-- 
0 
0 
0 
(end of 
infusion) 
0.25 
0.5 
2 
4 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Unit Admit 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant 
Medicationsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Assessmentf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ITP-BAT 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xs 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
Xu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xu 
Drug Screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weightc 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Height and Body Mass 
Index 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsd 
X 
X 
X 
Xt 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
 
Xt 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
Safety Labsg 
Xg 
X 
 
 
 
 
 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version: 8 Global 28 April 2020   
 
MOMENTA CONFIDENTIAL INFORMATION 
24  
Table 1-2. 
Part B Schedule of Activities (USA sites included) 
(Schedule of Activities below is repeated when the patient receives their second infusion, which will be IVIg) 
 
Day 
-28 
to -2 
-1 n 
1 n 
1 
1 
1 
1 
1 
2 
3b 
4b 
5b 
8±1b 
10 
±3 
12 
±3b 
15 
±3b 
18 
±3b 
22 
±3b 
29 
±3n 
Procedurea 
Hour 
Screening 
Pre-infusion 
Infusion 
Post-infusion 
Follow-up 
-- 
0 
0 
0 
(end of 
infusion) 
0.25 
0.5 
2 
4 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Serology: HBsAg, 
anti-HCV, anti-HIV 1 
and 2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Platelet Counth 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood type, if unknown 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Platelet Autoantibodies, 
if unknown 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total IgGj 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
X 
Blood Samples for PKr 
 
 
Xv 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
X 
Blood Samples for 
Biomarkers and ADAw 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
Urinalysis 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
Pregnancy Testi 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Telemetry (set on 
alarm)e 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M254 or IVIg IV 
Infusionk 
 
 
X 
(start) 
Xl 
(end) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Xq 
Infusion Reactionm 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
X 
Unit Discharge 
 
 
 
 
 
 
 
Xo 
 
 
 
 
 
 
 
 
 
 
 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version: 8 Global 28 April 2020   
 
MOMENTA CONFIDENTIAL INFORMATION 
25  
Table 1-2. 
Part B Schedule of Activities (USA sites included) 
(Schedule of Activities below is repeated when the patient receives their second infusion, which will be IVIg) 
 
Day 
-28 
to -2 
-1 n 
1 n 
1 
1 
1 
1 
1 
2 
3b 
4b 
5b 
8±1b 
10 
±3 
12 
±3b 
15 
±3b 
18 
±3b 
22 
±3b 
29 
±3n 
Procedurea 
Hour 
Screening 
Pre-infusion 
Infusion 
Post-infusion 
Follow-up 
-- 
0 
0 
0 
(end of 
infusion) 
0.25 
0.5 
2 
4 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Discharge from Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xp 
ADA = anti-drug antibody; AE = adverse event; ECG = electrocardiogram; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
IgG = immunoglobulin G; ITP-BAT = immune thrombocytopenic purpura bleeding assessment tool; IV = intravenous; PK = pharmacokinetics. 
a 
Procedures should occur in the order presented above from top to bottom if more than 1 procedure occurs at the same nominal time. Urine sampling or anything with a 
specific footnote may be done out of order. 
b 
Only visits required to be at the study site are screening, infusions, the day after infusion, Day 10 after M254 infusion (as this is last safety visit prior to dose escalation 
decision), and Day 29, all others can be done by visiting nurse if patient prefers this option. Visit windows of ±1 day should be used whenever possible; ±3 day windows 
shouldonly be used when required due to clinical site closures (eg, for holidays or COVID-19-related limited schedules). When visit windows overlap, they must not be 
combined into a single actual day. Note: the first patient in the 500 mg/kg cohort must be seen in clinic at the Day 15 visit as there will be a 14-day safety monitoring period 
between enrollment of the first and second patients in the 500 mg/kg cohort.  
c 
Screening weight will be used to determine eligibility and dosing, and will allow up to 1 month for weight variability. 
d 
Vital signs includes body temperature, supine (after 5 minutes) blood pressure, pulse rate, and respiratory rate. Vital signs will be assessed every 30 minutes during an 
infusion. For infusions <35 minutes, vital signs assessments may occur just after starting the infusion and just prior to the end of the infusion. Refer to Footnote t for 
exception. 
e 
Telemetry should start at or before beginning of the M254 infusion and stop at or after end of infusion. Telemetry does not need to be performed during the IVIg infusion. 
f 
Concomitant Medications and AEs will be assessed throughout the infusion and the study. Subjects will be queried and observed for AEs daily during the confinement period, 
then at each subsequent clinic visit. Should there be a bleeding event reported by the patient or observed by the physician during examination, the ITP-BAT must be 
completed, see ITP-BAT in Appendix 6, as well as an AE form. 
g 
Safety labs will include complete blood count (CBC), serum chemistry, coagulation, and coagulation screening lab (at screening only) (see Table 10-1). All safety labs will be 
assessed by the Central lab except for platelet counts, which should be done locally at all the visits where they are scheduled. In case of an AE that requires additional 
sampling and the Investigator needs to review the results to determine patient care, additional safety labs can be assessed by the local lab.  
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version: 8 Global 28 April 2020   
 
MOMENTA CONFIDENTIAL INFORMATION 
26  
h 
The platelet measurement for eligibility must be taken within 96 hours of start of infusion. Platelet sample may be combined with safety labs if sample is taken at the same 
time. All scheduled platelet measurements must be sent to the central lab. If there is insufficient time to review the central lab results an additional local lab sample may be 
obtained in order to assess eligibility for infusion.  
i 
Women of childbearing potential, only. Urine test on Day -1 for Day 1 prior to infusion; serum test during Screening and on Day 29. Central lab should assess serum sample 
collected at screening and on Day 29, but the local lab can assess the urine test on Day -1/Day 1 prior to the infusion.  
j 
Duplicate samples for IgG should not be drawn if sample was already taken with safety labs collection.  
k 
Duration of infusion is based on dosing instructions (details provided in the pharmacy manual). Patients will be required to drink 2 glasses of liquid in the morning before the 
start of infusion. Just before infusion, patients will be provided the opportunity to urinate. Patients receiving M254 or IVIg can be discharged 4 hours post-infusion. 
l 
If infusion duration is <20 minutes, end of infusion activities may be scheduled as logistically feasible with the PK sample drawn from 1 minute before the end of infusion to 
2 minutes after the end of infusion. For infusion durations ≥20 minutes, activities should occur in the order of the table (top to bottom) unless a footnote indicates otherwise. 
m 
All systemic infusion reactions and associated AEs will be graded using Common Terminology Criteria for Adverse Events (CTCAE)  
n 
Patients with ITP may be admitted to the unit the morning of Day 1so any procedure specified on Day -1 can occur on Day 1, but all results must be back before infusion 
begins. Likewise, any pre-infusion assessment specified on Day 1 can occur on Day -1 and does not need to be duplicated.  
o 
Study staff should follow-up with the patient approximately 12 hours post-discharge for safety via phone call. 
p 
Discharge from study after final study period unless further follow-up of open AEs is deemed necessary by the Investigator. 
q 
IVIg infusion will occur on this day if patient’s platelet count meets criteria, and then the Schedule of Activities should be followed starting at Day 1. For Period 2, Day 1, any 
assessments completed on the same date for Period 1 follow-up do not need to be duplicated.  
r 
Blood sample for PK is required during the M254 treatment period only. It is NOT needed for the IVIg treatment period.  
s 
ITP-BAT to be completed separately at Day 1 and 29 of each period (M254- and IVIg-treatment). Only 1 ITP-BAT assessment is needed if Day 29 of the first period is the 
same as Day 1 of the second period. 
t 
ECG and vital signs assessments required at the end of the infusion may be initiated 15 minutes prior to the end of infusion  
u 
These should be conducted as abbreviated physical exams 
v 
PK sample is required prior to the start of infusion (on the day of the infusion). 
w 
Biomarker samples are collected at pre-infusion, Day 2, and Day 8; ADA samples are collected at pre-infusion and Day 29 follow-up. Please refer to the lab manual for 
specific instructions. 
 
 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version: 8 Global 28 April 2020   
 
MOMENTA CONFIDENTIAL INFORMATION 
27  
Table 1-3. 
Part C Schedule of Activities (USA sites included) 
(Schedule of Activities below is repeated when the patient receives their second infusion, which will be either M254 or IVIg) 
 
Day 
-28 
to -2 
-1 m 
1 m 
1 
1 
1 
1 
1 
2 
3b 
4b 
5b 
8±1b 
10 
±3 b 
12 
±3b 
15 
±3b 
18 
±3b 
22 
±3b 
29 
±3n 
Procedurea 
Hour 
Screening 
Pre-infusion 
Infusion 
Post-infusion 
Follow-up 
-- 
0 
0 
0 
(end of 
infusion) 
0.25 
0.5 
2 
4 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant 
Medicationse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Assessmente 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ITP-BAT 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xr 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
Xt 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xt 
Drug Screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weightc 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Height and Body Mass 
Index 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsd 
X 
X 
X 
Xs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
 
Xs 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
Safety Labsf 
Xg 
X 
 
 
 
 
 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version: 8 Global 28 April 2020   
 
MOMENTA CONFIDENTIAL INFORMATION 
28  
Table 1-3. 
Part C Schedule of Activities (USA sites included) 
(Schedule of Activities below is repeated when the patient receives their second infusion, which will be either M254 or IVIg) 
 
Day 
-28 
to -2 
-1 m 
1 m 
1 
1 
1 
1 
1 
2 
3b 
4b 
5b 
8±1b 
10 
±3 b 
12 
±3b 
15 
±3b 
18 
±3b 
22 
±3b 
29 
±3n 
Procedurea 
Hour 
Screening 
Pre-infusion 
Infusion 
Post-infusion 
Follow-up 
-- 
0 
0 
0 
(end of 
infusion) 
0.25 
0.5 
2 
4 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Serology: HBsAg, 
anti-HCV, anti-HIV 1 
and 2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Platelet Countg 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bloodtype, if unknown 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Platelet Autoantibodies, 
if unknown 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total IgGi 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
 
X 
X 
Blood Samples for PKq 
 
 
Xu 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
 
X 
X 
Blood Samples for 
Biomarkers and ADAv  
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
Urinalysis 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
X 
 
 
X 
 
X 
X 
Pregnancy Testh 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
M254 or IVIg IV 
Infusionj 
 
 
X 
(start) 
Xk 
(end) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Xp 
Infusion Reactionl 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
X 
Unit Discharge 
 
 
 
 
 
 
 
Xn 
 
 
 
 
 
 
 
 
 
 
 
Discharge from Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xo 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version: 8 Global 28 April 2020   
 
MOMENTA CONFIDENTIAL INFORMATION 
29  
ADA = anti-drug antibody; AE = adverse event; ECG = electrocardiogram; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
IgG = immunoglobulin G; ITP-BAT = immune thrombocytopenic purpura bleeding assessment tool; IV = intravenous; PK = pharmacokinetics. 
a 
Procedures should occur in the order presented above from top to bottom if more than 1 procedure occurs at the same nominal time. Urine sampling or anything with a 
specific footnote may be done out of order. 
b 
Only visits required to be at the study site are screening, infusions, the day after an infusion, and Day 29, all others can be done by visiting nurse if patient prefers this option. 
Visit windows of ±1 day should be used whenever possible; ±3 day windows should only be used when required due to clinical site closures (eg, for holidays or COVID-19-
related limited schedules). When visit windows overlap, they must not be combined into a single actual day.  
c 
Screening weight will be used to determine eligibility and dosing, and will allow up to 1 month for weight variability. 
d 
Vital signs includes body temperature, supine (after 5 minutes) blood pressure, pulse rate, and respiratory rate. Vital signs will be assessed every 30 minutes during an 
infusion. For infusions <35 minutes, vital signs assessments may occur just after starting the infusion and just prior to the end of the infusion. Refer to Footnote s for 
exception. 
e 
Concomitant Medications and AEs will be assessed throughout the infusion and the study. Subjects will be queried and observed for AEs daily during the confinement period, 
then at each subsequent clinic visit. Should there be a bleeding event reported by the patient or observed by the physician during examination, the ITP-BAT must be 
completed, see ITP-BAT in Appendix 6, as well as an AE form. 
f 
Safety labs will include complete blood count (CBC), serum chemistry, coagulation, and coagulation screening lab (at screening only) (see Table 10-1). All safety labs will be 
assessed by the central lab, except for platelet counts, which should be done locally at all the visits where they are scheduled. In case of an AE that requires additional 
sampling and the Investigator needs to review the results to determine patient care additional safety labs can be assessed by the local lab.  
g 
The platelet measurement for eligibility must be taken within 96 hours of start of infusion. Platelet sample may be combined with safety labs if sample is taken at the same 
time. All scheduled platelet measurements must be sent to the central and local lab. If there is insufficient time to review the central lab results an additional local lab sample 
may be obtained in order to assess eligibility for infusion. 
h 
Women of childbearing potential, only. Urine test on Day -1 for Day 1 prior to infusion; serum test during Screening and on Day 29. Central lab should assess serum sample 
collected at screening and on Day 29, but the local lab can assess the urine test on Day -1/Day 1 prior to the infusion.  
i 
Duplicate samples for IgG should not be drawn if sample was already taken with safety labs collection.  
j 
Duration of infusion is based on dosing instructions (details provided in the pharmacy manual). Patients will be required to drink 2 glasses of liquid in the morning before the 
start of infusion. Just before infusion, patients will be provided the opportunity to urinate. Patients receiving M254 or IVIg can be discharged 4 hours post-infusion. 
k 
If infusion duration is <20 minutes, end of infusion activities may be scheduled as logistically feasible with the PK sample drawn from 1 minute before the end of infusion to 
2 minutes after the end of infusion. For infusion durations ≥20 minutes, activities should occur in the order of the table (top to bottom) unless a footnote indicates otherwise. 
l 
All systemic infusion reactions and associated AEs will be graded using Common Terminology Criteria for Adverse Events (CTCAE).  
m 
Patients with ITP may admit to the unit the morning of Day 1so any procedure specified on Day -1 can occur on Day 1, but all results must be back before infusion begins. 
Likewise, any pre-infusion assessment specified on Day 1 can occur on Day -1 and does not need to be duplicated.  
n 
Study staff should follow-up with the patient approximately 12 hours post-discharge for safety via phone call. 
o 
Discharge from study after final study period unless further follow-up of open AEs is deemed necessary by the Investigator. 
p 
M254 or IVIg infusion will occur on this day if patient’s platelet count meets criteria, and then the Schedule of Activities should be followed starting at Day 1. For Period 2, 
Day 1, any assessments completed on the same date for Period 1 follow-up do not need to be duplicated.  
q 
Blood sample for PK is required during the M254 treatment period only. It is NOT needed for the IVIg treatment period.  
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version: 8 Global 28 April 2020   
 
MOMENTA CONFIDENTIAL INFORMATION 
30  
r 
ITP-BAT to be completed separately at Day 1 and 29 of each period (M254- and IVIg-treatment). Only 1 ITP-BAT assessment is needed if Day 29 of the first period is the 
same as Day 1 of the second period. 
s 
ECG and vital signs assessments required at the end of the infusion may be initiated 15 minutes prior to the end of infusion  
t 
These should be conducted as abbreviated physical exams 
u 
PK sample is required prior to the start of infusion (on the day of the infusion). 
v 
Biomarker samples are collected at pre-infusion, Day 2, and Day 8; ADA samples are collected at pre-infusion and Day 29 follow-up. Please refer to the lab manual for 
specific instructions. 
 
 
 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version: 8 Global 28 April 2020   
 
MOMENTA CONFIDENTIAL INFORMATION 
31  
Table 1-4.  
Part D Schedule of Activities (USA sites included) 
Day (M254 Naïve) 
-28 to -2 
-1 o 
1-54 
57 
±3 
71 ±3 
Day (Part B/C Patients) 
-28 to -2 
-1a, o 
1-40 
43 
±3 
57 
±3 
Procedurec 
Hour 
Screeningb 
Pre-
infusion 
 
Post-
infusion 
Follow-up 
-- 
0 
0 
0 
Informed Consent 
X 
 
See Table D2 
 
 
Demographics 
X 
 
 
 
Prior/Concomitant Medicationsg 
X 
X 
X 
X 
AE Assessmentg 
X 
X 
X 
X 
ITP-BATs 
 
X 
 
 
Medical History 
X 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
Physical Examination 
X 
Xu 
 
Xu 
Drug Screening 
X 
 
 
 
Body Weighte 
X 
X 
 
X 
Height and Body Mass Index 
X 
 
 
 
Vital signsf, t 
X 
X 
X 
X 
12-lead ECG t 
X 
X 
 
X 
Safety Labsh 
X 
X 
X 
X 
Serology: HBsAg, anti-HCV, anti-HIV 1 and 2 
X 
 
 
 
Platelet Counti 
X 
X 
X 
X 
Bloodtype, if unknown 
X 
 
 
 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version: 8 Global 28 April 2020   
 
MOMENTA CONFIDENTIAL INFORMATION 
32  
Table 1-4.  
Part D Schedule of Activities (USA sites included) 
Day (M254 Naïve) 
-28 to -2 
-1 o 
1-54 
57 
±3 
71 ±3 
Day (Part B/C Patients) 
-28 to -2 
-1a, o 
1-40 
43 
±3 
57 
±3 
Procedurec 
Hour 
Screeningb 
Pre-
infusion 
 
Post-
infusion 
Follow-up 
-- 
0 
0 
0 
Platelet Autoantibodies, if unknown 
X 
 
 
 
Total IgGk 
X 
X 
X 
X 
Blood Samples for PKl 
 
 
X 
X 
Blood Samples for ADAx 
 
X 
 
X 
Urinalysis 
X 
X 
X 
X 
Pregnancy Testj 
X  
X  
 
X 
Infusion Reactionn 
 
X 
 
X 
Discharge from Study 
 
 
 
Xq 
Footnotes are described on the last page of Table D2. 
 
 
 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version: 8 Global 28 April 2020   
 
MOMENTA CONFIDENTIAL INFORMATION 
33  
Table D2 (USA sites included) 
Day (M254 Naïve) 
All visit windows are relative  
to the most recent dose 
1 o 
1 
1 
1 
1 
1 
2 
3d 
4 d 
5 d 
8±1 d 
10±3 d 
12±3 d 
15±1 o 
15 
15 
15 
15 
15 
Skip w 
22±1 d 
Skipw 
29±1 o 
29 
29 
29 
29 
29 
Skipw 
36±1 d 
Skipw 
43±1 o 
43 
43 
43 
43 
43 
44 
45d 
46 d 
47 d 
50±1 d 
52±3 d 
54±3 d 
Day (Part B/C Patients) 
All visit windows are relative  
to the most recent dose 
1a, o 
1 
1 
1 
1 
1 
2 
3 d 
4 d 
5 d 
8±1 d 
10±3 d 
12±3 d 
15±1 o 
15 
15 
15 
15 
15 
Skipw 
22±1 d 
Skipw 
29±1 o 
29 
29 
29 
29 
29 
30 
31 d 
32 d 
33 d 
36±1 d 
38±3 d 
40±3 d 
Procedurec 
Hour 
Infusion 
Post-infusion 
0 
0 
(end of 
infusion) 
0.25 
0.5 
2 
4 
0 
0 
0 
0 
0 
0 
0 
Unit Admit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Assessmentg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsf, t 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGt 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Safety Labsh 
X 
 
 
 
 
X 
X 
 
 
 
X 
 
 
Platelet Counti 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Total IgGk 
X 
 
X 
 
 
X 
X 
 
 
X 
X 
 
 
Blood Samples for PKl 
Xv 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
Urinalysis 
X 
 
 
 
 
X 
X 
 
 
 
X 
 
 
M254 IV Infusionl 
Xr 
(start) 
Xm 
(end) 
 
 
 
 
 
 
 
 
 
 
 
Infusion Reactionn 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Unit Discharge 
 
 
 
 
 
Xp 
 
 
 
 
 
 
 
ADA = anti-drug antibody; AE = adverse event; ECG = electrocardiogram; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
IgG = immunoglobulin G; ITP-BAT = immune thrombocytopenic purpura bleeding assessment tool; IV = intravenous; PK = pharmacokinetics. 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version: 8 Global 28 April 2020   
 
MOMENTA CONFIDENTIAL INFORMATION 
34  
a 
Patients continuing from Part C may have the procedures from Part C, Period 2, Day 29 (or the last day of Part C, Period 2 if follow-up is extended for any reason); Part D, 
Day -1, and Part D, Day 1 combined into a single visit, if preferred and if logistics for assessment allow. 
b 
See Section 5 for the screening requirements for patients transitioning from Part B or C to Part D. 
c 
Procedures should occur in the order presented above from top to bottom if more than 1 procedure occurs at the same nominal time. Urine sampling or anything with a 
specific footnote may be done out of order. 
d 
Only visits required to be at the study site are screening, infusions, the day after an infusion, and the last follow-up, all others can be done by visiting nurse if patient prefers 
this option. Visit windows of ±1 day should be used whenever possible; ±3 day windows should only be used when required due to clinical site closures (eg, for holidays or 
COVID-19-related limited schedules). When visit windows overlap, they must not be combined into a single actual day. 
e 
Screening weight will be used to determine eligibility and dosing, and will allow up to 1 month for weight variability. 
f 
Vital signs includes body temperature, supine (after 5 minutes) blood pressure, pulse rate, and respiratory rate. Vital signs will be assessed every 30 minutes during an 
infusion. For infusions <35 minutes, vital signs assessments may occur just after starting the infusion and just prior to the end of the infusion. Refer to Footnote t for 
exception. 
g 
Concomitant Medications and AEs will be assessed throughout the infusion and the study. Subjects will be queried and observed for AEs daily during the confinement period, 
then at each subsequent clinic visit. Should there be a bleeding event reported by the patient or observed by the physician during examination, the ITP-BAT must be 
completed, see ITP-BAT in Appendix 6, as well as an AE form. 
h 
Safety labs will include complete blood count (CBC), serum chemistry, coagulation, and coagulation screening lab (at screening only) (see Table 10-1). All safety labs will 
assessed by the Central lab, except for platelet counts, which should be done locally at all the visits where they are scheduled. In case of an AE that requires additional 
sampling and the Investigator needs to review the results to determine patient care, additional safety labs can be assessed by the local lab.  
i 
The platelet measurement for eligibility must be taken within 96 hours of start of infusion. Platelet sample may be combined with safety labs if sample is taken at the same 
time. All scheduled platelet measurements must be sent to the local and central lab. If there is insufficient time to review the central lab results an additional local lab sample 
may be obtained in order to assess eligibility for infusion.  
j 
Women of childbearing potential, only. Urine test on Day -1; serum test during Screening and on Day 29. Central lab should assess serum sample collected at screening and 
on final follow-up, but the local lab can assess the urine test on Day -1/Day 1 prior to the infusion. 
k 
Duplicate samples for IgG should not be drawn if sample was already taken with safety labs collection.  
l 
Duration of infusion is based on dosing instructions (details provided in the pharmacy manual). Patients will be required to drink 2 glasses of liquid in the morning before the 
start of infusion. Just before infusion, patients will be provided the opportunity to urinate. Patients receiving M254 can be discharged 4 hours post-infusion. 
m 
If infusion duration is <20 minutes, end of infusion activities may be scheduled as logistically feasible with the PK sample drawn from 1 minute before the end of infusion to 
2 minutes after the end of infusion. For infusion durations ≥20 minutes, activities should occur in the order of the table (top to bottom). 
n 
All systemic infusion reactions and associated AEs will be graded using Common Terminology Criteria for Adverse Events (CTCAE).  
o 
Patients with ITP may be admitted to the unit the morning of Day 1 instead of Day -1. Any procedure specified on Day -1 can occur on Day 1, but all results must be back 
before infusion begins. Likewise, any pre-infusion assessment specified on Day 1 can occur on Day -1 and does not need to be duplicated. 
p 
Study staff should follow-up with the patient approximately 12 hours post-discharge for safety via phone call. 
q 
Discharge from study after final study period unless further follow-up of open AEs is deemed necessary by the Investigator. 
r 
M254 infusion will occur on this day if patient’s platelet count meets criteria, and then the Schedule of Activities should be followed starting from whichever infusion the 
patient is scheduled for in Part D, ie, 2nd, 3rd, or 4th. Any assessments completed on the same date from the prior infusion period follow-up do not need to be duplicated.  
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version: 8 Global 28 April 2020   
 
MOMENTA CONFIDENTIAL INFORMATION 
35  
s 
ITP-BAT to be completed at Day 1 prior to infusion. 
t 
ECG and vital sign assessments required at the end of the infusion may be initiated 15 minutes prior to the end of infusion  
u 
These should be conducted as abbreviated physical exams 
v 
PK sample is required prior to the start of infusion (on the day of the infusion). 
w 
Skip indicates that no assessments occur on these days. 
x 
ADA samples are collected at each pre-infusion and the final follow-up visit. Please refer to the lab manual for specific instructions. 
 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 36 of 127 
2 
INTRODUCTION 
2.1 
Study Rationale 
Intravenous immunoglobulin (IVIg) is a therapeutic blood product prepared from the pooled 
plasma of 3,000 to 60,000 healthy donors per batch [1, 3, 7]. It is a complex heterogeneous 
mixture of immunoglobulin (Ig) G subclasses and low amounts of immunoglobulin A (IgA), 
immunoglobulin M (IgM), and other plasma proteins [15]. Intravenous immunoglobulin 
contains a variety of antibodies present in human serum, and the large number of donors 
ensures diversity in the Ig repertoire that far exceeds that of an individual donor [13]. 
Intravenous immunoglobulin has been used for the treatment of a variety of acute and 
chronic autoimmune and systemic inflammatory diseases for decades [1, 3, 15, 13]. At the 
current maximal dosing regimens, only partial and transient responses are obtained in many 
clinical instances [3, 15]. In addition, the long infusion times (4 to 6 hours) associated with 
the high volume of IVIg treatment consume significant resources at infusion centers [6] and 
negatively affect patient-reported outcomes, such as convenience and quality of life [9]. 
M254 is expected to be many fold more potent compared to commercially available IVIg 
based on preclinical pharmacological experiments. This may lead to reduced infusion time 
for patients compared to commercially available IVIg. Hypersialylation may increase IVIg-
related anti-inflammatory and immune-modulating activities. 
Alterations in endogenous IgG sialylation have been reported to be associated with treatment 
response in inflammatory/autoimmune diseases [1, 4]. M254 is a hypersialylated 
immunoglobulin engineered from commercially available IVIg (
). M254 has 
demonstrated increased anti-inflammatory activity over IVIg in several animal models, 
including collagen antibody-induced arthritis and pemphigoid skin blistering [23], K/BxN – 
sera-induced arthritis model and an immune thrombocytopenia (ITP) mouse model [23]. 
These findings support the clinical development of M254 for ITP and (antibody-induced) 
inflammatory diseases.  
Intravenous immunoglobulin is an approved therapy for the treatment of ITP with prompt 
increases in platelet counts as early as a day after treatment with peak platelet response 
occurring within 2 to 7 days. This known treatment effect with easily measurable 
pharmacodynamics (PD) endpoint of increasing platelet count makes ITP patients a suitable 
population for investigation of M254. The present 4-part (each part will be initiated 
sequentially), first in-human study will be conducted first in healthy subjects and 
subsequently in ITP patients to evaluate the safety, tolerability, pharmacokinetics (PK), and 
PD platelet response of M254 administered as single followed by multiple intravenous (IV) 
doses. 
The study will be executed in 4 distinct parts. Part A (Netherlands only) will assess safety, 
tolerability, and PK of M254 after administration of a single ascending dose in healthy 
volunteers. Part B will assess safety, tolerability, and PK of M254 after administration of a 
single ascending dose followed by 1000 mg/kg IVIg administration in ITP patients. Part C 
will be a 2 arm, crossover design comparing the PD platelet response of M254 with IVIg in 
C
C
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 37 of 127 
patients with ITP. Part C will have 2 cohorts at M254 dose levels to be selected from Part A 
and Part B. Part D will be a repeat dose study of M254 for the evaluation of safety, 
tolerability, PK, and PD platelet response in patients with ITP. 
2.2 
Background 
2.2.1 
Disease Background 
Primary ITP is an acquired autoimmune disorder affecting both children and adults, 
characterized by a platelet count below 100 × 109/L. The incidence of ITP in adults is around 
4 per 100,000 people per year. Clinical manifestations include petechiae, purpura, bruising, 
and overt bleeding. Previously, ‘acute ITP’ was used to describe a self-limited form of 
disease and ‘chronic ITP’ thrombocytopenia described the disease if it lasted for more than 
6 months. In 2009, new terminology for ITP was agreed upon based on the duration of the 
disease. The new terms for ITP are: ‘newly diagnosed’ (from diagnosis until 3 months), 
‘persistent ITP’ (3 to 12 months) and ‘chronic ITP’ (ITP lasting for more than 12 months) 
[21, 20]. 
Bleeding is highly variable and there is great heterogeneity in primary ITP. Bleeding is most 
commonly mucocutaneous, involving gum bleeding, blood blisters in the mouth and 
menorrhagia. Major bleeding is not common if the platelet count is above 30 × 109/L. The 
most serious form of bleeding, intracranial hemorrhage, is rare and is most often seen in 
older patients who have additional comorbidities and in patients who fail to respond to 
therapy [20]. 
Diagnosis of ITP is mainly based on exclusion, when the history, physical examination, 
complete blood count (CBC) and examination of peripheral blood smear do not suggest other 
etiology for the thrombocytopenia. The low peripheral blood platelet count is caused by 
premature platelet destruction by self-reacting antibodies in addition to an impairment of 
platelet production. Autoantibodies reacting with glycoprotein (GP) IIb/IIIa may affect 
platelet aggregation; these are the most common autoantibodies seen in primary ITP [17]. 
The disease is heterogeneous in its pathophysiology, clinical features, and responses to 
treatment. To date, most of the treatments used have been immune-modulating drugs. Initial 
first-line treatment has remained unchanged for decades and comprises corticosteroids, IVIg, 
and less commonly anti-D in countries where the anti-D is available [18]. There have been 
several trials of IVIg in ITP since its first use in the mid-1980s. Intravenous 
immunoglobulins are sterile, purified IgG products manufactured from pooled human plasma 
and typically contain more than 95% unmodified IgG, which has intact fragment 
crystallizable (Fc)-dependent effector functions and only trace amounts of IgA or IgM. The 
recommended dose for commercially available approved IVIg is 1 g/kg (10 mL/kg) for 
2 consecutive days. The response rate in ITP is similar to that of corticosteroids but the time 
to response is shorter, with a response normally seen within 24 hours although most are 
transient rarely exceeding 3 to 4 weeks. Toxicities include headache, renal impairment and 
thrombosis. 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 38 of 127 
2.2.2 
Background of Investigational Product, M254 
M254 is a novel hypersialylated IgG therapeutic candidate derived from commercially 
available IVIg, with potentially greater potency when compared to IVIg. In M254, the IgG 
fraction containing sialic acids has been increased. The design of M254 is based on scientific 
evidence illustrating the relevance of glycosylation on immunoglobulin function. In 
particular, it has been shown that the anti-inflammatory activity of IVIg is dependent on 
Fc-sialylation [18, 5]. 
To generate M254, IVIg is exposed to a sequential enzymatic reaction 
 
 For IVIg, the sum of the all the 
nonsialylated glycans is >80% and the sum of all sialylated glycans is <20% [11]. For M254, 
the 
  
A detailed description of the chemistry, pharmacology, efficacy, and safety of M254 is 
provided in the Investigator’s Brochure [11]. 
2.2.3 
Background of Study Product, 
IVIg 
 IVIg is commercially available. It is usually prepared from pooled plasma from not 
fewer than 1,000 donors. It has a distribution of IgG subclasses closely proportional to that in 
native human plasma. Adequate doses of this medicinal product may restore abnormally low 
IgG levels to the normal range.  
The mechanism of action in disease indications other than replacement therapy is not fully 
elucidated but includes immunomodulatory effects.  
The safety and efficacy of IVIg was evaluated in 6 prospective, open-label, single-arm, 
multicenter studies performed in Europe (ITP [16, 19], primary immunodeficiency [PID] 
[16], and chronic inflammatory demyelinating polyneuropathy [CIDP] [16, 22, 10] studies) 
and the United States of America (USA) (PID [16] study). The safety and efficacy profile of 
IVIg can be found in the respective European Medicines Agency (EMA) and Food and Drug 
Administration (FDA) prescribing information [16, 2]. 
2.3 
Benefit/Risk Assessment 
M254 is predominantly a hyper-sialylated immunoglobulin (
 
 engineered from commercially available IVIg. This increase in 
sialyation was demonstrated to increase anti-autoimmune and anti-inflammatory activity in 
preclinical pharmacological experiments. M254 has been evaluated in preclinical 
pharmacology and nonclinical toxicology studies. Intravenous immunoglobulin is considered 
standard of care in multiple disease settings notably in ITP. This study has been designed to 
start with Part A (Netherlands only) where ascending single doses of M254 will be evaluated 
for safety and tolerability in healthy individuals with all doses of M254 lower than doses 
considered safe in nonclinical toxicological studies. In Part B, patients with ITP will be 
administered a dose of M254, which has expected minimum biological activity, escalating up 
to clinical efficacious doses of increasing platelet counts. Part C will evaluate efficacious 
CCI
CCI
C
C
C
CCI
NCT03866577


NCT03866577


NCT03866577


NCT03866577


NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 43 of 127 
for each cohort is provided in the pharmacy manual. More information can also be found in 
Section 6.1.1.1. 
For Parts B, C, and D of the study, during the post-discharge follow-up period, participants 
may have laboratory assessments, vital signs, electrocardiogram (ECG), and PK samples 
assessed at home or another location mutually agreed with the site, but can be seen by the 
study staff if complications arise or for participant comfortability. 
Subject enrollment in the USA will begin with Part B of this study. No subjects from the 
USA will be enrolled in Part A.  
4.1.1 
Part A (Netherlands only) 
Part A is a single-ascending-dose, randomized, double blinded sponsor unblind, safety, 
tolerability, and PK assessment of M254 or placebo in 6 cohorts of healthy volunteers. 
Planned doses include 3, 10, 30, 60, 120, and 250 mg/kg. In Cohort 1, 5 subjects will be 
enrolled with 3:2 (active:placebo) randomization. In all other cohorts, subjects will be 
randomized 3:1 (active:placebo) with total of 4 subjects in each cohort. There will be 
approximately 25 subjects in Part A. Up to 2 additional cohorts may be added based on 
findings in prior cohorts. Additional dosing cohorts may be added on the recommendation of 
the SRC. 
Following screening to confirm eligibility to participate, subjects will be randomized to 
receive M254 or placebo. Please refer to Section 4.3.1 and Figure 1-2 for dosing details. 
At the first dose level (3 mg/kg), a sentinel group of 2 subjects (1 M254, 1 placebo) will be 
dosed and closely monitored for 48 hours before dosing the remainder of the cohort (2 M254, 
1 placebo). The subjects in this sentinel group will be closely observed by the Investigator for 
any safety signals for the first 48 hours following drug administration. The general 
tolerability of the study drug will be monitored during this time and the ECG recordings and 
vital signs data will be reviewed. In addition, any reported AEs will be considered by the 
Investigator. If the safety and tolerability results of the first 48 hours following dosing for the 
initial subjects are acceptable to the Investigator, the other subjects of Cohort 1 of Part A 
may be dosed. There will be no additional sentinel groups in the study beyond this cohort 
(Cohort 1 Part A) 
Safety assessments will be conducted out to Day 28 post M254 dosing. The SRC will review 
all available safety data after each cohort has completed at least 10 days of assessments after 
the single dose of M254. Dose escalation will only proceed after the recommendation of the 
SRC. 
The SRC will review all safety data for all subjects in Part A out to Day 28. Cohorts in Part B 
may start before the completion of Part A; however, prior to initiation of any cohort in 
Part B, either the same or a higher dose level will have been given in Part A and have a 
positive recommendation by the SRC, with the exception of doses greater than 250 mg/kg. 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
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Dose escalation and continuation to the next study part may only occur when the SRC has 
given a positive recommendation and the Ethical Committee has given a statement of no 
objection, as per local requirement (where required). 
Blood for safety labs and PK will be collected as defined in the Schedule of Activities 
(Table 1-1). 
4.1.2 
Part B (USA sites included) 
Initiation of any cohort in Part B will only proceed on the recommendation of the SRC after 
safety data from Part A Cohort 4 at the 60-mg/kg dose level has been reviewed and 
confirmed by SRC. 
Part B is a single-ascending-dose, fixed-sequence, open-label part to assess safety, 
tolerability, PK, and PD of M254 followed by 1000 mg/kg IVIg in approximately 4 cohorts 
of 2 ITP patients per cohort. Planned doses include 60, 120, 250, and 500 mg/kg. Up to 
2 additional cohorts may be added based on findings in prior cohorts to better understand the 
safety of M254 and/or to better understand the efficacy to assist with dose selection for 
Part C. The maximum dose for Part B will not exceed 500 mg/kg. (The no-observed-adverse-
event-level [NOAEL] of 1000 mg/kg was determined in the toxicology study in cynomolgus 
monkeys.) Additional patients to dosing cohorts may be added on the recommendation of the 
SRC.  
Following screening to confirm eligibility to participate, patients will be dosed with M254. 
Please refer to Section 4.3.1 and Figure 1-3 for dosing details. There will be a 14-day safety 
monitoring period between enrollment of the first and second patients in the 500 mg/kg 
cohort. 
Safety and platelet assessments will be conducted initially out to Day 28 post M254 
administration. Patients will receive a fixed dose of IVIg at 1000 mg/kg on Day 29 if the 
patients’ platelet count returns to ≤15% above baseline level. Patients whose platelets have 
not returned to ≤15% above baseline dosing level by Day 28 will have platelet 
determinations weekly until platelets return to ≤15% above baseline, up to 56 days postdose. 
If these conditions are not met by Day 57, IVIg will be administered, as long as the patients’ 
platelets have returned to <50 × 109/L. If the platelets have not returned to ≤15% above 
baseline and are ≥50 × 109/L, the patient will complete Follow-Up assessments and be 
discharged from Part B. After dosing with IVIg, safety and the other assessments listed in the 
Schedule of Activities will be conducted for 28 days following IVIg administration.  
The SRC will review all available safety data after each cohort has completed at least 10 days 
of assessments after the single dose of M254. Dose escalation will only proceed on the 
recommendation of the SRC after review of the safety data for each cohort (see Section 6.6). 
If 1 of the 2 ITP patients experiences any dose-limiting toxicity (DLT), the cohort will be 
repeated with 2 additional ITP patients either at the same or lower dose per the 
recommendation of the SRC. If at a given dose level, 2 patients (either 2 of 2 or 2 of 4) 
experience a DLT, that dose level will not be repeated, though a lower dose may be selected 
by the SRC. 
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Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
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The SRC will review all safety data for all patients in Part B up to at least 28 days following 
M254 administration for the last patient. Initiation to Part C will only proceed on the 
recommendation of the SRC. Dose escalation and continuation to the next study part may 
only occur when the SRC has given a positive recommendation and the Ethical Committee 
has given a statement of no objection, as per local requirement (where required). 
Blood for safety labs, PK, and PD will be collected as defined in the Schedule of Activities 
(Table 1-2). 
4.1.3 
Part C (including sites within the USA) 
Part C consists of 2 randomized, unblinded crossover cohorts to assess safety and PD of a 
single dose of M254 compared to a single dose of IVIg in ITP patients. The dose of M254 for 
each of these 2 cohorts will be determined after analysis of the data from Part A and Part B. 
Each cohort consists of 10 patients with 2 arms in each cohort consisting of 5 patients in each 
arm, for an overall total of 20 patients in Part C. 
Following screening to confirm eligibility to participate, in crossover Cohort 1 or Cohort 2, 
5 patients in each cohort will be randomized to M254 by IV administration and 5 patients 
will be randomized to 1000 mg/kg IVIg. Please refer to Section 4.3.1 and Figure 1-4 for 
dosing details. 
Safety and platelet assessments will be conducted initially out to Day 28 post M254 or IVIg 
administration. Patients will receive their dose of either M254 or IVIg, depending on their 
assigned arm within the cohort, on Day 29 if the patients’ platelet count returns to ≤15% 
above baseline level. Patients whose platelets have not returned to ≤15% above baseline 
dosing level by Day 28 will have platelet determinations weekly until platelets return to 
≤15% above baseline up to 56 days post the first M254 or IVIg administration. Patients who 
do not meet this criteria will receive the second administration of M254 or IVIg, as long as 
the platelets have returned to <50 × 109/L. If the platelets have not returned to ≤15% above 
baseline and are ≥50 × 109/L, the patient will complete Follow-Up assessments on or around 
Day 57 post first infusion and be discharged from Part C; and the patient may be replaced. 
After patients are crossed over to the second administration of M254 or IVIg, they are 
followed for an additional 28 days with safety and platelet assessments or until platelet 
counts return to ≤15% above their baseline level following similar rules to the first dose in 
Part C. 
The SRC will review all safety data from both crossover cohorts in Part C; however, the 
initiation of Part D will proceed after the SRC reviews all safety data from Cohort 1 and the 
recommendation is to proceed with Part D. Dose escalation and continuation to the next 
study part may only occur when the SRC has given a positive recommendation and the 
Ethical Committee has given a statement of no objection, as per local requirement (where 
required). 
Blood for safety labs, PK, and PD will be collected as defined in the Schedule of Activities 
(Table 1-3). 
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Protocol: MOM-M254-001 
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4.1.4 
Part D (USA sites included) 
Part D is a repeated, fixed-dose, open-label study of M254. Any patients who participate in 
Parts B or C are allowed to participate in Part D if they meet inclusion criteria during 
screening for Part D. Part D may have up to 2 dose levels with up to approximately 15 to 
34 ITP patients in total. The initial dose level for Part D will be less than or equal to the 
maximum tolerated dose, and it will be selected based on review of Part B data and available 
data from Part C. Following completion of Part C, the dose for new patients in Part D may be 
revised (the dose level will not be modified for patients who have already received at least 
1 dose). Patients who have participated in Part B or C may be allowed to participate in 
Part D, prior to completion of randomization in Part C. New patients not in Part B or C may 
participate in Part D following complete randomization in Part C. The dose levels of M254 
for Part D will be determined after analysis of available data from Part A, Part B, and Part C.  
Following screening to confirm eligibility to participate (including rescreening patients who 
participated in Part B or C), M254 naïve patients will receive 4 doses of M254, and patients 
from Part B or C will receive 3 doses of M254 every 14 days. Patients in Part C may roll 
over into Part D by including any data after the last dose of IVIg or M254 in Part C for 
assessment of screening in Part D as long as those data are within the screening window 
specified. Please refer to Section 4.3.1 and Figure 1-5 for dosing details. 
If the patient’s platelet count has not returned to ≤100 × 109/L, their platelet count will be 
monitored weekly until platelets return to ≤100 × 109/L. If these conditions are not met, 
M254 will not be administered further. Patients will be followed for safety assessments and 
platelet counts up to at least 28 days post their last dose of M254. Safety will be reviewed by 
the SRC quarterly (or more often as required). 
Blood for safety labs, PK, and PD will be collected as defined in the Schedule of Activities 
(Table 1-4). 
4.1.5 
Study Duration for Participants 
The total duration of study participation for each cohort in Part A will be up to 8 weeks; up to 
4 weeks for screening and 4 weeks observation and follow-up. The total duration of 
participation in Parts B and C will be 12 to 20 weeks: up to 4 weeks for screening and 4 to 
8 weeks for M254 period and 4 to 8 weeks for IVIg period based on platelet measurements 
returning to baseline as described above. The total duration of study participation in Part D 
will be 12 to 14 weeks: 4 weeks for screening and 8 (patients from Parts B or C) or 
10 (M254-naïve patients) weeks observation and follow-up. 
4.1.6 
Number of Participants 
In Part A (Netherlands only), approximately 25 healthy volunteers will be included, 
18 subjects will receive M254 and 7 will receive placebo. In Part B, up to approximately 
20 patients will receive 1 dose of M254 and 1 dose of IVIg (2 each in 4 planned cohorts; 
2 each in 2 optional cohorts; and 8 in optional expansions of existing cohorts). In Part C, 
20 patients will receive a dose of M254 and IVIg. In Part D, up to approximately 15 to 
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Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
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34 patients will receive repeated doses of M254. Patients from Part B and C can continue to 
Part D. In total for Parts B, C, and D, there will be up to 74 patients who will receive at least 
1 dose of M254 or IVIg. 
4.1.7 
Replacement of Participants 
In this study, participants may be replaced in the Parts A, B, or C if they discontinue study 
treatment prior to completing the protocol defined safety observation period in absence of 
treatment-related toxicity. 
4.1.8 
Number of Sites 
For Part A there will be 1 site in the Netherlands. Up to approximately 40 additional sites 
may be added for Parts B, C, and D. 
4.2 
Scientific Rationale for Study Design 
The initial dose of M254 3 mg/kg in Part A given for the first time in adults is designed to 
provide a sentinel dose to assess initial safety and tolerability. 
The subsequent doses of M254 in Part A Cohort 1 and increased doses in Parts A, B, C, 
and D is designed based on expected efficacious doses in adults. 
4.3 
Justification for Dose 
4.3.1 
Justification for M254 Dose 
Doses are selected for safety, to allow for minimal biological activity for the starting dose, to 
reach the lower end of the potential efficacious dose range for the top dose in Part A, and to 
span the potential efficacious dose range for the top dose in Part B. Doses in Parts C and D 
will be determined based on safety and efficacy observed in the study to date. Doses will not 
exceed the NOAEL of 1000 mg/kg determined in the toxicology study in cynomolgus 
monkeys. 
The initially planned dose levels for Part A are 3, 10, 30, 60, 120, and 250 mg/kg of M254 
administered intravenously. The NOAEL (1000 mg/kg) as determined in preclinical 
toxicology studies is 4-fold higher than the highest dosing level in healthy volunteers. The 
starting dose is 330-fold below the NOAEL in cynomolgus monkeys and approximately 
30-fold below the dose anticipated to potentially provide efficacy in patients with ITP. The 
maximum dose represents a dose expected to be efficacious in patients.  
The initially-planned M254 dose levels for Part B are: 60, 120, 250, and 500 mg/kg 
administered intravenously. The starting dose will be less than or equal to a dose previously 
found tolerated in Part A, and the maximum dose will not exceed 500 mg/kg. A higher safety 
margin could not be evaluated in preclinical studies due to dosing volume limitations, so the 
maximum repeat-dose level tested (1000 mg/kg) was set as the NOAEL. 
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Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
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The M254 doses for Part C will be determined following analysis of data from Parts A and B.  
The M254 dose for Part D will be determined following review of available data from 
Parts A, B, and C.  
Doses may be adjusted from the planned doses without exceeding limits defined in 
Section 6.7.2 and without exceeding a dose previously found not to be tolerated. 
4.3.2 
Justification for IVIg Dose 
The IVIg dose administered in Parts B and C will be 1000 mg/kg. It was selected based on 
the approved and commonly used dose level of IVIg for the treatment of ITP [16, 2, 14]. 
4.4 
End of Study 
4.4.1 
End of Study Definition 
End of Study (Individual Participant): A participant is considered to have completed the 
study if he/she has completed all phases of the study including the last visit or the last 
scheduled procedure shown in the Schedule of Activities. 
Primary Completion: The primary completion date is defined as the date when the last 
participant is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s) for the purposes of conducting the primary analysis (ie, Part C, 
Cohort 1).  
End of Study (End of trial): The end of the study is defined as the date of the last visit of 
the last participant in the study or last scheduled procedure shown in the Schedule of 
Activities for the last participant in the trial globally. 
4.5 
Patient Input on Study Design 
Subject input was not obtained while designing this protocol. 
5 
STUDY POPULATION 
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Appendix 1).  
Eligibility criteria will be evaluated during screening. For patients continuing from Part C to 
Part D, the most recent available assessments that are both after the last dose of M254 or 
IVIg in Part C, Period 2 and within the screening interval for Part D (as defined in the 
Schedule of Activities, Section 1.2) may be used for screening into Part D. 
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Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
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5.1 
Eligibility Criteria for Healthy Volunteers (Netherlands only) 
5.1.1 
Inclusion Criteria for Healthy Volunteers 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Participant must be ≥18 and ≤55 years of age inclusive, at the time of signing the 
informed consent form (ICF). 
2. Good health as indicated by medical history (without hemolysis or thrombosis that 
may impact current study), physical examination, vital signs (with systolic blood 
pressure below 140 mmHg), clinical laboratory tests, and 12-lead ECG, and all 
abnormal findings are assessed as not clinically significant by the Investigator. 
3. Body weight must be between 50 and 110 kg, inclusive, and body mass index (BMI) 
between 18.5 and 30 kg/m2, inclusive, at screening. 
4. Healthy male and females are eligible. 
a. Male participants: 
• If male, surgically or biologically sterile. If not sterile, agreement to use an 
acceptable form of birth control with sexual partner (as described in 
Appendix 4) or abstain from sexual relations for 100 days following the last 
treatment. 
b. Female participants:  
• A female participant is eligible to participate if she is not pregnant (see 
Appendix 4), not breastfeeding, and at least 1 of the following conditions 
applies: 
◦ 
Not a woman of childbearing potential (WOCBP) as defined in 
Appendix 4 (surgically sterilized via hysterectomy, bilateral 
oophorectomy, or bilateral tubal ligation) or of nonchildbearing potential 
(ie, postmenopausal for at least 1 year). 
OR 
◦ 
A WOCBP who agrees to follow the contraceptive guidance in 
Appendix 4 during the treatment period and for at least 90 days after the 
last dose of study intervention. 
• Of childbearing potential, with a fertile male sexual partner, willing to use 
2 adequate methods of contraception from 30 days prior to dosing until 
90 days after the last dose of study treatment. Adequate contraception is 
defined as using hormonal contraceptives or an intrauterine device combined 
with at least 1 of the following forms of contraception: a diaphragm or 
cervical cap, or a condom. Also, total abstinence, in accordance with the 
lifestyle of the subject, is acceptable.  
5. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol. 
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Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
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6. Ability to speak, read, and understand primary medical care language(s) at the site. 
7. If female, a negative serum pregnancy test at screening and a negative urine or serum 
pregnancy test at check-in to the clinic for the baseline visit, and not nursing or 
planning a pregnancy through 90 days following the last dose of study medication. 
5.1.2 
Exclusion Criteria for Healthy Volunteers 
Participants are excluded from the study if any of the following criteria apply: 
1. Previously received M254. 
2. History of any drug allergy, hypersensitivity, or intolerance to any drug product that 
in the opinion of the Investigator would place the subject at particular risk and 
compromise the safety of the subject in the study. 
3. History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, 
hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, 
oncologic, psychiatric disease, or any other condition, that in the opinion of the 
Investigator would jeopardize the safety of the subject or the validity of the study 
results. 
4. History of splenectomy, asthma (with the exception of childhood asthma that has 
resolved), chronic obstructive pulmonary disease, or recurrent or current 
gastrointestinal or respiratory infections. 
5. Any illness within 5 days, or clinically significant airway infections within 30 days, 
prior to first study drug dosing. 
6. On fluid restriction. 
7. Any prescription medication(s) within 14 days of dose administration (or 5 half-lives, 
whichever is longer) or any nonprescribed systemic or topical medication (including 
any herbal product) within 7 days prior to dose administration. 
8. Plans to participate in another clinical trial while enrolled in this study and/or 
received an investigational drug and/or device within 60 days prior to dose 
administration. 
9. Positive urine drug screen at screening. 
10. Positivity for human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg), or hepatitis C virus (HCV) at screening. 
11. History or current diagnosis of substance dependence (except nicotine and caffeine) 
or alcohol abuse over the past 2 years, according to the criteria of the Diagnostic and 
Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR). 
12. Smokes or has smoked more than 5 cigarettes per day in the last 90 days and is 
unable to stop smoking during in-patient observation period in clinic. 
13. Unwilling to abstain from alcohol for at least 24 hours prior to dosing with study 
medication until the time of discharge from the study unit and at least 24 hours prior 
to each ambulatory visit. 
14. Donation or significant loss of whole blood (480 mL or more) within 30 days or 
plasma within 14 days prior to admission. 
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Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
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15. Vaccination within 1 month before dosing, or plans to receive vaccination within 
3 months after the last dose. 
16. Veins unsuitable for cannulation or multiple venipunctures on either arm. 
17. Patients with any prior history of arterial or venous thrombosis, AND ≥2 of the 
following risk factors: hormone replacement therapy, systemic contraception 
(containing estrogen), smoking, diabetes, hypercholesterolemia, medication for 
hypertension, cancer, hereditary thrombophilic disorders (eg, Factor V Leiden, 
antithrombin III deficiency, antiphospholipid syndrome, etc), hyperviscosity 
(cryoglobulines and chylomicronemia) 
18. Patients with selective IgA deficiency with known anti-IgA antibodies. 
 
5.2 
Eligibility Criteria for ITP Patients 
5.2.1 
Inclusion Criteria for ITP Patients (USA sites included) 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Participant must be 18 years of age or greater at the time of signing the ICF. 
2. Diagnosed with primary ITP (with or without splenectomy) according to the 
Hematology Guidelines for at least 3 months prior to screening. 
3. Must have received at least 1 prior treatment for ITP 
NOTE: if received prior treatment with IVIg, and if known from medical history, 
must have responded as defined by an increase of platelet count above 50 × 109/L 
within 14 days of IVIg treatment.  
4. Platelet count ≥15 × 109/L and <50 × 109/L within 96 hours prior to start of study 
drug infusion on Day 1.  
5.  Body weight must be within a range that allows for the planned M254 infusion time 
to be completed in ≤4 hours. Please refer to the infusion rate schedule in the Infusion 
Manual and Section 6.1.1.1.M254 
6. Maintenance immunosuppressive therapy, steroid therapy, cyclosporine A, 
mycophenolate mofetil, azathioprine, thrombopoietin receptor agonists, or danazol 
are allowed, but the dosages of all these medications must be stable for at least 
4 weeks prior to Visit 1 (Day 1). 
7. No history of clotting disorder other than ITP including no myocardial infarction 
within the last 6 months. No arrhythmia known to increase the risk of thrombotic 
events (eg, atrial fibrillation). 
8. Male and females are eligible. 
a. Male participants: 
• If male, surgically or biologically sterile. If not sterile, agreement to use an 
acceptable form of birth control with sexual partner (as described in 
Appendix 4) for 2 weeks prior to administration of study medication, during 
study treatment, and for 100 days following the last treatment (ie, study 
NCT03866577


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Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
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completion or premature discontinuation from the study), or abstain from 
sexual relations for the same duration. 
b. Female participants:  
• A female participant is eligible to participate if she is not pregnant (see 
Appendix 4), not breastfeeding, and at least 1 of the following conditions 
applies: 
◦ 
Not a WOCBP as defined in Appendix 4 (surgically sterilized via 
hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or of 
nonchildbearing potential (ie, postmenopausal for at least 1 year). 
OR 
◦ 
A WOCBP who agrees to follow the contraceptive guidance in 
Appendix 4 during the treatment period and for at least 90 days after the 
last dose of study intervention (ie, study completion or premature 
discontinuation from the study). 
• Of childbearing potential, with a fertile male sexual partner, willing to use 
2 adequate methods of contraception for 2 weeks prior to administration of 
study medication, during study treatment, and for 90 days following the last 
treatment (ie, study completion or premature discontinuation from the study). 
Adequate contraception is defined as using hormonal contraceptives or an 
intrauterine device combined with at least 1 of the following forms of 
contraception: a diaphragm or cervical cap, or a condom. Also, total 
abstinence, in accordance with the lifestyle of the subject, is acceptable.  
9. If female, a negative serum pregnancy test at screening and a negative urine 
pregnancy test at check-in to the clinic for the baseline visit, and not nursing or 
planning a pregnancy through 90 days following the last dose of study medication. 
10. Subject is capable of giving signed informed consent as described in Appendix 1 
which includes compliance with the requirements and restrictions listed in the ICF 
and in this protocol. 
11. Prothrombin time (PT) and activated partial thromboplastin time ≤1.4-fold above the 
upper limit of normal. 
 
5.2.2 
Exclusion Criteria for ITP Patients (USA sites included) 
Participants are excluded from the study if any of the following criteria apply: 
1. Patients with any prior history of arterial or venous thrombosis, AND ≥2 of the 
following risk factors: hormone replacement therapy, systemic contraception 
(containing estrogen), smoking, diabetes, hypercholesterolemia, medication for 
hypertension, cancer, hereditary thrombophilic disorders (eg, Factor V Leiden, 
antithrombin III deficiency, antiphospholipid syndrome, etc), hyperviscosity 
(cryoglobulines and chylomicronemia) 
NCT03866577


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Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
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2. Any clinically relevant abnormality, other than ITP, which in the opinion of the 
Investigator makes the patient unsuitable for participation in the study. 
3. Female patients who are nursing or pregnant at screening or predose on Day 1. 
4. History of alcohol/drug abuse or dependence within 12 months of the study. 
5. Rituximab within 3 months of screening. 
6. Patient has consumed aspirin, aspirin-containing compounds, salicylates, 
anticoagulants, quinine or nonsteroidal anti-inflammatories (NSAIDs) for 
>3 consecutive days within 2 weeks of the study start and until the end of the study. 
7. Consumption of any herbal or dietary supplements, excluding vitamin or mineral 
supplements, within 1 week of the study start. 
8. History of platelet agglutination that prevents reliable measurement of platelet counts. 
9. Any laboratory or clinical evidence for HIV infection. 
10. Any clinical history for hepatitis C infection, chronic hepatitis B infection, or any 
evidence for active hepatitis at the time of patient screening. Laboratory test shows 
positive serology for hepatitis C or hepatitis B defined as a positive test for HBsAg. 
Patients who have been treated for HCV and demonstrate a negative serum HCV 
RNA level at 12 weeks or longer after the completion of HCV therapy may be 
included in the study after consultation with the Medical Monitor. 
11. Patients with known history of chronic kidney disease. 
12. Patients with primary immunodeficiency. 
13. Patients with selective IgA deficiency with known anti-IgA antibodies. 
14. Patients who have had an anaphylactic or severe systemic reaction to the 
administration of human immunoglobulins. 
15. Patients with hyperprolinaemia Type I or II or hypersensitivity to proline in Parts B 
and C only as 
will be administered. 
16. Patients with a history of myocardial infarction, ischemic stroke, pulmonary 
embolism and deep vein thrombosis within 6 months. 
17. Patients with a history of hemorrhagic stroke.  
18. Patients expected to require rescue on Day 1 of the study. 
19. Patients with severe or clinically significant bleeding (eg, Grade 3 for skin, ≥ Grade 2 
for mucosal domains, or ≥ Grade 1 for organ domain) using the ITP bleeding 
assessment tool (ITP-BAT). 
20. Patients taking thrombopoietin receptor agonist AND have albumin ≤35 g/L. 
 
5.3 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
CCI
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Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
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respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Rescreened participants should be assigned the same participant number as for 
the initial screening. See Section 10.1.3 for Informed Consent Process details.  
6 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), non-investigational 
product(s), marketed product(s), placebo, or medical device(s) intended to be administered to 
a study participant according to the study protocol. 
Refer to the Investigator’s Brochure for more detailed information regarding the storage, 
preparation, destruction, and administration of each treatment. 
6.1 
Study Intervention(s) Administered 
6.1.1 
Investigational Products 
M254 will be supplied to the study site by Momenta or its agent for dosing by IV 
administration. Details of dose preparation will be provided in the Pharmacy Manual.  
All participants will receive study drug as an IV infusion. A peripheral IV catheter will be 
inserted before dosing for administration of study drug. M254 is administered by IV infusion 
at a rate of up to a maximum of 
 (see Section 6.1.1.1 for more details). 
Subjects and patients should be hydrated prior to the start of infusion with approximately 
2 glasses of liquid to avoid a possible thromboembolic event. Additionally, subjects and 
patients should be mobilized immediately following the end of infusion to decrease the risk 
of thromboembolic events. 
The date, time, and volume of administration of all doses are to be recorded. 
For Part A, the placebo to be used is commercially available Glucose 5% solution for 
injection. 
For Part B and C, 
IVIg will be supplied to the study site by Momenta or its agent 
for dosing by IV administration. IVIg is a liquid solution administered via IV infusion. 
Additional information on dosage and administration can be found in the 
 
 
 
 
 
6.1.1.1 
M254 and IVIg Infusion Rate 
M254 and IVIg is administered by IV infusion at a rate of up to a maximum of 
 
, whichever is lower (
 is less than infusion rates recommended for 
CCI
C
C
C
C
I
CCI
CCI
CCI
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Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
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IVIg). After completion of the infusion, the IV line should be flushed with approximately 
50 mL of 5% dextrose in water (D5W) within 10 minutes of completion of the infusion to 
ensure that the entire intended dose of drug product has been infused and none is retained in 
the IV tubing; other methods for ensuring accurate dosing may be used upon agreement of 
the Sponsor. Additional dosing information is provided in the study Infusion Manual. 
The initially-planned infusion rate schedule is described in Table 6-1; the infusion rate and 
duration at an infusion rate may be increased or decreased as part of the dose escalation 
decision with the restriction that it may not be >4 mg/kg/min. 
Table 6-1. 
M254 and IVIg Infusion Rate 
Start Time (minutes relative to 
Infusion Start) 
End Time (minutes relative to 
Infusion Start) 
Infusion Rate (mg/kg/minute) 
0 
30 
0.5 
30 
60 
1 
60 
90 
2 
90 
360 
4 
 
Two specific examples of implementing the above infusion rate table for the 
 rate are: 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.2 
Non-investigational Products 
Not applicable. 
6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Study Drug Packaging and Storage 
Study drugs must be stored in a secure area (eg, a locked refrigerator or locked cabinet within 
a refrigerator), protected from moisture and light, and be stored at 
 
 Further instructions regarding storage and handling, dose preparation, 
and administration of study drugs are detailed in the Pharmacy Manual.  
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6.2.2 
Study Drug Accountability 
In accordance with Good Clinical Practices (GCP), each study site will account for all study 
drug supplies. The pharmacy will maintain accurate records, including information regarding 
the receipt and subject administration of all test articles. Reasons for departure from the 
expected dispensing regimen must also be recorded. At the completion of the study, to satisfy 
regulatory requirements regarding drug accountability, all study drug will be reconciled. 
Drug will be retained and returned to the drug distribution center. Destruction at site may be 
considered per site standard operating procedures (SOPs) and approval of the Sponsor. The 
arrangement for destruction must be communicated to the Sponsor or delegated contract 
research organization (CRO). Refer to the Pharmacy Manual for further information. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
Part A is double-blind, sponsor open; subjects and the Investigator will be blinded to 
individual subjects’ treatment throughout this part. The sponsor will be unblinded throughout 
this part (and throughout the study). Specified individuals at the Investigator site (such as the 
unblinded pharmacist) will be unblinded throughout this part (and throughout the study). 
When interacting with the Investigator or site personnel, the sponsor will maintain care in the 
communication not to unblind. 
Parts B, C, and D are open-label investigations; patients and Investigators will not be blinded 
throughout these parts of the study.  
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded 
study intervention records at the site(s) to verify that dispensing has been done accurately. 
A randomization schema will be developed for Part A and Part C and managed by the 
pharmacy at PRA in Netherlands for the study. The process will be described in detail in the 
applicable study plan. 
6.4 
Study Intervention Compliance 
Administration of each IV infusion of study drug and all assessments will be performed by 
qualified personnel under the direction of the Investigator. Clinic personnel will confirm that 
study drug was administered and record start and end time of each infusion. Deviation(s) 
from the prescribed dosage regimen will be recorded in the electronic case report form 
(eCRF). 
6.5 
Concomitant Therapy 
Subjects participating in the study should avoid concomitant administration of any new 
medications other than antihistamine or acetaminophen (or corticosteroids for moderately 
severe acute reactions) during the course of the study, except as prescribed for newly-
emerging AEs. Participants must abstain from taking prescription or nonprescription drugs 
(including vitamins and dietary or herbal supplements) throughout the study, unless, in the 
opinion of the Investigator and sponsor, the medication will not interfere with the study. 
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Premedication should not be administered systematically. If a patient develops an infusion 
reaction related to the M254 or IVIg infusion, standard management should be applied (see 
the Infusion Manual for detail). 
During the study subjects should remain on the dose of the ITP medications they were on at 
screening. 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or 
receives during the study must be recorded in the subject’s eCRF along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
•  
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.6 
Dose-Cohort Study Escalation Rules 
In this study, Parts A and B are dose-escalating; Parts C and D are not dose-escalating. 
A dose escalation report (DER) will be provided by the Investigator to the Independent 
Ethics Committee (IEC) (where required) following completion of each dose level. The SRC 
will approve escalation to the next dose only if none of the stopping criteria have been 
reached, the safety and tolerability (and PD for Part B) out to Day 10 are acceptable, and 
there are no concerns regarding delayed significant AEs in earlier cohorts. 
The minimum number of participants required to decide on dose escalation is 2 participants 
on active treatment (ie, a total of at least 3 subjects in Part A at all dose levels; and 2 patients 
in Part B); in Part B for dose levels precedented as tolerated with safety reviewed in Part A, 
only 1 subject is required for dose escalation though 2 will remain planned for the cohort.  
Based on absence of significant toxicity in the Good Laboratory Practice (GLP) toxicity 
studies, escalation to the next higher dose will be up to approximately 
. Based on 
emerging safety data (and PD data in Part B), lower or other intermediate dose(s) may be 
used, for instance when anticipated that after a planned dose escalation stopping criteria will 
be met. Pharmacokinetic data is not deemed necessary for dose escalation since IV dosing of 
this modified IgG has predictive exposures (100% bioavailability, volume of distribution 
[Vd] and clearance expected to be similar to endogenous IgG). There are no significant 
toxicity findings in the preclinical studies, and the maximum exposure in healthy volunteers 
is expected to remain well below exposures of the high dose (1000 mg/kg) used in GLP 
toxicity studies. In patients the maximum exposure is not expected to be above the high dose 
(1000 mg/kg) used in GLP toxicity studies. 
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A more conventional 3+3 escalation design was considered but not employed in this study. A 
notable difference between the expectation of the design in the current study with 2 patients 
compared to a 3+3 design in literature is how the dose is used in the future. In the current 
study, 
 
 In a more conventional 3+3 design, a dose that triggers the 3+3 rule would 
be considered tolerable, and would be used for future study. 
6.7 
Stopping Rules 
6.7.1 
Dose-Cohort Study Stopping Rules 
Dosing within a cohort and dose escalation to a next cohort will be halted pending evaluation 
by Sponsor and SRC recommendation if 1 of the following circumstances occurs and it is 
determined by the Investigator that the occurrence is possibly related to the administration of 
study drug:  
• A serious adverse reaction (ie, a SAE considered at least possibly related to the study 
drug administration) in 1 subject.  
• Grade 3 or higher AE per National Cancer Institute (NCI) CTCAE version 5.0 criteria (ie, 
severe nonserious AEs considered at least possibly related to the study drug 
administration) in 2 participants in the same cohort, or in 1 subject in the sentinel cohort.  
• Grade 4 or higher grade AE per NCI CTCAE version 5.0 criteria. 
• Other findings that, at the discretion of the Investigator in consultation with Sponsor’s 
Medical Monitor and SRC recommendation, indicate that further dosing should be 
stopped.  
 
When stopping rules for a cohort are met, the randomization code for participants meeting 
the stopping rules will be unblinded. If after de-blinding it is concluded that participants on 
active medication meet the stopping rules, dosing in the cohort will be stopped and no further 
dose escalation will be performed. 
6.7.2 
Dose Limiting Toxicities 
Dose-limiting toxicities will include any NCI CTCAE v.5 Grade 3 or higher adverse reaction 
occurring within 4 weeks following the administration of M254. 
Note: Events considered by the sponsor as clearly unrelated to the study drug will not be 
considered a DLT, eg, thrombocytopenia related to ITP, accidents, and lab results attributed 
to other therapies or illnesses. 
6.7.3 
Rules for Dosing Adjustments, Withholding or Restarting, Permanent 
Discontinuation 
Unless participant safety precludes doing so, the Medical Monitor should be consulted prior 
to stopping or modifying the dosing schedule of study drug. 
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If more than 1 subject or patient with CTCAE Grade 3 or 4, not reasonably related to an 
alternative etiology (eg, motor vehicle accident-related injury or gunshot wound) the sponsor 
will discuss already collected data from the healthy subjects in Part A prior to discontinuation 
for the Part A (if already more than 1 dose level has been evaluated prior to the Part A being 
discontinued) with the Investigators and may modify other parts of the study as needed. 
If 1 of the 2 ITP patients in Part B experiences any DLT, the cohort may be repeated with 
2 additional ITP patients either at the same or lower dose per the recommendation of the 
SRC. If at a given dose level, 2 patients (either 2 of 2 or 2 of 4) experience a DLT that dose 
level will not be repeated, though a lower dose may be selected by the SRC. 
6.7.4 
Study Stopping Rules 
Dosing in the study will be halted pending evaluation by Sponsor and SRC recommendation 
if one of the following circumstances occurs: 
• Grade 5 AE considered related to study treatment, in which case the review process will 
also include regulatory agencies and IRBs/Ethics Committees 
• The following Grade 3 or greater treatment-related AE in 2 or more patients:  
- 
thromboembolic AE 
- 
renal impairment AE 
- 
hemolysis AE 
- 
creatinine elevation  
 
NOTE: Events that are definitely not related to study treatment (eg, accidents or other 
external causes) will not trigger study-stopping rules. 
6.8 
Intervention After the End of the Study 
There is no intervention planned after participants complete the study. 
7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Intervention 
In accordance with the Declaration of Helsinki, International Council for Harmonisation 
(ICH) GCP Guidelines, and the US FDA Regulations, a research subject has the right to 
withdraw at any time for any reason without prejudice to future medical care. However, in 
the absence of a medical contraindication, the Investigator should encourage the subject to 
remain in the study and, at a minimum, follow the subject for safety data collection.  
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The Sponsor and Investigator also have the right to withdraw participants. Subjects or 
patients may be discontinued from study treatment if they experience intolerable toxicity 
related to any study treatment despite dose reduction, or for any of the following reasons: 
• Withdrawal of subject informed consent 
• AE 
• Significant noncompliance with protocol requirements 
• Need for prohibited therapy 
• Termination of the study 
• Any other reason which, in the opinion of the Investigator or Sponsor, would justify the 
subject’s removal 
• Subject lost to follow-up 
 
All reasons for early termination or withdrawal will be documented in the eCRF. 
The Sponsor and the Investigator may decide to halt dosing for safety reasons, including 
emerging nonclinical data, clinically relevant AEs, or relevant data from other sources 
indicating safety concerns.  
Termination of the study by the Sponsor may take place upon written notice to PRA 
Netherlands for the following reasons: 1) if the Ethics Committee irrevocably revokes 
approval for the study; 2) if it is necessary to protect the safety, health, or welfare of 
participants; 3) if it transpires that continuation of the study cannot serve any scientific 
purpose, and this is confirmed by the Ethics Committee; 4) if conducting the study becomes 
prohibitive by law, rule, regulation, or any amendment thereof; or 5) if the Investigator is no 
longer capable of performing the tasks of the Investigator, and no replacement agreeable to 
both parties can be found. 
7.2 
Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, 
or administrative reasons. This is expected to be uncommon. 
An Investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
• Any treatment-related Grade 3 or higher AE per NCI CTCAE version 5.0 criteria 
• Pregnancy (see Appendix 4 and Section 8.4.5) 
• If in the opinion of the Investigator, patient with ITP is not responding adequately or for 
adequate duration in Part D (ie, no platelet count increase from baseline or return to 
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baseline within 1 weeks), subject should be discontinued from the study to timely 
administer treatment per local standard of care. 
• Protocol deviation 
- 
Noncompliance to intervention 
- 
Requires treatment not allowed in the protocol for disease flare 
- 
If the participant meets an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation 
• Sponsor decision 
• Participant request to discontinue study intervention  
 
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted, as shown in the Schedule of Activities (Section 1.2). See activities for the final 
follow-up to be performed. 
The participant will be permanently discontinued both from the study intervention and from 
the study at that time. 
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
7.3 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and 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. 
• Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
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Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Adherence to the study design requirements, including those specified in the Schedule of 
Activities (Section 1.2), is essential and required for study conduct. 
8.1 
General Study Periods 
8.1.1 
Screening, Enrollment, and/or Randomization 
All patients must personally sign and date the IRB/IEC approved informed consent before 
any study-specific procedure can be performed. All screening evaluations (see Schedule of 
Activities [Section 1.2]) must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. During screening, a complete medical history will be 
obtained from each subject/patient. Demographic data will also be collected in order to 
examine their possible association with patient safety and treatment effectiveness during 
initial screening. 
Screening in Part B will proceed only when all single ascending dose cohorts in healthy 
volunteers up to 60 mg/kg have been reviewed for safety by the SRC, and if according to the 
Investigator and SRC, an interim summary of all safety data from Part A, through the 
60 mg/kg cohort, concludes that the anticipated exposure in the first cohort of Part B does not 
impose unnecessary risk. The interim summary will be sent to the IEC, where required.  
The SRC will review all safety data for all patients in Part B up to at least 28 days following 
M254 administration for the last patient. Initiation to Part C will only proceed on the 
recommendation of the SRC. 
The SRC will review all safety data from both crossover cohorts in Part C; however, the 
initiation of Part D will proceed after the SRC reviews all safety database from Cohort 1 and 
the recommendation is to proceed with Part D with approval of the Investigator. 
8.1.2 
Treatment Period 
Individual study assessments are presented in Schedule of Activities (Section 1.2). Where 
possible, a window for each study visit is described in the Schedule of Activities. Visit 
windows noted in the Schedule of Activities apply throughout all sections of the protocol. 
Subjects and patients should remain with a similar level of physical activity during the study 
and not initiate new or strenuous exercise from randomization to the final follow-up. Subjects 
and patients should be hydrated prior to the start of infusion with approximately 2 glasses of 
liquid to avoid a possible thromboembolic event. Additionally, subjects and patients should 
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be mobilized immediately following the end of infusion to decrease the risk of 
thromboembolic events. 
If 1 assessment in a series is missed, “not done” should be recorded in the clinic record and 
eCRF. The original schedule for postdose sample collection will be adhered to rather than 
adjusting the postdose scheduling from the point of the missed sample. 
All collected data will be attributed to the closest nominal/scheduled time point for analysis; 
unscheduled assessments will be collected separately. The Sponsor does accept any 
institution-specific time allowances that are documented as part of the local standard 
operating procedures. 
8.1.3 
Follow-up 
A follow-up visit will be completed 29 ± 2 days after the last dose of study drug for Parts A, 
B, and C. For Part D, the follow-up visit will be completed 71 ± 3 days (M254 naïve 
patients) or 57 ± 3 days (Part B/C patients). Refer to the Schedule of Activities (Section 1.2) 
for required procedures during this visit.  
8.2 
Efficacy Assessments 
Efficacy endpoints are based on platelet levels and are collected at times described in the 
Schedule of Activities (Section 1.2).  
8.3 
Safety Assessments 
Safety endpoints will be summarized using the Safety Analysis Set (SAF) and are collected 
at times described in the Schedule of Activities (Section 1.2).  
Clinical significance for safety assessments is defined as any variation in assessment results 
that has medical relevance and may result in an alteration in medical care (eg, active 
observation, diagnostic measures, or therapeutic measures). If a clinically significant change 
from screening values is noted, the clinically significant value and reason for clinical 
significance will be documented on the AE page of the subject’s eCRF. The Investigator will 
continue to monitor the subject with additional assessments until the values have reached 
reference range and/or the values at Screening, or until the Investigator determines that 
follow-up is no longer medically necessary. 
8.3.1 
Adverse Events 
Adverse events will be assessed and recorded by the study staff. If an AE requires medical 
attention, it should be reported to the Investigator immediately. The Investigator must meet 
with the subject to assess all medical and psychiatric AEs reported by the subject, as well as 
those recorded by the study staff. After current AEs are assessed, the Investigator must 
review with the subject and assess any AEs unresolved from the previous assessment. After 
each AE assessment, the Investigator will record in the subject’s source document and AE 
eCRF, according to the procedures described in Section 10.3, the type of AE and whether 
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serious or nonserious, severity of each AE, and the relationship to the study agent. These 
categories are asking for the Investigator’s best judgment of the severity and relatedness of 
each AE. 
Any study subject with a related AE will be followed by the Investigator until the event is 
resolved to the satisfaction of the Site Investigator and Medical Monitor. During Part A, if 
the AE is unrelated, the subject will not be discharged until medically stable, and then will be 
referred, at the subject’s sole expense, for ongoing care and/or treatment, which may include 
psychological and lifestyle counseling, support groups, or pharmacological and medical 
treatment. 
Refer to Section 8.4 for information regarding AEs. 
8.3.2 
Vital Signs  
Vital signs measurements will include supine blood pressure (after 5 minutes in supine 
position), pulse rate, respiratory rate, and body temperature.  
The Investigator will determine if any of the vital signs measurements are clinically 
significant or not clinically significant. 
See Schedule of Activities (Section 1.2) for the timing and frequency. Vital signs will be 
assessed every 30 minutes during an infusion. For infusions <35 minutes, vital signs 
assessments may occur at the beginning and end of infusion. 
8.3.3 
12-Lead ECG 
Triplicate (3 ECGs within a 10-minute period) 12-lead ECGs will be obtained after the 
subject has been in the supine position for at least 5 minutes. Electrocardiogram assessments 
will include comments on whether the tracings are normal or abnormal, rhythm, presence of 
arrhythmia or conduction defects, morphology, any evidence of myocardial infarction, or 
ST segment, T Wave, and U Wave abnormalities. In addition, the following intervals will be 
measured and reported: RR, PR, QRS, and QTc. 
The Investigator will determine if the ECG results are clinically significant or not clinically 
significant. 
See Schedule of Activities (Section 1.2) for the timing and frequency. 
8.3.4 
Physical Examinations  
A complete physical examination will include assessments of the head, eyes, ears, nose, 
throat, skin, thyroid, neurological, lungs, cardiovascular system, abdomen (liver and spleen), 
lymph nodes, and extremities. Height and weight will also be measured. 
An abbreviated physical examination will include assessments of skin, lungs, cardiovascular 
system, and abdomen (liver and spleen).  
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See Schedule of Activities (Section 1.2) for the timing and frequency. 
8.3.5 
Infusion Reaction Evaluation 
Systemic infusion reactions are not uncommon with administration of biologics and in 
particular with therapeutic antibodies, including IVIg, as described below.  
The Investigator will evaluate and record the signs and symptoms of infusion reactions as 
individual AEs. All systemic infusion reactions and associated AEs will be graded using 
CTCAE. The occurrence of a moderate or severe systemic infusion reaction should prompt a 
meeting of the SRC to review the clinical circumstances and make a determination as to 
whether dosing should continue. 
Premedication prior to M254 administration should not be administered systematically. 
Most systemic infusion reactions are either acute or subacute, occurring within 24 hours of 
the infusion. Delayed reactions are less common; by definition these occur more than 
24 hours after the infusion; in practice most occur 5 to 10 days after the infusion [25]. 
Infusion reactions are often described in terms that are related to a presumed mechanism 
(eg, allergic, IgE mediated, immune complex mediated, target-engagement mediated, 
cytokine release, anaphylactic, anaphylactoid); in practice, determination of mechanism is 
often challenging and based on observation, course, laboratory assessments, and 
expertise.Acute infusions should be classified as mild moderate or severe. Mild reactions 
may present with flushing, dizziness, diaphoresis, nausea, palpitations, and hyperemia. 
Moderate reactions may present with chest pain, hypertension, hypotension, fever, urticaria, 
dyspnea, chills, and/or rash. Severe reactions may present with marked hypertension or 
hypotension, severe dyspnea, bronchospasm, stridor, wheezing, and rigors. Most reactions 
tend to be mild, and related to the rate of the infusion [25], and can be managed by slowing 
or temporarily stopping the infusion. If necessary, antihistamines or acetaminophen may be 
given according to the clinical judgment of the Investigator. With moderately severe acute 
reactions, the infusion should be discontinued, and the subject should be treated with 
acetaminophen and antihistamines, and if necessary with corticosteroids. Once the reaction 
has been arrested, the infusion may be cautiously restarted, if deemed appropriate by the 
Investigator. With severe reactions the infusion should be discontinued, and the subject 
should be treated immediately with acetaminophen, antihistamines, and systemic 
corticosteroids. If anaphylaxis if present, epinephrine should be administered before the 
corticosteroids. The infusion should not be restarted even if the reaction is brought under 
control.  
Delayed reactions (after 24 hours) most likely represent a mild type III immune complex 
reaction, typically secondary to anti-drug antibodies. The most common symptoms that have 
been reported associated with delayed reactions include joint pains, rash, arthritis, myalgia, 
jaw pain, fatigue, headaches, edema, sore throat, and fever. If the symptoms are mild, 
acetaminophen alone may be sufficient. Persistent severe symptoms may require a short 
course of corticosteroids, and discontinuation of further study drug administration.  
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8.3.6 
Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical laboratory tests to be performed and to the Schedule of 
Activities (Section 1.2) for the timing and frequency.  
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the Investigator to be more severe than expected for the participant’s condition, 
and will be considered AEs. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline or 
are no longer considered clinically significant by the Investigator. If such values do not 
return to normal/baseline within a period of time judged reasonable by the Investigator, the 
etiology should be identified and the sponsor notified. 
Subjects will be in a seated or supine position during blood collection. Instructions for blood 
collection, processing, storage, and shipping are described in the Laboratory Manual. 
8.3.7 
Pregnancy Screen 
A serum pregnancy test will be conducted at screening and on Day 29 for all female 
participants of childbearing potential. A urine pregnancy test will be conducted on Day -1. 
8.4 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3. 
Adverse event(s) may be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative) or by the Investigator. 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or study 
procedures, or that caused the participant to discontinue the study (see Section 7). 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information 
All SAEs will be collected from the time of consent until the end of study at the time points 
specified in the Schedule of Activities (Section 1.2). 
All AE will be collected from the time of consent until the end of study at the time points 
specified in the Schedule of Activities (Section 1.2). 
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All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours from becoming aware of the event, as indicated in 
Appendix 3. The Investigator will submit any updated SAE data including but not limited to 
previously missing information, corrections, or additional details of the event, to the sponsor 
or designee within 24 hours of the Investigator becoming aware. 
Investigators are not obligated to actively seek information about AEs or SAEs occurring 
after conclusion of the study participation. However, if the 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 to be reasonably related to the study intervention or study 
participation, the Investigator must promptly notify the sponsor. 
8.4.2 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
8.4.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and nonserious AEs of special interest 
(systemic infusion reactions, hemolysis, infections, flu-like symptoms, rash, myalgia and 
arthralgia, fever, chills), will be followed until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is given in Appendix 3. 
8.4.4 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the Investigator to the sponsor of an SAE is essential so that 
regulatory obligations and ethical responsibilities towards the safety of participants and 
the safety of a study intervention 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 study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and Investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy and forwarded to 
Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 68 of 127 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
 
8.4.5 
Pregnancy 
• Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until 30 days after 
the final study visit. 
• If a pregnancy is reported, the Investigator should inform the sponsor or designee within 
24 hours of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
 
8.5 
Treatment of Overdose 
Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
M254 can no longer be detected systemically. 
3. Obtain a plasma sample for PK analysis if requested by the Medical Monitor 
(determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in 
the case report form (CRF). 
 
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. 
8.6 
Pharmacokinetics 
All participants will undergo blood sampling at designated time points to determine serum 
M254 concentration following a single dose of blinded study drug. Instructions for blood 
collection, processing, storage, and shipping are described in the Laboratory Manual. Serial 
blood sampling for PK will be done after the participants have remained in the same posture 
(supine or sitting) for at least 15 minutes and will be obtained at the time points listed in the 
Schedule of Activities (Section 1.2). Posture per time point will be identical between 
participants. 
PK parameters (maximum plasma concentration [Cmax], time to maximum plasma 
concentration [tmax], area under the concentration–time curve from zero to time of last 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 69 of 127 
measurable concentration area [AUC(0-last)], area under the concentration-time curve from 
zero to infinity [AUC(0-∞)], Vd, clearance of drug [CL], mean residence time [MRT], and 
apparent terminal-phase half-life [t½]) will be computed using noncompartmental methods. 
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment. The IRB/IEC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICF. 
8.7 
Pharmacodynamics 
Blood sampling for PD will be done after the participants have remained in the same posture 
(supine or sitting) for at least 15 minutes. Posture per time point will be identical between 
participants. 
For the purpose of PD parameters, a “therapeutic platelet count” will be defined as 
≥50 × 109/L. 
The PD parameters will include: 
• Time to onset of a therapeutic platelet count 
• Maximum platelet count following dosing 
• Time to maximum platelet count following dosing 
• Maximum and percentage platelet count change from baseline 
• Duration of a therapeutic platelet count 
• Time to therapeutic platelet count 
• Area under the change from baseline platelet count-time curve for 14 and 28 days 
 
8.8 
Exploratory Biomarkers and Anti-drug Antibodies 
Approximately 16 mL of blood will be collected and processed to both plasma and serum for 
assessment of biomarkers associated with inflammation and for assessment of anti-drug 
antibodies (ADA) to residual enzymes from exposure to M254. Instructions for blood 
collection, processing, storage, and shipping are described in the Laboratory Manual. 
8.9 
Health Economics/Medical Resource Utilization and Health Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 70 of 127 
9 
STATISTICAL CONSIDERATIONS 
9.1 
Sample Size Determination 
The sample size has been chosen to provide adequate numbers of subjects and patients to 
characterize the safety, tolerability, PK, and PD of M254 and the study has not been formally 
powered.  
No formal sample size calculation was performed for this study (Parts A, B, and D).  
Part C is an exploratory study designed to obtain preliminary information on the safety and 
efficacy of M254 for the treatment of ITP.  
Assuming ratio of M254 to IVIg in maximum change from baseline of platelet counts as 
 
 
 
.  
9.2 
Populations for Analyses 
For purposes of analysis, the following 4 population sets are defined: 
• The SAF will include all participants who received at least 1 dose of study drug.  
• The PK Set will include all randomized participants who received at least 1 dose of study 
drug with at least 4 evaluable data points adequate to create an evaluable plasma 
concentration profile of M254. 
• The Full Analysis Set (FAS) population will include all randomized participants in the 
SAF for whom at least 1 PD assessment was completed. 
• The Per Protocol Set (PP) is a subset of the intent-to-treat (ITT) population and will 
include participants who complete the study with all planned safety, PD, and PK 
assessments and no major protocol deviations impacting safety or PD assessments. 
Assignment to the PP population will be determined prior to unblinding the study. 
 
Categorical variables will be summarized by the number and percentage of participants in 
each category. Continuous variables will be analyzed in terms of summary statistics. 
Summaries will separate the populations by study part (A, B, C, or D), by dose level, and by 
dose regimen (single or repeated dose). 
9.3 
Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock and will 
describe the participant populations to be included in the analyses, and procedures for 
CCI
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 71 of 127 
accounting for missing, unused, and spurious data. This section is a summary of the planned 
statistical analyses of the primary and secondary endpoints. 
All demographic, safety, PK, and PD data will be listed and summarized in tabular and 
graphical formats using descriptive statistics for continuous variables and frequency and 
percentages for discrete variables. Missing data will not be imputed.  
9.3.1 
Efficacy Analyses  
Endpoint 
Statistical Analysis Methods 
Primary 
Efficacy analyses will be performed using Full Analysis Set (FAS). For 
Part C, for the ratio of effects between M254 and IVIg, a linear mixed 
effect model will be performed on the natural logarithms of maximum 
platelet counts, maximum change from baseline, and area under the curve 
(AUC), with factors for baseline platelet count, sequence, subject nested 
within sequence, period, and regimen. The factor of subject nested within 
sequence will be random effect and others are fixed effects. The estimated 
ratio will be obtained by exponentiation of the difference of least squares 
means in natural log-transformed parameters between M254 and IVIg. 
Secondary 
Overall platelet response rate and its 90% exact binomial confidence 
interval in each treatment period will be presented. Duration of a clinically 
significant platelet response will be presented descriptively.  
Exploratory 
Will be described in the statistical analysis plan finalized before database 
lock. 
 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 72 of 127 
9.3.2 
Safety Analyses 
All safety analyses will be performed on the SAF. 
Endpoint 
Statistical Analysis Methods 
Primary 
Analysis of all safety data will be performed on the Safety Analysis Set 
(SAF) and will be presented by the treatment received. Adverse events will 
be coded using Medical Dictionary for Regulatory Authorities (MedDRA). 
The occurrence of adverse events (AEs), serious AEs (SAEs), and AEs of 
Special Interest will be summarized in terms of incidence, as well as in 
terms of total number of AEs. Analysis of AEs in terms of incidence by 
severity and by relatedness will also be provided. Prior and concomitant 
medications will be coded by the World Health Organization Drug 
Dictionary Enhanced and will be listed. Medical history will be listed by 
subject and coded using the MedDRA. Descriptive statistics and a 
summary of clinically significant abnormalities using shift tables will be 
presented for safety laboratory tests, vital signs, electrocardiogram 
(ECGs), and other laboratory parameters. For vital signs and ECGs, 
descriptive statistics at each visit and change from baseline at each visit 
will be provided. Physical examinations will be summarized as shift tables. 
Listings will also be provided for each type of safety data. 
Secondary 
Not applicable. 
Exploratory 
Not applicable. 
 
9.3.3 
Other Analyses 
Pharmacodynamic exploratory analyses will be described in the statistical analysis plan 
finalized before database lock. The population PK analysis and pharmacodynamic analyses 
will be presented separately from the main clinical study report (CSR).  
9.4 
Interim Analyses  
There will be 3 interim analyses in this study: Part A (after 
 End of Part B, 
and End of Cohort 1 Part C. 
The Statistical Analysis Plan will describe the planned interim analyses in greater detail. 
9.5 
Handling of Missing Data 
In general, there will be no substitutions made to accommodate missing data points. All data 
recorded on the CRF will be included in data listings that will accompany the CSR.  
For AEs, missing dates will not be imputed; however, if partial dates are available, they will 
be used to assess if the AE occurred during the treatment period. Missing severities of AEs 
CCI
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 73 of 127 
will not be imputed and will be considered missing in any tabulations of AE severity. If an 
AE is missing a response to the question regarding relationship to treatment, the event will be 
considered to be related. 
No other data imputation will be performed. 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines 
• Applicable laws and regulations 
 
The protocol, protocol amendments, informed consent form (ICF), Investigator Brochure, 
and other relevant documents (eg, participant recruitment advertisements) must be submitted 
to an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) by the 
Investigator and reviewed and approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
• Notifying the IRB/IEC of serious adverse events (SAEs) or other significant safety 
findings as required by IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 74 of 127 
10.1.2 
Financial Disclosure 
Investigators and sub-Investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
10.1.3 
Informed Consent Process 
• An initial sample ICF is provided for the Investigator to prepare the informed consent 
document to be used at his or her site. Updates to the sample ICF are to be communicated 
formally in writing from the Sponsor Trial Manager to the Investigator. The written ICF 
is to be prepared in the language(s) of the potential patient population. 
- 
For those enrolling in Part A (Netherlands only), there will be 1 consent form for the 
healthy volunteers. 
- 
For those enrolling in Part B, there will be 1 consent form. 
- 
For those enrolling in Part C, there will be 1 consent form. 
- 
For those enrolling in Part D, there will be 1 consent form. Patients from Parts B or C 
will need to sign a new consent form for participation in Part D. 
• The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study. 
• Participants must be informed that their participation is voluntary. Participants (and/or 
legally authorized representative if the subject is mentally incompetent or physically 
incapacitated) will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the 
IRB/IEC or study center. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• The original signed ICF is to be retained in accordance with institutional policy, and a 
copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
 
Participants who are rescreened are required to sign a new ICF. 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 75 of 127 
10.1.4 
Data Protection 
• Participants will be assigned a unique identifier by the sponsor. Any participant records 
or datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant. 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• The Investigator must ensure that the participant’s confidentiality is maintained for 
documents submitted to Sponsor. 
• For SAEs reported to Sponsor or designee, participants are to be identified by their 
unique participant identification number, initials (for faxed reports, in accordance with 
local laws and regulations), and age (in accordance with local laws and regulations). 
• Documents that are not submitted to Sponsor (eg, signed ICFs) are to be kept in 
confidence by the Investigator, except as described below. 
• In compliance with governmental regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the participant’s original 
medical records for verification of study-related procedures and data. Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.  
• The Investigator is obligated to inform and obtain the consent of the participant to permit 
such individuals to have access to his/her study-related records, including personal 
information.  
 
10.1.5 
Committees Structure 
The Safety Review Committee (SRC) will, at a minimum, consist of a therapeutic expert in 
hematology, the Sponsor Medical Monitor, and a Sponsor Clinical Operations representative. 
10.1.6 
Dissemination of Clinical Study Data 
A clinical study report (CSR) will be prepared in accordance with the ICH guideline on 
structure and contents of CSRs and any applicable regulatory and legal requirements. 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 76 of 127 
10.1.7 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic case 
report form (eCRF) unless transmitted to the sponsor or designee electronically (eg, 
laboratory data). The Investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan. 
• The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organizations). 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 2 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor. 
 
10.1.8 
Source Documents 
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 77 of 127 
10.1.9 
Study and Site Closure 
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or Investigator may include but 
are not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• Discontinuation of further study intervention development 
 
10.1.10 Publication Policy 
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments. 
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 78 of 127 
10.2 Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 10-1 and Table 10-2  will be performed by the central laboratory. 
No more than 500 mL of blood will be collected for any distinct study part and for any 
patient from Part B or C who also participates in Part D will not have greater than 500 mL of 
blood taken in a 2 month time frame.  
Local laboratory results are required for platelet counts and pregnancy testing. Results of all 
local labs preformed during the study must be entered in the CRF. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. Additional tests may be performed at any time during the study as 
determined necessary by the Investigator or required by local regulations. 
Investigators must document their review of each laboratory  report by signing and dating the 
lab report. 
For Part A, laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded. 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 79 of 127 
Table 10-1. 
Protocol-required Laboratory Assessments Parts A and B 
Hematology: 
 
Hematocrit (Hct) 
 
Hemoglobin (Hgb) 
 
Mean corpuscular 
hemoglobin (MCH) 
 
Mean corpuscular 
hemoglobin concentration 
(MCHC) 
 
Mean corpuscular volume 
(MCV) 
 
Platelet count 
 
Red blood cell (RBC) count  
 
White blood cell (WBC) 
count with differential  
Urinalysis:  
 
Appearance 
 
Bilirubin 
 
Color 
 
Glucose 
 
Ketones 
 
Microscopic examination of 
sediment  
 
Nitrite  
 
pH 
 
Protein 
 
Specific gravity 
 
Urobilinogen 
Serum Chemistry: 
 
Albumin (ALB) 
 
Alkaline phosphatase 
(ALK-P) 
 
Alanine aminotransferase 
(ALT; SGPT) 
 
Aspartate aminotransferase 
(AST; SGOT) 
 
Blood urea nitrogen (BUN) 
 
Calcium (Ca) 
 
Chloride (Cl) 
 
Creatinine 
 
Creatine kinase (CK) and 
subtypes (MB 
[muscle/brain] fraction – if 
CK is elevated) 
 
Gamma-glutamyl 
transferase (GGT) 
 
Glucose 
 
Lactate dehydrogenase 
(LDH) 
 
Inorganic phosphate 
 
Potassium (K) 
 
Sodium (Na) 
 
Total bilirubin 
 
Direct bilirubin 
 
Total cholesterol 
 
Total protein 
 
Triglycerides 
 
Troponin I 
 
Uric acid 
Coagulation Screening Labs: 
 
Antithrombin III (ATIII) 
deficiency 
 
Factor V Leiden 
 
Protein S deficiency 
 
Protein C deficiency 
Serology: 
 
HBsAg, HCV, and HIV 
Coagulation:  
 
Activated partial 
thromboplastin time (PTT) 
 
D-dimer 
 
Prothrombin time (PT) 
Immunoglobulins:  
 
Total IgG 
 
IgG Subclasses: IgG1, 
IgG2, IgG3, IgG4 
Platelet autoantibodies 
 
 
Serum and urine human chorionic gonadotropin (hCG) (only for females who are not diagnosed as 
postmenopausal) 
HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
IgG = immunoglobulin G 
 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 80 of 127 
Table 10-2. 
Protocol-required Laboratory Assessments Part C and Part D 
Hematology: 
 
Hematocrit (Hct) 
 
Hemoglobin (Hgb) 
 
Mean corpuscular 
hemoglobin (MCH) 
 
Mean corpuscular 
hemoglobin concentration 
(MCHC) 
 
Mean corpuscular volume 
(MCV) 
 
Platelet count 
 
Red blood cell (RBC) count  
 
White blood cell (WBC) 
count with differential  
Urinalysis (dipstick):  
 
Glucose 
 
Hemoglobin 
 
Leukocytes 
 
Protein 
Serum Chemistry: 
 
Albumin (ALB) 
 
Alkaline phosphatase 
(ALK-P) 
 
Alanine aminotransferase 
(ALT; SGPT) 
 
Aspartate aminotransferase 
(AST; SGOT) 
 
Blood urea nitrogen (BUN) 
 
Calcium (Ca) 
 
Chloride (Cl) 
 
Creatinine 
 
Gamma-glutamyl 
transferase (GGT) 
 
Glucose 
 
Lactate dehydrogenase 
(LDH) 
 
Inorganic phosphate 
 
Potassium (K) 
 
Sodium (Na) 
 
Total bilirubin 
 
Direct bilirubin 
 
Total protein 
Coagulation Screening Labs: 
(only for patients with a history of 
thrombosis): 
 
Antithrombin III (ATIII) 
deficiency 
 
Factor V Leiden 
 
Protein S deficiency 
 
Protein C deficiency 
Serology: 
 
HBsAg, HCV, and HIV 
Coagulation:  
 
Activated partial 
thromboplastin time (PTT) 
 
Prothrombin time (PT) 
Immunoglobulins:  
 
Total IgG 
 
IgG Subclasses: IgG1, 
IgG2, IgG3, IgG4 
Platelet autoantibodies 
 
 
 
Serum and urine human chorionic gonadotropin (hCG) (only for females who are not diagnosed as 
postmenopausal) 
HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
IgG = immunoglobulin G 
 
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NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 86 of 127 
10.4 Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), Investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
- 
A high follicle stimulating hormone level in the postmenopausal range may be used 
to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than 1 follicle stimulating hormone 
measurement is required.  
- 
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 87 of 127 
Contraception Guidance: 
Male Participants 
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 100 days after the last dose of study intervention:  
• Refrain from donating sperm 
Plus either:  
• Be abstinent from heterosexual or homosexual intercourse as their preferred and usual 
lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent  
OR 
• Must agree to use contraception/barrier as detailed below 
- 
Agree to use a male condom and should also be advised of the benefit for a female 
partner to use a highly effective method of contraception as a condom may break or 
leak when having sexual intercourse with a woman of childbearing potential who is 
not currently pregnant 
- 
Agree to use male condom when engaging in any activity that allows for passage of 
ejaculate to another person 
 
Female Participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described below. 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 88 of 127 
Highly Effective Contraceptive Methods That Are User Dependenta  
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulationb  
• Oral  
• Intravaginal  
• Transdermal  
Progestogen only hormonal contraception associated with inhibition of ovulation 
• Oral  
• Injectable  
Highly Effective Methods That Are User Independenta  
Implantable progestogen only hormonal contraception associated with inhibition of 
ovulationb 
• Intrauterine device  
• Intrauterine hormone-releasing system  
• Bilateral tubal occlusion 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used.  
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study 
intervention. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.  
NOTES:  
a. Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods 
for participants participating in clinical studies.  
b. Hormonal contraception may be susceptible to interaction with the study intervention, 
which may reduce the efficacy of the contraceptive method. In this case, 1 highly 
effective method of contraception and 1 barrier method (ie, condom, cervical cap, 
diaphragm) should be utilized during the treatment period and for at least 90 days after 
the last dose of study intervention  
 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 89 of 127 
Pregnancy Testing: 
• Women of childbearing potential should only be included after a confirmed menstrual 
period and a negative highly sensitive serum pregnancy test. 
• Additional pregnancy testing is required during Day 1 of the treatment period and at 
follow-up visit, corresponding to protocol-defined time frame in Section 5.1 after the last 
dose of study intervention and as required locally. 
• Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
 
Collection of Pregnancy Information 
Male participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure.  
 
Female Participants who become pregnant 
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the sponsor within 24 hours of learning of a 
participant's pregnancy.  
• The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the sponsor. Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of anomalies) 
or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or SAE. A 
spontaneous abortion is always considered to be an SAE and will be reported as such. 
Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the sponsor as described in 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 90 of 127 
Section 8.4.5. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 91 of 127 
10.5 Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments 
and Study Intervention Rechallenge Guidelines 
Phase I liver chemistry stopping criteria are designed to assure participant safety and to 
evaluate liver event etiology. 
Liver Chemistry Stopping Criteria 
ALT-absolute 
Alanine aminotransferase (ALT) ≥3 x ULN 
If ALT ≥3 x upper limit of normal (ULN) AND bilirubin  2 x ULN (>35% direct 
bilirubin) or international normalized ratio (INR) >1.5, report as a serious adverse event 
(SAE)a,b 
See additional actions and follow-up assessments below 
Required Actions and Follow-up Assessments  
Actions 
Follow-up Assessments 
• Immediately discontinue study intervention 
• Report the event to the sponsor within 24 hours 
• Complete the liver event case report form (CRF), 
and complete an SAE data collection tool if the 
event also met the criteria for an SAEb 
• Perform liver function follow-up assessments 
• Monitor the participant until liver function test 
abnormalities resolve, stabilize, or return to 
baseline (see MONITORING) 
 
MONITORING: 
If ALT ≥3 x ULN AND bilirubin ≥2 x ULN or INR 
>1.5 
• Repeat liver function tests (include ALT, 
aspartate transaminase [AST], alkaline 
phosphatase, bilirubin) and perform liver 
function follow-up assessments within 24 hours. 
• Monitor participant twice weekly until liver 
function test abnormalities resolve, stabilize, or 
return to baseline. 
• A specialist or hepatology consultation is 
recommended. 
• Viral hepatitis serologyc 
• Obtain INR and recheck with each liver 
chemistry assessment until the transaminases 
values show downward trend 
• Obtain blood sample for pharmacokinetic (PK) 
analysis after the most recent dosed 
• Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH) 
• Fractionate bilirubin, if total bilirubin  2 x 
ULN 
• Complete blood count with differential to 
assess eosinophilia 
• Record the appearance or worsening of clinical 
symptoms of liver injury, or hypersensitivity, 
on the adverse event (AE) CRF 
• Record use of concomitant medications 
(including acetaminophen, herbal remedies, and 
other over-the-counter medications) on the 
concomitant medications CRF 
• Record alcohol use on the liver event alcohol 
intake CRF 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 92 of 127 
If ALT ≥3 x ULN AND bilirubin <2 x ULN and 
INR ≤1.5: 
• Repeat liver function tests (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform liver 
function follow-up assessments within 
24 to 72 hours 
• Monitor participants weekly until liver function 
abnormalities resolve, stabilize, or return to 
baseline 
If ALT ≥3 x ULN AND bilirubin ≥2 x ULN or 
INR >1.5: 
• Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total 
immunoglobulin G (IgG) or gamma globulins 
• Serum acetaminophen adduct high performance 
liquid chromatography (HPLC) assay 
(quantifies potential acetaminophen 
contribution to liver injury in participants with 
definite or likely acetaminophen use in the 
preceding week [8])  
• Liver imaging (ultrasound, magnetic resonance, 
or computerized tomography) and/or liver 
biopsy to evaluate liver disease; complete liver 
imaging and/or liver biopsy CRFs 
a 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is 
not immediately available, discontinue study intervention if ALT ≥3 x ULN and bilirubin ≥ 2 x ULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record the absence/presence of 
detectable urinary bilirubin on dipstick which is indicative of direct bilirubin elevations suggesting liver 
injury.  
b 
All events of ALT ≥3 x ULN and bilirubin ≥2 x ULN (>35% direct bilirubin) or ALT ≥3 x ULN and 
INR >1.5 may indicate severe liver injury (possible ‘Hy’s Law’) and must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis). The INR measurement is not required and the stated 
threshold value will not apply to participants receiving anticoagulants.  
c 
Includes: Hepatitis A immunoglobulin M (IgM) antibody; hepatitis B surface antigen (HBsAg) and 
hepatitis B core antibody (HBcAb); hepatitis C RNA; cytomegalovirus IgM antibody; Epstein-Barr viral 
capsid antigen IgM antibody (or if unavailable, heterophile antibody or monospot testing); and hepatitis E 
IgM antibody.  
d 
PK sample may not be required for participants known to be receiving placebo or noncomparator 
interventions. Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
intervention prior to the PK blood sample draw on the CRF. If the date or time of the last dose is unclear, 
provide the participant’s best approximation. If the date/time of the last dose cannot be approximated OR a 
PK sample cannot be collected in the time period indicated above, do not obtain a PK sample. Instructions 
for sample handling and shipping are in the Study Reference Manual. 
 
NCT03866577


NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 94 of 127 
2. 
Skin: Ecchymoses  
 
 
 
 
2.1 
Has the patient had ecchymoses? 
(see pictures) 
 
 Yes 
 No  
2.2 
Ecchymoses present at this visit  
 
 Yes 
 No  
2.3 
If answer to 2.2 is yes, please 
specify how many  
 
 1-2 in the same body area, smaller than a 
patient’s palm-sized area, spontaneous or 
disproportionate to trauma/constriction  
 3 or more in the same body area, smaller than a 
patient’s palm-sized area, spontaneous or 
disproportionate to trauma/constriction  
 At least 2 in two different body regions, smaller 
than a patient’s palm-sized area, spontaneous or 
disproportionate to trauma/constriction 
 1 to 5 larger than a patient’s palm-sized area, 
spontaneous or disproportionate to 
trauma/constriction, with or without smaller ones 
 More than 5 larger than a patient’s palm-sized 
area, spontaneous or disproportionate to 
trauma/constriction, 
 
Comments 
      
 
NCT03866577


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NCT03866577


NCT03866577


NCT03866577


NCT03866577


NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 103 of 127 
10. 
Organ: Gastrointestinal bleeding not explained by visible mucosal bleeding or lesion 
(Hematemesis, Melena, Hematochezia, Rectorrhagia) 
 
 
 
 
10.1 
Has the patient had gastrointestinal 
bleeding? 
 
 Yes 
 No  
10.2 
Gastrointestinal bleeding at this visit 
or described in a medical report 
exhibited by the patient 
 
 Yes 
 No  
10.3 
If answer to 10.2 is yes, please 
specify  
 
 
 
   Type of bleeding 
 
 Hematemesis 
 Melena 
 Hematochezia 
 Rectorrhagia 
 
10.4 
Has the symptom ever required 
medical attention? 
 
 Yes  
 No  
10.5 
If answer to 10.4 is yes, please 
specify  
 
 
 Prescription of endoscopy or other therapeutic 
procedures or in-hospital evaluation at the time of 
this visit 
 Medical report provided by the patient 
prescribing endoscopy or other therapeutic 
procedures or in-hospital evaluation  
 RBC transfusion  
 Hb drop >2 g/dL 
 
Comments 
      
 
NCT03866577


NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 105 of 127 
11. 
Organ: Lung bleeding (Hemoptysis, Tracheobronchial bleeding) 
 
 
 
 
11.1 
Has the patient had lung bleeding? 
 
 Yes 
 No  
11.2 
Lung bleeding present at this visit or 
described in a medical report 
exhibited by the patient 
 
 Yes 
 No  
11.3 
If answer to 11.2 is yes, please 
specify  
 
 
 
 
   Type of bleeding 
 
 Hemoptysis 
 Tracheobronchial bleeding 
11.4 
Has the symptom ever required 
medical attention? 
 
 Yes  
 No  
11.5 
If answer to 11.4 is yes, please 
specify 
 
 
 Requiring bronchoscopy or other therapeutic 
procedures or in-hospital evaluation at the time of 
this visit 
 An equivalent episode if described in a medical 
report exhibited by the patient 
 RBC transfusion  
 Hb drop >2 g/dL 
 
Comments 
      
 
NCT03866577


NCT03866577


NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 108 of 127 
13. 
Organ: Menorrhagia (compared with pre-ITP or with a phase of disease with normal platelet 
count) 
 
 
 
 
13.1 
Has the patient had very heavy 
menstrual bleeding 
(menorrhagia)? 
 
 Yes 
 No  
13.2 
If answer to 13.1 is yes, please 
describe your last cycle 
 
 Doubling nr. of pads/tampons in last cycle compared 
to pre-ITP or to a phase of disease with normal platelet 
count 
 Score >100 using PBAC in the last cycle if normal 
score in pre-ITP cycles or in a phase of disease with 
normal platelet count 
 Changing pads more frequently than every 2 hours 
or clot and flooding  
13.3 
Has the symptom required 
medical attention? 
 
 Yes 
 No  
13.4 
If answer to 13.3 is yes, please 
specify 
 
 Requiring combined treatment with antifibrinolytics 
and hormonal therapy or gynecological investigation 
(either at this visit or described in a medical report 
exhibited by the patient) 
 Acute menorrhagia requiring hospital admission or 
endometrial ablation (either at this visit or described in a 
medical report exhibited by the patient) 
 RBC transfusion  
 Hb drop >2 g/dL 
 
Comments 
      
 
NCT03866577


NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 110 of 127 
14. 
Organ: Intramuscular hematomas (only if diagnosed by a physician with an objective 
method) 
 
 
 
 
14.1 
Intramuscular hematomas present 
at this visit 
 
 Yes 
 No  
 
If yes, please specify 
 
 Post trauma, if judged disproportionate to 
trauma  
 Spontaneous 
14.2 
Have the symptom required 
medical attention? 
 
 Yes 
 No 
 
If yes, please specify 
 
Requiring hospital admission or surgical 
intervention 
 RBC transfusion 
14.3 
Intramuscular hematomas 
described in a medical report 
exhibited by the patient 
 
 Yes 
 No  
 
If yes, please specify  
 
 Post trauma, if judged disproportionate to 
trauma  
 Spontaneous 
14.4 
Has the symptom required medical 
attention? 
 
 Yes 
 No 
 
If yes, please specify 
 
 Requiring hospital admission or surgical 
intervention  
 RBC transfusion  
 Hb drop >2 g/dL 
 
Comments 
      
 
NCT03866577


NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 112 of 127 
15. 
Organ: Hemarthrosis (only if diagnosed by a physician with an objective method) 
 
 
 
 
15.1 
Hemarthrosis present at this 
visit  
 
 Yes 
 No  
 
If yes, please specify 
 
 Post trauma, function conserved or minimally 
impaired, if judged disproportionate to trauma 
 Spontaneous, function conserved 
15.2 
Have the symptom required 
medical attention? 
 
 Yes 
 No 
 
If yes, please specify 
 
 Requiring immobilization or joint aspiration 
 Requiring surgical intervention 
15.3 
Hemarthrosis described in a 
medical report exhibited by 
the patient, function 
conserved 
 
 Yes 
 No  
 
If yes, please specify  
 
 Post trauma, function conserved or minimally 
impaired, if judged disproportionate to trauma 
 Spontaneous, function conserved 
15.4 
Has the symptom required 
medical attention? 
 
 Yes 
 No 
 
If yes, please specify 
 
 Requiring immobilization or joint aspiration 
 Requiring surgical intervention 
 
Comments 
      
 
NCT03866577


NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 114 of 127 
16. 
Organ: Ocular bleeding (for subconjunctival hemorrhage see mucosal section) 
(only if diagnosed by a physician with an objective method) 
 
 
 
 
16.1 
Ocular bleeding present at this 
visit 
 
 Yes 
 No  
 
If yes, please specify 
 
 Any post-trauma, vitreous or retinal hemorrhage, 
involving one or both eyes  
with or without impaired/blurred vision if judged 
disproportionate to trauma 
 Spontaneous, vitreous or retinal, involving one eye 
without impaired/blurred vision 
 Spontaneous, vitreous or retinal, with 
impaired/blurred vision, involving one or both eyes 
16.2 
Ocular bleeding described in a 
medical report exhibited by the 
patient 
 
 Yes 
 No  
 
If yes, please specify  
 
 Any post-trauma, vitreous or retinal hemorrhage, 
in one or both eyes  
with or without impaired/blurred vision if judged 
disproportionate to trauma 
 Spontaneous, vitreous or retinal hemorrhage, 
involving one or both eyes with impaired/blurred 
vision 
 Spontaneous, vitreous or retinal hemorrhage, with 
loss of vision in one or both eyes 
 
Comments 
      
 
NCT03866577


NCT03866577


NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 117 of 127 
18. 
Organ: Other internal bleedings (only if diagnosed by a physician with an objective method) 
 
 
 
 
18.1 
Other internal bleeding, either present at this 
visit or described in a medical report 
exhibited by the patient 
 
 Yes 
 No  
18.2 
If yes, please specify 
 
 Hemoperitoneum 
 Hemopericardium 
 Hemothorax 
 Retroperitoneal bleeding 
 Hepatic peliosis (with organ rupture) 
 Splenic peliosis (with organ rupture) 
 Retroorbital bleeding 
 Metrorrhagia  
 Other       
18.3 
Have the symptoms required medical 
attention? 
 
 Yes  
 No 
 
If yes, please specify 
 
 Hospitalization <48 hrs 
 Hospitalization >48 hrs 
 RBC transfusion 
 Hb drop >2 g/dL 
 
Comments 
      
 
NCT03866577


NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 119 of 127 
19. 
Organ: Bleeding after Surgery, invasive procedures (biopsy, epidural anesthesia, 
catheter insertion), hemostatic challenges (extraction of a permanent or deciduous 
tooth, or parturition) 
 
 
 
 
19.1 
Have you ever had bleeding after 
surgery, invasive procedures, 
parturition or tooth extraction? 
 
 Yes 
 No 
19.2 
If yes, please specify 
 
 
 
 Tooth extraction 
 Tonsillectomy/Adenoidectomy 
 Pharynx/Nose surgery 
 Vaginal parturition  
 Major-abdominal surgery 
 Major-thoracic surgery 
 Major-gynecology and cesarean section 
 Biopsy 
 Epidural anesthesia 
 Catheter insertion 
 Arthroscopy 
 Other       
19.3 
Have the symptoms required 
medical attention? 
 
 Yes  
 No 
 
If yes, please specify 
 
 Revisiting 
 Antifibrinolytics 
 Prolonged in-hospital stay 
 Iron therapy 
 Resuturing or packing 
 Return to operating room 
 Caused organ damage 
 Occurred in critical areas (eg, CNS) 
 RBC transfusion  
 Hb drop >2 g/dL 
 Requiring critical care or surgical intervention 
 Directly contributing to death 
 
NCT03866577


NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 121 of 127 
10.7 Appendix 7: Abbreviations 
Abbreviation or Term 
Definition 
ADA 
Anti-drug Antibody 
AE 
Adverse event 
ALB 
Albumin 
ALK-P 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATIII 
Antithrombin III 
AUC 
Area above the curve 
AUC (0-last) 
Area under the concentration–time curve from zero to time of last 
measurable concentration area 
AUC (0-∞) 
Area under the concentration–time curve from zero to infinity 
BAT 
Bleeding assessment tool 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
Ca 
Calcium 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CIDP 
Chronic inflammatory demyelinating polyneuropathy 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
Creatine kinase 
Cl 
Chloride 
CL 
Clearance  
Cmax 
Maximum concentration in plasma 
CONSORT 
Consolidated Standards of Reporting Trials 
CPK 
Creatine phosphokinase 
CRF 
Case report form 
CRO 
Clinical Research Organization 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV% 
Coefficient of variation 
D5W 
5% dextrose injection 
DER 
Dose escalation report 
DLT 
Dose-limiting toxicity 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 122 of 127 
Abbreviation or Term 
Definition 
DSM-IV-TR 
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text 
Revision 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EMA 
European Medicines Agency 
EU 
European Union 
FAS 
Full analysis set 
Fc 
Fragment crystallizable 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
GP 
Glycoprotein 
HBcAb 
Hepatitis B core antibody 
HBsAg 
Hepatitis B surface antigen 
hCG 
Human chorionic gonadotropin 
Hct 
Hematocrit 
HCV 
Hepatitis C virus; 
Hgb 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HRT 
Hormonal replacement therapy 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IgA, IgG, IgM 
Immunoglobulin A, immunoglobulin G, immunoglobulin M 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITP 
Immune thrombocytopenic purpura; Immune thrombocytopenia 
ITT 
Intent-to-treat 
IV 
Intravenous 
IVIg 
Intravenous immunoglobulin 
K 
Potassium 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 123 of 127 
Abbreviation or Term 
Definition 
LDH 
Lactate dehydrogenase 
MB 
Muscle/brain 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean residence time 
Na 
Sodium 
NCI 
National Cancer Institute 
NOAEL 
No-observed-adverse-event-level 
NSAID 
Nonsteroidal anti-inflammatory drug 
PD 
Pharmacodynamics 
PID 
Primary immunodeficiency 
PK 
Pharmacokinetics 
PP 
Per protocol set 
PR interval 
Interval that begins at the onset of the P wave and ends at the onset of the 
QRS complex; represents the time the impulse takes to reach the ventricles 
from the sinus node 
PRA 
Pharmaceutical Research Associates Inc 
PT 
prothrombin time 
PTT 
Activated partial thromboplastin time 
Q2W 
Every 2 weeks 
QRS interval 
Interval corresponding to the depolarization of the right and left heart 
ventricles 
QT interval 
Measure of time between the start of the Q wave and the end of the T wave 
in the heart’s electrical cycle 
QTc 
QT interval corrected  
RBC 
Red blood cell 
RR interval 
Time interval between the R wave of 1 heartbeat and the R wave of the 
preceding heartbeat; measures heart rate 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SGOT 
Aspartate aminotransferase 
SGPT 
Alanine aminotransferase 
SOP 
Standard operating procedure 
SRC 
Scientific Review Committee 
NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 124 of 127 
Abbreviation or Term 
Definition 
t½  
Terminal elimination half-life 
tmax 
Time to reach maximum plasma concentration 
ULN 
Upper limit of normal 
USA 
United States of America 
Vd 
Volume of distribution 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
 
 
 
NCT03866577


NCT03866577


Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020 
MOMENTA CONFIDENTIAL INFORMATION 
Page 126 of 127 
12. McMillan R, Durette C. Long-term outcomes in adults with chronic ITP after
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13. Negi VS, Elluru S, Sibéril S, Graff-Dubois S, Mouthon L, Lacroix-Desmmazes S, et al.
Intravenous immunoglobulin: an update on the clinical use and mechanisms of action.
J Clin Immunol. 2007;27:233-45.
14. Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr, Crowther MA, et al. The
American Society of Hematology 2011 evidence-based practice guideline for immune
thrombocytopenia. Blood. 2011;117:4190-207.
15. Prins C, Gelfand EW, French LE. Intravenous immunoglobulin: properties, mode of
action and practical use in dermatology. Acta Derm Venereol. 2007;87:206-18.
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17. Provan D, Newland A. Fifty years of idiopathic thrombocytopenic purpura (ITP):
management of refractory ITP in adults. Br J Haematol. 2002;118:933-44.
18. Provan D, Stasi R, Newland AC, Blanchette VS, Bolton-Maggs P, Bussel JB, et al.
International consensus report on the investigation and management of primary immune
thrombocytopenia. Blood. 2010;115:168-86.
19. Robak T, Salama A, Kovaleva L, Vyhovska Y, Davies S, Mazzucconi MG, et al.
Efficacy and safety of a new intravenous immunoglobulin product in patients with
chronic immune thrombocytopenic purpura. Blood. 2007;110(11):1307.
20. Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, et al.
Standardization of terminology, definitions and outcome criteria in immune
thrombocytopenic purpura of adults and children: report from an international working
group. Blood. 2009;113:2386-93.
21. Stasi R, Provan D. Management of immune thrombocytopenic pupura in adults. Mayo
Clin Proc. 2004;79:504-22.
22. van Schaik IN, van Geloven N, Bril V, Hartung HP, Lewis RA, Sobue G, et al.
Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory
demyelinating polyneuropathy (the PATH study): study protocol for a randomized
controlled trial. Trials. 2016;17:345.
23. Washburn N, Schwab I, Ortiz D, Bhatnagar N, Lansing JC, Medeiros A, et al. Controlled
tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced
anti-inflammatory activity. PNAS. 2015;112:E1297-306.
C
C
I
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Compound: M254 
Momenta Pharmaceuticals, Inc. 
Protocol: MOM-M254-001 
Protocol Date and Version:8 Global  28 April 2020  
 
MOMENTA CONFIDENTIAL INFORMATION 
 
Page 127 of 127 
24. Wolf HH, Davies SV, Borte M, Caulier MT, Williams PE, Bernuth HV, et al. Efficacy, 
tolerability, safety and pharmacokinetics of a nanofiltered intravenous immunoglobulin: 
studies in patients with immune thrombocytopenic purpura and primary 
immunodeficiencies. Vox Sang. 2003;84:45-53. 
25. Feuerstein JD and Cheifetz AS. Miscellaneous adverse events with biologic agents 
(excludes infection and malignancy). Gastroenterol Clin North Am. 2014;43:543-563. 
 
 
NCT03866577

SAP_001.pdf: 
CLINICAL STUDY REPORT 
MOM-M254-001/MMT102EC-170091 
Final 2.0 – 08-Feb-2022 
PRA-QMS-02686 2.0 
16.1.9 
Documentation of Statistical Methods and Analysis Output 
16.1.9.1 Statistical Analysis Plan 
16.1.9.1.1 Statistical Analysis Plan Version 2.0 (14 July 2021) 
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Statistical Analysis Plan
Sponsor:
Momenta Pharmaceuticals, Inc.
Protocol No:
MOM-M254-001
Protocol Title:
A 4-Part Phase 1/2 Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of M254 in Healthy 
Volunteers and in Patients with Immune Thrombocytopenic Purpura
PRA Project ID:
MMT102EC-170091
Version:
2.0
Version Date:
14-Jul-2021
1.0 Approvals
The undersigned have approved this Statistical Analysis Plan for use in this study.
Name of Sponsor 
Representative /
Title:
Signature of 
Sponsor 
Representative /
Date:
Name of Sponsor 
Representative / 
Title:
Signature of 
Sponsor 
Representative /
Date:
Name of Author /
Title:
Signature of Author /
Date:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
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2.0 Table of Contents
1.0 Approvals............................................................................................................................ 1
2.0 Table of Contents................................................................................................................. 2
3.0 Introduction.......................................................................................................................... 4
4.0 Changes from Previous Version of Approved SAP..................................................................... 4
5.0 Study Objectives .................................................................................................................. 4
5.1 Primary............................................................................................................................ 4
5.1.1 Primary Endpoint ........................................................................................................ 4
5.2 Secondary ....................................................................................................................... 5
5.2.1 Secondary Endpoint.................................................................................................... 5
5.3 Exploratory....................................................................................................................... 5
5.3.1 Exploratory Endpoint ................................................................................................... 6
6.0 Study Design....................................................................................................................... 6
6.1 Sample Size Considerations..............................................................................................10
6.2 Randomization.................................................................................................................10
7.0 Overview of Planned Analysis................................................................................................11
7.1 Changes from Protocol .....................................................................................................11
7.2 Interim Analysis and Key Results........................................................................................11
7.3 Final Analysis..................................................................................................................11
8.0 Data Review.......................................................................................................................11
8.1 Data Management............................................................................................................11
8.2 Acceptance of Data for Summarization................................................................................11
9.0 Definitions and General Analysis Methods...............................................................................11
9.1 Analysis Data Presentation................................................................................................11
9.1.1 Rounding..................................................................................................................11
9.1.2 Imputation.................................................................................................................11
9.1.3 Descriptive Statistics ..................................................................................................12
9.1.4 Pooling.....................................................................................................................12
9.1.5 Unscheduled Measurements........................................................................................12
9.2 Analysis Data Definitions...................................................................................................12
9.2.1 Baseline Definition.....................................................................................................12
9.2.2 Treatment/Subject Grouping........................................................................................13
9.2.3 Common Variable Derivations......................................................................................13
9.2.4 QC...........................................................................................................................13
9.2.5 ADaM Datasets and Metadata.....................................................................................14
9.3 Software.........................................................................................................................14
9.4 Statistical Methods...........................................................................................................14
9.4.1 Statistical Outlier Determination....................................................................................14
9.4.2 Predetermined Covariates and Prognostic Factors..........................................................14
9.4.3 Hypothesis Testing.....................................................................................................14
9.5 TFL Layout......................................................................................................................14
10.0 Analysis Sets ....................................................................................................................16
10.1 Safety Set .....................................................................................................................16
10.2 Pharmacokinetic Set.......................................................................................................16
10.3 Full Analysis Set.............................................................................................................16
10.4 Per Protocol Set.............................................................................................................16
10.5 Randomized Set.............................................................................................................16
11.0 Subject Disposition.............................................................................................................16
12.0 Protocol Deviations and Violations........................................................................................17
13.0 Demographic and Baseline Characteristics............................................................................17
13.1 Demographics................................................................................................................17
13.2 Medical History ..............................................................................................................17
13.3 Other Baseline Characteristics .........................................................................................17
14.0 Concomitant Medications....................................................................................................17
 
 
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15.0 Treatment Compliance and Exposure ...................................................................................17
16.0 Pharmacokinetic Analyses...................................................................................................17
16.1 Pharmacokinetic Variables...............................................................................................17
16.1.1 Serum Variables ......................................................................................................18
16.2 Pharmacokinetic Summaries............................................................................................21
16.2.1 Pharmacokinetic Concentrations.................................................................................21
16.2.2 Pharmacokinetic Parameters .....................................................................................21
17.0 Pharmacodynamic Analysis.................................................................................................22
17.1 Pharmacodynamic Variables............................................................................................22
17.1.1 Platelet Counts ........................................................................................................22
17.1.2 Platelet Parameters..................................................................................................22
17.2 Pharmacodynamic Summaries.........................................................................................23
17.2.1 Platelet Counts ........................................................................................................23
17.2.2 Platelet Parameters..................................................................................................23
17.3 Exploratory biomarkers....................................................................................................24
18.0 Safety Analyses.................................................................................................................24
18.1 Safety Variables.............................................................................................................24
18.1.1 Adverse Events........................................................................................................25
18.1.2 Deaths and Serious Adverse Events ...........................................................................26
18.1.3 Laboratory Data.......................................................................................................26
18.1.4 Vital Signs...............................................................................................................26
18.1.5 Electrocardiograms...................................................................................................26
18.1.6 Physical Examination................................................................................................27
19.0 References.......................................................................................................................27
Appendix 1: Glossary of Abbreviations.........................................................................................28
Appendix 2: Schedule of Assessments.........................................................................................30
Appendix 3: List of In-Text Outputs..............................................................................................46
Appendix 4: List of End of Text Outputs........................................................................................47
Document History .....................................................................................................................52
 
 
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3.0 Introduction
This Statistical Analysis Plan (SAP) describes the statistical methods that will be used during the analysis 
and reporting of data collected under Momenta Pharmaceuticals, Inc. Protocol MOM-M254-001.
This SAP should be read in conjunction with the study protocol and electronic case report form (eCRF). 
This version of the plan has been developed using the protocol dated 24 April 2020 (including all 
amendments up to this protocol date).
An approved and signed SAP is a requirement for database lock. An approved SAP is also required for 
unblinding of the study treatments.
This SAP only covers the results that will be processed by the PRA Early Development Services (EDS) 
Biostatistics Department.
PRA EDS will perform the pharmacokinetic (PK), pharmacodynamic (PD) and safety and tolerability
evaluation. 
This SAP supersedes the statistical considerations identified in the protocol; where considerations are 
substantially different, they will be so identified. Any post-hoc or unplanned analyses, or significant changes 
from the planned analysis in this SAP performed to provide results for inclusion in the clinical study report 
(CSR)but not included in this SAP, will be clearly identified in Section 9.8.2of the CSR. Changes to planned 
analyses do not require an updated SAP but should be included in the CSR, if significant.
4.0 Changes from Previous Version of Approved SAP
This is the second version of the SAP.
5.0 Study Objectives
5.1 Primary
Part A: 
To assess the safety and tolerability of a single ascending dose of intravenous administration of 
M254 in healthy volunteers
Part B:
To assess the safety and tolerability of a single intravenous administration of M254 in immune 
thrombocytopenia (previously called idiopathic thrombocytopenic purpura; ITP) patients compared 
to 1000 mg/kg intravenous immunoglobulin (IVIg)
Part C:
To assess the safety of a single intravenous administration of M254 compared to 1000 mg/kg of 
IVIg
To characterize the PD of single intravenous administration of M254 compared to 1000 mg/kg IVIg
Part D:
To assess the safety and tolerability of repeated intravenous administration of M254 in ITP patients
5.1.1 Primary Endpoint
Part A:
Incidence and severity of adverse events (AEs) following administration of M254 at single dose 
levels
 
 
 
 
 
 
 
 
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Clinically significant changes in clinical safety labs, vital signs, and electrocardiograms (ECGs) with 
M254 administration
Part B:
Incidence and severity of AEs following administration of M254 at single dose levels and 
1000 mg/kg IVIg
Clinically significant changes in clinical safety labs, vital signs, and ECGs following M254 
administration and 1000 mg/kg IVIg
Part C:
Incidence and severity of AEs of M254 and 1000 mg/kg IVIg
Clinically significant changes in clinical safety labs, vital signs, and ECGs following M254 
administration and 1000 mg/kg IVIg
Platelet response after M254 administration compared to IVIg
Part D:
Incidence and severity of AEs with repeated administration of M254
Clinically significant changes in clinical safety labs, vital signs, and ECGs with M254 administration
5.2 Secondary
Part A:
To characterize the PK of a single intravenous administration of M254 at different doses in healthy 
volunteers
Part B:
To characterize the PK of a single intravenous administration of M254 at different doses in ITP 
patients
Part C:
To characterize the PK of a single intravenous administration of M254 at different doses
Part D:
To characterize the PK of repeated intravenous doses of M254 in ITP patients
To assess PD of repeated intravenous doses of M254 in ITP patients
5.2.1 Secondary Endpoint
Part A, B and C:
Measurements of PK parameters of M254 following the administration of a single intravenous dose
Part D:
Measurements of PK parameters of M254 following the administration of a repeated intravenous 
doses
Platelet response after repeated M254 administration
5.3 Exploratory
Part A:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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To characterize the PD of a single intravenous administration of M254 at different doses in healthy 
volunteers
Part B:
To characterize the PD of a single intravenous administration of M254 at different doses in ITP 
patients compared to IVIg
Part C:
To characterize the PD of single intravenous administration of M254 compared to 1000 mg/kg IVIg
5.3.1 Exploratory Endpoint
Part A, B and C:
Exploratory biomarkers relating M254 exposure to potential efficacy in autoimmune diseases and 
the M254 mechanism of action may be analyzed
Additionally for Part B:
Platelet response after M254 administration compared to IVIg
6.0 Study Design
This is a Phase 1/2, study investigating single and repeated administration of M254 in a 4-part study.
Figure 1: Study Schema
Part A is a single ascending dose, randomized, double blinded sponsor unblind, safety, tolerability, and PK 
assessment of M254 or placebo in 6 cohorts of healthy volunteers. Planned doses include 3 mg/kg, 
10 mg/kg, 30 mg/kg, 60 mg/kg, 120 mg/kg, and 250 mg/kg. In Cohort 1, 5 subjects will be enrolled with 3:2 
(active: placebo) randomization. In all other cohorts, subjects will be randomized 3:1 (active: placebo) with 
total of 4 subjects in each cohort. There will be approximately 25 subjects in Part A. Up to 2 additional 
cohorts may be added based on findings in prior cohorts. Additional dosing cohorts may be added on the 
recommendation of the SRC (Safety Review Committee). At the first dose level (3 mg/kg), a sentinel group 
of 2 subjects (1 M254, 1 placebo) will be dosed and closely monitored for 48 hours before dosing the 
remainder of the cohort (2 M254, 1 placebo). There will be no additional sentinel groups in the study beyond 
this cohort (Cohort 1 Part A).
 
 
 
 
 
 
 
  
  
  
 
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Figure 2: Part A Schema
Initiation of any cohort in Part B will only proceed on the recommendation of the SRC after safety data from 
Part A Cohort 4 at the 60 mg/kg dose level has been reviewed and confirmed by SRC. Part B is a single
ascendingdose, fixed-sequence, open-label part to assess safety, tolerability, PK, and PD of M254 followed 
by 1000 mg/kg IVIg in approximately 4 cohorts of 2 ITP patients per cohort. Planned doses include 60 
mg/kg, 120 mg/kg, 250 mg/kg and 500 mg/kg. Up to 2 additional cohorts may be added based on findings 
in prior cohorts to better understand the safety of M254 and/or to better understand the efficacy to assist 
with dose selection for Part C. The maximum dose for Part B will not exceed 500 mg/kg (the NOAEL of 
1000 mg/kg determined in the toxicology study in Cynomolgus monkeys). Additional patients to dosing 
cohorts may be added on the recommendation of the SRC. Patients will receive a fixed dose of IVIg at 1000 
mg/kg on Day 29 if the patients’ platelet count returns to
15% above baseline level. Patients whose 
platelets havenot returned to 15% above baseline dosing level by Day 28 will have plateletdeterminations 
weekly until platelets return to 15% above baseline, up to 56 days post-dose. If these conditions are not 
met by Day 57, IVIg will be administered, as long as the patients’ platelets have returned to < 50 × 109/L.  
If the platelets have not returned to 15% above baseline and are > 50 × 109/L, the patient will complete 
Follow-Up assessments and be discharged from Part B. After dosing with IVIg, safety and the other 
assessments listed in the Schedule of Activities will beconducted for 28 days following IVIg administration..
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Figure 3: Part B Schema
The SRC will review all safety data for all patients in Part B up to at least 28 days following M254 
administration for the last patient. Initiation to Part C will only proceed on the recommendation of the SRC. 
Part C consists of 2 randomized, unblinded crossover cohorts, to assess safety and PD of a single dose of 
M254 compared to a single dose of IVIg in ITP patients. The dose of M254 for each of these 2 cohorts will 
be determined after analysis of the data from Part A and Part B. Each cohort consists of 10 patients with 2 
arms in each cohort consisting of 5 patients in each arm, for an overall total of 20 patients in Part C.
Following screening to confirm eligibility to participate, in crossover Cohort 1 or Cohort 2, 5 patients in each 
cohort will be randomized to M254 by IV administration and 5 patients will be randomized to 1000 mg/kg 
IVIg. Patients will receive 1 dose of either M254 or IVIg, depending on their assigned arm within the cohort 
on Day 29 if the patients’ platelet count returns to 15%above baseline level. Patients whose platelets have 
15% above baseline dosing level by Day 28 will have platelet determinations weekly until 
15% above baseline up to 56 days post the first M254 or IVIg administration. Patients 
who do not meet this criteria will receive the second administration of M254 or IVIg, as long as the platelets 
have returned to < 50 × 109/L. If the platelets have not returned to 15% above baseline and are > 50 × 
109/L, the patient will complete Follow-Up assessments on or around Day 57 post first infusion and be 
discharged from Part C; and the patient may be replaced. After patients are crossed over to M254 or IVIg, 
they are followed for an additional 28 days with safety and platelet assessments or until platelet counts 
15% above their baseline level following similar rules to the first dose in Part C.
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
  
 
 
  
 
  
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Figure 4: Part C Schema
The SRC will review all safety data from both crossover cohorts in Part C; however the initiation of Part D 
will proceed after the SRC reviews all safety data from Cohort 1 and the recommendation is to proceed 
with Part D. Part D is a repeated, fixed-dose, open-label study of M254. Any patients who participate in 
Parts B or C are allowed to participate in Part D if they meet the eligibility criteria during screening for Part 
D. Part D may have up to 2 dose levels with up to approximately 15 to 34 ITP patients in total.The initial 
dose level for Part D will be less than or equal to the maximum tolerated dose, and it will be selected based 
on review of Part B data and available data from Part C. Following completion of Part C, the dose for new 
patients in Part D may be revised (the dose level will not be modified for patients who have already received 
at least 1 dose). Patients who have participated in Part B or C may be allowed to participate in Part D, prior 
to completion of randomization in Part C. New patients not in Part B or C may participate in Part D following 
complete randomization in Part C. The dose levels of M254 for Part D will be determined after analysis of 
available data from Part A, Part B and Part C. Following screening to confirm eligibility to participate 
(including rescreening patients who participated in Part B or C), M254 naïve patients will receive 4 doses 
of M254, and patients from Part B or C will receive 3 doses of M254 every 14 days. Patients in Part C may 
roll over into Part D by including any data after the last dose of IVIg or M254 in Part C for assessment of 
 
 
  
  
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
  
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
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screening in Part D as long as those data are within the screening window specified. If the patient’s platelet 
9/L, their platelet count will be monitored weekly until platelets return 
100 × 109/L. If these conditions are not met, M254 will not be administered further.
Figure 5: Part D Schema
6.1 Sample Size Considerations
This is an exploratory trial for which no formal statistical hypothesis testing will be performed and therefore 
no formal sample size calculations have been done. For Part A, sample size of n=5 subjects in group 1 (3 
active and 2 placebo) and n=4 in the following groups 1 (3 active and 1 placebo) are commonly accepted 
numbers of healthy volunteers for single ascending dose studies and are considered sufficient to achieve 
the objectives of the study. For the Part B a sample size of n=2 patients per dose level is also commonly 
accepted number for a single ascending dose patient study. In Part C a linear mixed effect model will be 
performed on the platelet data to calculate the confidence intervals for the ratio of effects between M254 
and IVIg. Due to the exploratory nature of this part, no formal sample size calculation was performed here 
as well. A sample size of n=20 patients is considered sufficient to meet the objectives of this part of the 
study. A sample size of n=15-34 patients in Part D is also deemed acceptable for a repeated dose study 
and sufficient to achieve the objectives of this part as well.
6.2 Randomization
A randomization schema will be developed for Part A and Part C and managed by the pharmacy at PRA in 
Netherlands for the study. Subjects will be randomized according to a randomization code generated by 
the Biostatistics Department of PRA.
Part A is randomized and double blind (sponsor unblind). Following screening to confirm eligibility to 
participate, subjects will be randomized to receive M254 or placebo. In Cohort 1, 5 subjects will be enrolled 
with 3:2 (active: placebo) randomization. In this cohort a sentinel group of 2 subjects (1 M254, 1 placebo) 
will be dosed and closely monitored for 48 hours before dosing the remainder of the cohort (2 M254, 1 
placebo). In all other cohorts, subjects will be randomized 3:1 (active: placebo) with total of 4 subjects in 
each cohort.
Part C consists of 2 randomized, unblinded crossover cohorts. Each cohort consists of 10 patients with 2 
arms in each cohort consisting of 5 patients in each arm, for an overall total of 20 patients in Part C.
Following screening to confirm eligibility to participate, in each cohort subjects will be allocated to treatment 
sequence (M254-IVIg or IVIg-M254) in a 1:1 ratio (5 subjects will be allocated to sequence M254/IVIg and 
5 subjects will be allocated to sequence IVIg/M254).
 
 
 
 
 
  
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
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7.0 Overview of Planned Analysis
7.1 Changes from Protocol
To align with published reports of platelet response, an additional requirement of ‘an increase from baseline 
.
7.2 Interim Analysis and Key Results
After the completion of Part A the database was locked and unblinded and an interim reportprovided. 
Dose escalation reports during Part A and B will be prepared by a process not covered by this SAP.
7.3 Final Analysis
Draft TFLs (Tables Figures and Listings) will be provided after database lock. After Sponsor comments 
have been incorporated, the TFLs will be incorporated in the first draft CSR.
8.0 Data Review
8.1 Data Management
Data handling and transfer will take place under the PRA Data Management Plan for the study.
8.2 Acceptance of Data for Summarization
Programming of analysis datasets and TFLs may be ongoing during the data management of the study. 
However, programming of analysis datasets and TFLs will be completed and quality controlled (QC’d) after 
database lock. Only quality assured (QA’d) results released by the Safety Laboratory, Bioanalytical 
Laboratory, or other external data source will be used for the programming of analysis datasets and TFLs 
for the final report. Any data values requiring investigation or corrections that are identified while 
programming the analysis datasets and TFLs will be sent to the project Data Manager. If the issue affects 
the TFLs the Programmer or Statistician who identified the issue will follow it to resolution.
9.0 Definitions and General Analysis Methods
9.1 Analysis Data Presentation
9.1.1 Rounding
In listings, data will be presented with the same precision as the original data.  Derived data will be rounded 
for presentation purposes.
Individual values and descriptive statistics of PK concentrations and PK parameters will generally be 
presented with 3 significant figures. Values greater than 999 will be presented as integers. The tmax will be 
reported with 2 decimals.
For all other summaries, all descriptive statistics will be presented with the same precision (number of 
decimals) as the data they are calculated from.
P-values will be reported to four decimal places; p-value less than 0.0001 will be reported as p <0.0001.
9.1.2 Imputation
Unless otherwise noted, data will not be imputed.
 
 
 
  
 
 
 
 
 
 
  
 
 
 
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9.1.3 Descriptive Statistics
Unless otherwise indicated, continuous variables will be summarized with the following descriptive 
statistics: n (number of observations), (arithmetic) mean, standard deviation (SD), minimum (min) value, 
median, and maximum (max) value. For PK and PD data, nblq (number of observations below the limit of 
quantification), CV, geometric mean, and coefficient of variation of the geometric mean (geoCV) will be 
presented additionally. If the total number of subjects per treatment is lower than 3 then the only descriptive 
statistics presented will be arithmetic mean, minimum and maximum.
Categorical data will be summarized with frequencies and percentages. Percentages by categories will be 
based on the number of subjects exposed within a treatment.
For categorical data the categories will be presented in the tables exactly as they appear in the eCRF / 
Database. 
9.1.4 Pooling
Summary statistics will be calculated by population (healthy volunteers or ITP), treatment (investigational 
product [placebo, M254, or IVIG], dose, and dose frequency) and time point (if applicable). Summary 
statistics in Part B and C will be calculated by cohort and treatment. Summary statistics in Part D will be 
calculated by total planned number of doses received, by total actual number of doses received and overall.
Placebo data will be pooled for Part A. For the AEs presentation data from different dose levels per part will 
be summarized per dose and also different M254 doses will be pooled and summarized together (M254 
overall). Data from the corresponding M254 dose levels in Parts B and C will be pooled together (in addition 
to presentation by part, cohort and treatment).
9.1.5 Unscheduled Measurements
Unscheduled measurements will be included in the listings.  For Part A, unscheduled measurements will 
be excluded from the descriptive statistics and statistical analysis (with the exception of unscheduled 
measurements used for baseline).
9.2 Analysis Data Definitions
9.2.1 Baseline Definition
Unless otherwise stated, baseline for post-dose evaluations is defined as the last observation recorded 
before the first study drug administration.  In case of Part B, C and D, baseline will be the last observation 
recorded before the first study drug administration in each period. The last observation can be an 
unscheduled / repeated measurement. If a pre-treatment observation is missing in a given period then the 
screening value may be used.
 
 
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9.2.2 Treatment/Subject Grouping 
In tables the data will be presented by study part and treatment, and where applicable by sequence. Parts 
B and C will also have pooled analysis (see Section 9.5).   
Label
Definition
Study Part
Part A – SAD HV, Part B – SAD ITP patients, Part C – cross over ITP 
patients, Part D – fixed dose ITP patients
Study Drug
M254, IVIg, Placebo
Treatment
Part A:
Placebo, 3 mg/kg M254, 10 mg/kg M254, 30 mg/kg M254, 60 mg/kg M254, 
120 mg/kg M254, and 250 mg/kg M254
Part B:
60 mg/kg M254, 120 mg/kg M254, 250 mg/kg M254, 500 mg/kg M254, 
1000 mg/kg IVIg
Part C:
The dose of M254 will be determined after analysis of the data from Part A 
and Part B
1000mg/kg IVIg
Part D:
3 or 4 doses of M254 (planned treatment) ; possibly more than one dose 
level of M254 as well
9.2.3 Common Variable Derivations
Variable
Data Type
Definition/Calculation
Change from Baseline
All
Post-dose Observation minus Baseline 
Observation
Analysis Relative Day 
(Prior to Dose)
All
Date of Measurement minus Dose Date. In case 
of Part B and C it will be Date of Measurement 
minus Dose Date in a given treatment period.
Analysis Relative Day 
(Post-Dose)
All
Date of Measurement minus Dose Date +1. In 
case of Part B and C it will be Date of 
Measurement minus Dose Date in a given 
treatment period +1.
9.2.4 QC
The analysis datasets and the TFLs will be QC’d according to the general PRA EDS QC plan.
9.2.4.1 Critical Data
The QC plan requires datasets be classified as critical or non-critical. As the primary objective of this study 
is to assess safety, tolerabilityand PDthe datasets considered critical are subject level, AEsand PD(ADSL, 
 
 
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ADAE, ADPD). As these are related to the primary objectives these datasets will be double programmed 
per the QC plan.
9.2.5 ADaM Datasets and Metadata
The analysis datasets will be generated in accordance with Clinical Data Interchange Standard Consortium 
(CDISC) Analysis Data Model (ADaM) Version 2.1. At least the following datasets will be generated:
Subject-Level Analysis Dataset (ADSL)
Adverse Events Analysis Dataset (ADAE)
Laboratory Analysis Dataset (ADLB)
Vital Signs Analysis Dataset (ADVS)
ECG Analysis Dataset (ADEG)
Pharmacokinetic Concentrations Analysis Dataset (ADPC)
Pharmacokinetic Parameters Analysis Dataset (ADPP)
Pharmacodynamic Concentrations Analysis Dataset (ADPD)
Pharmacodynamic Parameters Analysis Dataset (ADPDP)
ADaM compliant datasets will be delivered to the sponsor. A define.xml file version 2 with the corresponding 
metadata will be included. Analysis results metadata are excluded. 
9.3 Software
The statistical analysis and reporting will be done using SAS® for WindowsTM Version 9.4 or higher (SAS 
Institute, Inc.).
PK parameter calculations will primarily be done using Phoenix® WinNonlin® version 8.1 or higher 
(Pharsight, Inc.). Additional PK computations may be performed in SAS®.
9.4 Statistical Methods
9.4.1 Statistical Outlier Determination
No statistical outlier analysis is planned.
9.4.2 Predetermined Covariates and Prognostic Factors
In Part C there will be a subanalysis performed for patients with baseline platelet level of
30 vs >30×109/L.
9.4.3 Hypothesis Testing
No formal hypothesis testing will be done.
9.5 TFL Layout
Report layout will be according to the PRA EDS – ICH E3 compliant – CSR Template. The layout of TFLs 
will be according to the PRA EDS standards.
No table shells will be provided. The TFLs will be provided in Adobe PDF format.
Format:
Page size: A4
Data in listings will be sorted by study part, cohort, site number (if applicable: each site on a new 
page), subject number and time point.
Data in tables will be sorted by study part, treatment and time point.
 
 
 
 
 
 
 
 
 
 
 
  
 
 
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Column titles will be in title case letters.
All tables and listings will be in landscape format.
The treatment labels listed below will be used in the TFLs. Treatments will be sorted by 
investigational product (placebo then M254 then IVIg) then dose level (increasing mg/kg) then 
number of doses.  These labels will be modified to account for the dose selected as part of dose 
escalation and the initiation of each part:
Part A:
o
Placebo
o
3 mg/kg M254 HV (Healthy Volunteers)
o
10 mg/kg M254 HV
o
30 mg/kg M254 HV
o
60 mg/kg M254 HV
o
120 mg/kg M254 HV
o
250 mg/kg M254 HV
o
M254 HV total
Part B and C:
Data will be first presented by cohort and within cohort by treatment period according to following 
layout:
60 mg/kg M254
120 mg/kg M254
Total
M254 period
IVIg period
Diff
M254 period
IVIg period
Diff
M254 period
IVIg period
Diff
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
The following cohort labels will be used in Part B:
o
60 mg/kg M254
o
120 mg/kg M254
o
250 mg/kg M254
o
500 mg/kg M254
o
Total
The following cohort labels will be used in Part C:
o
XXX mg/kg M254 (XXX will be replaced by the actual dose level)
o
Total
Pooled Part B and C:
o
XXX mg/kg M254 (XXX will be replaced by the actual dose level)
o
M254 total
o
1000 mg/kg IVIg
Part D (planned treatment): 
o
XXX mg/kg M254, 3 doses (XXX will be replaced by the selected mg/kg dose level)
o
XXX mg/kg M254, 4 doses (XXX will be replaced by the selected mg/kg dose level)
o
For the safety tables: XXX mg/kg M254 md (pooled)
Treatments in Part D will also be presented by actual treatment – that is if the number of doses 
differs from planned a separate summary will be presented.
 
 
 
 
 
 
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10.0 Analysis Sets
Analyses
Randomized 
Set
Safety Set
Pharmacokinetic 
Set
Full Analysis 
Set
Per Protocol 
Set
Disposition 
Summaries
Safety 
Assessments
Baseline 
Characteristics
PK 
Concentrations
PK Parameters
PD 
Concentrations
PD Parameters
10.1 Safety Set
The safety set will consist of subjects who receive at least one dose of M254 or IVIg or placebo. This set 
will be used for the safety data summaries and baseline characteristic summaries.
10.2 Pharmacokinetic Set
The PK set will consist of all subjects who receive at least 1 dose of M254 or IVIg with at least 4 evaluable 
data points adequate to create an evaluable serum concentration profile. This set will be used for PK 
concentration and parameter summaries.
10.3 Full Analysis Set
The FAS (Full Analysis Set) will consist of all subjects included in the safety set for whom at least 
1 post-infusion PD assessment was completed.
10.4 Per Protocol Set
The PP (Per Protocol) set is a subset of the FAS and will include participants who complete the study with 
all planned safety, PD, and PK assessments and no major protocol deviations impacting safety or PD 
assessments.
10.5 Randomized Set
The Randomized Population set will include all subjects who were randomized (subjects who have received 
a randomization number). This set will be used for the disposition summaries.
11.0 Subject Disposition
The number and percentage of subjects randomized, dosed, and members of each analysis set will be 
presented. The number and percentage of subjects who withdrew from the study prematurely and a 
breakdown of the corresponding reasons for withdrawal will also be presented.
 
 
 
 
 
 
 
 
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12.0 Protocol Deviations and Violations
Protocol deviations/violations will be included in the CSR.
13.0 Demographic and Baseline Characteristics
13.1 Demographics
All demographic data as collected during the screening visits will be listed by subject. Site identification 
number will be included in this listing. 
Subject demographics will be summarized descriptively for all subjects by part and treatment or in case of 
Part C by treatment sequence. The summary will include the subjects’ age (in years), gender, race, 
ethnicity, weight (in kg), height (in cm), and BMI (in kg/m2). Demographics will be summarized for the safety 
and PP sets.
13.2 Medical History
Medical history will be listed.The medical history will be coded according to the latest version of the Medical 
Dictionary for Regulatory Activities. For Parts B,C and D, a separate listing of ITP history will be created, 
including date of diagnosis, platelet level at screening, information if splenectomy was performed and if 
patient has received IVIg therapy before. 
13.3 Other Baseline Characteristics
Drug and alcohol screen results will be listed.
Serology results will be listed (hepatitis B surface antigen, Hepatitis C virus, and human immunodeficiency 
virus).
Non-compliance to inclusion or exclusion criteria (if any) will be listed.
14.0 Concomitant Medications
Medication and coding will be listed. There will be a separate listing of previous ITP medications for 
ITP patients in Parts B, C and D. The medications will be coded using the latest version of World Health 
Organization (WHO) Drug Dictionary Enhanced (DDE). Medications with an end date prior to the first dose 
of study drug will be considered prior medications and will be in a separate listing. If a partial date allows a 
medication to be considered concomitant, it will be categorized as such.
15.0 Treatment Compliance and Exposure
Study drug administration data will be listed, including date, start and end times of infusion, amount, volume, 
infusion completion / interruption details and comments.
16.0 Pharmacokinetic Analyses
16.1 Pharmacokinetic Variables
PK concentrations will be collected in serum and analyzed by PRA Bioanalytical Laboratory. The analysis 
described below will be performed at the end of the study.
 
 
 
 
 
 
 
 
 
 
 
 
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16.1.1 Serum Variables
16.1.1.1 Concentrations
Serum concentration of M254 (if receiving M254 in the current period)
Total IgG serum levels and changes from baseline (if receiving IVIG in the current period)
16.1.1.2 Parameters
PK Parameters for M254 as defined in Table 1: PK Parameters
PK Parameters for total IgG (Immunoglubulin G) changes from baseline as defined in Table 1: PK 
Parameters
Table 1: PK Parameters
Parameter
Description
Part A
Part B
Part C
Part D
SAS Programming 
Notes
In all parts WNL inputs are:
Absolute values for M254
Changes from baseline for 
total IgG
Cmax
Maximum serum
concentration. 
Observed peak 
analyte concentration 
obtained directly from 
the experimental data 
without interpolation, 
expressed in 
concentration units
x
x
x
x
Cmax from WNL
tmax
Time to maximum 
serum concentration. 
First observed time to 
reach peak analyte 
concentration 
obtained directly from 
the experimental data 
without interpolation, 
expressed in time 
units.
x
x
x
x
Tmax from WNL
AUC0-last
Area under the 
concentration-time 
curve (time 0 to time 
of last quantifiable 
concentration).
x
x
x
AUClast from WNL
AUC0-tau
Area under the serum 
concentration-time 
curve over the dosing 
interval (time 0 to15 
days).
x
AUC0-tau from WNL 
where tau is equal to 
15 days.
AUC0-inf
Area under the serum 
concentration-time 
x
x
x
AUCINF_obs from 
WNL
 
 
 
 
 
 
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Parameter
Description
Part A
Part B
Part C
Part D
SAS Programming 
Notes
In all parts WNL inputs are:
Absolute values for M254
Changes from baseline for 
total IgG
curve (time 0 to 
infinity). 
If 
AUC_%Extrap_obs 
>20% then 
parameter will be 
flagged, but not 
excluded from 
descriptive statistics
%AUCextra
Percentage of 
estimated part for the 
calculation of AUC0-inf. 
((AUC0-inf-AUC0-
t)/AUC0-inf)*100%
x
x
x
AUC_%Extrap_obs
from WNL
kel
Terminal phase rate 
constant calculated by 
linear regression of 
the terminal log-linear 
portion of the 
concentration vs. time 
curve. Linear 
regression of at least 
three points is
required to obtain a 
reliable kel.
x
x
x
Lambda_z from 
WNL
If Rsq adjusted
then parameter will 
be flagged, but not 
excluded from 
descriptive statistics.
t1/2
Terminal phase half-
life expressed in time 
units..
x
x
x
HL_Lambda_z from 
WNL
If 
AUC_%Extrap_obs 
then parameter will 
be flagged, but not 
excluded from 
descriptive statistics.
Vz
Volume of distribution 
at terminal phase, 
calculated as CL/kel.
x
(M254 
only)
x
(M254 
only)
x
(M254 
only)
Vz_obs from WNL
CL
Clearance, calculated 
as dose/AUC0-inf
x
(M254 
only)
x
(M254 
only)
x
(M254 
only)
CL_obs from WNL
MRT
Mean residence time 
will be approximated 
to constant infusion 
rate, MRT = MRTtotal-
Tiv/2
x
(M254 
only)
x
(M254 
only)
x
(M254 
only)
x
(M254 
only)
MRTINF_obs from 
WNL
 
 
 
 
 
 
  
 
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Parameter
Description
Part A
Part B
Part C
Part D
SAS Programming 
Notes
In all parts WNL inputs are:
Absolute values for M254
Changes from baseline for 
total IgG
Where Tiv. = infusion 
duration
Note: AUCs will be calculated using linear up / log down, expressed in units of concentration x time.  
 
 
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16.2 Pharmacokinetic Summaries
16.2.1 Pharmacokinetic Concentrations
In calculation of total IgG changes from baseline the absolute BLQ values will be set to ½ LLOQ. Serum 
concentrations for M254 and absolute total IgG below the quantifiable limit (BQL) will be set to ½ lower limit 
of quantification (LLOQ)in the computation of mean concentration values. Continuous descriptive statistics 
( as defined in Section 9.1.3) will be used to summarize the serum concentrations of M254 (absolute values) 
and total IgG (absolute values and changes from baseline) . These data will be summarized as described 
in Section 9.1.4. CV will not be presented for changes from baseline summaries. If over ½ the subjects in 
a given cell in the absolute values tablehavevalues BQL then the descriptive statistics will not be presented 
for both the absolute values and the changes from baseline table and will instead display as BQL for the 
arithmetic mean, median and minimum. With the exception of maximum all other statistics will be missing.
Negative change from baseline values will not be imputed for the linear plots. For the semi-logarithmic plots 
negative change from baseline values will be considered nearly zero and show on the figure.
Linear and semi-logarithmic plots of the median M254 serum concentration (absolute values) and total IgG 
(absolute values and changes from baseline) by scheduled sampling time will be provided by study part
and treatment with one panel per study part and one line per treatment. For Part D these plots will be 
provided for both planned and actual treatment summaries. These plots will show time in hours. The plots 
will match the summary table results and will not have an observation at a given time point if more than half 
of the subjects have values BQL.
Linear and semi-logarithmic plots of the combined individual serum concentration profiles by actual 
sampling time (spaghetti plots) will be provided for M254 (absolute values) and total IgG (absolute values 
and changes from baseline) by study part and treatment. For Part D these plots will be provided for both 
planned and actual treatment summaries.
Linear and semi-logarithmic plots of the individual M254 serum concentration (absolute values) and total 
IgG (absolute values and changes from baseline) by actual sampling time will be provided by part, 
treatment, analyte and subject. These plots will show time in hours. Individual plots will use the BQL 
handling procedure described below for “Pharmacokinetic Parameters”.
Individual M254 serum concentration (absolute values) and total IgG (absolute values and changes from 
baseline) data will be presented together with descriptive statistics by part and treatment.
16.2.2 Pharmacokinetic Parameters
PK parameters for M254 and total IgG changes from baseline will be estimated using non-compartmental 
methods.
The serum PK parameters will be estimated from the concentration-time profiles. In estimating the PK 
parameters for the M254, BQL values at the beginning of the profile will be set to zero. BQL values that 
occur after the first quantifiable point will be considered missing. Values that are embedded between BQLs, 
or quantifiable values occurring after two or more BQLs, will be set to missing at the discretion of the 
pharmacokineticist. In estimating the PK parameters for the total IgG negative change from baseline values 
will be included in the calculation of AUC. Actual sampling times, rather than scheduled sampling times, 
will be used in all computations involving sampling times. If the actual time or dose time is missing, the 
scheduled time may be substituted in order to calculate the PK parameter.
Continuous descriptive statistics (as defined in Section 9.1.3) will be used to summarize the calculated PK 
parameters by study part and treatment. For tmax, only median, min and max will be presented. If the total 
number of subjects per treatment is lower than 3 then the only descriptive statistics presented will be 
arithmetic mean, median, minimum and maximum
 
 
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The points to be included in the kel range will be determined by the pharmacokineticist after inspection of 
the semi-log concentration-time profiles. At least 3 points will be required to be used. The Cmax data point 
will not be included.
Parameters based on adjusted r2 below 0.80 or %AUCextra above 20% will be flagged but not excluded from 
descriptive statistics.
Additionally, plots of dose normalized Cmax, AUC0-inf (individual values and geometric mean) versus dose 
level will be provided to evaluate dose proportionality.
17.0 Pharmacodynamic Analysis
The platelet counts will be assessed in Part B, C and D. The analysis described below will be performed at 
the end of the study, it will not be included in the interim reports. This analysis will be performed on the FAS 
and repeated on the PP set.
17.1 Pharmacodynamic Variables
17.1.1 Platelet Counts
Platelet counts 
17.1.2 Platelet Parameters
A therapeutic platelet count is defined as
× 109/ L
9/L (this
will be referred to as threshold in Table 2: PD Parameters).
Platelet parameters as defined in Table 2: PD Parameters
Table 2: Platelet PD Parameters calculated in WinNonLin.
Parameter
Description
Absolute 
values
Changes 
from 
baseline
% 
changes 
from 
baseline
SAS 
Programming 
Notes
tonset
Time to onset of a therapeutic platelet 
count. Time that the response first crosses 
the threshold coming from the direction of 
the baseline value.
x
Tonset 
from 
WNL
Rmax
Maximum platelet count following dosing, 
maximum and percentage platelet count 
change from baseline. Maximum observed 
response value.
x
x
x
Rmax 
from 
WNL
tmax
Time to maximum platelet count following 
dosing. Time of maximum observed 
response value.
x
Tmax 
from 
WNL
DaboveT
Duration of a therapeutic platelet count. 
Total time that Response >= Threshold.
x
Time_Above_T 
from WNL
toffset
Time greater than Tonset at which the 
curve first crosses back to the baseline 
side of threshold.
x
Toffset 
from 
WNL
 
 
 
 
 
 
 
 
 
 
 
    
 
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17.2 Pharmacodynamic Summaries
17.2.1 Platelet Counts
Continuous descriptive statistics ( as defined in Section 9.1.3) will be used to summarize the serum levels 
and changes from baseline (absolute values and percentages) by study part and treatment. Data from Part 
D will be summarized by planned and actual treatment (if the actual number of doses received differs from 
planned). CV will not be presented for changes from baseline summaries. If the total number of subjects 
per treatment is lower than 3 then the only descriptive statistics presented will be arithmetic mean, minimum 
and maximum 
Linear plots of the arithmetic mean absolute values and changes from baseline (absolute and % change)
by scheduled sampling time will be provided by part and treatment.   For Part D these plots will be provided 
for both planned and actual treatment. 
Linear plots of the combined individual serum levels(absolute values) and changes from baseline (absolute 
and % changes from baseline) by actual sampling time (spaghetti plots) will be provided by part and
treatment.  For Part D these plots will be provided for both planned and actual treatment. 
Linear plots of the individual serum levels (absolute values) and changes from baseline (absolute and 
% changes from baseline) by actual time will be provided by subject. 
All individual subject platelet counts and changes from baseline (absolute change and percentages) will be 
provided in the tables.
17.2.2 Platelet Parameters
Missing values in the calculation of any PD parameters will not be imputed and handled as missing values.
The PD parameters for all subjects in the FAS set will be estimated from the platelet count-time profiles and 
platelet count change from baseline-time profiles (as specified in Table 2: PD Parameters). The calculation 
will be performed using the actual sampling times. If the actual time is missing, the scheduled time will be 
substituted in order to calculate the PD parameter.
Baseline is defined as the pre-dose sample of each period.
In calculation of AUC, the linear trapezoidal calculation method will be used. Descriptive statistics will be 
calculated and presented for all derived PD parameters by study part and treatment. In case of Part D by 
these data will be presented by planned and actual treatment (if the actual number of doses received differs 
from planned).
Individual PD parameters will be listed, and descriptive statistics will be summarized in tables.
17.2.2.1 Primary Statistical Analysis of Platelet Parameters
Efficacy analyses will be performed on Part C data using FAS. This is considered primary analysis. The 
ratio of effects between M254 and IVIg will be estimated from a linear mixed effect model on the natural 
AUC0-14d
Area under the change from baseline 
platelet count-time curve for 14 days. 
x
AUC0-14 from 
WNL
AUC0-28d
Area under the change from baseline 
platelet count-time curve for 28 days.
x
AUC0-28 from 
WNL
 
 
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logarithms of absolute values Rmax and change from baseline Rmax, AUC0-14 and AUC0-28, with factors for 
baseline platelet count, sequence, subject nested within sequence, period and treatment. The factor of 
subject nested within sequence will be random effect and others are fixed effects. The estimated ratio will 
be obtained by exponentiation of the difference of least squares means in natural log-transformed 
parameters between M254 and IVIg. The ratios of geometric means and their 95% CIs will be presented.
The same analysis will be performed for patients with baseline platelet level of 30 vs 30× 109/ L as 
exploratory analysis and only if there is sufficient number of patients in both groups. Otherwise the platelet 
baseline category and category covariate interaction term will be added to the model (as exploratory 
analysis). 
17.2.2.2 Secondary Statistical Analysis of Platelet Parameters
For Part C the frequency counts of the responders and non-responders will be provided, according to the 
Table 3.
Table 3: Patient PD parameters.
For Part C overall platelet response rate and its 90% exact binomial CI in each treatment period will be 
presented for the FAS and PP set as secondary analysis. Overall platelet response rate is defined as
reaching the therapeutic platelet count.
17.3 Exploratory biomarkers   
Exploratory biomarkers will be reported under a separate report, if analyzed.
18.0 Safety Analyses
18.1 Safety Variables
The following safety variables will be summarized:
AEs
Vital Signs
Parameter
Description
SAS 
Programming 
Notes
Patients with response 
(R) for patients with 
9/ L
9/ L and at least 2-fold 
increase of the baseline count, confirmed on at least 
2 separate occasions at least 7 days apart and the 
absence of bleeding during the 28 days after dose.
Count and count of 
patients with baseline 
9/ L
Patients with complete 
response (CR) for 
patients with baseline 
9/ L
9/ L and at least 2-fold 
increase of the baseline count, confirmed on at least 
2 separate occaions at least 7 days apart and the 
absence of bleeding during the 28 days after dose.
Count and count of 
patients with baseline 
9/ L
Patients with no 
response (NR) for 
patients with baseline 
9/ L
Platelet count <30 × 109/ L or less than 2-fold 
increase of baseline platelet count, confirmed on at 
least 2 separate occasions approximately 1 day 
apart, or bleeding during the 28 days after dose.
Count and count of 
patients with baseline 
9/ L
Patients with loss of 
CR or R for  patients 
109/ L
Platelet count below 100 × 109/ L or bleeding (from 
CR) or below 30 × 109/ L or less than 2-fold increase 
from baseline platelet count or bleeding (from R).  
Platelet counts confirmed on at least 2 separate 
occasions at least 1 day apart.
Count and count of 
patients with baseline 
9/ L
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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o
Supine Blood Pressure 
Systolic Blood Pressure (SBP)
Diastolic Blood Pressure (DBP)
o
Pulse Rate
o
Tympanic Body Temperature
o
Respiratory Rate
Electrocardiograms (ECG)
o
Heart Rate
o
RR Interval
o
PR Interval
o
QRS-Duration
o
QTc (Fridericia) Interval
o
ST Segment Assessment
o
T-Wave Assessment
o
U-Wave Assessment
Clinical Laboratory Evaluations
o
Clinical Chemistry 
o
Hematology
o
Urinalysis
o
Coagulation
Physical Examination
Evaluation of Infusion Site
18.1.1 Adverse Events
All AE summaries will include only treatment-emergent adverse events (TEAE). TEAEs are those starting 
or increasing in severity on or after the first dose of study drug.
TEAEs occurring following dosing in a specific period but before dosing in the next period will be attributed 
to that specific period. If the time is missing for an AE on a dosing day then the AE will be attributed to the 
treatment given on that day.
A TEAE overview table will be included, presenting the number and percentage of subjects reporting 
TEAEs, subjects reporting TEAEs with outcome=Death, subjects reporting serious TEAEs, subjects who 
discontinue study drug due to a TEAE,  subjects reporting treatment related TEAEs, subjects reporting 
injection site reactions.
A breakdown of the number of AEs, number and percentage of subjects reporting each AE, categorized by 
body system and preferred term coded according to the latest version of Medical Dictionary for Regulatory 
Activities (MedDRA), will be presented by part, treatment and also M254 overall. Subjects will only be 
counted once within each body system or preferred term. There will be one such table presented for:
All TEAEs
TEAEs considered related to study drug
Serious AEs (SAEs)
AEs of Special Interest (AESI: systemic and local reactions, hemolysis, infections, flu-like 
symptoms, rash, myalgia and arthralgia, fever, chills)
Severe AEs.
A summary of AEs reported, categorized by relationship (categories: related, not related) will also be 
provided by part, treatment and also M254 overall. AEs reported in the eCRF as ‘Possibly’, ‘Likely’ and 
‘Definitely’ will be considered related to study drug, while categories ‘None’ and ‘Unlikely’ will be considered 
not related. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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A summary of AEs reported, categorized by severity as recorded on eCRF, will also be provided by part, 
treatment and also M254 overall. 
All AEs recorded on the eCRF will be listed together with MedDRA coding. One listing will contain TEAEs 
and one listing will contain non-treatment-emergent AEs.
A listing of AEs leading to study drug discontinuation will be provided (‘Adverse Event’ is reported as primary 
reason for early termination/study non-completion).
The following missing data will be imputed as defined (for calculations only / will not be presented):
Missing AE start and / or end times for the calculation of onset and duration will be assumed to be 
at 00:01 for a start time and 23:59 for end times
Missing AE severity or relationship will be assumed to be severe or related, respectively
Missing AE start times for the determination of treatment emergence will be assumed to occur after 
treatment unless partial date documents the AE as happening prior to treatment
Missing AE start times for the determination of treatment assignment will be assumed to occur after 
treatment on the recorded date one minute after dosing
Missing AE start date will be assumed to be after treatment for the determination of TEAE and on 
treatment for single treatment studies but will not be attributed to treatment in studies with multiple 
treatments
18.1.2 Deaths and Serious Adverse Events
If applicable, a listing of deaths and other SAEs will be provided by subject.
18.1.3 Laboratory Data
Safety laboratory data for Part A will be analyzed by PRA Clinical Laboratory, while the safety laboratory 
data for Part B, C and D will be analyzed by Medpace.
Clinical laboratory data will be presented using units from the study data tabulation model (SDTM)
Controlled Terminology.
All laboratory data (absolute values and derived changes from baseline) will be listed, including laboratory 
variables not listed in the protocol. A separate listing, including out-of-range values will also be provided. 
Normal ranges will be used directly from the clinical laboratory.
Descriptive statistics summarizing continuous laboratory results of clinical chemistry, hematology and 
coagulation (observed and derived changes from baseline) by treatment and scheduled time will be 
included. 
Summary of clinically significant abnormalities using shift tables will be presented for safety laboratory tests.
These tables will present shifts from baseline to all post-dose time points according to categories: Non-
Clinically Significant vs Clinically Significant. It will only be prepared for parameters for which >25% of 
subjects have a clinically-significant shift from baseline.
18.1.4 Vital Signs
Vital signs data (absolute values and changes from baseline) will be listed and summarized descriptively.
Summary of clinically significant abnormalities using shift tables will be presented for vital signs. These 
tables will present shifts from baseline to all post-dose time points according to categories: Non-Clinically 
Significant vs Clinically Significant. It will only be prepared for parameters for which >25% of subjects have 
a clinically-significant shift from baseline.
18.1.5 Electrocardiograms
The observed measurements for all ECG parameters and the corresponding abnormalities will be listed for 
all timepoints. The means of triplicate measurements for continuous parameters and the change from 
baseline of the mean triplicate measurements at each scheduled timepoint will be listed by subject.
 
 
 
 
 
 
 
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Descriptive statistics will be provided to summarize mean ECG parameters (observed and changes from 
baseline) by part, treatment and scheduled time.
Summary of clinically significant abnormalities using shift tables will be presented for ECGs. These tables 
will present shifts from baseline to all post-dose time points according to categories: Non-Clinically 
Significant vs Clinically Significant. It will only be prepared for parameters for which >25% of subjects have 
a clinically-significant shift from baseline.
18.1.6 Physical Examination
The findings (abnormalities) at screening and changes from/new findings since screening will be listed. If 
abnormalities in the physical examinations are reported, physical examinations will be summarized as shift 
tables (categories: Normal vs Abnormal).
19.0 References
SAS Institute, Inc., SAS® Version 9.4 software, Cary, NC.
Clinical Study Protocol. A 4-part Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, 
and Pharmacodynamics of M254 in Healthy Volunteers and in Patients with Immune Thrombocytopenic 
Purpura. Version 8.0, Final, 24 Apr 2020.
 
 
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Appendix 1: Glossary of Abbreviations
Glossary of Abbreviations:
AE
Adverse event
ADaM
Analysis data model
ANOVA
Analysis of variance
BMI
Body mass index
BQL
Below the quantifiable limit
CDISC
Clinical Data Interchange Standard Consortium
CI
Confidence interval
CSR
Clinical study report
CV
Coefficient of variation
DBP
Diastolic blood pressure
ECG
Electrocardiogram
eCRF
Electronic case report form
EDS
Early Development Services
FAS
Full Analysis Set
ICH
The International Council for Harmonization of Technical Requirements for
Pharmaceuticals for Human Use
IgG
Immunoglobulin G
LLOQ
Lower limit of quantification
max
Maximum value
MedDRA
Medical Dictionary for Regulatory Activities
min
Minimum value
PD
Pharmacodynamic
PK
Pharmacokinetic
PP
Per Protocol
PRA
PRA Health Sciences
QA’d
Quality assured
QC(’d)
Quality control(led)
SAP
Statistical analysis plan
SAE
Serious adverse event
SBP
Systolic blood pressure
SD
Standard deviation
SDTM
Study data tabulation model
TEAE
Treatment-emergent adverse event
 
 
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TFL(s)
Tables, figures and listings
WNL
WinNonlin
 
 
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Appendix 3: List of In-Text Outputs
The planned tables, figures and subject data listings for the CSR are listed below. The placement and 
numbering presented is for tracking / development purpose and may deviate from the placement order and 
numbering listed in the CSR. This list defines the tables to be produced by programming. The Medical 
Writer can decide to insert any of the figures or create more tables for the CSR text independently of this 
plan.
List of CSR In-Text Tables and Figures:
TFL Section
Output Type
Title 
Population Set
14.1
Table 
Subject Demographics and Characteristics
Randomized
Table 
Extent of Exposure
Safety
14.2
Figure 
Arithmetic Mean PK Serum 
Concentrations
PK
Table 
Summary of PK Parameters
PK
Figure 
Dose normalized PK Parameters versus 
Dose
PK
Table 
Summary of Platelet Counts (Absolute 
Values and Changes from Baseline)
FAS/PP
Figure 
Arithmetic Platelet Counts  (Absolute 
Values and Changes from Baseline)
FAS/PP
14.3
Table 
Summary of all TEAEs by System Organ 
Class and Preferred Term
Safety/PP
Table 
Related TEAEs by System Organ Class 
and Preferred Term per Study Part and 
Treatment
Safety/PP
Table 
SAE by SOC, PT per Study Part and 
Treatment
Safety/PP
Table 
TEAEs of Special Interest by System 
Organ Class and Preferred Term per 
Study Part and Treatment
Safety/PP
Table 
Summary of TEAEs by Relationship, per 
Study Part and Treatment
Safety/PP
Table 
Summary of TEAEs by Severity, per Study 
Part and Treatment
Safety/PP
 
 
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Appendix 4: List of End of Text Outputs
List of End of Text Tables and Figures:
Output
Title 
Population 
Set
Interim
(Y/N)
Section 14.1 – Disposition and Demographic Data
Table 14.1.1
Summary of Subject Disposition – Part A, B, C, D
Safety
Table 14.1.2.1
Summary of Demographics – Part A, B, C, D
Safety/PP
Section 14.2 – Pharmacokinetic Data and Pharmacodynamic Data
14.2.1 Pharmacokinetic Data
Table 14.2.1.1
Individual Values and Descriptive Statistics of M254 
Serum Concentrations - Part A, B, C, D
PK
Table 14.2.1.2
Individual Values and Descriptive Statistics of Total 
IgG Serum Levels Absolute Values - Part A, B, C, D
PK
Table 14.2.1.3
Individual Values and Descriptive Statistics of Total 
IgG Serum Levels Changes from Baseline - Part A, 
B, C, D
PK
Table 14.2.1.4
Individual Values and Descriptive Statistics of M254 
Serum PK Parameters - Part A, B, C, D
PK
Table 14.2.1.5
Individual Values and Descriptive Statistics of Total 
IgG Serum PK Parameters - Part A, B, C, D
PK
Figure 14.2.1.6
Median M254 Serum Concentrations versus Time 
Profile (Linear and Semi-logarithmic) - Part A, B, C, D
PK
Figure 14.2.1.7
Median Total IgG Serum Levels Absolute Values 
versus Time Profile (Linear and Semi-logarithmic) -
Part A, B, C, D
PK
Figure 14.2.1.8
Median Total IgG Serum Levels Changes from 
Baseline versus Time Profile (Linear and Semi-
logarithmic) - Part A, B, C, D
PK
Figure 14.2.1.9
Combined Individual M254 Serum Concentrations 
versus Time Profile (Linear and Semi-logarithmic) –
Part A, B, C, D
PK
Figure 14.2.1.10
Combined Individual Total IgG Serum Levels 
Absolute Values versus Time Profile (Linear and 
Semi-logarithmic) – Part A, B, C, D
PK
Figure 14.2.1.11
Combined Individual Total IgG Serum Levels 
Changes from Baseline versus Time Profile (Linear 
and Semi-logarithmic) – Part A, B, C, D
PK
Figure 14.2.1.12
Individual M254 Serum Concentrations versus Time 
Profile (Linear and Semi-logarithmic) - Part A, B, C, D
Safety
 
 
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Figure 14.2.1.13
Individual Total IgG Serum Levels Absolute Values
versus Time Profile (Linear and Semi-logarithmic) -
Part A, B, C, D
Safety
Figure 14.2.1.14
Individual Total IgG Serum Levels Changes from 
Baseline versus Time Profile (Linear and Semi-
logarithmic) - Part A, B, C, D
Safety
Figure 14.2.1.15
Dose Normalized (mg/kg) PK Serum Parameters vs 
Dose - Part A, B
PK
Section 14.2.2 – Pharmacodynamic Data
14.2.2.1 Platelet Counts
Table 14. 2.2.1.1
Individual Values and Descriptive Statistics of Platelet 
Counts – Part B, C, D
FAS/PP
Table 14. 2.2.1.2
Individual Values and Descriptive Statistics of Platelet 
PD Parameters – Part B, C, D
FAS/PP
Table 14. 2.2.1.3
Primary Statistical Platelet PD Parameters Analysis: 
Efficacy Analysis of M254 vs IVIg PD Parameters 
Ratios – Part C
FAS
Table 14. 2.2.1.4
Frequency counts of the responders and non 
responders
FAS/PP
Table 14. 2.2.1.5
Secondary Statistical Platelet PD Parameters 
Analysis: Overall Platelet Response Rate – Part B, C, 
D
FAS/PP
Figure 14. 2.2.1.6
Arithmetic Mean Platelet Counts Absolute Values 
versus Time Profile (Linear and Semi-logarithmic) -
Part B, C, D
FAS/PP
Figure 14. 2.2.1.7
Arithmetic Mean Platelet Counts Changes from 
Baseline versus Time Profile (Linear and Semi-
logarithmic) - Part B, C, D
FAS/PP
Figure 14. 2.2.1.8
Arithmetic Mean Platelet Counts % Changes from 
Baseline versus Time Profile (Linear and Semi-
logarithmic) - Part B, C, D
FAS/PP
Figure 14. 2.2.1.9
Combined Individual Platelet Counts Absolute Values 
versus Time Profile (Linear and Semi-logarithmic) –
Part B, C, D
FAS
Figure 14.
2.2.1.10
Combined Individual Platelet Counts Changes from 
Baseline versus Time Profile (Linear and Semi-
logarithmic) – Part B, C, D
FAS
Figure 14.
2.2.1.11
Combined Individual Platelet Counts % Changes 
from Baseline versus Time Profile (Linear and Semi-
logarithmic) – Part B, C, D
FAS
Figure 14.
2.2.1.12
Individual Platelet Counts Absolute Values versus 
Time Profile (Linear and Semi-logarithmic) - Part B, 
C, D
FAS
 
 
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Figure 14.
2.2.1.13
Individual Platelet Counts Changes from Baseline 
versus Time Profile (Linear and Semi-logarithmic) -
Part B, C, D
FAS
Figure 14.
2.2.1.14
Individual Platelet Counts % Changes from Baseline 
versus Time Profile (Linear and Semi-logarithmic) -
Part B, C, D
FAS
Section 14.3 – Safety Data
14.3.1 Adverse Events
Table 14.3.1.1
Overview TEAE
Safety
Y1
Table 14.3.1.2
Summary of Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term – Part A, B, 
C, D
Safety
Y1
Table 14.3.1.3
Summary of Related Treatment-Emergent Adverse 
Events by System Organ Class and Preferred Term –
Part A, B, C, D
Safety
Y1
Table 14.3.1.4
Summary of Serious Adverse Events by System 
Organ Class and Preferred Term – Part A, B, C, D
Safety
Y1
Table 14.3.1.5
Summary of Adverse Events of Special Interest by 
System Organ Class and Preferred Term – Part A, B, 
C, D
Safety
Y1
Table 14.3.1.6
Summary of Treatment-Emergent Adverse Events by 
Relationship to Study Drug – Part A, B, C, D
Safety
Y1
Table 14.3.1.7
Summary of Treatment-Emergent Adverse Events by 
Severity – Part A, B, C, D
Safety
Y1
14.3.2 Deaths, Other Serious And Significant Adverse Events
Table 14.3.2
Listing of Deaths and Other Serious Adverse Events 
Y1
Table 14.3.3
Not part of TFL – Reserved for Narratives in CSR
14.3.3 Clinical Laboratory
Table 14.3.3.1
Listing of Abnormal Laboratory Values – Part A, B, C, 
D
Safety
Table 14.3.3.2
Summary of Clinical Laboratory Data - Clinical 
Chemistry – Part A, B, C, D
Safety
Table 14.3.3.3
Summary of Clinical Laboratory Data – Hematology –
Part A, B, C, D
Safety
Table 14.3.3.4
Summary of Clinical Laboratory Data – Coagulation –
Part A, B, C, D
Safety
Table 14.3.3.5
Shift Table Clinically Significant Results – Clinical 
Chemistry – Part A, B, C, D – if applicable
Safety
Table 14.3.3.6
Shift Table Clinically Significant Results –
Hematology – Part A, B, C, D – if applicable
Safety
Table 14.3.3.7
Shift Table Clinically Significant Results –
Coagulation – Part A, B, C, D – if applicable
Safety
 
 
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14.3.4 Other Safety Data
Table 14.3.4.1
Summary of Vital Signs – Part A, B, C, D
Safety
Table 14.3.4.2
Shift Table of Clinically Significant Vital Signs Results 
– Part A, B, C, D – if applicable
Safety
Table 14.3.4.3
Summary of 12-Lead Electrocardiogram Part A, B, C, 
D
Safety
Table 14.3.4.4
Shift Table of Clinically Significant ECG Results –
Part A, B, C, D – if applicable
Safety
Table 14.3.4.5
Shift Table of Physical Examination – Part A, B, C, 
D– if applicable
Safety
1 Table based on the safety set will be included in the interim report after Part B and interim 
report after cohort 1 of Part C.
List of End of Text Listings:
Output
Title 
Interim
Section 16.2.1 – Disposition
Listing 16.2.1.1
Subject Disposition - Part A, B, C, D
Section 16.2.2 – Protocol Deviations
Listing 16.2.2.1
Not part of TFL – Reserved for protocol deviations in CSR
Section 16.2.3 – Excluded Subjects
Listing 16.2.3.1
Overview of Analysis Sets - Part A, B, C, D
Section 16.2.4 – Demographics and Baseline Characteristics
Listing 16.2.4.1
Subject Demographics - Part A, B, C, D
Listing 16.2.4.2
Medical History ITP - Part B, C, D
Listing 16.2.4.3
Medical History Other – Part A, B, C, D
Listing 16.2.4.4
Previous ITP Medications – Part B, C, D
Listing 16.2.4.5
Previous Medications (non-ITP) - Part A, B, C, D
Listing 16.2.4.6
Drug and Alcohol Screen - Part A, B, C, D
Listing 16.2.4.7
Serology - Part A, B, C, D
Listing 16.2.4.8
Pregnancy (beta-hCG) - Part A, B, C, D
Listing 16.2.4.9
Deviations from In- and Exclusion Criteria - Part A, B, C, D
Section 16.2.5 – Compliance and Serum Concentration Data
Listing 16.2.5.1
Study Dates - Part A, B, C, D
Listing 16.2.5.2
Study Drug Administration - Part A, B, C, D
Listing 16.2.5.3
PK Time Deviations and Comments - Part A, B, C, D
Listing 16.2.5.4
PD Time Deviations and Comments - Part B, C, D
 
 
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Section 16.2.6 – Adverse Events Data
Listing 16.2.6.1
Treatment-Emergent Adverse Events - Part A, B, C, D
Y1
Listing 16.2.6.2
Non-Treatment-Emergent Adverse Events - Part A, B, C, D
Y1
Listing 16.2.6.3
Concomitant Medications - Part A, B, C, D
Section 16.2.7 – Laboratory Data
Listing 16.2.7.1
Clinical Laboratory Results – Chemistry - Part A, B, C, D
Y2
Listing 16.2.7.2
Clinical Laboratory Results – Hematology - Part A, B, C, D
Y2
Listing 16.2.7.3
Clinical Laboratory Results – Coagulation - Part A, B, C, D
Y2
Listing 16.2.7.4
Clinical Laboratory Results – Urinalysis - Part A, B, C, D
Y2
Listing 16.2.7.5
Clinical Laboratory Results – Reference Ranges - Part A, B, C, D
Y2
Listing 16.2.7.6
Clinical Laboratory Results – Comments - Part A, B, C, D
Section 16.2.8 – Other Safety Data
Listing 16.2.8.1
Vital Signs - Part A, B, C, D
Y2
Listing 16.2.8.2
12-Lead Electrocardiogram Results - Part A, B, C, D
Y2
Listing 16.2.8.3
Physical Examination Findings and Changes from Baseline- Part A, 
B, C, D
1 Listing will be included in the interim report after Part B and interim report after cohort 1 of Part C.
2 Only clinically significant findings will be included in the interim report after Part B and interim report 
after Cohort 1 of Part C.
Other Appendix Outputs:
Output
Title 
Appendix 16.1.7
Randomization
Appendix 16.1.9.2
Statistical Appendices
 
 
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Document History
Version Date
Modified/Reviewed 
By
Brief Summary of Changes (if created from a 
template, include template code)
21-12-2018
First draft
07-01-2019
Review comments Biostatistics, Science and Medical 
Writing addressed
25-03-2019
Sponsor review comments addressed
25-06-2019
Sponsor review comments addressed
28-06-2019
Sponsor review comments addressed
08-07-2019
Update due to protocol amendment and sponsor 
comments
29-06-2021
Update due to protocol amendment
14-07-2021
Sponsor review comments addressed
 
 
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NCT03866577


CLINICAL STUDY REPORT 
MOM-M254-001/MMT102EC-170091 
Final 2.0 – 08-Feb-2022 
PRA-QMS-02686 2.0 
16.1.9.2 Statistical Methods and Analysis Output 
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NCT03866577


Statistical Methods 
MOM2-M254-001/ MMT102EC-170091 
30-Nov-2021  
 
 
Page 1 of 9
 
STATISTICAL METHODS AND ANALYSIS OUTPUT 
 
 
 
A 4-Part Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of M254 in Healthy Volunteers and in Patients with Immune 
Thrombocytopenic Purpura 
 
CONFIDENTIAL 
 
PRA code: MMT102EC-170091 
Sponsor code: MOM-M254-001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SPONSOR 
Momenta Pharmaceuticals, Inc. 
 
 
 
AUTHOR 
 
 
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PPD
NCT03866577


Statistical Methods 
MOM2-M254-001/ MMT102EC-170091 
30-Nov-2021  
 
 
Page 2 of 9
TABLE OF CONTENTS 
1. GENERAL .......................................................................................................................... 3 
2. DEVIATIONS FROM THE SAP ........................................................................................ 3 
3. STATISTICAL ANALYSES ............................................................................................... 3 
4. RAW STATISTICAL ANALYSIS OUTPUT ...................................................................... 4 
4.1 
Statistical Analysis of Platelet Parameters...................................................................... 4 
 
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Statistical Methods 
MOM2-M254-001/ MMT102EC-170091 
30-Nov-2021  
Page 3 of 9
1.
General
The safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) evaluation was
conducted by the Biostatistics Department of PRA. This document describes deviations from the
statistical analysis plan (SAP), additional decisions made during analysis and reporting and output
of statistical analysis that were not included in the Tables, Figures or Listings.
Statistical analysis was performed using the computer program SAS for Windows Version 9.4
(SAS Institute Inc.).
PK parameters were derived using validated Phoenix™ WinNonlin®, Version 8.1 (Certara USA Inc).
2.
Deviations from the SAP
In section 16 of the SAP it was planned that the PK parameters of M254 will be calculated from the
concentration profiles versus time. However during analysis predose concentrations were observed
(as for the IgG). Therefore, the PK parameters calculation for M254 was also based on the changes 
from baseline of the plasma concentrations versus time profiles. In the M254 change from baseline
calculations values below LLOQ were set to the LLOQ value. As the absolute concentration values
for PK were not used in the analysis, the TFLs and CSR present figures with change from baseline
data only. Section 9.2.1 plans to impute the missing baselines with screening values. In case
baseline in period 2 was missing, baseline from period 1 was used instead of the screening value
for the PK and PD data. Also: the SAP does not foresee how to treat negative AUC values in the
statistical analysis of the platelet data (section 17.2.2.1 of the SAP). These values were not included 
in the analysis. The statistical analysis for platelet data was repeated for the subjects with baseline
below or equal to 30, but in this model baseline as covariate was not included.
3.
Statistical Analyses
Primary Statistical Analysis of Platelet Parameters
Statistical analysis of platelet parameters was performed according to the SAP and results of it are
shown in Table 15.2.2-3. Negative AUC values were not included in this analysis. The statistical
analysis for platelet data was repeated for the subjects with baseline below or equal to 30, but in 
this model baseline as covariate was not included. The raw statistical output for the comparison 
between test treatments versus reference treatment can be found in Section 4.1 of this document.
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Statistical Methods 
MOM2-M254-001/ MMT102EC-170091 
30-Nov-2021  
 
 
Page 4 of 9
4. 
Raw Statistical Analysis Output  
4.1 
Statistical Analysis of Platelet Parameters 
Summary of Primary Statistical Analysis of Platelet Parameters 
Comparison: PD Variable Platelets, All subjects -  Parameter: Max Response (10^9/L) 
 
Parameter Category 1 (N)=10 Parameter Category 1=Platelets, All subjects Parameter (N)=1 Parameter 
Code=RMAX  
 
The Mixed Procedure 
 
          Number of Observations 
 
Number of Observations Read              21 
Number of Observations Used              21 
Number of Observations Not Used           0 
 
 
    Covariance Parameter 
         Estimates 
  
Cov Parm            Estimate 
 
SUBJID(TRTSEQP)       0.1077 
Residual             0.06513 
 
 
        Type 3 Tests of Fixed Effects 
  
              Num     Den 
Effect         DF      DF    F Value    Pr > F 
 
TRTA            1    9.23      36.28    0.0002 
APERIOD         1    8.73       2.54    0.1467 
TRTSEQP         1    8.32       3.10    0.1150 
BL              1    11.4       0.32    0.5806 
 
 
                                              Estimates 
  
                            Standard 
Label           Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
M254 vs IVIg     -0.7061      0.1172    9.23      -6.02      0.0002      0.05     -0.9702     -0.4419 
 
 
                           Least Squares Means 
  
          Actual                   Standard 
Effect    Treatment    Estimate       Error      DF    t Value    Pr > |t| 
 
TRTA      IVIG           4.7980      0.1308    12.1      36.69      <.0001 
TRTA      PT3            4.0919      0.1264    11.6      32.36      <.0001 
Summary of Primary Statistical Analysis of Platelet Parameters 
Comparison: PD Variable Platelets, All subjects -  Parameter: Max CFB Response (10^9/L) 
 
Parameter Category 1 (N)=10 Parameter Category 1=Platelets, All subjects Parameter (N)=2 Parameter 
Code=RMAXB  
 
The Mixed Procedure 
 
          Number of Observations 
 
Number of Observations Read              21 
Number of Observations Used              21 
Number of Observations Not Used           0 
 
 
    Covariance Parameter 
         Estimates 
  
Cov Parm            Estimate 
 
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Statistical Methods 
MOM2-M254-001/ MMT102EC-170091 
30-Nov-2021  
 
 
Page 5 of 9
SUBJID(TRTSEQP)       0.3740 
Residual              0.1970 
 
 
        Type 3 Tests of Fixed Effects 
  
              Num     Den 
Effect         DF      DF    F Value    Pr > F 
 
TRTA            1    9.02      40.15    0.0001 
APERIOD         1    8.46       1.14    0.3146 
TRTSEQP         1    8.11       2.29    0.1685 
BL              1    11.5       0.63    0.4432 
 
 
                                              Estimates 
  
                            Standard 
Label           Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
M254 vs IVIg     -1.2981      0.2049    9.02      -6.34      0.0001      0.05     -1.7614     -0.8348 
 
 
                           Least Squares Means 
  
          Actual                   Standard 
Effect    Treatment    Estimate       Error      DF    t Value    Pr > |t| 
 
TRTA      IVIG           4.4418      0.2374    11.7      18.71      <.0001 
TRTA      PT3            3.1437      0.2299    11.1      13.68      <.0001 
Summary of Primary Statistical Analysis of Platelet Parameters 
Comparison: PD Variable Platelets, All subjects -  Parameter: AUEC 0-14 Days CFB (10^9/L*h) 
 
Parameter Category 1 (N)=10 Parameter Category 1=Platelets, All subjects Parameter (N)=15  
 
The Mixed Procedure 
 
          Number of Observations 
 
Number of Observations Read              21 
Number of Observations Used              19 
Number of Observations Not Used           2 
 
 
    Covariance Parameter 
         Estimates 
  
Cov Parm            Estimate 
 
SUBJID(TRTSEQP)       0.3807 
Residual              0.9899 
 
 
        Type 3 Tests of Fixed Effects 
  
              Num     Den 
Effect         DF      DF    F Value    Pr > F 
 
TRTA            1       8       9.00    0.0171 
APERIOD         1    7.94       1.76    0.2213 
TRTSEQP         1    7.06       3.03    0.1248 
BL              1    8.21       2.16    0.1785 
 
 
                                              Estimates 
  
                            Standard 
Label           Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
M254 vs IVIg     -1.4084      0.4696       8      -3.00      0.0171      0.05     -2.4914     -0.3255 
 
 
                           Least Squares Means 
  
          Actual                   Standard 
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Statistical Methods 
MOM2-M254-001/ MMT102EC-170091 
30-Nov-2021  
 
 
Page 6 of 9
Effect    Treatment    Estimate       Error      DF    t Value    Pr > |t| 
 
TRTA      IVIG           9.3800      0.3972      13      23.62      <.0001 
TRTA      PT3            7.9716      0.3709    12.7      21.49      <.0001 
Summary of Primary Statistical Analysis of Platelet Parameters 
Comparison: PD Variable Platelets, All subjects -  Parameter: AUEC 0-28 Days CFB (10^9/L*h) 
 
Parameter Category 1 (N)=10 Parameter Category 1=Platelets, All subjects Parameter (N)=16  
 
The Mixed Procedure 
 
          Number of Observations 
 
Number of Observations Read              21 
Number of Observations Used              17 
Number of Observations Not Used           4 
 
 
    Covariance Parameter 
         Estimates 
  
Cov Parm            Estimate 
 
SUBJID(TRTSEQP)       0.3509 
Residual              0.6203 
 
 
        Type 3 Tests of Fixed Effects 
  
              Num     Den 
Effect         DF      DF    F Value    Pr > F 
 
TRTA            1     6.8      13.58    0.0082 
APERIOD         1     6.8       1.05    0.3397 
TRTSEQP         1    7.16       0.89    0.3766 
BL              1     8.8       0.51    0.4951 
 
 
                                              Estimates 
  
                            Standard 
Label           Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
M254 vs IVIg     -1.5289      0.4149     6.8      -3.68      0.0082      0.05     -2.5158     -0.5419 
 
 
                           Least Squares Means 
  
          Actual                   Standard 
Effect    Treatment    Estimate       Error      DF    t Value    Pr > |t| 
 
TRTA      IVIG          10.1392      0.3648    11.7      27.79      <.0001 
TRTA      PT3            8.6103      0.3319    11.2      25.95      <.0001 
Summary of Primary Statistical Analysis of Platelet Parameters 
Comparison: PD Variable Platelets, Base <=30 -  Parameter: Max Response (10^9/L) 
 
Parameter Category 1 (N)=20 Parameter Category 1=Platelets, Base <=30 Parameter (N)=1 Parameter 
Code=RMAX  
 
The Mixed Procedure 
 
          Number of Observations 
 
Number of Observations Read              11 
Number of Observations Used              11 
Number of Observations Not Used           0 
 
 
    Covariance Parameter 
         Estimates 
  
Cov Parm            Estimate 
 
SUBJID(TRTSEQP)       0.1688 
Residual              0.1170 
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Statistical Methods 
MOM2-M254-001/ MMT102EC-170091 
30-Nov-2021  
 
 
Page 7 of 9
 
 
        Type 3 Tests of Fixed Effects 
  
              Num     Den 
Effect         DF      DF    F Value    Pr > F 
 
TRTA            1    3.48       9.45    0.0447 
APERIOD         1    3.48       0.19    0.6876 
TRTSEQP         1    4.15       0.40    0.5597 
BL              0                              
 
 
                                              Estimates 
  
                            Standard 
Label           Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
M254 vs IVIg     -0.6844      0.2226    3.48      -3.07      0.0447      0.05     -1.3407    -0.02795 
 
 
                           Least Squares Means 
  
          Actual                   Standard 
Effect    Treatment    Estimate       Error      DF    t Value    Pr > |t| 
 
TRTA      IVIG           4.7101      0.2412    6.28      19.52      <.0001 
TRTA      PT3            4.0258      0.2182     5.6      18.45      <.0001 
Summary of Primary Statistical Analysis of Platelet Parameters 
Comparison: PD Variable Platelets, Base <=30 -  Parameter: Max CFB Response (10^9/L) 
 
Parameter Category 1 (N)=20 Parameter Category 1=Platelets, Base <=30 Parameter (N)=2 Parameter 
Code=RMAXB  
 
The Mixed Procedure 
 
          Number of Observations 
 
Number of Observations Read              11 
Number of Observations Used              11 
Number of Observations Not Used           0 
 
 
    Covariance Parameter 
         Estimates 
  
Cov Parm            Estimate 
 
SUBJID(TRTSEQP)       0.8253 
Residual              0.1436 
 
 
        Type 3 Tests of Fixed Effects 
  
              Num     Den 
Effect         DF      DF    F Value    Pr > F 
 
TRTA            1    3.11      22.87    0.0160 
APERIOD         1    3.11       0.38    0.5815 
TRTSEQP         1    4.01       0.19    0.6885 
BL              0                              
 
 
                                              Estimates 
  
                            Standard 
Label           Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
M254 vs IVIg     -1.1790      0.2465    3.11      -4.78      0.0160      0.05     -1.9483     -0.4098 
 
 
                           Least Squares Means 
  
          Actual                   Standard 
Effect    Treatment    Estimate       Error      DF    t Value    Pr > |t| 
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Statistical Methods 
MOM2-M254-001/ MMT102EC-170091 
30-Nov-2021  
 
 
Page 8 of 9
 
TRTA      IVIG           4.4921      0.4176    4.99      10.76      0.0001 
TRTA      PT3            3.3131      0.4019    4.49       8.24      0.0007 
Summary of Primary Statistical Analysis of Platelet Parameters 
Comparison: PD Variable Platelets, Base <=30 -  Parameter: AUEC 0-14 Days CFB (10^9/L*h) 
 
Parameter Category 1 (N)=20 Parameter Category 1=Platelets, Base <=30 Parameter (N)=15 Parameter 
Code=AUEC14DB 
 
The Mixed Procedure 
 
          Number of Observations 
 
Number of Observations Read              11 
Number of Observations Used              11 
Number of Observations Not Used           0 
 
 
    Covariance Parameter 
         Estimates 
  
Cov Parm            Estimate 
 
SUBJID(TRTSEQP)       0.9433 
Residual              0.8034 
 
 
        Type 3 Tests of Fixed Effects 
  
              Num     Den 
Effect         DF      DF    F Value    Pr > F 
 
TRTA            1    3.58       2.52    0.1962 
APERIOD         1    3.58       1.31    0.3225 
TRTSEQP         1    4.19       0.85    0.4074 
BL              0                              
 
 
                                              Estimates 
  
                            Standard 
Label           Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
M254 vs IVIg     -0.9238      0.5824    3.58      -1.59      0.1962      0.05     -2.6192      0.7716 
 
 
                           Least Squares Means 
  
          Actual                   Standard 
Effect    Treatment    Estimate       Error      DF    t Value    Pr > |t| 
 
TRTA      IVIG           9.3023      0.6021    6.45      15.45      <.0001 
TRTA      PT3            8.3785      0.5396    5.81      15.53      <.0001 
Summary of Primary Statistical Analysis of Platelet Parameters 
Comparison: PD Variable Platelets, Base <=30 -  Parameter: AUEC 0-28 Days CFB (10^9/L*h) 
 
Parameter Category 1 (N)=20 Parameter Category 1=Platelets, Base <=30 Parameter (N)=16 Parameter 
Code=AUEC28DB 
 
The Mixed Procedure 
 
          Number of Observations 
 
Number of Observations Read              11 
Number of Observations Used              10 
Number of Observations Not Used           1 
 
 
    Covariance Parameter 
         Estimates 
  
Cov Parm            Estimate 
 
SUBJID(TRTSEQP)       0.3200 
Residual              1.3058 
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Statistical Methods 
MOM2-M254-001/ MMT102EC-170091 
30-Nov-2021  
 
 
Page 9 of 9
 
 
        Type 3 Tests of Fixed Effects 
  
              Num     Den 
Effect         DF      DF    F Value    Pr > F 
 
TRTA            1     3.9       3.78    0.1254 
APERIOD         1     3.9       0.05    0.8267 
TRTSEQP         1    4.54       0.05    0.8375 
BL              0                              
 
 
                                              Estimates 
  
                            Standard 
Label           Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
M254 vs IVIg     -1.7917      0.9213     3.9      -1.94      0.1254      0.05     -4.3743      0.7909 
 
 
                           Least Squares Means 
  
          Actual                   Standard 
Effect    Treatment    Estimate       Error      DF    t Value    Pr > |t| 
 
TRTA      IVIG          10.4641      0.8273    5.98      12.65      <.0001 
TRTA      PT3            8.6724      0.5205    5.91      16.66      <.0001 
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NCT03866577