Conditions: Preeclampsia Severe Preeclampsia Eculizumab HELLP HELLP Syndrome HELLP Syndrome Second Trimester Pregnancy Related AHUS PNH Complement Regulatory Factor Defect Complement Abnormality HELLP Syndrome Third Trimester
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 2
Healthy volunteers: no

Brief summary:
This is a Phase II, single arm, open-label study to determine if treatment with eculizumab prolongs pregnancy compared to historical controls in women with preeclampsia between 23-30 weeks gestation.

Detailed description:
The purpose of this study is to determine if eculizumab is an effective treatment to prolong pregnancy in women with preeclampsia, compared to a historical control group of women that received standard of care alone. Eligible subjects will be women with preeclampsia before 30 weeks gestation, who have been deemed suitable for prolongation of pregnancy.

The primary research procedure is administration of the study drug, eculizumab, by intravenous infusions weekly for four weeks, then every other week. Eculizumab is approved by the FDA for the treatment of women with atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria and is frequently used in pregnant women with these disorders. However, eculizumab is considered investigational in this study because it has not been approved by the FDA for use in patients with preeclampsia. Subject participation will last approximately 8-12 weeks on average, and the study drug will be continued until 48 hours after delivery in the treatment arm. All subjects will be followed at 2 weeks and 6 weeks after delivery to assess maternal and neonatal outcomes. A later visit may be required to complete the meningococcal vaccine schedule.

The investigators believe that eculizumab will prolong pregnancy in women with preeclampsia diagnosed before 30 weeks gestation with overactive complement. As there is no effective treatment for preeclampsia other than delivery currently, women with preeclampsia before 30 weeks gestation are managed using a "watch and wait" approach (i.e., expectant management). Due to the unpredictable nature of preeclampsia, expectant management places mother and child at significant risk until delivery occurs. Eculizumab may be an improvement over current standard of care as it provides a treatment option for patients who would otherwise be managed with expectant management alone. If the study aims are achieved, eculizumab will emerge as an effective treatment option for women with preeclampsia.

Arms:
arm 1: Twelve subjects in the interventional arm will receive eculizumab at an induction dose of 900mg IV weekly (q7 days) for 4 weeks followed by a dose of 1200mg IV at week 5. Thereafter, patients will receive a maintenance dose of 1200mg IV every two weeks (q14 days). The last dose of eculizumab will be given up to 48 hours post-partum, with a dose that is dependent on the dosing schedule (i.e. whether the last dose is given within the 4-week induction period or is during the maintenance phase).

Interventions: intervention 1: Eculizumab
Intervention descriptions: intervention 1: Eculizumab Intravenous Solution

Protocol document:
Prot_SAP_002.pdf: 
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Complement Regulation to Undo Systemic Harm in 
Preeclampsia: The CRUSH Study 
Protocol Number: STUDY 00000039 
National Clinical Trial (NCT) Identified Number: NCT04725812 
Principal Investigator/IND Sponsor: Richard Burwick, MD MPH 
Funded by: Alexion Pharmaceuticals 
Version Number:  v.4.0 
17December 2021 


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Complement Regulation to Undo Systemic Harm in 
Preeclampsia: The CRUSH Study 
Protocol Number: STUDY 00000039 
National Clinical Trial (NCT) Identified Number: NCT04725812 
Principal Investigator/IND Sponsor: Richard Burwick, MD MPH 
Funded by: Alexion Pharmaceuticals 
Version Number:  v.4.0 
17December 2021 
 
Summary of Changes from Previous Version: 
Affected 
Sections 
Summary of Revisions Made 
Rationale 
Headers and 
Footers 
Updated headers and footers to current 
protocol version  
Headers and footers were outdated 
1.2 Study 
Schema 
Modified study schema to clarify that study 
drug is given on Day 1 and then every 7 days.  
Thus, dose 2 is given on study Day 8, dose 3 on 
study day 15, etc. and this regimen was updated 
on study schema. 
In addition, eculizumab may be dosed until 48-
hours postpartum, and that postpartum follow 
up visits may include telephone calls 
The study protocol called for dosing of 
eculizumab every 7 days, but the study 
schema initially noted that dose 2 would be 
given on study day 7.  Since study drug is 
given on Day 1, then the second dose should 
be given on study Day 8, etc.  This was 
corrected in schema and SOA.  
The study protocol also allowed for dosing of 
eculizumab until 48-hours postpartum, but 
this was not clear in the initial study schema 
and was thus revised.    
Text was revised to clarify that telephone 
calls to the participant may be performed as 
part of postpartum follow up visits 


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1.3 Schedule 
of Activities 
Modified schedule of activities (SOA) table for 
greater clarity for study team.  Separated out 
rows for screening, consent, research labs, 
vaccines, antibiotics, and study drug infusion, 
and outlined postpartum follow up visits on a 
separate table.  Expanded footnotes to provide 
greater clarity on dosing of eculizumab and 
collection of blood and urine samples for clinical 
and research purposes.   
Modified SOA to clarify that study drug is given 
on Day 1 and then every 7 days.  Thus, dose 2 is 
given on study Day 8, dose 3 on study day 15, 
etc. 
 
The schedule of activities (SOA), postpartum 
follow up visits and footnotes were modified 
to improve clarity of the protocol activities 
for the study team.    
 
 
The study protocol called for dosing of 
eculizumab every 7 days, but the study SOA 
initially noted that dose 2 would be given on 
study day 7.  Since study drug is given on Day 
1, the second dose should be given on study 
Day 8 (7 days later), etc. and this regimen 
was updated throughout the SOA.   
5.2 Exclusion 
criteria 
Condensed exclusion criteria for HELLP 
syndrome onto one line 
Under initial exclusion list, laboratory criteria 
for HELLP syndrome were listed on two 
separate lines.     
5.2 Exclusion 
criteria 
Condensed exclusion criteria for coagulopathy 
onto one line  
Under initial exclusion list, laboratory criteria 
for coagulopathy were listed on two separate 
lines.    
7.1, 8.1 
Clarified that urine protein assessment could be 
done by one of three methods (urine 
protein/creatinine ratio, 24hr urine collection, 
or urinalysis).  Testing all three is not required.  
Initial description of urine protein testing did 
not clarify that only one method was 
necessary 
7.3  
Clarified that a participant will be deemed lost 
to follow up if they are unable to be reached 
after 3 telephone calls for postpartum visits 
Updated to clarify lost to follow up criteria by 
telephone calls postpartum 
8.1, 8.2, 9.4 
Updated protocol text to clarify which 
laboratory assays will be run in Karumanchi 
laboratory, Alexion Pharmaceutical Laboratory, 
or Cedars-Sinai Laboratory 
Updated protocol text to clarify which 
laboratory assays will be run in Karumanchi 
laboratory, Alexion Pharmaceutical 
Laboratory, or Cedars-Sinai Laboratory 


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8.1 
Updated protocol text to clarify that maternal 
and neonatal outcomes during postpartum 
visits may be gathered by medical record review 
or phone visit 
Updated protocol text to clarify that 
maternal and neonatal outcomes during 
postpartum visits may be gathered by 
medical record review or phone visit 
10.1.5 
Added Dr. John Williams III as DSMB member  
Dr. Williams was previously listed as DSMB 
member in a separate section, but his name 
was mistakenly left out of section 10.1.5 and 
therefore this was corrected. 
Appendix 
Appendix A and Appendix B in Protocol ver. 3.0 
removed.  Old Appendix C renamed to Appendix 
A.  
Appendix A (in Protocol ver. 3.0) contained 
the staff’s monitoring plan, which was not 
needed because the post approval 
monitoring team at Cedars-Sinai Medical 
Center will provide quality assurance 
monitoring services.  
Appendix B (in Protocol ver. 3.0) was 
removed and will be filed in the study binder 
through SourceDrive at Cedars-Sinai Medical 
Center. 
 
 
 


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Table of Contents 
STATEMENT OF COMPLIANCE ...................................................................................................................................... 1 
1. 
PROTOCOL SUMMARY ..................................................................................................................................... 1 
1.1. 
Synopsis ................................................................................................................................................. 1 
1.2. 
Schema .................................................................................................................................................. 3 
1.3. 
Schedule of Activities (SoA) ................................................................................................................... 4 
2. 
INTRODUCTION ................................................................................................................................................ 6 
2.1. 
Study Rationale ..................................................................................................................................... 6 
2.2. 
Background ............................................................................................................................................ 7 
2.3. 
Risk/Benefit Assessment ....................................................................................................................... 9 
2.3.1. 
Known Potential Risks ........................................................................................................ 9 
2.3.2. 
Known Potential Benefits ................................................................................................ 10 
2.3.3. 
Assessment of Potential Risks and Benefits .................................................................... 10 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................................................................ 11 
4. 
STUDY DESIGN ................................................................................................................................................ 14 
4.1. 
Overall Design ..................................................................................................................................... 14 
4.2. 
Scientific Rationale for Study Design ................................................................................................... 15 
4.3. 
Justification for Dose ........................................................................................................................... 16 
4.4. 
End of Study Definition........................................................................................................................ 16 
5. 
STUDY POPULATION ...................................................................................................................................... 16 
5.1. 
Inclusion Criteria.................................................................................................................................. 16 
5.2. 
Exclusion Criteria ................................................................................................................................. 17 
5.3. 
Lifestyle Considerations ...................................................................................................................... 18 
5.4. 
Screen Failures .................................................................................................................................... 18 
5.5. 
Strategies for Recruitment and Retention .......................................................................................... 18 
6. 
STUDY INTERVENTION ................................................................................................................................... 19 
6.1. 
Study Intervention(s) Administration .................................................................................................. 19 
6.1.1. 
Study Intervention Description ........................................................................................ 19 
6.1.2. 
Dosing and Administration .............................................................................................. 19 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................... 20 
6.2.1. 
Acquisition and accountability ......................................................................................... 20 
6.2.2. 
Formulation, Appearance, Packaging, and Labeling ........................................................ 20 
6.2.3. 
Product Storage and Stability .......................................................................................... 20 
6.2.4. 
Preparation ...................................................................................................................... 21 
6.3. 
Measures to Minimize Bias: Randomization and Blinding .................................................................. 21 
6.4. 
Study Intervention Compliance ........................................................................................................... 21 
6.5. 
Concomitant Therapy .......................................................................................................................... 21 
6.5.1. 
Rescue Medicine .............................................................................................................. 21 
7. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL ............ 22 
7.1. 
Discontinuation of Study Intervention ................................................................................................ 22 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................................... 22 
7.3. 
Lost to Follow-Up ................................................................................................................................ 23 
8. 
STUDY ASSESSMENTS AND PROCEDURES ...................................................................................................... 23 
8.1. 
Efficacy Assessments ........................................................................................................................... 23 
8.2. 
Safety and Other Assessments ............................................................................................................ 26 
8.3. 
Adverse Events and Serious Adverse Events ....................................................................................... 30 
8.3.1. 
Definition of Adverse Events (AE) .................................................................................... 30 


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8.3.2. 
Definition of Serious Adverse Events (SAE) ..................................................................... 30 
8.3.3. 
Classification of an Adverse Event ................................................................................... 31 
8.3.3.1. 
Severity of Event .................................................................... 31 
8.3.3.2. 
Relationship to Study INTERVENTION ................................... 31 
8.3.3.3. 
Expectedness ......................................................................... 32 
8.3.4. 
Time Period and Frequency for Event Assessment and Follow-Up ................................. 33 
8.3.5. 
Adverse Event Reporting ................................................................................................. 34 
8.3.6. 
Serious Adverse Event Reporting..................................................................................... 34 
8.3.7. 
Reporting Events to Participants ..................................................................................... 34 
9. 
STATISTICAL CONSIDERATIONS ...................................................................................................................... 35 
9.1. 
Statistical Hypotheses ......................................................................................................................... 35 
9.2. 
Sample Size Determination ................................................................................................................. 35 
9.3. 
Populations for Analyses ..................................................................................................................... 37 
9.4. 
Statistical Analyses .............................................................................................................................. 37 
9.4.1. 
General Approach ............................................................................................................ 37 
9.4.2. 
Analysis of the Primary Efficacy Endpoint(s) ................................................................... 37 
9.4.3. 
Analysis of the Secondary Endpoint(s) ............................................................................ 38 
9.4.4. 
Safety Analyses ................................................................................................................ 39 
9.4.5. 
Baseline Descriptive Statistics ......................................................................................... 39 
9.4.6. 
Planned Interim Analyses ................................................................................................ 40 
9.4.7. 
Sub-Group Analyses ......................................................................................................... 40 
9.4.8. 
Tabulation of Individual participant Data ........................................................................ 40 
9.4.9. 
Exploratory Analyses ....................................................................................................... 40 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ..................................................... 41 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations ................................................................... 41 
10.1.1. 
Informed Consent Process ............................................................................................... 41 
10.1.1.1. 
Consent/assent and Other Informational Documents Provided 
to participants ........................................................................ 41 
10.1.1.2. 
Consent Procedures and Documentation .............................. 41 
10.1.2. 
Study Discontinuation and Closure .................................................................................. 42 
10.1.3. 
Confidentiality and Privacy .............................................................................................. 42 
10.1.4. 
Future Use of Stored Specimens and Data ...................................................................... 43 
10.1.5. 
Key Roles and Study Governance .................................................................................... 44 
10.1.6. 
Safety Oversight ............................................................................................................... 45 
10.1.7. 
Clinical Monitoring ........................................................................................................... 45 
10.1.8. 
Quality Assurance and Quality Control ............................................................................ 45 
10.1.9. 
Data Handling and Record Keeping ................................................................................. 46 
10.1.9.1. 
Data Collection and Management Responsibilities ............... 46 
10.1.9.2. 
Study Records Retention ....................................................... 46 
10.1.10. 
Protocol Deviations .......................................................................................................... 47 
10.1.11. 
Publication and Data Sharing Policy ................................................................................ 47 
10.1.12. 
Conflict of Interest Policy ................................................................................................. 47 
10.2. 
Abbreviations ...................................................................................................................................... 48 
10.3. 
Protocol Amendment History ................................................................................................................ 1 
11. 
Principal Investigator Signature Page .............................................................................................................. 2 
12. 
REFERENCES ..................................................................................................................................................... 3 
 


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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and applicable United States (US) Code of Federal Regulations (CFR). The Principal 
Investigator will assure that no deviation from, or changes to the protocol will take place without prior 
agreement from the Investigational New Drug (IND), funding agency and documented approval from the 
Institutional Review Board (IRB), except where necessary to eliminate an immediate hazard(s) to the 
trial participants. All personnel involved in the conduct of this study have completed Human Subjects 
Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval.  Approval of both the protocol and the consent form must 
be obtained before any participant is enrolled.  Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study.  All changes to the consent form 
will be IRB approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent, using a previously approved consent form. 
1. 
 
PROTOCOL SUMMARY 
1.1. 
SYNOPSIS  
Title: Complement Regulation to Undo Systemic Harm in Preeclampsia: The CRUSH Study. 
 
Study Description: 
This is a Phase II, single-arm, open-label, case-control study to determine if treatment with eculizumab 
prolongs pregnancy compared to historical controls in women with preeclampsia between 230/7 and 
296/7 weeks gestation. Based on the substantial evidence that preeclampsia is a complement-mediated 
disease and on case reports of the successful, safe treatment of preeclampsia with eculizumab, we 
believe that treatment with eculizumab will prolong gestation in women with preeclampsia between 
230/7 and 296/7 weeks gestation compared with historical controls receiving expectant management 
(standard of care). 
 
Objectives: 
Primary Objective: To determine if treatment with eculizumab prolongs pregnancy, compared to 
historical controls, in women with preeclampsia between 230/7 and 296/7 weeks gestation. 
 
Secondary Objectives:  
1. To determine if treatment with eculizumab for early-onset preeclampsia between 230/7 and 296/7 
weeks gestation decreases adverse maternal and neonatal outcomes, compared to historical controls. 
2. To determine if treatment with eculizumab reduces terminal complement activation in women with 
preeclampsia between 230/7 and 296/7 weeks gestation. 
3. To determine if treatment with eculizumab improves laboratory measures of end-organ injury and 
improves anti-angiogenic imbalance in women with preeclampsia between 230/7 and 296/7 weeks 
gestation. 
4. To determine the safety of eculizumab in the setting of early-onset preeclampsia between 230/7 and 
296/7 weeks gestation. 


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5.  To assess eculizumab pharmacokinetics and pharmacodynamics in pregnant women with early-onset 
preeclampsia between 230/7 and 296/7 weeks gestation. 
 
Endpoints: 
Primary endpoint: Latency (in days) from enrollment to delivery 
 
Secondary endpoints:  
1. Composite measures of adverse maternal and neonatal outcomes. 
a. Composite maternal outcome: Syndrome of hemolysis, elevated liver enzyme, and low 
platelet count (HELLP), eclampsia, placental abruption, stroke, venous thrombosis or 
pulmonary embolism, pulmonary edema, posterior reversible encephalopathy 
syndrome, postpartum hemorrhage (>1000 cc), blood transfusion, admission to the 
intensive care unit, acute kidney injury, acute tubular necrosis, dialysis, or death 
b. Composite neonatal outcome: Respiratory distress syndrome, bronchopulmonary 
dysplasia, intraventricular hemorrhage, retinopathy of prematurity, necrotizing 
enterocolitis, seizure, hypoxic-ischemic encephalopathy, metabolic acidosis, infection, 
sepsis, previously unrecognized major malformation detected at birth, patent ductus 
arteriosus requiring indomethacin, or death 
2. Blood and urine concentrations of terminal complement proteins C5a and C5b-9, before and 
after each treatment. 
3. Laboratory measures of end-organ injury and anti-angiogenic imbalance, before and after each 
treatment. 
a. Measures of end-organ injury: Serum creatinine, aspartate transaminase, alanine 
transaminase, hemoglobin, platelet count, lactate dehydrogenase, urine 
protein/creatinine ratio, and CD59 
b. Measures of anti-angiogenic imbalance: soluble fms-like tyrosine kinase 1 (sFLT-1), 
placental growth factor (PlGF). 
 
4.  Serious adverse events: 
a. Neisseria meningitidis infection or development of invasive meningococcal disease, 
Neisseria gonorrhoeae, Neisseria sicca/subflava, and Neisseria spp unspecified and 
Aspergillus infections.    
b. Graded clinical and laboratory abnormalities, according to the U.S. Department of Health 
and Human Services, National Institutes of Health, National Institute of Allergy and 
Infectious Diseases, Division of AIDS; DAIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events, Corrected Version 2.1. [July 2017].  
 
5. Pharmacokinetics and pharmacodynamic studies, utilizing peak and trough eculizumab levels.   
 
Study Population: 12 female patients ≥ 13 years old (with body weight ≥40kg), between 230/7 and 296/7 
weeks gestation diagnosed with preeclampsia per the American College of Obstetricians and 
Gynecologists (ACOG) guidelines and undergoing expectant management at Cedars-Sinai Medical Center 
(CSMC). 36 patients between 230/7 and 296/7weeks gestation previously diagnosed with preeclampsia per 
ACOG guidelines who underwent expectant management at CSMC between October 1, 2014 and 
September 30, 2019 will be used as historical controls. 
 
 


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Phase: 2 
 
Description of Sites/Facilities Enrolling Participants: Single-center, single-arm trial at CSMC.  
 
Description of Study Intervention: Eculizumab per standard dosing for atypical hemolytic uremic 
syndrome (aHUS): 900 mg IV every 7 days for 4 weeks, 1200 mg IV on week 5, followed by 1200 mg IV 
every 14 days until 48 hours postpartum  
 
Study Duration: 24 months 
 
Participant Duration: 
Participants will be enrolled until 6-8 weeks after delivery. Enrollment periods will be variable depending 
on delivery latency from enrollment and gestational age at enrollment. Maximum time enrolled will be 
20 weeks.  
1.2. 
SCHEMA 
 
 
 
 


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1.3. 
SCHEDULE OF ACTIVITIES (SOA) 
 
 
Schedule of Activities 
 
Screening 
Day -7 to 
Day -1 
Visit 1
Day  
1 
Visit 2
Day 
 4 
Visit 3
Day  
8 
Visit 4
Day  
11 
Visit 5
Day  
15 
Visit 6
Day 
 18 
Visit 7
Day  
22 
Visit 8 
Day 
25 
Visit 9
Day 
29 
… 
*** 
Eligibility checklist  
X 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical history and 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
Physical exam 
(pre-infusion on treatment 
days) 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Screening labs 
Platelet count, ALT, AST, LDH, 
Cr, PT/PTT, INR 
X 
 
 
 
 
 
 
 
 
 
 
Quadrivalent meningococcal 
conjugate vaccine 
(MenACWY) * 
X 
X 
 
 
 
 
 
 
 
 
X 
Meningococcus serogroup B 
vaccine (MenB)* 
X 
X 
 
 
 
 
 
 
 
 
X 
Prophylactic Antibiotics** 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Eculizumab 900 mg IV 
 
X 
 
X 
 
X 
 
X 
 
 
 
Eculizumab 1200 mg IV  
 
 
 
 
 
 
 
 
 
X 
X 
Safety Labs:†
CBC, CMP, LDH (pre-infusion 
on treatment days) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lab Tests for Research†C3, 
C4, CH50, Haptoglobin 
(pre-infusion on treatment 
days) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood collection for Research 
Labs † 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine collection†† 
(pre-infusion on treatment 
days) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical record review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Assessment for adverse 
maternal/fetal outcomes‡ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Total time 
 
60 
 min 
20 
 min 
60  
min 
20  
min 
60  
min 
20  
min 
60  
min 
20  
min 
60  
min 
20-60 
min 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sample and Procedure Table: 
Visit days above refer to the number of days from initiation of study drug (Day 1 = first day of 
eculizumab), they do not refer to antepartum or postpartum state.    
*  For subjects without meningococcal vaccination in the prior 5 years, administer Quadrivalent 
meningococcal conjugate vaccine (MenACWY): 2 doses of Menactra or Menveo with the first dose of the 
vaccine on Day 1 (prior to the first dose of eculizumab) or up to 7 days prior to Day 1 (after informed 
Consent), and the second dose of the vaccine at least 2 months later. Also, administer Meningococcus 
serogroup B vaccine (MenB): 2 doses of Bexsero with the first dose of the vaccine on Day 1 (prior to the 
first dose of eculizumab) or up to 7 days prior to Day 1 (after informed Consent), and the second dose of 
the vaccine at least 1 month later. For subjects with prior vaccination, revaccinate in accordance with 
the recommendation of the Advisory Committee on Immunization Practices, considering the duration of 
eculizumab therapy.  The second dose of the two meningococcal vaccines may be administered up to 8 
weeks postpartum, however in some subjects, the second dose may become due prior to delivery. 
** Penicillin 500 mg PO bid, or Azithromcyin 250 mg PO daily (if allergy to penicillin), until 4 weeks after 
the last dose of eculizumab 
Postpartum follow up 
1-2 weeks 
postpartum 
6-8 weeks 
postpartum 
0-8 weeks 
Postpartum 
Quadrivalent meningococcal conjugate 
vaccine (MenACWY), 2nd dose  
(at least 2 months from 1st dose)* 
 
 
X 
Meningococcus serogroup B vaccine 
(MenB)  
(at least 1 month from 1st dose)* 
 
 
X 
Prophylactic Antibiotics** 
X 
X 
 
Medical record review 
X 
X 
 
Assessment for adverse maternal 
outcomes (chart review / telephone 
visit)‡‡ 
X 
X 
 
Assessment for adverse neonatal
outcomes (chart review / telephone 
visit)‡‡ 
X 
X 
 
Total time
20 min 
20 min 
20 min 


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*** Following induction dose of eculizumab (900 mg IV every 7 days x 4 weeks), eculizumab will be given 
at maintenance dose of 1200 mg IV on week 5, followed by 1200 mg every 2 weeks.  Eculizumab should 
be given until 48 hours postpartum.  Alternating study visits for specimen collection & medical record 
review will continue until hospital discharge.  Blood draws and urine samples are to be drawn the day of 
and prior to every eculizumab infusion and 3 days after every eculizumab infusion, even if patient is in 
the postpartum period.  If the patient discontinues participation in the study before hospital discharge, a 
final discontinuation visit will be performed on that day, including collection of blood and urine samples 
and assessment of maternal and fetal status.  Blood and urine collections will be discontinued upon 
hospital discharge 
 † Safety labs (CBC, CMP, and LDH), as well as other labs specific to the research study (C3, C4, CH50, and 
haptoglobin), will be sent to the Cedars-Sinai Laboratory.  Additional research samples to be collected 
will include one 10ml purple-top tube for plasma and one 10ml red-top tube for serum. To assess peak 
and trough effects of the study drug, subjects will have blood collected three days after each study drug 
administration (peak) and just prior to the study drug infusion on each subsequent treatment day 
(trough).  These additional research samples will be processed and stored in Karumanchi laboratory.   
Future research assays, including measurements of C5a, C5b-9, CD59, sFLT1, PlGF and PK/PD assays, will 
be performed in the Karumanchi laboratory or Alexion Pharmaceuticals laboratory, and such results will 
not be available to the treatment team or study participant.   
† † Urine sample to be sent clinically for protein assessment (one of the following: urine 
protein/creatinine ratio, 24hr urine protein or urinalysis), and an additional research sample will be 
collected up to 20ml. Future research assays, including measurements of urinary C5a, C5b-9, CD59, 
sFLT1 and PlGF, will be performed in the Karumanchi laboratory, and such results will not be available to 
the treatment team or study participant.   
‡ In addition to the study visits designated in the table, a member of the study team will write a brief 
progress note daily assessing maternal and fetal status.   
‡‡ For postpartum visits, maternal and neonatal outcomes will be assessed by chart review and 
telephone call to the patient.  Up to three telephone calls will be made to reach the study participant, 
after which they will be deemed lost to follow up. 
 
2. 
 
INTRODUCTION 
 
2.1. 
STUDY RATIONALE  
Preeclampsia occurs in 3-4% of pregnancies and is characterized by hypertension and proteinuria or 
end-organ injury (1-2).  Severe forms of the disease may be life-threatening, and complications include 
kidney and liver failure, seizure and stroke.  Unfortunately, the only treatment for preeclampsia is 
interruption of the pregnancy (delivery), often resulting in a premature neonate.  To improve neonatal 
outcomes, providers attempt to prolong pregnancy when preeclampsia is diagnosed <34 weeks 
gestation (3-4).   As no treatment is available for preeclampsia, this approach is termed “expectant 
management,” which means to watch and wait.  Given the unrelenting and unpredictable nature of 
preeclampsia, expectant management places mother and child at significant risk until delivery occurs (5-
6).  There is a compelling need for therapeutic measures, in lieu of expectant management, for women 
with early-onset preeclampsia <34 weeks gestation.  Prolongation of pregnancy for 7 days or more, in 


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the setting of preterm preeclampsia, is expected to greatly improve neonatal outcomes.  This potential 
benefit is greatest in women <30 weeks gestation.  Moreover, days gained for the fetus prior to delivery 
usually translate directly to days saved in the neonatal intensive care unit.  
There is increasing evidence that preeclampsia is a complement-mediated disorder, which closely 
resembles atypical hemolytic uremic syndrome (aHUS), a complement-mediated thrombotic 
microangiopathy (TMA) disorder (7-9).  Like aHUS, preeclampsia predisposes to microangiopathic 
hemolytic anemia, thrombocytopenia, and kidney injury, usually in the form of HELLP (hemolysis, 
elevated liver enzymes, low platelet count) syndrome (10).  There is strong evidence that preeclampsia 
and HELLP syndrome are propagated by increased complement activation or decreased complement 
regulation (11-17).  Though no treatment exists for preeclampsia, eculizumab is a terminal (C5) 
complement blocker and an FDA-approved treatment for complement mediated disorders (28).  
Eculizumab has been used safely and efficaciously to treat aHUS and paroxsysmal nocturnal 
hemoglobinuria (PNH) in pregnancy (22-25). Given that preeclampsia is also a complement-mediated 
disorder, there is clinical equipoise regarding the use of eculizumab in the treatment of preeclampsia.  
Figure 1.  Complement activation in pregnancy and disease severity 
 
2.2. 
BACKGROUND  
The safety of eculizumab for treatment of preeclampsia is supported by its use in pregnant women with 
paroxysmal nocturnal hemoglobinuria (PNH) (22).  There is also an increasing number of reports 
describing eculizumab treatment for pregnancy-associated aHUS prior to delivery (23-25).    Importantly, 
while effective as a maternal terminal complement blocker, eculizumab treatment during pregnancy 
does not impair the complement system activity of the newborn (26). A human case study described 
successful off-label use of eculizumab for treatment of early-onset preeclampsia and HELLP syndrome 
(18).  To our knowledge, it is the first and only published case of its kind.  In that case, eculizumab 
treatment led to cessation of red cell hemolysis, normalization of platelet count, and reduction in 
soluble C5b-9 (terminal complement complex) in plasma and urine. Furthermore, eculizumab treatment 


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led to the prolongation of pregnancy by 17 days, compared to a historical average of less than 7 days 
using expectant management. Eculizumab not only benefited the neonate, by allowing extra time for 
fetal maturation, but also benefited maternal health by reversing HELLP syndrome and avoiding major 
sequelae, such as disseminated intravascular coagulation, acute kidney injury, and admission to the 
intensive care unit. Eculizumab also proved safe for the neonate, who had an uncomplicated neonatal 
course.   Moreover, there were insufficient levels of eculizumab observed in the cord blood to block 
complement in the neonate (18). 
In addition to the human case report, there is strong evidence in the literature that complement 
mediates severe preeclampsia (11, 18-20).  Urinary MAC (C5b-9) levels correlate strongly with high 
levels of sFLT-1 and low levels of PlGF (i.e. the anti-angiogenic state), a characteristic feature of 
preeclampsia (20). Recently, utilizing a large cohort of patients in Colombia, urinary C5b-9 levels were 
found to distinguish severe preeclampsia from mild preeclampsia, and alterations in plasma C5b-9 levels 
were found to correlate with features of severe disease, including low platelet count, elevated lactate 
dehydrogenase, and elevated serum creatinine. Furthermore, urinary excretion of the terminal 
complement complex (MAC) has been shown to be specific to severe preeclampsia, suggesting it might 
be a useful biomarker for distinguishing severe disease from chronic hypertension (11).   
Given the mounting data of preeclampsia as a complement-mediated disorder, we hypothesize that 
disease severity correlates with increasing complement activation, with HELLP syndrome and pregnancy 
associated aHUS at the most extreme (Figure 1).   This is emphasized by the fact that women entering 
pregnancy with aHUS have severe complications including early-onset preeclampsia (21).  Given the 
similarity between aHUS, HELLP and severe preeclampsia as complement-mediated TMA disorders, we 
hypothesize that the two conditions will respond similarly to eculizumab treatment.   Therefore, we aim 
to treat women with early-onset preeclampsia <34 weeks with eculizumab to prolong pregnancy, as 
compared to standard management without eculizumab (historical controls).  
In the documented human case report of eculizumab-treated HELLP syndrome (18), eculizumab was 
dosed at 1200 mg weekly, which was enough to prolong pregnancy in the setting of active hemolysis.  
However, the 1200 mg induction dose of eculizumab is not well studied in pregnancy.   The current FDA-
approved dose of eculizumab for aHUS is 900 mg IV weekly, 1200 mg IV on week 5, and 1200 mg IV 
every 14 days.  This regimen has been used effectively in women with aHUS in pregnancy and 
postpartum, and we believe it will be an effective regimen to treat preeclampsia (a less severe form of 
disease compared to HELLP syndrome).  Thus, we hypothesize that eculizumab, dosed in accordance 
with FDA-approved regimen for aHUS, will prolong pregnancy in women with preeclampsia.  In the 
existing human preeclampsia case report, eculizumab was dosed at 1200 mg IV weekly, above the FDA 
package label, and there was no evidence of fetal or neonatal harm. Furthermore, cord blood levels of 
eculizumab were insufficient to block complement (18).  This suggests that a lower dose of eculizumab, 
given in accordance with the FDA label for treatment of aHUS, will also be safe for use in preeclampsia.  
In summary, there is strong evidence that preeclampsia is a complement-mediated disorder, which may 
progress to end-organ injury and hemolytic anemia, similar to aHUS.  The published case report of 
eculizumab to treat preeclampsia gives proof-of-concept for a pilot study to evaluate the efficacy of 
eculizumab for treatment of preeclampsia. Given the serious and life-threatening nature of HELLP 
syndrome and eclampsia, and the significant maternal risk of prolonging pregnancy in the setting of 
these conditions, we will exclude women with HELLP syndrome and eclampsia from our study.  
Finally, the use of eculizumab in treatment of severe preeclampsia has significant potential as a cost-
saving therapy, particularly as a salvage therapy at early gestational ages.   Delivery for preeclampsia <28 


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weeks gestation results in an average maternal cost of $29,131 and infant cost of $282,570 per birth 
(27).  In 2012, the total health care cost in the United States attributed to preeclampsia deliveries <34 
weeks was $1.2-2.0 billion.  At early gestational age, prolongation of pregnancy by 7 days reduces 
adverse outcomes such as intracranial hemorrhage, respiratory failure, seizure, and death.   Due to 
these benefits, prolongation of pregnancy by 1-2 weeks results in cost savings of $50-150,000 per infant 
delivered for preeclampsia <28 weeks and $25-50,000 per infant delivered at 28-34 weeks.   There is 
also a large global market for preeclampsia therapy as it is a leading cause of maternal morbidity and 
mortality worldwide. Therefore, the use of eculizumab as a preeclampsia therapeutic has the potential 
to reduce healthcare costs in the United States and in developing countries, where burden of disease is 
greatest.  
 
2.3. 
RISK/BENEFIT ASSESSMENT   
 
2.3.1. KNOWN POTENTIAL RISKS  
 
There is a known risk of meningococcal infection with eculizumab (28). In clinical trials of patients with 
PNH, aHUS, and non-PNH treated with eculizumab, <1% of subjects developed meningococcal infection. 
The risk of meningococcal infection is mitigated with immunization with meningococcal vaccines, 
prophylactic antibiotics, and close monitoring of patients for early signs of infection. As eculizumab 
blocks terminal complement activation, there is also some unknown risk for infection with encapsulated 
bacteria (28). To minimize risk of infection, our protocol will require meningococcal vaccination with the 
first dose of eculizumab as well as prophylactic antibiotics through for 4 weeks following the last dose of 
eculizumab. Finally, subjects will be closely monitored for signs of infection and all participants will be 
provided a patient safety information card regarding the risk of meningococcal infection. The participant 
safety card will describe signs and symptoms of meningitis for the patient (e.g., fever, headache and a 
fever, headache and a stiff neck, etc.) and will provide information for healthcare providers regarding 
risk of meningococcal infection following C5 blockade with eculizumab.  The study drug will be stopped 
immediately if an infection, other than simple urinary or yeast infection, is suspected.  Treatment 
decisions for known or suspected meningococcal infection will be made in conjunction with infectious 
disease specialists. Neisseria meningitidis infection will be reported as an adverse event of special 
interest (AESI) and will be reported to the FDA and the Data Safety Monitoring Board (DSMB). 
 
As a biologic, eculizumab carries some unknown risk of infusion reaction. However, in clinical trials of 
eculizumab, no subject experienced an infusion reaction requiring discontinuation of treatment (28). 
Subjects in this trial will be closely monitored in an inpatient setting throughout infusion, and treatment 
will be stopped immediately with any signs of anaphylaxis or hypersensitivity.  
 
Safety measures and adverse maternal / neonatal events will also be assessed daily throughout the trial.  
There are no available data to inform drug-associated risk of major birth defects and miscarriage. 
However, there is an abundance of safety data from on-label use of eculizumab in PNH and aHUS (22-
25). In a study of 10 women with PNH who breastfed their infants while on eculizumab, the drug was 
not detected in any of the 10 breastmilk samples (22). In that same study, 64 children exposed to 
eculizumab in pregnancy had long-term follow up, with form development assessments performed at an 
average of 31 months (range 4-94). Of those, 64 of 64 (100%) met developmental milestones for vision, 
hearing, locomotion, fine-motor skills, behavior and physical health; 63 out of 64 (98.4%) achieved 
milestones for speech and language (1 child was referred to a speech and language specialist for delayed 
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this data suggests that eculizumab is safe for use in pregnant and breastfeeding women (22,28). As fetal 
and neonatal risks from eculizumab appear to be minimal, there is a compelling rationale to treat 
preeclampsia and prevent severe maternal adverse outcomes, in lieu of expectant management, in 
women with early-onset disease.   
 
There is minimal risk associated with venipuncture for a research blood draw, including bleeding, 
bruising or infection at the puncture site. There is also a small risk of fainting. Subjects will be closely 
monitored for any signs of venipuncture-related injury at the time of study blood draw.  
 
 
2.3.2. KNOWN POTENTIAL BENEFITS  
 
As demonstrated in the human case report (18), there is significant potential for benefit in the 
treatment of preeclampsia with eculizumab. Current management of preeclampsia prior to 30 weeks 
gestation consists of watchful waiting, which carries the risk of maternal end-organ damage— including 
seizures and death — and prolongation of gestation of less than 1 week. The reported use of eculizumab 
in severe preeclampsia/HELLP syndrome mitigated end-organ damage with cessation of hemolysis, 
normalization of platelet counts, and prolongation of pregnancy by 17 days (17). Additionally, given the 
abundance of data suggesting preeclampsia is a complement-mediated disorder, complement blockade 
with eculizumab — in lieu of expectant management— is expected to improve outcomes for women 
with severe, early-onset (<30 weeks) preeclampsia.  
 
In the short term, potential benefits include mitigation of severe disease, including maternal end-organ 
damage, and prolongation of gestation and increased fetal maturation with less risk of the complications 
of prematurity. However, it is well established in the literature that women with a history of 
preeclampsia are at long-term risk of cardiovascular and renal complications (29). Potential intermediate 
and long-term risks include acute kidney injury, cardiomyopathy, vascular dementia, end-stage renal 
disease, acute myocardial infarction, and hypertension (29-33). Given that this constellation of 
complications is secondary to vascular injury, attenuation of vascular damage through complement 
blockade may decrease the long-term risk of cardiovascular and renal disease. However, the follow-up 
time-frame of this study (6-8 weeks post-partum) does not allow for assessment of these long-term 
risks.  
 
 
2.3.3. ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
Currently no therapy exists for the treatment of early-onset preeclampsia. Expectant management of 
these patients until the late preterm period carries the risk of maternal end-organ damage, diseases of 
prematurity of the newborn, and maternal and fetal mortality. Therefore, the possibilities of mitigating 
progression of end-organ damage in the mother and improving fetal maturation with the treatment of 
eculizumab suggest significant benefit over current management. Though treatment with eculizumab 
does carry some risk of meningococcal infection, <1% of subjects treated with eculizumab developed 
meningococcal infection in clinical trials (28). To minimize risk of possible infection with encapsulated 
bacteria (such as Neisseria meningitidis), our protocol will include meningococcal vaccination and 
prophylactic antibiotics until 4 weeks after the last dose of eculizumab, a sufficient amount of time for 
the effects of complement blockade to wane and sufficient time for subjects to develop adaptive 
immunity following meningococcal vaccine. Furthermore, subjects will be closely monitored for 
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interventions will be stopped immediately for the subject. Given the potential for maternal and fetal 
benefit and the mitigating steps of vaccination and prophylactic antibiotics, we believe that treatment 
with eculizumab outweighs the risk of infection for this population. 
 
The risk of infusion reaction is minimal with eculizumab and has not necessitated discontinuation of 
treatment. Therefore, we believe that treatment of eculizumab for early-onset preeclampsia outweighs 
the risk of infusion reaction. However, given the known risk, subjects will be monitored for anaphylaxis 
and hypersensitivity reactions in an inpatient setting while the subject is undergoing infusion.  
 
Though no clinical trial evidence exists for the study of eculizumab in pregnancy, an abundance of case 
reports documenting the use of eculizumab in pregnancy suggests that eculizumab is safe and does not 
affect the complement system of the fetus/neonate (18, 22-26). Given the risk of severe neonatal 
morbidity and mortality in early-onset preeclampsia and the minimal risk of neonatal complement 
blockade, we believe the potential benefit of prolonged gestation with treatment of eculizumab 
outweighs the risks of prematurity for the neonate. The risks of transmission of eculizumab through 
breast-milk is minimal, as drug levels are undetectable in the breastmilk of nursing mothers on 
eculizumab for on-label indications (22). 
 
 
3. 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS
JUSTIFICATION FOR
ENDPOINTS 
Primary
To determine if treatment with
eculizumab prolongs pregnancy, 
compared to historical controls, in 
women with preeclampsia between 
23+0/7 - 29 +6/7 weeks gestation.  
Latency (in days) from enrollment to
delivery.  
When preeclampsia
develops between 
23+0/7 - 29 +6/7 weeks 
gestation, the primary 
aim is to prolong 
pregnancy for 
additional fetal 
maturation, without 
compromising maternal 
health.  Latency (in 
days) from enrollment 
to delivery is the best 
marker to gauge clinical 
response to treatment 
because pregnancy is 
only prolonged when 
both maternal and fetal 
health are reassuring. 
Days gained for the 
fetus prior to delivery, 
usually translate 


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OBJECTIVES 
ENDPOINTS
JUSTIFICATION FOR
ENDPOINTS 
directly to days saved in
the neonatal intensive 
care unit.  
Secondary
To determine if treatment with
eculizumab for early-onset 
preeclampsia <30 weeks gestation 
decreases adverse maternal and 
neonatal outcomes, compared to 
historical controls.  
Composite maternal outcome:
Syndrome of hemolysis, elevated liver 
enzyme, and low platelet count 
(HELLP), eclampsia, placental 
abruption, stroke, venous thrombosis 
or pulmonary embolism, pulmonary 
edema, posterior reversible 
encephalopathy syndrome, 
postpartum hemorrhage (>1000 cc), 
blood transfusion, admission to the 
intensive care unit, acute kidney 
injury, acute tubular necrosis, dialysis, 
or death 
 
Composite neonatal outcome: 
Respiratory distress syndrome, 
bronchopulmonary dysplasia, 
intraventricular hemorrhage, 
retinopathy of prematurity, 
necrotizing enterocolitis, seizure, 
hypoxic-ischemic encephalopathy, 
metabolic acidosis, infection, sepsis, 
previously unrecognized major 
malformation detected at birth, 
patent ductus arteriosus requiring 
indomethacin, or death 
  
Composite adverse
maternal and neonatal 
outcomes were chosen 
because of the rarity of 
individual outcomes.  In 
addition, preeclampsia 
predisposes to a range 
of maternal 
complications due to its 
heterogeneous nature.  
The maternal outcomes 
listed are all established 
complications from 
preeclampsia (42).   
 
Neonatal outcomes are 
related to preeclampsia 
indirectly, because they 
are primarily 
complications 
secondary to premature 
delivery. The outcomes 
listed are those directly 
relating to premature 
delivery.    
To determine if treatment with
eculizumab reduces terminal 
complement activation in women 
with preeclampsia <30 weeks 
gestation 
 
Blood and urine concentrations of
terminal complement proteins C5a 
and C5b-9, before and after each 
treatment. 
Terminal complement
proteins C5a and C5b-9 
are increased in women 
with preeclampsia, and 
eculizumab is a C5 
inhibitor designed to 
reduce concentrations 
of C5a and C5b-9.  Thus, 
we aim to show that 
C5a and C5b-9 
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OBJECTIVES 
ENDPOINTS
JUSTIFICATION FOR
ENDPOINTS 
effectively decreased in
women with 
preeclampsia treated 
with eculizumab. 
To determine if treatment with
eculizumab improves laboratory 
measures of end-organ injury and 
reduces anti-angiogenic imbalance 
in women with preeclampsia <30 
weeks gestation. 
Measures of end-organ injury: serum
creatinine, aspartate transaminase, 
alanine transaminase, hemoglobin, 
platelet count, lactate 
dehydrogenase, urine 
protein/creatinine ratio, and CD59 
 
Measures of anti-angiogenic 
imbalance: soluble fms-like tyrosine 
kinase 1 (sFLT-1), placental growth 
factor (PlGF), and their ratio. 
Preeclampsia is
associated with end-
organ injury, but effects 
on end-organs are 
heterogeneous.  Thus, 
we will evaluate the 
impact of eculizumab 
treatment on various 
markers of kidney, liver, 
and hematologic injury.  
We selected laboratory 
markers that are 
commonly deranged in 
the setting of 
preeclampsia, 
particularly those 
associated with severe 
or progressive disease. 
CD59 is a specific 
marker for 
complement-mediated 
end-organ injury. 
 
Preeclampsia is also 
associated with the 
anti-angiogenic state, 
with increased sFLT1 
and decreased PlGF 
concentrations, and an 
increased sFLT1/PlGF 
ratio (42).  Complement 
activation correlates 
with the anti-angiogenic 
state. We will assess 
whether sFLT1 and PlGF 
concentrations improve 
in conjunction with 
complement blockade.  


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OBJECTIVES 
ENDPOINTS
JUSTIFICATION FOR
ENDPOINTS 
To determine safety of eculizumab
in the setting of early-onset 
preeclampsia between 23-30 weeks 
gestation 
Neisseria meningitidis infection or
development of invasive 
meningococcal disease, Neisseria 
gonorrhoeae, Neisseria 
sicca/subflava, and 
Neisseria spp unspecified and 
Aspergillus infections  
 
Graded clinical and laboratory 
abnormalities, according to the U.S. 
Department of Health and Human 
Services, National Institutes of Health, 
National Institute of Allergy and 
Infectious Diseases, Division of AIDS; 
DAIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events, 
Corrected Version 2.1. [July 2017]. 
Available at: 
https://rsc.niaid.nih.gov/sites/default
/files/daidsgradingcorrectedv21.pdf 
We will monitor the
occurrence of Neisseria 
or Aspergillus infections 
due to the increased 
risk in the setting of 
complement blockade 
with the study drug. 
 
In addition, to assess 
safety of the study drug 
we will monitor graded 
clinical and laboratory 
abnormalities.  This will 
help determine if the 
eculizumab is safe in 
the study population. 
To assess eculizumab
pharmacokinetics in pregnant 
women with early-onset 
preeclampsia between 230/7 and 
296/7 weeks gestation. 
Peak and trough serum eculizumab
levels for pharmacokinetic and 
pharmacodynamic assessment. 
Pharmacokinetic and
pharmacodynamic 
modeling will help 
determine if eculizumab 
dosing regimen is 
adequate in pregnant 
women, considering 
increased volume of 
distribution and other 
physiologic changes of 
pregnancy.  
 
 
 
4. 
STUDY DESIGN  
 
4.1. 
OVERALL DESIGN 
 
Hypothesis:  Complement blockade with eculizumab to treat early-onset preeclampsia (< 30 weeks 
gestation) will prolong pregnancy and decrease adverse maternal and neonatal outcomes, 
compared to historical controls not treated with eculizumab. 
 


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Phase: 2 
 
Design:  Single-center, single-arm trial at Cedars-Sinai Medical Center 
 
Bias: To minimize bias, all eligible subjects meeting inclusion and exclusion criteria will be 
approached for enrollment in the study, until the enrollment target of 12 subjects is met. 
 
Study Arms: 12 female patients ≥ 13 years old (body weight ≥40kg) between 230/7 and 296/7 weeks 
gestation diagnosed with preeclampsia per the American College of Obstetricians and Gynecologists 
(ACOG) guidelines undergoing expectant management at Cedars-Sinai Medical Center (CSMC). 36 
patients between 230/7 and 296/7 weeks gestation previously diagnosed with preeclampsia per ACOG 
guidelines who underwent expectant management at CSMC between October 1, 2014 and 
September 30, 2019 will be used as historical controls. 
 
Study Intervention: Eculizumab per standard dosing for atypical hemolytic uremic syndrome (aHUS): 
900 mg IV every 7 days for 4 weeks, 1200 mg IV on week 5, followed by 1200 mg IV every 14 days  
until 48 hours postpartum  
 
Participant duration: Participants will be enrolled until 6 weeks postpartum. Enrollment periods will 
be variable depending on delivery latency from enrollment. Maximum time enrolled will be 20 
weeks.  
 
1. Selection of controls:  Historical controls will be those women with early-onset preeclampsia 
(between 230/7 and 296/7 weeks gestation), managed at Cedars-Sinai Medical Center but not treated 
with eculizumab between October 1, 2014 and September 30, 2019.  Following inclusion/exclusion 
criteria, 36 controls will be matched 3:1 to 12 cases by 
i) 
parity (nulliparous / multiparous) 
ii) gestational age at diagnosis (± 7 days) 
iii) fetal count of current gestation 
iv) race (white/non-white)  
The designated team member selecting control subjects will otherwise be blinded to details of 
the corresponding case, including clinical outcome. 
 
4.2. 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
This is a phase 2, open-label study of eculizumab for treatment of early-onset preeclampsia between 
230/7 and 296/7 weeks gestation.  To determine whether eculizumab prolongs pregnancy in women with 
preeclampsia, we will compare pregnancy latency in cases treated with eculizumab to pregnancy latency 
in matched historical controls not treated with eculizumab.  It is well-established that pregnancy latency 
in early-onset preeclampsia (<30 weeks) is 7-10 days or less.  However, there is variation in latency 
based on patient population and clinical characteristics.  It is critical to evaluate historical controls from 
within our own institution, rather than historical controls from the medical literature.  In addition, 
practice patterns change over time and we will therefore select a contemporaneous group of controls 
from the last 5 years at our institution. To limit differences between the control group and the case 
group, which might confound our results, we will match controls (3:1) to cases by gestational age, parity, 


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and race.   Such clinical characteristics are major factors associated with pregnancy latency in 
preeclampsia. By matching for these characteristics we will strengthen the argument that any change in 
latency in the intervention group is due to study drug.  Controls will be matched to cases in a 3:1 ratio to 
increase our statistical power to detect a difference in the primary outcome between groups and to 
minimize the number of cases that need to be enrolled.  
 
4.3. 
JUSTIFICATION FOR DOSE 
 
All 12 subjects in the intervention group will receive the study drug, eculizumab, at an induction dose of 
900 mg IV (every 7 days for 4 weeks), followed by a maintenance dose of 1200 mg IV on week 5 and 
then 1200 mg every 14 days until 48 hours postpartum.  Eculizumab is only available as an intravenous 
infusion.   The dosing regimen is identical to the FDA-approved eculizumab dosing schedule for non-
pregnant adults (≥18 years old), as well as pediatric and adolescent patients aged 13 to 18 years with 
body weight ≥40kg, with atypical hemolytic uremic syndrome (aHUS).  The safety profile observed in 
pediatric and adolescent patients (aged 13 to 18 years with body weight ≥40kg) is similar to that 
observed in the adult population. 
In adults with aHUS, as well as pediatric and adolescent patients (aged 13 to 18 years with body weight 
≥40kg), eculizumab is dosed at 900 mg IV weekly for 4 weeks, then 1200mg for the 5th dose, then 
1200mg every 2 weeks.   We are proposing an identical dosing regimen for treatment of preeclampsia.  
The FDA-approved regimen for aHUS has been used effectively to treat aHUS arising during pregnancy 
(21, 24).  Higher doses of eculizumab have also been used, with the rationale that pregnancy is 
characterized by increased complement activation and increased volume of distribution (21).  In a 
human case report, eculizumab was given at induction dose of 1200 mg IV weekly, above FDA-label, for 
treatment of preeclampsia and HELLP syndrome (18, 35).   While higher doses have been used 
successfully in pregnancy, without evidence of fetal or neonatal harm, there is very limited safety data 
at this higher dose.  The FDA-approved dosing regimen of eculizumab for aHUS has been well studied, 
with numerous case reports and case studies in pregnancy and postpartum, and we believe that the 
same dosing regimen will be efficacious in preeclampsia (a less severe form of disease compared to 
HELLP syndrome). 
 
4.4. 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if she has completed all phases of the study 
including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), Section 
1.3.  
 
5. 
STUDY POPULATION 
 
5.1. 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria:  
1. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study procedures & availability for study duration  
3. Biologically female, aged 13, body weight ≥40 kg 
4. Diagnosed with preeclampsia between 230/7 and 296/7 weeks gestation, by following criteria: 


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a. Blood pressure 160 mmHg systolic or 110 mmHg diastolic OR 
b. Blood pressure 140 mmHg systolic or 90 mmHg diastolic and at least one of the 
following 
i. Proteinuria (spot protein/creatinine 0.3mg/mg or 24Hr protein 300 mg) 
ii. Platelet count <100,000/l 
iii. Aspartate or alanine transaminase >2x upper limit of normal 
iv. Creatinine >1.1 mg/dl or oliguria 
v. Pulmonary edema 
5. Ability to take intravenous medication and be willing to adhere to the eculizumab regimen 
6. Ability to receive meningococcal vaccine and be willing to adhere to antibiotic regimen 
 
5.2. 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria prior to enrollment will be excluded from 
participation in this study:  
1. Body weight <40kg  
2. Known allergic reactions to eculizumab or meningococcal vaccine 
3. Febrile illness within prior 2 weeks to enrollment 
4. Treatment with another investigational drug within previous 6 months 
5. Inpatient expectant management for preeclampsia >72 hours prior to enrollment 
6. Fetal contraindication to expectant management of pregnancy 
7. Platelet count <50,000/μl 
8. Diagnosis of hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome 
(All of the following: LDH >600 U/L, platelet count < 100,000/l, AST >2x upper limit of normal, 
ALT >2x upper limit of normal) 
9. Diagnosis of Eclampsia 
10. Diagnosis of Placental abruption 
11. Intrauterine fetal demise 
12. Coagulopathy (INR ≥ 1.5 or fibrinogen <200 mg/dL) 
13. Persistent, severe headache unresponsive to medications 
14. Persistent, severe visual disturbances 
15. Persistent, severe epigastric or RUQ pain unresponsive to medications 
16. Diagnosis of Systemic lupus erythematosus 
17. Diagnosis of Anti-phospholipid antibody syndrome 
18. Diagnosis of Atypical hemolytic uremic syndrome 
19. Diagnosis of Paroxysmal nocturnal hemoglobinuria 
20. Known complement deficiency 
21. Diagnosis of Venous thromboembolism active or within 6 months of enrollment 
22. Diagnosis of Human immunodeficiency virus (HIV) 
23. Diagnosis of Hepatitis C virus (active viremia) 
24. Diagnosis of Cancer (not in remission) 
25. History of Solid organ transplant 
26. Systemic viral or bacterial infection (active, untreated) 
27. Active use of eculizumab at time of enrollment 
28. Contraindication to eculizumab treatment or complement system blockade 
29. Contraindication to meningococcal vaccine 
30. Neutropenia (<1500/mm3) 


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31. Gonorrhea, chlamydia, or syphilis in current pregnancy 
32. Illicit substance use in current pregnancy 
33. Currently homeless or incarcerated 
34. Alcoholism 
35. Liver cirrhosis 
36. Insulin dependent diabetes 
37. Active use of immunosuppressive therapies, other than use of corticosteroids for fetal lung 
maturity  
38. Use of prophylactic or therapeutic heparin, or low molecular weight heparin, in pregnancy for 
hypercoagulable condition 
 
5.3. 
LIFESTYLE CONSIDERATIONS 
 
There will be no lifestyle and/or diet restrictions required by this protocol. Participants may be subject 
to lifestyle restrictions (e.g., bedrest) at the discretion of their treating physicians.  
 
5.4. 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial 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 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 trial (screen failure) because of a 
misdiagnosis may be rescreened. Rescreened participants should be assigned the same participant 
number as for the initial screening.  
 
5.5. 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Sample size: For the prospective, treatment arm, we are targeting enrollment of 12 pregnant women, 
age 18, with preeclampsia between 230/7 and 296/7 weeks gestation. Our disease of interest – early 
onset preeclampsia – is unique to pregnant women, a vulnerable population.  We will screen all women 
presenting to the labor and delivery triage unit, regardless of race/ethnicity until enrollment targets are 
met.   
 
Anticipated accrual rate: We anticipate enrollment of 1 subject every 2 months, with completion of 
enrollment over a 24-month period. 
 
All subjects will be enrolled at Cedars-Sinai Medical Center. All study interventions (i.e. eculizumab, 
antibiotic, and vaccine administration) will be administered while the study subject is in an inpatient or 
hospital-like setting. Given the severity of disease of this population, we anticipate that all subjects will 
require inpatient management. Therefore, we anticipate a high retention rate.  
 


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All subjects will be enrolled from the inpatient hospital setting, including Labor and Delivery ward or 
antepartum unit. 
 
Subjects will not receive payment for study participation. 
 
For the retrospective, matched-controlled arm, 36 historical controls who previously underwent 
expectant management for preeclampsia between October 1, 2014 and September 30, 2019 will be 
matched 3:1 to cases in the prospective, treatment arm by gestational age (± 7 days), parity 
(nulliparous/multiparous), fetal count of current gestation, and race/ethnicity (white/non-white). 
Controls will be selected in reverse chronological order as they appear in the database by research staff 
blinded to the clinical outcomes of the case group.   
 
6. 
STUDY INTERVENTION 
 
6.1. 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1. STUDY INTERVENTION DESCRIPTION 
 
Eculizumab (Soliris) is a C5 inhibitor biological product that is administered intravenously and is currently 
FDA-approved for treatment of paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic 
syndrome (aHUS), and anti-acetylcholine receptor antibody-positive myasthenia gravis. We propose the 
off-label use of eculizumab for the treatment of early-onset preeclampsia, a complement-mediated 
disease. Eculizumab will be administered intravenously in accordance with its approved administration 
method. Dosing will be within the on-label use range as described in section 6.1.2.  
 
This is a non-blinded single-arm study with historical controls, therefore there is no control product.  
6.1.2. DOSING AND ADMINISTRATION 
 
As described in section 4.3, all subjects in the prospective, interventional arm will receive the study 
drug, eculizumab, at an induction dose of 900 mg IV weekly (q7 days) for 4 weeks, followed by a 
maintenance dose of 1200 mg IV on week 5 and then 1200 mg IV every 14 days. The last dose will be 
administered up to 48 hours postpartum. The specific dose (900 mg vs. 1200 mg) will depend on where 
the subject is on the dosing schedule (i.e. post-partum dose will be 1200 mg if it is the 5th dose or 
greater).  The dosing regimen is identical to the FDA-approved package insert for dosing in adults (≥18 
years old) with atypical hemolytic uremic syndrome (aHUS).  In adults with aHUS, eculizumab is dosed at 
900 mg IV weekly for 4 weeks, then 1200 mg for the 5th dose, then 1200mg every 2 weeks.  We are 
proposing an identical dosing regimen for treatment of preeclampsia.   
 
We propose dosing in accordance with the maintenance schedule outlined by the FDA-approved 
package insert, as clinical stability of the subject allows. Given the elevated levels of complement 
activation immediately post-partum, the last dose may be administered up to 48 hours post-partum.  
 
Eculizumab will be administered intravenously, the only currently FDA-approved method of 
administration. In accordance with the FDA-approved package insert administration guidelines, the 
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pediatric patients via gravity feed, a syringe-type pump, or an infusion pump.  Patients will be 
monitored for signs/symptoms of infusion reaction.  
 
6.2. 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1. ACQUISITION AND ACCOUNTABILITY 
 
The Cedars-Sinai Medical Center investigational pharmacy will be used for study drug storage, 
reconstitution, and preparation. Eculizumab vials will be stored under light-protected, refrigerated 
conditions at 2-8C per the FDA-approved package insert. Investigators will obtain study drug directly 
from the investigational pharmacy. Study drug will be administered by the antepartum or L&D nursing 
staff. Expired or unused study drug will be return to Alexion Pharmaceuticals, provider of the study drug, 
for disposal.  
 
6.2.2. FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Eculizumab (Soliris) is supplied as 300 mg single-dose vials containing 30 mL of 10 mg/mL sterile, 
preservative-free solution. 90-120 mL of normal saline (diluent) will be used to constitute three-four 300 
mg vials, depending on dosing schedule (900 mg or 1200 mg). Each vial will be labeled per FDA-
approved package insert instructions:  
 
Alexion Pharmaceuticals, Inc. 
100 College Street 
New Haven, CT 06510 USA  
 
US License Number 1743 
 
Infusion bag will be labeled with study protocol number and ID, study drug name (eculizumab), dose 
(900mg or 1200 mg), and subject number. 
 
Information in the FDA-approved package insert medication guide and expected side effects as 
elaborated in section 8.3.3 will be included in the patient informed consent for this trial.  
 
There is no control product being used in this study. Instead, matched, historical controls will be used.  
 
6.2.3. PRODUCT STORAGE AND STABILITY 
 
Eculizumab (study drug) will be stored under light-protected, refrigerated (2-8C) conditions in the 
Cedars-Sinai Medical Center investigational pharmacy. Vials will not be shaken or frozen. Study drug will 
not be used beyond the expiration date stamped on the vial carton. If the vial seal is broken for 
reconstitution but not used, the vial will be considered expired. If the vial seal is broken or there is 
particulate matter or discoloration visible in the vial, the vial will be considered expired and will be 
marked and returned to Alexion Pharmaceuticals. Expired vials will be stored in a separate location from 
the un-expired study drug per investigational pharmacy standards.  
 
Admixed solutions of eculizumab are stable for 24 hours at room temperature.  
 


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6.2.4. PREPARATION 
900 mg (3 vials of 300 mg) diluted in 90 mL of normal saline for a final volume of 180 mL or 1200 mg (4 
vials of 300 mg) of eculizumab will be diluted in 120 mL of normal saline by pharmacy staff to achieve a 
final volume of 240 mL.  Any unused portion left in the vials will be discarded. The infusion bag will be 
gently inverted to ensure thorough mixing and the admixture will be allowed to adjust to room 
temperature prior to administration. No heat source will be used to accelerate adjustment. Once 
adjusted to room temperature, the study drug admixture will be administered by IV infusion over 35 
minutes in adults and 1 to 4 hours in pediatric patients via gravity feed, a syringe-type pump, or an 
infusion pump.   
 
6.3. 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Randomization not-applicable:  The interventional phase of this trial is a single-arm non-blinded study. 
Matched, historical cases treated with expectant management will be used for control groups.  
 
Historical controls with preeclampsia at our institution between October 1, 2014 and September 30, 
2019 will be identified, and data abstracted, according to Cedars-Sinai IRB Study #00052119.    To avoid 
selection bias, research staff blinded to the clinical outcomes of the case group will be utilized to select 
controls.  Controls will be selected in reverse chronological order by delivery date. Research staff will be 
asked to select two controls to match each case, based on gestational age (±1 week), parity (multiparous 
or nulliparous), fetal count in current gestation, and race/ethnicity.  
 
6.4. 
STUDY INTERVENTION COMPLIANCE 
 
All study interventions (i.e., infusions of study drug, prophylactic antibiotics, and vaccines) will be 
performed while the study subject is in a hospitalized setting. A participant drug log will be maintained 
by the investigational pharmacy and periodically reviewed by study staff. Therefore, subjects will be 
closely monitored by research staff and by treating physicians for completion of study interventions.  
 
Study samples will be collected at the timepoints detailed in the schema (section 1.2) and the schedule 
of activities above. Samples will be centrifuged within 6 hours of collection, transferred into cryovials, 
and stored in -80C freezers to ensure protein stability.  
 
Other data points will be collected from the electronic medical record and transcribed onto electronic 
case report forms maintained behind the firewall.  
 
6.5. 
CONCOMITANT THERAPY 
Not applicable: No concomitant therapy for preeclampsia is currently FDA approved. Therefore study 
subjects should not be on concomitant therapy for preeclampsia. Patients on other interventional trials 
will be excluded. Standard clinical care, such as treatment with anti-hypertensives, low-dose aspirin, 
magnesium for seizure prophylaxis, and steroids for fetal lung development, is permitted.  
 
6.5.1. RESCUE MEDICINE 
   


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Not-applicable: There are no rescue treatments for eculizumab. Prophylactic antibiotics and 
meningococcal vaccines will be administered prior to the first dose of study drug to mitigate risk of 
infection with encapsulated bacteria.  
 
7. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1. 
DISCONTINUATION OF STUDY INTERVENTION 
Subjects will be discontinued from eculizumab treatment if they develop any signs or symptoms of 
infection, including but not limited to fever (100.4F). The subject’s primary physician may elect to 
discontinue the subject’s eculizumab treatment at any time.  
 
Discontinuation from eculizumab treatment does not mean discontinuation from the study, and 
remaining study procedures should be completed as indicated by the study protocol. The data collected 
in this study is observational and does not affect clinical management. Therefore, continued data 
collection should not affect the study subject’s ongoing clinical care.  Any observed events that qualify as 
an adverse event (AE) will be reported as such. 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
 
Hospital laboratory tests 
- Hemoglobin (g/dl) 
- Platelet count (k/μl) 
- Lactate dehydrogenase (U/L) 
- Creatinine (mg/dl) 
- Aspartate transaminase (U/L) 
- Alanine transaminase (U/L) 
- Haptoglobin (mg/dl) 
- C3, C4 (mg/dl) 
- CH50 (U/ml) 
- Urine protein analysis by one of the following: 
- Urine protein / creatinine ratio (mg/mg) or  
- 24-hour urine protein (mg) or  Urinalysis 
 
Specimen Samples 
-Urine 
-Serum 
-Plasma 
 
7.2. 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
 
Signs or symptoms of meningococcal or invasive fungal infection.  
 
Signs or symptoms of hypersensitivity or anaphylaxis to study drug. 


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 
If participant is discharged prior to being given study drug.  
 
Significant study intervention non-compliance  
 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
 
Disease progression does not preclude further study participation.  
 
Participant unable to receive study drug for >8 days from previous dose. 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
electronic Case Report Form (eCRF). Subjects who sign the informed consent form but do not receive 
the study drug – even if they undergo a research blood draw – will be counted as a screen failure may be 
replaced. Subjects who sign the informed consent form and receive at least one dose of the study drug, 
and subsequently withdraw, or are withdrawn or discontinued from the study. Subjects who receive at 
least one dose of the study drug but decline any further doses or are unable to receive further doses (i.e. 
development of hypersensitivity/anaphylaxis or severe infection) may be followed for maternal and 
neonatal adverse outcomes.  
7.3. 
LOST TO FOLLOW-UP 
 
All subjects will receive the study drug in a hospital-like setting. Therefore, it is unlikely that subjects will 
be lost to follow-up antepartum. Subjects who are discharged prior to receiving study drug will be 
considered screen failures for misdiagnosis.  
 
A participant may be lost to follow-up in the postpartum period if she fails to respond to 3 follow up 
telephone calls at the 1-2 week postpartum visit or at the 6-8 week postpartum visit . 
 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1. 
EFFICACY ASSESSMENTS  
 
1. Pre-screening: 
- Potential subjects will be pre-screened for study eligibility by a member of the research study team 
(research assistant or co-investigator) 
- Subjects will be pre-screened from labor and delivery (L&D) or maternal fetal care unit (MFCU) at 
Cedars-Sinai Medical Center 
- Eligible subjects will meet the following criteria: 
 
Admitted for inpatient care 
 
Gestational age ≥23.0 AND <30.0 weeks  
 
Clinical diagnosis of gestational hypertension or preeclampsia 
 
2. Subject consent: 
-  Subjects will be approached for enrollment in the study after they are identified as eligible candidates.   
-  The research study team will contact the primary provider of the eligible subject, to obtain approval to 
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-  Once approval is obtained, the research study team will consent the patient for enrollment in the 
study. 
 
3. Inclusion / Exclusion criteria- After obtaining informed consent, the research team will perform 
detailed chart review to assess the full list of inclusion / exclusion criteria as detailed in this study 
protocol. 
 
4. Laboratory evaluation- Subjects will be excluded if they have a platelet count <50,000/μl prior to 
enrollment, or a diagnosis of HELLP syndrome defined by the constellation of three findings: platelet 
count <100,000/μl, lactate dehydrogenase >600 U/L, and aspartate or alanine transaminase >2x upper 
limit of normal.  Subjects will also be excluded if they have a fibrinogen level <200 mg/dl or INR ≥1.5.  
 
5. Physical examination and symptom evaluation- In addition to chart review, subjects will be 
evaluated by the research team to determine final study eligibility.  Subjects will be excluded if they 
have persistent and severe headache, visual disturbances, or right upper quadrant abdominal pain.   
Subjects will also be excluded if they are incapacitated, or have an altered mental status, and are unable 
to provide written, informed consent.  
 
6. Meningococcal vaccine- Subjects must agree to, and have no contraindication, to receiving the 
meningococcal vaccine.   Subjects without prior history of meningococcal vaccination will be given the 
vaccine prior to administering the first dose of eculizumab.  A second dose will be administered either 2 
months later (Quadrivalent meningococcal conjugate vaccine) or 1 month later (Meningococcus 
serogroup B vaccine). Second doses of the vaccines may be given while the subject is still pregnant or in 
the postpartum period (up to 8 weeks postpartum). For subjects with prior vaccination, revaccinate in 
accordance with the recommendation of the Advisory Committee on Immunization Practices, 
considering the duration of eculizumab therapy.  
 
Efficacy 
 
Laboratory measures in blood and urine 
Subjects will have blood and urine samples collected prior to the first dose of the study drug 
(eculizumab) on day 1.   Measurements from these samples will represent baseline, or pre-treatment, 
values.   Subsequent blood and urine collections will be performed the day of (and prior to) every 
eculizumab infusion and 3 days after every infusion, to monitor efficacy of the study drug.    At every 
study visit which includes a blood draw and urine collection, specimens will also be collected for 
research purposes to test secondary study objectives.  Blood and urine will be collected by a member of 
the research team, the patient’s nurse, or inpatient phlebotomist.   These samples will be processed and 
stored in the Karumanchi laboratory.  Analyses will occur in the Karumanchi Laboratory or Alexion 
Pharmaceuticals Laboratory. 
 
Blood samples: 
 
Tube types 
 
- Purple top: plasma separator tube (EDTA) 
 
- Red top: serum separator tube (SST) 
 
- Green top: lithium or sodium heparin 
 
- Cedars-Sinai Laboratory (clinical tests) 
 
 
- Complete blood count (purple top) 


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- Complete metabolic panel (red or green top) 
 
 
- Lactate dehydrogenase (red top) 
 
 
- Haptoglobin (red top) 
 
 
- C3, C4, CH50 (red top) 
 
- Research samples to Karumanchi Lab (complement and angiogenic markers, PK/PD studies) 
 
 
- 10 cc Serum (red top) 
 
 
- 10 cc Plasma (purple top) 
 
Urine samples: 
 
- Cedars-Sinai Laboratory (clinical tests) 
 
One of the following: 
 
 
- Urine protein/creatinine ratio  
 
 
- Urinalysis 
 
 
- 24-hour urine collection for total protein and creatinine 
 
- Research sample to Karumanchi lab (complement and angiogenic markers) 
 
 
- 20 cc into sterile plastic cup 
 
Testing from blood and urine specimens for determination of efficacy, as outlined as secondary 
objectives in this protocol: 
1. Blood and urine concentrations of terminal complement proteins C5a and C5b-9, before and 
after treatment with eculizumab. 
2. Laboratory measures of end-organ injury and anti-angiogenic imbalance, before and after 
treatment with eculizumab. 
3. Measures of end-organ injury: Serum creatinine, aspartate transaminase, alanine transaminase, 
hemoglobin, platelet count, lactate dehydrogenase, urine protein/creatinine ratio, and CD59. 
4. Measures of anti-angiogenic imbalance: soluble fms-like tyrosine kinase 1 (sFLT-1), placental 
growth factor (PlGF) 
Blood and urine collection and processing methods for research samples 
 
- 
See detailed blood and urine collection Manual of Procedures (MOP) 
 
Maternal assessment for adverse outcomes for determination of efficacy, as outlined as secondary 
objectives in this protocol: 
 
All subjects will have a baseline assessment for adverse outcomes on Visit Day 1, which will establish 
baseline clinical status.  Adverse outcomes will be assessed daily by a member of the study team, with 
unsettled diagnoses reviewed by the study PI for final classification.  Subsequent assessments for 
adverse maternal or fetal outcomes will be performed daily.   Maternal and fetal assessments will 
enable clinical determination of drug efficacy over time, in comparison to historical controls.  In 
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allowing early detection of adverse events or worsened disease.  All participants will have a follow up 
assessment for adverse maternal outcomes at 1-2 weeks and 6-8 weeks postpartum (by medical record 
review or phone visit). 
 
Newborn assessment for adverse outcomes for determination of efficacy, as outlined as secondary 
objectives in this protocol: 
 
All participants will have a follow up assessment for adverse neonatal outcomes at 1-2 weeks and 6-8 
weeks postpartum (by medical record review or phone visit).  These assessments will be performed by a 
member of the study team, with unsettled diagnoses reviewed by the study PI for final classification.  
Neonatal assessments will be used to determine the safety of drug administration in pregnancy, by 
comparing neonatal outcomes in those exposed to study drug to matched controls not exposed to study 
drug.   
 
8.2. 
SAFETY AND OTHER ASSESSMENTS 
 
Screening 
Screening as described in section 8.1 will be a rigorous process to include subjects with preeclampsia at 
230/7 and 296/7 weeks gestations and to exclude any subjects with contraindication to expectant 
management or any risk from meningococcal vaccination. Subjects will be identified by gestational age 
and diagnosis of preeclampsia or gestational hypertension. After informed consent, a thorough review 
of the subject’s electronic medical record using clinical labs drawn through Cedars-Sinai laboratory and 
clinical assessment by the treating physician will be performed to identify any exclusions for expectant 
management or study enrollment as outlined in section 8.1 and to identify risk to meningococcal 
vaccination or infusion reaction. The risk of receiving the study drug (i.e. history of infusion reaction with 
eculizumab), antibiotics, or meningococcal vaccination will exclude the subject from the study. This 
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Laboratory assessment for safety 
To assure the safety of subjects to receive study drug, all subjects must have a baseline laboratory 
assessment of their condition, to include complete blood count, liver enzymes, and kidney function.  
Those with severe thrombocytopenia <50 k/ul or HELLP syndrome will be excluded for safety, as 
expedited delivery is recommended in this scenario.  In addition, subjects with evidence of 
coagulopathy, with fibrinogen <200 mg/dl or INR ≥1.5 will be excluded due to their advanced disease 
requiring urgent intervention.   Subjects with other forms of laboratory abnormalities, such as liver 
enzyme elevation, mild thrombocytopenia (platelet count 50-150 k/ul), or mild kidney injury, will be 
eligible for inclusion if the primary provider has deemed the patient a candidate for expectant 
management of pregnancy.    
 
Physical examination for safety 
The research study team will initially consent the study subject and review the chart for 
inclusion/exclusion criteria.   When the subject is deemed eligible for study inclusion, a physical 
examination and symptom screen via the patient’s medical record will be performed to rule out severe 
headache, visual disturbances or right upper quadrant abdominal pain, which would preclude the 
patient from receiving study drug due to safety concerns.   
 
Specimen Collection Drug Monitoring 
1 tube (~10 cc.) of serum, 1 tube (~10 cc.) of plasma and 1 urine collection (~20 cc.) will be obtained for 
research purposes on day 1 prior to administration of study drug (pre-treatment baseline).  Research 
samples will be processed and stored in the Karumanchi laboratory.  Research samples will be collected 
on the day of (and prior to) every eculizumab infusion and 3 days after every infusion through the last 
dose of eculizumab. The final serum, plasma, and urine specimen collections will be 3 days following the 
last dose of eculizumab administered or just prior to the patient’s discharge. Specimens will be 
processed and stored in -80 degree Celsius research freezer and will be analyzed after the last study 
subject has completed the study. Results from these specimen analyses will not contribute to the study 
subject’s clinical care.  
 
All plasma and urine research specimens will be assessed for complement levels including C5b-9 (MAC 
complex) and C5a. CD59, sFLT-1, and PlGF levels will also be assessed in plasma and urine specimens 
Serum specimens will be assessed for Eculizumab level (PK) and activity (PD, % hemolysis) to determine 
peak and trough levels.  These assays will be performed in the Karumanchi laboratory at Cedars-Sinai 
Medical Center, or with Alexion Pharmaceuticals, and results will not be made available to the 
treatment team or the study participant. 
 
Maternal and fetal safety monitoring and duration of treatment 
Maternal and fetal safety assessments will be performed daily by the study team, in addition to standard 
daily evaluations by the primary treatment team.  All study patients will remain hospitalized for the 
duration of the study.  Standard inpatient monitoring of preeclampsia will include maternal vital signs at 
least every 8 hours and fetal heart assessment at least every 12 hours.   Subjects will continue study 
drug until maternal and/or fetal indications for delivery necessitate cessation of expectant management 
or until 34 0/7 weeks of gestation (for preeclampsia with severe features) or 37 0/7 weeks of gestation 
(for preeclampsia without severe features).  Expectant management is expected to extend pregnancy 
for approximately 7 days on average. It is assumed that treatment with eculizumab will provide an 
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study drug is therefore estimated to be approximately 7 to 14 days on average. However, it is possible 
that the duration on study drug could be 13 weeks if a patient enters the trial at 24 0/7 weeks of 
gestation and reaches 37 0/7 weeks of gestation. 
Clinician guide for patient management-  
The primary treatment team will guide clinical management of the patient and timing of delivery, but 
the following may be used as a guide for preeclampsia management among study patients: 
I. 
Indications for delivery may include one or more of the following: 
- 
Refractory hypertension despite maximal medical intervention 
- 
HELLP syndrome (defined as all three of the following: AST or ALT >2x upper limit of normal, 
platelet count ˂100,000/μL, LDH ≥ 600 U/L)  
- 
Platelet count <50,000/μL 
- 
Eclampsia 
- 
Placental abruption 
- 
Intrauterine fetal demise 
- 
Coagulopathy with INR ≥1.5 or Fibrinogen <200 mg/dl 
- 
Pulmonary Edema 
- 
Reverse end diastolic flow on umbilical Doppler ultrasound 
- 
Biophysical score ≤4/10 on 2 occasions 
- 
Recurrent or prolonged fetal heart rate decelerations  
- 
Intractable headache unrelieved with analgesia 
- 
Intractable right upper quadrant abdominal pain or vomiting 
 
II. Magnesium sulfate for seizure prophylaxis 
- 
Magnesium sulfate, as a 4-6 gram intravenous (IV) bolus over 20-30 minutes, followed by 1-
2 gram IV infusion per hr x24 hours, should be given at initial diagnosis of preeclampsia with 
severe features, during labor and delivery, and 24 hour postpartum. 
- 
For patients undergoing expectant management of preeclampsia beyond 24 hours, 
magnesium sulfate may be stopped.  However, it should be reinitiated (per dosing regimen 
above) if new severe features of preeclampsia develop such as severe headache, visual 
disturbances, eclampsia, or HELLP syndrome. 
- 
All patients should be monitored for signs of magnesium toxicity every 2 hours and 
concerning signs may include loss of deep tendon reflexes, respiratory depression, blurred 
vision or slurred speech.  If concern for magnesium toxicity, stop magnesium sulfate infusion 
and check serum magnesium level.  Calcium gluconate 1g IV can be given for magnesium 
toxicity. 
 
III. Treatment of headaches 
- 
Persistent, severe headaches should raise suspicion for preeclampsia with severe features.  
Hyperreflexia and clonus are also suggestive of worsening preeclampsia.  If headaches do 
not respond to analgesics, delivery should be considered.   
- 
Possible analgesics may include: 
o Tylenol up to 1000mg q 6hr 


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o Reglan 10mg q 6hr 
o Benadryl 25mg q6hr 
 
IV. Betamethasone for fetal lung maturity 
- 
Betamethasone, at a dose of 12mg IM q24hr x2 doses, should be given for fetal lung 
maturity when delivery is anticipated between before 37 weeks gestation.   
- 
Among patients receiving a course of betamethasone <32 weeks gestation, a second 
“rescue” course may be given after 2 weeks have passed (up to 34 weeks gestation) if the 
patient remains pregnant.   
- 
An alternative to Betamethasone is Dexamethasone (6mg IM every 12hr x 4 doses) 
 
V. Magnesium sulfate for neuroprotection 
- 
Magnesium sulfate, as a 4-6 gram intravenous (IV) bolus over 20-30 minutes, followed by 1-
2 gram IV infusion per hr x12 hours, should be given for fetal neuroprotection when delivery 
is anticipated <32 weeks gestation.  If delivery does not occur after 12 hours and delivery is 
no longer considered, the infusion should be discontinued and resumed when delivery was 
deemed imminent again (at any point up to 32 weeks gestation). If at least 6 hours have 
passed since the discontinuation of the magnesium infusion, another loading dose may be 
given.   
 
VI. Prevention of venous thromboembolism (VTE) 
- 
Patients undergoing expectant management for preeclampsia are at high risk for VTE and 
they require mechanical or pharmacologic prophylaxis through delivery and immediate 
postpartum period. 
- 
Spontaneous compression devices (SCDs) are recommended on both legs while the patient 
is lying in bed.  
- 
Pharmacologic prophylaxis may be considered for VTE prophylaxis in patients at high risk 
including nephrotic range proteinuria, prior VTE, known thrombophilia, lupus, heart disease, 
sickle cell disease, or prolonged immobility >1 week in the hospital.  Options include 
unfractionated heparin (7500mg SC daily <28 weeks and 10,000mg SC daily >28 weeks) or 
prophylactic dose lovenox 40mg SC daily.   
- 
Pharmacologic prophylaxis should be stopped 24hr prior to epidural or spinal anesthesia.  
Anesthesiology should be consulted for preeclampsia patients receiving heparin or lovenox.   
 
VII. Discontinuation of study drug 
- 
The study drug may be stopped at any time upon patient request or the discretion of the 
treating provider. 
- 
Worsening of preeclampsia, as noted above under indications for delivery, is not an 
indication to stop study drug.    
- 
The study drug will be continued through delivery but will be discontinued at 48 hours 
postpartum.   
- 
Indications for discontinuation of study drug include severe allergic reaction or bacterial, 
viral or fungal infection (aside from uncomplicated urinary tract infections or vaginal 
candidiasis).  The study drug should be stopped for any signs of meningococcal infection, 
and appropriate treatment should be given.    


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- 
The data safety monitoring board will monitor all serious adverse events and will establish 
guidelines to determine if the study can be continued safely or if early termination is 
required.   
- 
Study patients will be followed until resolution of any adverse maternal or fetal outcomes. 
 
Additional Safety Monitoring   
 
Given the small number of subjects and the open-label study design, the ongoing safety of the study 
drug will be assessed after completion of each study subject by the Principal Investigator and the co-
investigators. If at any point the study drug is deemed unsafe, all further study procedures will be 
stopped and safety committee will be assembled for subject case review.  
 
Additional safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) 
composed of 1 expert in clinical trials research, 2 obstetrician-gynecologists, and 1 pediatrician. 
Members of the DSMB will be independent from the study conduct and free of conflict of interest, or 
measures will be taken to minimize perceived conflict of interest.  The DSMB will meet at least 
semiannually to assess safety and efficacy data on each arm of the study. The DMSB will operate under 
the rules of an approved charter that will be written and reviewed at the organizational meeting of the 
DSMB. At this time, each data element that the DSMB needs to assess will be clearly defined. The DSMB 
will provide its input to Alexion Pharmaceuticals and the Principal Investigator 
 
8.3. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1. DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). A medical condition that is 
present when the patient enters the study is not considered an AE unless this medical condition worsens 
after the patient undergoes a study-related intervention. Clinically significant laboratory abnormalities 
(for example, abnormal x-rays, ECGs, etc.) that occur or worsen with the intervention also are AEs. AEs 
in both mother and fetus/neonate will be recorded. Because this population is expected to have 
abnormal laboratory values, abnormal laboratory values should not be recorded as “Adverse Events” on 
the CRF unless medical intervention is necessitated (clinically significant). Abnormal laboratory results 
should be graded for severity by the Investigator only if they are considered AEs.  
 
8.3.2. DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
An adverse event (AE) or suspected adverse reaction at any dose in the subject or fetus/newborn is 
considered "serious" if, in the view of either the investigator or Alexion pharmaceuticals, it results in any 
of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of 
the ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical 
events that may not result in death, be life-threatening, or require hospitalization may be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the participant and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.  


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The following exceptions from expedited reporting as pertains to categorizing an event as serious, 
where serious is not the same as severe: 
 
Prolonged hospitalization due to resolution of signs and/or symptoms of preeclampsia or 
gestational hypertension as a result of the study therapy, as prolonging gestation is an intended 
side effect of the therapy and will not be considered an SAE. 
 
Premature delivery as this is an expected outcome in this patient population.  
 
 
8.3.3. CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1. SEVERITY OF EVENT 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
Mild (Grade 1)– Events require minimal or no treatment and do not interfere with the 
participant’s daily activities.  
• 
Moderate (Grade 2) – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with functioning. 
• 
Severe (Grade 3) – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
8.3.3.2. RELATIONSHIP TO STUDY INTERVENTION 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study intervention (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 


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• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician.] 
 
 
8.3.3.3. EXPECTEDNESS  
 
Expected adverse reactions are AEs that are known to occur for the study intervention being studied and 
will be collected in a standard, systematic format using a grading scale based on functional assessment 
or magnitude of reaction. Expected adverse reactions for eculizumab according to the approved labeling 
package insert (2/2018 update) include headache, diarrhea, abdominal pain, hypertension, upper 
respiratory infection, nasopharyngitis, back pain, and nausea/vomiting, anemia, cough, peripheral 
edema, urinary tract infections, and musculoskeletal pain. Percent adverse reactions reported in at least 
10% of adults and adolescent patients receiving eculizumab in aHUS clinical studies, include: 
 
 
Hypertension or hypotension – 33% 
 
Bronchitis – 12% 
 
Nasopharyngitis - 27% 
 
Gastroenteritis – 12% 
 
Respiratory tract infection – 19% 
 
Urinary tract infection – 22% 
 
Diarrhea – 37% 
 
Vomiting – 30% 
 
Nausea – 23% 
 
Abdominal pain – 19% 
 
Headache – 41% 
 
Anemia– 26% 
 
Leukopenia – 15% 
 
Insomnia – 14% 
 
Renal impairment – 18% 
 
Cough – 23% 
 
Fatigue – 13%  
 
Hypokalemia – 12% 
 
Rash – 14% 
 
Pruritus – 10% 
 
Joint pain – 13% 
 
Back pain – 10%  
 
Pyrexia - 21%  
 
Other expected serious adverse events include, 
 
Viral Infection (2%) 
 
Meningococcal infection (1-2%, in all studies) 


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 
Other infections  
o Streptococcus pneumoniae infection 
o Haemophilus influenza type b (Hib) infection 
o Aspergillus infection  
 
Infusion reaction, including anaphylaxis or other hypersensitivity reactions. 
 
Eculizumab is administered via IV infusion. In this trial a patient´s vascular access will be obtained using 
the antecubital veins. Adverse reactions of IV access are infection of puncture site at the worst leading 
to bacteremia with the requirement of hospitalization and antibiotic therapy, bleeding from puncture 
site due to dysfunctional coagulation or vascular trauma secondary to traumatic puncture, nerve 
damage as well as pain around the needle site or arm discomfort. All IV access sites will be examined 
each day and removed/changed if redness or pain (early signs of infection) at the site exists. 
 
The Principal Investigator will be responsible for determining whether an adverse event (AE) is expected 
or unexpected.  A copy of the package insert for the study drug will be available to guide determination 
of “expectedness vs. unexpectedness.” An AE will be considered unexpected if the nature, severity, or 
frequency of the event is not consistent with the risk information previously described for the study 
intervention. 
 
8.3.4. TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The Principal Investigator will record all reportable events with start dates occurring any time after 
informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last dose of 
study drug.  At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the 
last visit.  Specific, solicited events based on those reported in the eculizumab package insert (2/2018) 
will be listed in the CRF and will be asked at each visit. Unsolicited events will be captured by recording 
responses to the question, “Have you noticed anything different since you started the study?” Events 
will be followed for outcome information until resolution or stabilization. 


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8.3.5. ADVERSE EVENT REPORTING  
 
Investigators will notify the principal investigator of all adverse events for severity assessment. All 
adverse events will be recorded in the CRF. Severe (grade 3) or life-threatening (grade 4) adverse events 
will be immediately reported to the PI, the study sponsor. The PI will be responsible for notifying the 
Food and Drug Administration (FDA) of any unexpected fatal or life-threatening suspected adverse 
reaction as soon as possible, but in no case later than 7 calendar days after the PI's initial receipt of the 
information.  In addition, the PI must notify FDA and all participating investigators in an Investigational 
New Drug (IND) safety report of potential serious risks, from clinical trials or any other source, as soon as 
possible, but in no case later than 15 calendar days after the PI determines that the information qualifies 
for reporting. Unanticipated problems (regardless of severity) will be immediately reported to the PI. 
Unanticipated problems greater than or equal to grade 3 (severe) will be reported as above. 
Unanticipated problems less than grade 3 will be reported 10 days after the PI becomes aware of the 
event or receives an external report. Anticipated, non-serious adverse events will be reported in annual 
safety monitoring reports.  
 
8.3.6. SERIOUS ADVERSE EVENT REPORTING  
 
The study investigator will immediately report to the principal investigator (PI), the study sponsor, any 
serious adverse event, whether or not considered study intervention related, including those listed in 
the protocol or investigator brochure and must include an assessment of whether there is a reasonable 
possibility that the study intervention caused the event. Study endpoints that are serious adverse events 
(e.g., all-cause mortality) must be reported in accordance with the protocol unless there is evidence 
suggesting a causal relationship between the study intervention and the event (e.g., death from 
anaphylaxis). In that case, the investigator must immediately report the event to the PI. 
 
Neisseria Meningitidis infection will be reported as an adverse event of special interest (AESI) and will be 
reported to the FDA and DSMB.   In addition, all serious adverse events (SAEs) will be followed until 
satisfactory resolution or until the PI deems the event to be chronic or the participant is stable. Other 
supporting documentation of the event may be requested and should be provided as soon as possible.  
 
The PI, the study sponsor, will be responsible for notifying the Food and Drug Administration (FDA) of 
any unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case 
later than 7 calendar days after the PI's initial receipt of the information.  In addition, the PI must notify 
FDA and all participating investigators in an Investigational New Drug (IND) safety report of potential 
serious risks, from clinical trials or any other source, as soon as possible, but in no case later than 15 
calendar days after the PI determines that the information qualifies for reporting. 
 
8.3.7. REPORTING EVENTS TO PARTICIPANTS  
 
Common adverse events associated with the study drug identified in the package insert will be 
summarized in the consent form to inform subjects of the possible risks. If unexpected or serious 
expected events occur, the IRB will be notified per typical regulatory reporting standards. If an 
unexpected or serious, expected adverse event occurs, subjects will be notified through their care-
givers, who will be notified by the FDA and the Data Safety Monitoring Committee. A change will also be 
made to the informed consent, which will be submitted to the IRB for review.  
 


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No incidental findings are anticipated in this study. Should a reportable incidental finding be detected, 
the IRB will be notified and the subject will be notified through her care-giver.  
 
 
9. 
STATISTICAL CONSIDERATIONS  
 
9.1. 
STATISTICAL HYPOTHESES 
 
Primary endpoint: Latency (in days) from enrollment to delivery 
 
Hypothesis:  Treatment with eculizumab prolongs pregnancy, compared to historical controls, in women 
with preeclampsia between 230/7 - 296/7 weeks gestation 
 
Secondary endpoints: 
1. Composite adverse maternal and neonatal outcomes 
2. Terminal complement activation (C5a, C5b-9) in blood and urine 
3. End-organ injury and anti-angiogenic imbalance  
 
            Measures of end-organ injury: Serum creatinine, aspartate transaminase, alanine  
            transaminase, hemoglobin, platelet count, lactate dehydrogenase, urine protein/creatinine  
            ratio, and CD59 
 
            Measures of anti-angiogenic imbalance: soluble fms-like tyrosine kinase 1 (sFLT-1),  
            placental growth factor (PlGF) 
 
Hypotheses: 
1. Treatment with eculizumab decreases adverse maternal and neonatal outcomes in women with 
preeclampsia between 230/7 - 296/7 weeks gestation, compared to historical controls. 
 
2. Treatment with eculizumab reduces terminal complement activation (levels of C5a and C5b-9 in blood 
and urine) in women with preeclampsia between 230/7 - 296/7 weeks gestation. 
 
3. Treatment with eculizumab improves laboratory measures of end-organ injury (e.g., serum creatinine, 
platelet count) and reduces anti-angiogenic imbalance (ratio of sFLT1/PlGF) in women with 
preeclampsia between 230/7 - 296/7 weeks gestation. 
 
9.2. 
SAMPLE SIZE DETERMINATION 
 
In the medical literature, expectant management of early-onset preeclampsia (<34 weeks gestation) 
allows prolongation of pregnancy by a mean of 5-15 days and median of 5-9 days43-47.   Median latency is 
likely shorter than mean latency because some women remain pregnant for weeks, skewing the mean 
value.    
 
We performed sample size calculations by varying our assumptions for baseline latency with expectant 
management (7-10 days), varying our assumptions for standard deviation (4-7 days), and varying our 
effect size with study drug (gain of 3-7 days).  See sample size table below.  


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Assumptions for 
Latency with 
Standard of Care 
Expectant 
Management 
(days ± SD) 
Anticipated 
Latency with 
Eculizumab 
(days ± SD) 
Sample Size 
Needed in 
Eculizumab Arm 
(α=0.05; β=0.80) 
7 ± 3
11 ± 3
7
7 ± 3
14 ± 3
2
7 ± 7
11 ± 7
38
7 ± 7
14 ± 7
12
10 ± 3
14 ± 3
7
10 ± 3
17 ± 3
2
10 ± 7
14 ± 7
38
10 ± 7
17 ± 7
12
 
After evaluating this table, we designed the study to show a mean gain of 7 days in latency with study 
drug (eculizumab) compared to historical controls.   Although a gain of 4 days could be shown with a 
sample size of 2-7 subjects, we believe that a gain of 7 days is more reflective of clinical benefit to the 
neonate.   To show a gain of 7 days between groups (from 7 to 14 days, or 10 to 17 days) with 80% 
power and alpha=0.05, we require a sample size of 12 subjects in the eculizumab arm, assuming 
standard deviation of 7 days.    
 
To reach 80% power, our historical control group required 36 subjects (3:1 matching to eculizumab 
cases), see statistical analysis below. Thus, 36 controls will be matched 3:1 to 12 cases by gestational age 
(± 7 days), parity (nulliparous/multiparous), fetal count of current gestation, and race/ethnicity 
(white/non-white). 
 
Sample size calculation based on 3:1 enrollment with 80% power (Stata IC v15.1, Stata Corp, College 
Station, TX). 
 
Estimated sample sizes for a two-sample means test 
Satterthwaite's t test assuming unequal variances 
Ho: m2 = m1 versus  Ha: m2 != m1 
 
Study parameters: 
 
        alpha =    0.0500 
        power =    0.8000 
        delta =    7.0000 
           m1 =    7.0000 
           m2 =   14.0000 


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          sd1 =    7.0000 
          sd2 =    7.0000 
        N2/N1 =    0.3300 
 
Estimated sample sizes: 
 
            N =        48 
           N1 =        36 
           N2 =        12 
        N2/N1 =    0.3333 
 
M1= mean latency in control group; M2= mean latency in eculizumab group 
N1= number of subjects in control group; N1= number of subjects in eculizumab group 
N = total number of subjects 
Sd1, sd2 – standard deviation in latency from enrollment until delivery 
 
Summary statement: A sample size of 12 subjects in the treatment arm and 36 subjects in the historical 
control arm will allow us to detect a prolongation of pregnancy by 7 days in the eculizumab arm 
compared to standard of care (with 80% power and significance set at P<0.05).    
 
9.3. 
POPULATIONS FOR ANALYSES 
 
For analysis, we will utilize a modified intention-to-treat dataset.   Participants who received at least one 
dose of the study drug will be included in the treatment group.   Participants who were enrolled, but 
who never received study drug will be excluded from the analysis.   
 
9.4. 
STATISTICAL ANALYSES 
 
9.4.1. GENERAL APPROACH 
Baseline characteristics of subjects in the two arms will be presented with descriptive statistics.   Latency 
from enrollment to delivery, as the primary study endpoint, will be presented as mean days ± standard 
deviation, and statistical differences assessed by the Student’s t-test.   Data will be tested for normality.  
If non-normal distribution, median (interquartile range) values will be compared by a non-parametric 
test of medians.   Secondary endpoints, derived from continuous data, will be assessed by Student t-test 
or test of medians as appropriate.   Changes in lab values before and after treatment will be compared 
using the paired t-test.  Data derived from dichotomous outcomes will be compared by Pearson’s chi-
squared test.   Correlations between complement and laboratory measures will be assessed by 
Pearson’s or Spearman correlation coefficient, depending on data normality.  Significance for the 
primary endpoint will be determined by α=0.05.  Significance of secondary endpoints will be determined 
after Bonferroni correction for multiple comparisons, where α= 0.05/number of hypothesis tested.   
 
9.4.2. ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
Primary endpoint:  Latency in days from enrollment until delivery. 
 
For participants receiving study drug, the primary endpoint will be latency (in days) from enrollment in 
the study (day 1) until delivery.   For historical controls, we will determine latency from hospital 


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admission for preeclampsia until delivery.  For controls diagnosed with preeclampsia following 
hospitalization for other indication, we will determine latency from initial diagnosis of preeclampsia until 
delivery.   Some cases may have 1-3 days hospital stay for preeclampsia prior to receiving study drug.  
However, they will not have more than 72 hour hospital stay prior to enrollment, per the exclusion 
criteria.   To appropriately compare expectant management between groups, we will assess the average 
latency of cases prior to receiving the study drug. These days will be adjusted for when assessing the 
primary endpoint between groups.     
 
The difference in latency (in days) between cases in the study group and historical controls will be 
assessed by Student t-test or non-parametric test of medians, depending on data distribution (normal or 
non-normal, respectively).  Each participant receiving study drug will be matched to 3 controls, by 
gestational age (± 7 days), parity (nulliparous/multiparous), fetal count of current gestation, and 
race/ethnicity (white/non-white). This matching process was specifically designed to negate the impact 
of potential confounders, which could have impacted the primary endpoint in this small open-label 
study of 12 subjects.    
 
9.4.3. ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Secondary endpoints: 
 
1. Composite adverse maternal and neonatal outcomes. 
 
Composites were created for both adverse maternal and neonatal outcomes due to the small sample 
size (12 participants), which is underpowered to detect a difference in individual outcomes between 
groups.   However, while individual outcomes are rare, the range of potential outcomes in the 
composite measures are designed to capture potential differences between groups.   Adverse maternal 
outcomes were selected in the composite if they could be attributed to preeclampsia (e.g., pulmonary 
edema, HELLP syndrome, eclampsia).   Adverse neonatal outcomes were chosen if they could be 
attributed to preeclampsia directly (e.g., stillbirth) or indirectly, because of preterm delivery due to 
preeclampsia (e.g., respiratory distress syndrome, intraventricular hemorrhage).     
 
Differences in the composite (maternal or neonatal) outcome between groups will be assessed by the 
Chi-squared test.   Adjusted analyses will be performed using multivariable logistic regression, to control 
for potential confounders.   
 
2. Terminal complement activation (C5a, C5b-9) in blood and urine 
 
Concentrations of C5a and C5b-9 in blood and urine will be determined by enzyme linked 
immunosorbent assays (ELISA), performed in the Karumanchi laboratory at Cedars-Sinai Medical Center. 
These tests will be run after study completion and will not be made available to the treatment team or 
the study participant.  
 
Differences in the concentration of C5a and C5b-9 in blood and urine, before treatment compared to 
after treatment in each participant, will be determined by the paired t-test at each time point.  Visit day 
1 will serve as the baseline reference measure. 
 
3. End-organ injury and anti-angiogenic imbalance  
             


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          Measures of end-organ injury: serum creatinine, aspartate transaminase, alanine  
            transaminase, hemoglobin, platelet count, lactate dehydrogenase, urine protein/creatinine  
            ratio, and CD59 
             
            Measures of anti-angiogenic imbalance: soluble fms-like tyrosine kinase 1 (sFLT-1),  
            placental growth factor (PlGF) 
 
Concentrations of serum creatinine, aspartate transaminase, alanine transaminase, hemoglobin, platelet 
count, lactate dehydrogenase, urine protein/creatinine ratio, will be measured by the Cedars-Sinai 
laboratory and results will be available to the treatment team.     
 
Concentrations of CD59, sFLT-1 and PlGF will be determined by enzyme linked immunosorbent assays 
(ELISA), performed in the Karumanchi laboratory at Cedars-Sinai Medical Center.  These tests will be run 
after study completion and will not be made available to the treatment team or the study participant.  
 
Differences in the concentrations of creatinine, AST, ALT, hemoglobin, platelet count, LDH, urine 
protein/creatine, CD59, sFLT-1 and PlGF, will be compared before and after treatment in each 
participant, utilizing the paired t-test at each time point.  Visit day 1 will serve as the baseline reference 
measure. 
 
9.4.4. SAFETY ANALYSES 
 
Safety endpoints include the secondary endpoints 1) To determine if treatment with eculizumab for 
early-onset preeclampsia <30 weeks gestation decreases adverse maternal and neonatal outcomes, 
compared to historical controls, and 2) To determine if treatment with eculizumab improves laboratory 
measures of end-organ injury and reduces anti-angiogenic imbalance in women with preeclampsia <34 
weeks gestation. Differences in the composite (maternal or neonatal) outcome between groups will be 
assessed by the Chi-squared test.   Adjusted analyses will be performed using multivariable logistic 
regression, to control for potential confounders.  Differences in the concentrations of creatinine, AST, 
ALT, hemoglobin, platelet count, LDH, urine protein/creatine, sFLT-1 and PlGF, will be compared before 
and after treatment in each participant, utilizing the paired t-test at each time point.  Visit day 1 will 
serve as the baseline reference measure. Change scores from baseline will be analyzed as shift tables.  
 
Adverse events will be coded by the Medical Dictionary for Regulatory Activities (MedDRA) and counted 
once for each given participant. Severity, frequency, and relationship of each AE to the study 
intervention will be presented by System Organ class and preferred term groupings. For each AE, start 
date, stop date, location, severity, relationship, expectedness, outcome, and duration will be recorded 
and reported. Additionally, for SAEs, a brief description of the nature of the SAE, the category (e.g. life-
threatening, hospitalization, congenital anomaly, etc.), any intervention or treatments required, any 
follow-up testing, and whether the study intervention was discontinued will be recorded and reported. 
SAEs will be presented in a table. 
 
9.4.5. BASELINE DESCRIPTIVE STATISTICS 
 
Not applicable to this study.  
 
 
 


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9.4.6. PLANNED INTERIM ANALYSES  
 
Given the small number of participants (12) and the pilot nature of this study, no interim analyses will be 
performed.  
 
9.4.7. SUB-GROUP ANALYSES 
 
The difference in latency (in days) between cases in the study group and historical controls will be 
assessed by Student t-test or non-parametric test of medians, depending on data distribution (normal or 
non-normal, respectively).  Each participant receiving study drug will be matched to 3 controls, by 
gestational age (± 7 days), parity (nulliparous/multiparous), fetal count of current gestation, and 
race/ethnicity (white/non-white). This matching process was specifically designed to negate the impact 
of potential confounders, which could have impacted the primary endpoint in this small open-label 
study of 12 subjects. Men will be excluded as the condition – preeclampsia, a pregnancy disorder – only 
affects biologically female subjects. Adjusted analyses will be performed using multivariable logistic 
regression, to control for potential confounders. 
 
The 1:3 case-controls matched by gestational age, parity, and race/ethnicity will also be applied to all 
secondary outcomes to negate the impact of potential confounders. Adjusted analyses will also be 
performed using multivariable logistic regression, to control for other potential confounders.   
 
9.4.8. TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
In order to fully characterize this pilot study, individual participant presentation, number of doses 
received, and outcomes may be described in a table. Baseline presentation and outcomes may also be 
summarized if the subject develops a serious adverse advent or if the participant’s disease progresses to 
end-organ damage, such as the development of HELLP or eclampsia.  
 
9.4.9. EXPLORATORY ANALYSES 
 
Soluble fms-like tyrosine kinase (sFLT-1) and placental growth factor (PLGF) are well-described markers 
of progression of preeclampsia (36, 37). Therefore, plasma levels of sFLT-1 and PLGF will be measured to 
assess how treatment with eculizumab affects biochemical markers of disease and will be compared 
with clinical progression of disease.  Differences in the concentrations of sFLT-1, PLGF, and their ratios, 
will be compared before and after treatment in each participant, utilizing the paired t-test at each time 
point.  Visit day 1 will serve as the baseline reference measure. Similarly, complement activity (C5a and 
terminal complex C5b-9) in the plasma and urine will be assessed before and after treatment with 
eculizumab, using visit 1 C5a and C5b-9 activity in the serum and urine as a baseline. Differences in the 
concentrations of C5a and C5b-9 will also be compared before and after treatment in each participant, 
utilizing the paired t-test at each time point.   
 
There is evidence to suggest that terminal complement inhibitor CD59 is upregulated on placental 
trophoblast cells, micro-vesicles and endothelial cells in preeclampsia (38-40).  In response to 
complement-mediated cellular injury, CD59 may be released into maternal circulation in soluble form.  
Thus, to assess changes in terminal complement regulation with eculizumab, soluble CD59 
concentrations in plasma and urine will be monitored before and after treatment in each patient 
utilizing the paired t-test at each time point. CD59 levels at visit 1 will be used as baseline values.  
 


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1. REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1. INFORMED CONSENT PROCESS 
 
10.1.1.1. CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to administering study 
intervention.   
 
10.1.1.2. CONSENT PROCEDURES AND DOCUMENTATION 
 
Potential subjects will be identified from the labor & delivery unit, triage area, or antepartum wards at 
Cedars-Sinai Medical Center by a member of the research team.  Only patients admitted to the hospital 
will be included in the study. A member of the research team will pre-screen potential subject charts to 
determine eligibility. If the patient meets inclusion/exclusion criteria, the patient’s primary physician will 
be approached for active participation in the recruitment and treating process. If the patient’s primary 
physician assents to her participation, the primary physician or a consulting healthcare provider will 
introduce the study and obtain the patient’s verbal permission to be approached by a member of the 
research team while in the hospital. Study staff will coordinate a study visit with the patient in the 
hospital to review the consent form and to have a consent discussion.   Only physician-investigators will 
obtain consent. 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may arise.  
A verbal explanation will be provided in terms suited to the participant’s comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants.  
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing.  The participants will have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must be 
informed that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the participants for their records. 
The informed consent process will be conducted and documented in the source document (including the 
date), and the form signed, before the participant undergoes any study-specific procedures. A copy of 
the informed consent will be uploaded into the patient’s electronic medical record, and a consent note 
briefly describing the intervention and the patient’s consent will be added to the patient’s chart. The 
rights and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
 
All eligible patients regardless of primary language will be approached for enrollment. For non-English 
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the following languages: Arabic, Armenian, Chinese, Farsi, Korean, Russian and Spanish.  An official 
medical translator will be used to consent non-English speakers, including phone translators.  
 
Subjects that are mentally impaired or physically impaired due to medical illness and unable to give 
informed consent will not be enrolled in the study.  Subjects may consider participation in the study for 
the duration of the time until they are discharged from the hospital following delivery.   Consented 
subjects may withdraw from the study at any time.  
 
Study participants between ages 13-18 are considered emancipated minors in pregnancy and are 
eligible to consent as adults for this research study.  Pregnant adolescents may potentially benefit from 
this study therapy and are not likely to differ substantially from the adult population in relation to safety 
risks. To mitigate potential vulnerabilities among emancipated minors, participants <18 years old will be 
giving full opportunity to discuss the study with their family or surrogates or think about it prior to 
agreeing to participate.  A verbal explanation will be provided to suit their comprehension of the 
purposes, procedures, and potential risks of the study and their rights as research participants.   
 
Historical controls with preeclampsia at our institution between October 1, 2014 and September 30, 
2019 will be identified, and data abstracted, according to Cedars-Sinai IRB Study #00052119.  .  To avoid 
selection bias, research staff blinded to the clinical outcomes of the case group will be utilized to select 
controls.   Research staff will be asked to select two controls to match each case, based on gestational 
age (±1 week), parity (multiparous or nulliparous), and race/ethnicity.  
10.1.2. STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigators, funding agency, the 
Investigational New Drug (IND) sponsor (the Principal Investigator) and regulatory authorities.  If the 
study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study 
participants, the Institutional Review Board (IRB), and Alexion Pharmaceuticals and will provide the 
reason(s) for the termination or suspension.  Study participants will be contacted, as applicable, and be 
informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
 
Determination of unexpected, significant, or unacceptable risk to participants 
 
Demonstration of efficacy that would warrant stopping    
 
Insufficient compliance to protocol requirements 
 
Data that are not sufficiently complete and/or evaluable 
 
Determination that the primary endpoint has been met 
 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor (the PI), IRB and/or Food and Drug Administration (FDA). 
 
10.1.3. CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of 


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biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the PI.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study Data Safety and Monitoring Board, other authorized representatives of the PI, representatives 
of the Institutional Review Board (IRB), regulatory agencies or pharmaceutical company supplying study 
product may inspect all documents and records required to be maintained by the investigator, including 
but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants 
in this study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at Cedars-Sinai Medical Center. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management 
systems used by clinical sites and by Cedars-Sinai Medical Center research staff will be secured and 
password protected. At the end of the study, all study databases will be de-identified and archived at 
Cedars-Sinai Medical Center. 
 
10.1.4. FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored at Cedars-Sinai Medical Center. After the study 
is completed, the de-identified, archived data will be transmitted to and stored at Cedars-Sinai Medical 
Center, for use by other researchers including those outside of the study. Permission to maintain de-
identified data at Cedars-Sinai Medical Center will be included in the informed consent.  
 
With the participant’s approval and as approved by local Institutional Review Boards (IRBs), de-
identified biological samples will be stored at Cedars-Sinai Medical Center. These samples could be used 
to research the causes of hypertensive disorders of pregnancy such as preeclampsia, its complications 
and other conditions for which individuals with hypertensive disorders of pregnancy are at increased 
risk, and to improve treatment. Samples from this study will be stored in the Karumanchi laboratory, 
and a de-identified code will link the biological specimens with the phenotypic data from each 
participant, maintaining the blinding of the identity of the participant. 
 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage may not be possible after the study is completed.  
 
When the study is completed, access to study data and/or samples will be provided through the 
Karumanchi laboratory. 
 
 


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10.1.5. KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Data Safety and Monitoring Board
Chairperson 
Richard Burwick, MD MPH
Bobbie J. Rimel, MD
Cedars-Sinai Medical Center
Cedars-Sinai Medical Center
8635 W. 3rd St.
Medical Office Tower, Suite 160W 
Los Angeles, CA 90048 
Samuel Oschin Cancer Center
127 S. San Vicente Blvd. 
7th Floor 
Los Angeles, CA 
90048 
310-423-6454
310-423-1126
Richard.Burwick@CSHS.org
Bobbie.Rimel@cshs.org
 
Reviewing IRB: Cedars-Sinai Medical Center Institutional Review Board 
 
Pharmaceutical Sponsor:  
Alexion Pharmaceuticals, Inc. 
100 College Street 
New Haven, CT 06510 USA  
 
Basic Science Research Consultant:  
S. Ananth Karumanchi, MD 
Medallion Chair in Vascular Biology & Director of Nephrology Research 
Cedars-Sinai Medical Center 
Los Angeles, CA 
 
Clinical Research Coordinator: 
Martha Bautista, BS 
Clinical Research Coordinator II 
Department of Medicine, Nephrology 
Cedars-Sinai Medical Center 
Los Angeles, CA 
 
Data Safety & Monitoring Board Members: 
 
Experts in Obstetrics & Gynecology & Maternal Fetal Medicine: 
 
Sarah Kilpatrick, MD PhD 
Helping Hand of Los Angeles Chair in Obstetrics & Gynecology 
Associate Dean for Faculty Development 


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Cedars-Sinai Medical Center 
Los Angeles, CA 
 
John Williams III, MD 
Professor and Director of Reproductive Genetics 
Department of Obstetrics & Gynecology 
Cedars-Sinai Medical Center 
Los Angeles, CA 
 
Expert in Pediatrics & Neonatology: 
Kurlen Payton, MD 
Interim Director, Division of Neonatology 
Department of Pediatrics 
Assistant Professor of Pediatrics 
Cedars-Sinai Medical Center 
Los Angeles, CA 
 
10.1.6. SAFETY OVERSIGHT 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) composed of 
1 expert in clinical trials research, 2 obstetrician-gynecologists with expertise in maternal-fetal medicine, 
and 1 pediatrician. Members of the DSMB will be independent from the study conduct and free of 
conflict of interest, or measures will be taken to minimize perceived conflict of interest.  The DSMB will 
meet at least semiannually to assess safety and efficacy data on each arm of the study. The DMSB will 
operate under the rules of an approved charter that will be written and reviewed at the organizational 
meeting of the DSMB. At this time, each data element that the DSMB needs to assess will be clearly 
defined. The DSMB will provide its input to Alexion Pharmaceuticals and the Principal Investigator.  
 
10.1.7. CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  
 
• 
Monitoring for this study will be performed by the Cedars-Sinai Medical Center IRB post-
approval monitoring committee.  
• 
Monitoring visits will start within 1 month of approval for training purposes and assure of 
protocol adherence. Monitoring visits will then be held semi-annually with 100% data 
verification. Should data by less than 90% accordant, monitoring visits will increase to quarterly 
with 100% data verification.   
• 
Independent audits may be conducted by agents of the FDA or of Alexion Pharmaceuticals to 
ensure monitoring practices are performed consistently. 
 
10.1.8. QUALITY ASSURANCE AND QUALITY CONTROL 
 


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As a single-center study, Cedars-Sinai Medical Center will perform internal quality management of study 
conduct, data and biological specimen collection, documentation and completion.  An individualized 
quality management plan with study staff will be developed to describe a site’s quality management. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, documented (recorded), and 
reported in compliance with the protocol, International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 
10.1.9. DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1. DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.   
 
If source documents are required, hardcopies of the study visit worksheets will be provided for use as 
source document worksheets for recording data for each participant enrolled in the study.  Data 
recorded in the electronic case report form (eCRF) derived from source documents should be consistent 
with the data recorded on the source documents. If source documents are not required, the electronic 
medical record will be considered the source.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into RedCap Database, a 21 CFR Part 11-compliant data 
capture system provided by Cedars-Sinai Medical Center. The data system includes password protection 
and internal quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. Clinical data will be entered directly from the source documents. 
 
10.1.9.2. STUDY RECORDS RETENTION  
 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Conference on Harminosation (ICH) region and until there are no pending 
or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study intervention. These documents should be 
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without the written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform 
the investigator when these documents no longer need to be retained. 
 
10.1.10. 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within three (3) working days of identification of the protocol deviation, or within three (3) 
working days of the scheduled protocol-required activity.  All deviations must be addressed in study 
source documents, reported to the Cedars-Sinai Medical Center IRB Program Official per their policies. 
The site investigator is responsible for knowing and adhering to the reviewing IRB requirements. Further 
details about the handling of protocol deviations will be included in the MOP. 
 
10.1.11. 
PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals.  Data from this study may be requested from other researchers 2 years after the 
completion of the primary endpoint by contacting Richard Burwick, MD MPH, Cedars-Sinai Medical 
Center. 
 
10.1.12. 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership in conjunction with Cedars-Sinai Medical Center and its IRB have established policies and 


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procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest. All members of study staff with 
significant conflict of interest will not be eligible to recruit for the study. Furthermore, all significant 
financial interest will be disclosed on the informed consent.  
 
10.2. ABBREVIATIONS 
 
ACOG
American College of Obstetricians & Gynecologists
AE
Adverse Event
aHUS
Atypical Hemolytic Uremic Syndrome
ANCOVA
Analysis of Covariance
AST
Aspartate Transaminase
ALT
Alanine Transaminase
CFR
Code of Federal Regulations
CLIA
Clinical Laboratory Improvement Amendments
CMP
Clinical Monitoring Plan
COC
Certificate of Confidentiality
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form
CRUSH
Complement Regulation to Undo Systemic Harm in Preeclampsia
CSMC
Cedars-Sinai Medical Center
DCC
Data Coordinating Center
DHHS
Department of Health and Human Services
DSMB
Data Safety Monitoring Board
DRE
Disease-Related Event
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Forms
ELISA
Enzyme Linked Immunosorbent Assay
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act of 2007


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FFR
Federal Financial Report
GCP
Good Clinical Practice
GLP
Good Laboratory Practices
GMP
Good Manufacturing Practices
GWAS
Genome-Wide Association Studies
HELLP
Hemolysis Elevated Liver enzymes Low Platelets
Hib
Haemophilus Influenza Type B
HIPAA
Health Insurance Portability and Accountability Act
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IDE
Investigational Device Exemption
IND
Investigational New Drug Application
INR
International Normalized Ratio
IRB
Institutional Review Board
ISM
Independent Safety Monitor
ISO
International Organization for Standardization
ITT
Intention-To-Treat
IV
Intravenous
L&D
Labor and Delivery
LDH
Lactate Dehydrogenase
LSMEANS
Least-squares Means
MedDRA
Medical Dictionary for Regulatory Activities
MFCU
Maternal Fetal Care Unit
MOP
Manual of Procedures
MSDS
Material Safety Data Sheet
NCT
National Clinical Trial
NIH
National Institutes of Health
NIH IC
NIH Institute or Center


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OHRP
Office for Human Research Protections
PE
Preeclampsia
PI
Principal Investigator
PlGF
Placental Growth Factor
PO
By Mouth
PP
Post-partum
PNH
Paroxysmal Nocturnal Hemoglobinuria
QA
Quality Assurance
QC
Quality Control
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
sFLT-1
Fms-like Tyrosine Kinase
SMC
Safety Monitoring Committee
SOA
Schedule of Activities
SOC
System Organ Class
SOP
Standard Operating Procedure
TMA
Thrombotic Microangiopathy
UP
Unanticipated Problem
US
United States
WoA
Waiver of Authorization


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10.3. PROTOCOL AMENDMENT HISTORY 
 
Version 
Date
Description of Change
Brief Rationale
2.0
10/26/20
Modifications per FDA comments in
response to IND 146438 
Modifications per FDA
comments in response to IND 
146438 
3.0
12/11/20
Modifications per FDA comments in
response to IND 146438 
Modifications per FDA
comments in response to IND 
146438 


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11. PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
 
 
___________________________________ 
 
 
 
__________________________ 
Principal Investigator 
 
 
 
 
 
 
Date 
Richard M. Burwick, MD MPH 
Assistant Professor 
Obstetrics & Gynecology  
Division of Maternal Fetal Medicine 
Cedars-Sinai Medical Center 
 
COL MODIFICATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12. REFERENCES  
 
1. American College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy 
(2013). Hypertension in Pregnancy.  Retrieved December 23, 2013 from 
http://www.acog.org/Resources_And_Publications/Task_Force_and_Work_Group_Reports/Hyp
ertension_in_Pregnancy 
2. Gestational hypertension and preeclampsia.  ACOG Practice Bulletin No. 202.  American College 
of Obstetricians and Gynecologists.  Obset Gynecol 2019; 133:e1-25.  
3. Odendaal HJ, Pattinson RC, Bam R, Grove D, Kotze TJ. Aggressive or expectant management for 
patients with severe preeclampsia between 28-34 weeks' gestation: a randomized controlled 
trial. Obstet Gynecol. 1990 Dec;76(6):1070-5. 
4. Friedman SA, Schiff E, Lubarsky SL, Sibai BM.  Expectant management of severe preeclampsia 
remote from term. Clin Obstet Gynecol. 1999 Sep;42(3):470-8.  
5. Hall DR, Odendaal HJ, Steyn DW, Grové D. Expectant management of early onset, severe pre-
eclampsia: maternal outcome. BJOG. 2000 Oct;107(10):1252-7. 
6. Vigil-De Gracia P, Reyes Tejada O, Calle Miñaca A, Tellez G, Chon VY, Herrarte E, Villar A, Ludmir 
J.  Expectant management of severe preeclampsia remote from term: the MEXPRE Latin Study, a 
randomized, multicenter clinical trial. Am J Obstet Gynecol. 2013 Nov;209(5):425.e1-8.  
7. Shatzel JJ, Taylor JA.  Syndromes of Thrombotic Microangiopathy.  Med Clin North Am. 2017; 
101(2):395-415.  
8. Fakhouri F. Pregnancy-related thrombotic microangiopathies: Clues from complement biology. 
Transfus Apher Sci. 2016; 54(2):199-202 
9. Fang CJ, Richards A, Liszewski MK, Kavanagh D, Atkinson JP. Advances in understanding of 
pathogenesis of aHUS and HELLP. Br J Haematol. 2008 Nov;143(3):336-48.  
10. Weinstein L. Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe 
consequence of hypertension in pregnancy. Am J Obstet Gynecol 1982;142:159-67. 
11. Burwick RM, Fichorova RN, Dawood HY, Yamamoto HS, Feinberg BB. Urinary excretion of c5b-9 
in severe preeclampsia: tipping the balance of complement activation in pregnancy. 
Hypertension. 2013; 62:1040-1045. 
12. Lynch AM, Murphy JR, Byers T, Gibbs RS, Neville MC, Giclas PC, Salmon JE, Holers VM.  Alternative 
complement pathway activation fragment Bb in early pregnancy as a predictor of preeclampsia.  
Am J Obstet Gynecol.  2008; 198:385.e1-9. 
13. Haeger M, Unander M, Norder-Hansson B, Tylman M, Bengtsson A.  Complement, neutrophil, and 
macrophage activation in women with severe preeclampsia and syndrome of hemolysis, elevated 
liver enzymes, and low platelet count.  Obstet Gynecol. 1992; 79:19-26. 
14.  de Messias-Reason IJ, Aleixo V, de Freitas H, Nisihara RM, Mocelin V, Urbanetz A. Complement 
activation in Brazilian patients with preeclampsia.  J Investig Allergol Clin Immunol. 2000; 10:209-
214. 
15. Derzsy Z, Prohaszka Z, Rigo J, Fust G, Molvarec A.  Activation of the complement system in normal 
pregnancy and preeclampsia.  Mol Immunol. 2010; 47:1500-1506. 
16. Denny KJ, Coulthard LG, Finnell RH, Callaway LK, Taylor SM, Woodruff TM.  Elevated complement 
factor C5a in maternal and umbilical cord plasma in preeclampsia.  J Reprod Immunol.  2013; 
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17. Salmon JE, Heuser C, Triebwasser M, Liszewski MK, Kavanagh D, Roumenina L, Branch DW, 
Goodship T, Fremeaux-Bacchi V, Atkinson JP.  Mutations in complement regulatory proteins 
predispose to preeclampsia: a genetic analysis of the PROMISSE cohort.  PLoS Med.  2011; 
8:e1001013. 
18. Burwick RM, Feinberg BB. Eculizumab for the treatment of severe preeclampsia/HELLP syndrome. 
Placenta. 2013; 34:201–203. 
19. Burwick RM, Easter SR, Dawood H, Yamamoto H, Fichorova R, Feinberg BB.  Complement 
Activation and Kidney Injury Molecule-1-Associated Proximal Tubule Injury in Severe 
Preeclampsia. Hypertension. 2014 Oct; 64(4):833-8.  
20. Guseh SH, Feinberg BB, Dawood HY, Yamamoto HS, Fichorova RN, Burwick RM.  Urinary Excretion 
of C5b-9 is Associated with the Anti-Angiogenic State in Severe Preeclampsia. Am J Reprod 
Immunol. 2015 May; 73(5):437-44. 
21. Servais A, Devillard N, Frémeaux-Bacchi V, Hummel A, Salomon L, Contin-Bordes C, Gomer H, 
Legendre C, Delmas Y. Atypical haemolytic uraemic syndrome and pregnancy: outcome with 
ongoing eculizumab. Nephrol Dial Transplant. 2016 Dec;31(12):2122-2130. 
22. Kelly RJ, Höchsmann B, Szer J, Kulasekararaj A, de Guibert S, Röth A, Weitz IC, Armstrong E, 
Risitano AM, Patriquin CJ, Terriou L, Muus P, Hill A, Turner MP, Schrezenmeier H, Peffault de 
Latour R. Eculizumab in Pregnant Patients with Paroxysmal Nocturnal Hemoglobinuria. N Engl J 
Med. 2015 Sep 10;373(11):1032-9.  
23. Bruel A, Kavanagh D, Noris M, Delmas Y, Wong EKS, Bresin E, Provôt F, BrocklebankV, Mele C, 
Remuzzi G, Loirat C, Frémeaux-Bacchi V, Fakhouri F. Hemolytic Uremic Syndrome in Pregnancy 
and Postpartum.  Clin J Am Soc Nephrol. 2017 Aug 7;12(8):1237-1247 
24. Andries G, Karass M, Yandrapalli S, Linder K, Liu D, Nelson J, Pawar R, Chugh S. Exp Hematol 
Oncol. Atypical hemolytic uremic syndrome in first trimester pregnancy successfully treated 
with eculizumab. 2017 Jan 13; 6:4.  
25. Demir E, Yazici H, Ozluk Y, Kilicaslan I, Turkmen A.  Pregnant Woman with Atypical Hemolytic 
Uremic Syndrome Delivered a Healthy Newborn under Eculizumab Treatment. Case Rep Nephrol 
Dial. 2016 Dec 20;6(3):143-148.  
26. Hallstensen RF, Bergseth G, Foss S, Jæger S, Gedde-Dahl T, Holt J, Christiansen D, Lau C, Brekke 
OL, Armstrong E, Stefanovic V, Andersen JT, Sandlie I, Mollnes TE.  Eculizumab treatment during 
pregnancy does not affect the complement system activity of the newborn.  Immunobiology. 2015 
Apr;220(4):452-9.  
27. Stevens W, Shih T, Incerti D, Ton TGN, Lee HC, Peneva D, Macones GA, Sibai BM, Jena AB. Short-
term costs of preeclampsia to the United States health care system. Am J Obstet Gynecol. 2017 
Sep;217(3):237-248.e16 
28. Alexion Pharmaceuticals. (2017). SolirisTM (eculizumab) [Package Insert]. New Haven, CT: Author.  
29. Wu Y, Xiong X, Fraser WD and Luo ZC. Association of uric acid with progression to preeclampsia 
and development of adverse conditions in gestational hypertensive pregnancies. Am J 
Hypertens. 2012;25:711-7. 
30. Magee LA, von Dadelszen P, Rey E, Ross S, Asztalos E, Murphy KE, Menzies J, Sanchez J, Singer J, 
Gafni A, Gruslin A, Helewa M, Hutton E, Lee SK, Lee T, Logan AG, Ganzevoort W, Welch R, 
Thornton JG and Moutquin JM. Less-tight versus tight control of hypertension in pregnancy. N 
Engl J Med. 2015;372:407-17. 


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31. Tangren JS, Wan Md Adnan WAH, Powe CE, Ecker J, Bramham K, Hladunewich MA, Ankers E, 
Karumanchi SA and Thadhani R. Risk of Preeclampsia and Pregnancy Complications in Women 
With a History of Acute Kidney Injury. Hypertension. 2018;72:451-459. 
32. Patten IS, Rana S, Shahul S, Rowe GC, Jang C, Liu L, Hacker MR, Rhee JS, Mitchell J, Mahmood F, 
Hess P, Farrell C, Koulisis N, Khankin EV, Burke SD, Tudorache I, Bauersachs J, del Monte F, 
Hilfiker-Kleiner D, Karumanchi SA and Arany Z. Cardiac angiogenic imbalance leads to 
peripartum cardiomyopathy. Nature. 2012;485:333-8. 
33. Vikse BE, Irgens LM, Karumanchi SA, Thadhani R, Reisaeter AV and Skjaerven R. Familial factors 
in the association between preeclampsia and later ESRD. Clin J Am Soc Nephrol. 2012;7:1819-26. 
34. Burwick RM, Velásquez JA, Valencia CM, Gutiérrez-Marín J, Edna-Estrada F, Silva JL, Trujillo-
Otálvaro J, Vargas-Rodríguez J, Bernal Y, Quintero A, Rincón M, Tolosa JE.  Terminal Complement 
Activation in Preeclampsia. Obstet Gynecol. 2018;132(6):1477-1485. 
35. Burwick RM, Burwick NR, Feinberg BB. Eculizumab fails to inhibit generation of C5a in vivo. 
Blood 2014;124:3502–3. 
36. Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, Sennström M, Olovsson M, Brennecke SP, 
Stepan H, Allegranza D, Dilba P, Schoedl M, Hund M, Verlohren S.Predictive Value of the sFlt-
1:PlGF Ratio in Women with Suspected Preeclampsia. N Engl J Med. 2016 Jan 7;374(1):13-22. 
doi: 10.1056/NEJMoa1414838. PubMed PMID: 26735990. 
37. Rana S, Powe CE, Salahuddin S, Verlohren S, Perschel FH, Levine RJ, Lim KH, Wenger JB, 
Thadhani R, Karumanchi SA. Angiogenic factors and the risk of adverse outcomes in women with 
suspected preeclampsia. Circulation. 2012 Feb 21;125(7):911-9. doi: 
10.1161/CIRCULATIONAHA.111.054361. Epub 2012 Jan 18. PubMed PMID: 22261192; PubMed 
Central PMCID: PMC3319742. 
38. Buurma A, Cohen D, Veraar K, Schonkeren D, Claas FH, Bruijn JA, Bloemenkamp KW, Baelde HJ. 
Preeclampsia is characterized by placental complement dysregulation. Hypertension. 2012 
Nov;60(5):1332-7. doi: 10.1161/HYPERTENSIONAHA.112.194324. Epub 2012 Sep 24. PubMed 
PMID: 23006730. 
39. Sargent I. Microvesicles and pre-eclampsia. Pregnancy Hypertens. 2013 Apr;3(2):58. doi: 
10.1016/j.preghy.2013.04.004. Epub 2013 Jun 6. PubMed PMID: 26105839. 
40. Ueda M, Sato Y, Horie A, Tani H, Miyazaki Y, Okunomiya A, Matsumoto H, Hamanishi J, Kondoh 
E, Mandai M. Endovascular trophoblast expresses CD59 to evade complement-dependent 
cytotoxicity. Mol Cell Endocrinol. 2019 Apr 11. pii: S0303-7207(19)30106-6. doi: 
10.1016/j.mce.2019.04.006. [Epub ahead of print] PubMed PMID: 30981734. 
41. US Department of Health & Human Services & the National Institutes of Health (19 May 2016). 
Quick Statistics About Voice, Speech, Language. National Institute on Deafness and Other 
Communication Disorders. Retrieved from https://www.nidcd.nih.gov/health/statistics/quick-
statistics-voice-speech-language 
42. Rana S, Lemoine E, Granger J, Karumanchi SA. Preeclampsia. Circ Res. 2019 Mar 29;124(7):1094-
1112. doi: 10.1161/CIRCRESAHA.118.313276. PubMed PMID: 30920918. 
43. Vigil-De Gracia P, Reyes Tejada O, Calle Miñaca A, Tellez G, Chon VY, Herrarte E, Villar A, Ludmir 
J. Expectant management of severe preeclampsia remote from term: the MEXPRE Latin Study, a 


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randomized, multicenter clinical trial. Am J Obstet Gynecol. 2013 Nov;209(5):425.e1-8. doi: 
10.1016/j.ajog.2013.08.016. Epub 2013 Aug 14. PubMed PMID: 23954534. 
44. van Pampus MG, Wolf H, Westenberg SM, van der Post JA, Bonsel GJ, Treffers PE. Maternal and 
perinatal outcome after expectant management of the HELLP syndrome compared with pre-
eclampsia without HELLP syndrome. Eur J Obstet Gynecol Reprod Biol. 1998 Jan;76(1):31-6. 
PubMed PMID: 9481543. 
45. Odendaal HJ, Pattinson RC, Bam R, Grove D, Kotze TJ. Aggressive or expectant management for 
patients with severe preeclampsia between 28-34 weeks' gestation: a randomized controlled 
trial. Obstet Gynecol. 1990 Dec;76(6):1070-5. PubMed PMID: 2234715. 
46. Usta IM, Barton JR, Amon EA, Gonzalez A, Sibai BM. Acute fatty liver of pregnancy: an 
experience in the diagnosis and management of fourteen cases. Am J Obstet Gynecol. 1994 
Nov;171(5):1342-7. PubMed PMID: 7977544. 
47. Haddad B, Deis S, Goffinet F, Paniel BJ, Cabrol D, Siba BM. Maternal and perinatal outcomes 
during expectant management of 239 severe preeclamptic women between 24 and 33 weeks' 
gestation. Am J Obstet Gynecol. 2004 Jun;190(6):1590-5;discussion 1595-7. PubMed PMID: 
15284743. 
 
 


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Appendix A. Data Safety & Monitoring Board Signature Page 
 
 
 
 
_________________________________________  
 
_______________ 
Expert in Clinical Trials Research: 
 
 
Date 
Bobbie J Rimel, MD 
Associate Professor 
Department of Obstetrics & Gynecology 
Cedars-Sinai Medical Center 
Los Angeles, CA 
 
 
 
 
 
 
_________________________________________  
 
_______________ 
Expert in Obstetrics & Gynecology & Maternal Fetal Medicine:  
 
Date 
Sarah Kilpatrick, MD PhD 
Helping Hand of Los Angeles Chair in Obstetrics & Gynecology 
Associate Dean for Faculty Development 
Cedars-Sinai Medical Center 
Los Angeles, CA 
 
 
_________________________________________  
 
_______________ 
Expert in Obstetrics & Gynecology & Maternal Fetal Medicine:  
 
Date 
John Williams III, MD 
Professor and Director of Reproductive Genetics 
Department of Obstetrics & Gynecology 
Cedars-Sinai Medical Center 
Los Angeles, CA 
 
 
 
 
 
 


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_________________________________________  
 
_______________ 
Expert in Pediatrics & Neonatology: 
 
 
 
 
 
Date 
Kurlen Payton, MD 
Interim Director, Division of Neonatology 
Department of Pediatrics 
Assistant Professor of Pediatrics 
Cedars-Sinai Medical Center 
Los Angeles, CA 

ICF_003.pdf: 
 
 
 
COVER SHEET FOR  
CONSENT/PARENTAL PERMISSION FORM FOR RESEARCH 
Complement Regulation to Undo Systemic Harm in 
Preeclampsia: The CRUSH Study 
Protocol Number: STUDY 00000039 
National Clinical Trial (NCT) Identified Number: NCT04725812 
Principal Investigator/IND Sponsor: Richard Burwick, MD MPH 
Funded by: Alexion Pharmaceuticals 
 
 
 
Document date: 31 January 2022 


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CONSENT/PARENTAL PERMISSION FORM FOR RESEARCH
Title: COMPLEMENT REGULATION TO UNDO SYSTEMIC HARM IN PREECLAMPSIA: THE CRUSH 
STUDY 
STUDY SUPPORT PROVIDED BY:  ALEXION PHARMACEUTICALS
PRINCIPAL INVESTIGATOR:  RICHARD M. BURWICK MD, MPH
 
 
STUDY CONTACT PHONE NUMBER AT CSMC:  310-423-3277
AFTER HOURS CONTACT (24 HOURS):  310-423-3277
This research study is supported by Alexion pharmaceuticals.  Alexion pharmaceuticals only 
reimburses Cedars-Sinai Medical Center for the costs associated with running the study; Alexion 
pharmaceuticals is not providing additional compensation to Cedars Sinai Medical Center or the 
Principal Investigator for their participation in the study.
1.
WHAT IS THE PURPOSE OF THIS RESEARCH STUDY?
You are being asked to take part in this research study because you are pregnant between 23 and 30 
weeks and you have been diagnosed with preeclampsia.  We are doing this study to determine if the 
study drug, eculizumab, is an effective treatment for preeclampsia.  We want to know if treatment 
with eculizumab prolongs pregnancy in women with preterm preeclampsia, compared to a historical 
control group of women at our institution with preterm preeclampsia who did not receive 
eculizumab.  The ratio of the historical control group to the treatment group will be 3:1. This study 
will enroll up to 48 women in total with 12 enrolled to receive treatment. 
This research study is designed to test the investigational use of eculizumab (Soliris).  This drug is 
approved by the U.S. Food and Drug Administration (FDA) for treatment of certain blood disorders   
and has been used in pregnant women. However, it is not approved by the FDA for treatment of 
preeclampsia.   
2.
WHAT WILL HAPPEN DURING THE STUDY?
This section provides a general overview of what will happen during your participation in this study.  
Information included below should be considered along with the flowchart of procedures attached as 
Appendix C.  
The flowchart shows a timeline for research-related procedures that are involved in your 
participation in this study.  Research-related procedures are those performed solely for the 
research.  They would not be performed if you did not take part in the study. 
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A table describing common medical procedures done solely for the purposes of monitoring and 
assessing your condition during this study is attached as an Appendix D to the end of this consent 
form.  
Overview of study:
This is a single-arm, open label research study.  This means that all women enrolled in the study will 
receive the study drug. The study drug is eculizumab, which you will receive on day 1 of the study 
via intravenous infusion over 35 minutes in adults and 1 to 4 hours in pediatric patients via gravity 
feed, a syringe-type pump, or an infusion pump. You will continue to receive eculizumab weekly for 
the first 5 weeks of treatment and biweekly thereafter, until 48 hours after your delivery. 
Eculizumab is intended to prolong pregnancy in women with preeclampsia diagnosed before 30 
weeks gestation. As there is no currently effective treatment for preeclampsia other than delivery, 
women with preeclampsia before 30 weeks gestation are managed using a “watch and wait” 
approach. Due to the unpredictable nature of preeclampsia, this “watch and wait” approach places 
mother and child at significant risk until delivery occurs. Eculizumab may be an improvement over 
current standard of care as it provides a treatment option for patients who would otherwise be 
managed with expectant management alone.
Treatment with eculizumab is associated with an increased risk for meningococcal infection. 
Therefore, as part of this study, you will be given two meningococcal vaccines. The FDA warns that 
meningococcal vaccines should be given at least 2 weeks prior to starting eculizumab but as that 
would delay treatment with eculizumab, we will instead give you the first dose of both 
meningococcal vaccines before your first dose of eculizumab. To further decrease the risk of 
meningococcal infection, we will prescribe antibiotics which you will continue until 4 weeks after 
your last dose of eculizumab Finally, to complete meningococcal vaccination, you will receive the 
second dose of the meningococcal vaccines 1-2 months after the initial dose, as shown below in the 
study schema.  The study team will closely monitor you throughout your treatment for any infection 
and will stop treatment with eculizumab if any infection develops, other than urine or yeast 
infection, which will be treated with standard medications by your doctor.   
This study is designed to compare the medical results of women with preeclampsia, treated with 
eculizumab, to results from existing medical records of women with preeclampsia who did not use 
the drug. This comparison will allow the researchers to learn whether the study drug, eculizumab, is 
better, the same, or worse than the current standard of care for preeclampsia.  Standard of care for 
preterm preeclampsia is expectant management of pregnancy, the “watch and wait” method of 
monitoring the expectant mother. For this study, you will receive eculizumab in addition to standard 
of care, which may include treatment of high blood pressure or magnesium sulfate to prevent 
seizure.  There is no alternative treatment for preeclampsia other than delivery of the baby.   
Eculizumab has been tested for safety in pregnancy, but it is not part of current standard of care for 
the treatment of preeclampsia. 
In order to properly follow the study’s protocol (research plan), all the participants will receive 
treatments and procedures that have been pre-determined by the protocol. In effect, the protocol 
describes which medications you will receive, but would not interfere with those decisions being 
made by your personal doctor or based on your preference. There may be options available outside 
of this study that you will not be able to receive while participating in this study. We do not believe 
you should be at any increased risk due to this limitation.
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Treatments for your disease can cause side effects such as nausea, headache, back pain, cough, or 
other flu-like symptoms, so you will receive medications to help deal with these side effects.  The 
drugs you will receive are given as part of routine care for those symptoms. 
Another purpose of this study is for researchers to learn if biomarker tests are helpful to monitor the 
effectiveness of the study drug. A biomarker is a biological molecule found in blood, other body 
fluids, or tissues that may be a sign of a condition or disease. For these biomarker tests, two extra 
tubes of blood (10cc each) and a urine sample (20cc) will be collected before and after you receive 
the study drug. Biomarker testing will not be used to make decisions about eligibility, treatment 
assignment, or other clinical management.  
Another way to find out what will happen to you during the study is to read the chart below. Start 
reading at the left side and read across to the right, following the lines and arrows.
Study Schema
Optional Sub-study
Details of an optional sub-study are described in Appendix B of this consent form.  You are not 
required to participate in the sub-study in order to take part in this research study.  
How long will you be in the study?
You will be in this study until approximately 6-8 weeks after your delivery. The total time includes 
study visits every 3-4 days, weekly or biweekly intravenous infusions of the study drug, and 
monitoring of antibiotic use and vaccine administration up to 8 weeks after your delivery After that, 
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we would like to keep track of your medical condition and your baby’s health for 6-8 weeks 
postpartum. We would like to contact you by phone at 1-2 weeks and 6-8 weeks after your delivery, 
and review your medical records, to see how you and your baby are doing.  Keeping in touch with you 
and checking on your condition every so often helps us look at long-term effects. 
3.
WHAT ARE THE POSSIBLE RISKS?
Risks of common medical procedures performed solely for research purposes are described in a table 
attached to the end of this consent form as Appendix D.  Side effects and risks of standard of care 
procedures are not described in this consent form. 
This section describes the possible risks and/or discomforts we anticipate you could experience that 
are related to the study procedures. 
Unknown Risks
There may be other side effects or risks that we cannot predict.  Many side effects may go away 
shortly after the study medication or procedure is stopped.  However, in some cases they can be 
serious or long-lasting. 
Risks of Eculizumab
Likely, Some May Be Serious (Occurs in greater than 20% and up to 100 % of people)

Nausea, vomiting, diarrhea

Headache

Nasopharyngitis (common cold)

High or low blood pressure

Anemia or leukopenia (low blood cell count)
Less Likely, Some May Be Serious (Occurs in >3% - 20 % of people)

Back pain

Fatigue

Cough

Herpes simplex infections

Sinusitis

Respiratory tract infection

Constipation

Pain in extremity(ies)

Influenza-like illness

Decreased kidney function

Low levels of potassium in blood

Insomnia

Rash, itching
In the list below, “Serious,” refers to those side effects that 
may require hospitalization, may be irreversible, long-term, 
life-threatening or fatal.
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Rare AND Serious (Occurs in 3% or less of people and may require hospitalization or may be 
irreversible, long-term, life-threatening or fatal)

Infusion reaction, including anaphylaxis (serious allergic reaction) or other hypersensitivity 
reactions

Viral infection

Other infections

Streptococcus pneumoniae infection

Haemophilus influenza type b (Hib) infection

Aspergillus infection
In addition to the risks summarized above, the FDA has issued the following warning for eculizumab 
(Soliris):
There is limited data on the use of eculizumab for treatment of preeclampsia.  In one human case, a 
patient received eculizumab for treatment of preeclampsia at a dose of 1200 mg weekly and received 
three doses of the drug before delivery.  There were no reported adverse effects to the mother or 
baby from use of eculizumab and the pregnancy was extended by 17 days.   The authors reported 
trace levels of eculizumab in neonatal cord blood and no eculizumab in breast milk samples.    
In a long-term follow up study of 64 children exposed to eculizumab due to maternal use of the drug 
in pregnancy for a rare blood disorder called paroxysmal nocturnal hemoglobinuria (a condition 
characterized by immune destruction of red blood cells), 64 of 64 (100%) met developmental 
milestones for vision, hearing, locomotion, fine-motor skills, behavior and physical health.  In 
addition, 63 of 64 (98.4%) achieved milestones for speech and language (1 child was referred to a 
speech and language specialist for delayed speech).  The authors concluded that eculizumab is safe 
for use in pregnant women. There are no expected safety concerns, but some may be unknown.
Eculizumab is approved in many countries for use in adults and pediatric patients (< 18 years of age) 
to treat other rare blood disorders.   For pediatric and adolescent patients (aged 13 to <18 years with 
body weight ≥40kg) the dosing regimen for eculizumab is the same as for adults ≥18 years.  The 
safety profile observed in adolescent patients (aged 13 to <18 years with body weight ≥40kg) is 
similar to that observed in the adult population. 
Risks of Vaccines
Likely, Some May Be Serious (Occurs in greater than 20% and up to 100 % of people)

Pain or soreness at injection site
FDA Blackbox Warning: SERIOUS MENINGOCOCCAL INFECTION  
Soliris increases the risk of meningococcal infections
• Vaccinate patients with a meningococcal vaccine at least 2 weeks prior to 
receiving the first dose of Soliris; revaccinate according to current medical 
guidelines for vaccine use  
• Monitor patients for early signs of meningococcal infections, evaluate 
immediately if infection is suspected, and treat with antibiotics if necessary
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
Redness or swelling of the skin at injection site
Less Likely, Some May Be Serious (Occurs in >3% - 20 % of people)

Fever

Headache

Nausea 

Vomiting

Dizziness

Vasovagal reaction (fainting)
Rare AND Serious (Occurs in 3% or less of people and may require hospitalization or may be 
irreversible, long-term, life-threatening or fatal)

Infusion reaction, including anaphylaxis (serious allergic reaction) or other hypersensitivity 
reactions
The meningococcal vaccine does not contain any live organisms and it is given to prevent bacterial 
meningitis from the organism Neisseria meningitidis.  It is considered safe for use in women who are 
pregnant or breastfeeding, according to the American College of Obstetricians and Gynecologists. 
The meningococcal vaccine is not known to cause harm to the developing fetus and does not affect 
the neonate during breastfeeding.   The Centers for Disease Control and Prevention recommends the 
meningococcal vaccine in adolescents and adults being treated with a complement inhibitor, such as 
the study drug eculizumab, because it blocks part of the immune system necessary to protect against 
bacterial meningitis. 
Risks of Antibiotics
Penicillin
Likely, Some May Be Serious (Occurs in greater than 20% and up to 100 % of people)

Nausea or upset stomach
Less Likely, Some May Be Serious (Occurs in >3% - 20 % of people)

Vomiting

Diarrhea

Oral candidiasis (fungal infection of the mouth)
Rare AND Serious (Occurs in 3% or less of people and may require hospitalization or may be 
irreversible, long-term, life-threatening or fatal)

Anaphylaxis (serious allergic reaction) or other hypersensitivity reactions

Seizures

Kidney damage

Fever

Exfoliative dermatitis (redness and peeling of the skin over large areas of the body)

Severe anemia
Penicillin based antibiotics are not expected to increase the risk for adverse pregnancy outcomes.  
There is extensive data on use of penicillin during pregnancy, and there is no increased risk of birth 
defects or fetal harm.  Penicillins are excreted into human milk in small amounts but this exposure is 
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unlikely to have detectable effects in the newborn, and penicillins are considered compatible with 
breastfeeding. 
Risks of Azithromycin
Likely, Some May Be Serious (Occurs in greater than 20% and up to 100 % of people)

Nausea or upset stomach
Less Likely, Some May Be Serious (Occurs in >3% - 20 % of people)

Vomiting

Diarrhea

Liver inflammation
Rare AND Serious (Occurs in 3% or less of people and may require hospitalization or may be 
irreversible, long-term, life-threatening or fatal)

Anaphylaxis (serious allergic reaction) or other hypersensitivity reactions

Liver failure 

QT interval prolongation (heart rhythm disorder)
Based on experimental animal studies and human reports, azithromycin use during pregnancy is not 
expected to increase the risk of birth defects.  Azithromycin has been used widely in pregnancy 
without an increase in adverse fetal or neonatal effects, and its use is considered compatible with 
breastfeeding.  Azithromycin may present in breast milk, so any breastfed newborns and infants 
should be monitored for diarrhea, vomiting or rash.
Reproductive and Lactation Risks 
Taking part in this research study can affect an unborn baby. There is insufficient data to adequately 
characterize the safety of eculizumab in pregnant women with preeclampsia. However, data on 
reproductive and lactation risks from eculizumab have been largely gathered from pregnant women 
receiving the drug for treatment of the rare blood disorder paroxysmal nocturnal hemoglobinuria. 
That data, which includes data from clinical studies and registry data, indicates that eculizumab is 
unlikely to increase the risk of birth defects, or fetal and neonatal toxicity. Specifically, pregnancy 
data show no difference in the risk of overall major birth defects for eculizumab (0.94 per 100 live-
birth) compared with the background rate for major birth defects of 2.7% in the US reference 
population. The rate of fetal death (miscarriage and still birth) observed with use of eculizumab is 
16.2%, while the estimated background rate of miscarriage in the US general population is between 
15% - 20%.   
Limited available data suggest that eculizumab is not excreted in human milk. In one case, a patient 
received eculizumab for treatment of preeclampsia and had no detectable drug in breast milk 
samples. In a study of women with paroxysmal nocturnal hemoglobinuria, authors evaluated 
breastmilk samples from 10 women who breastfed their infants while taking eculizumab and the 
drug was not detected in any of the samples. The authors concluded that eculizumab is safe for use 
in breastfeeding women. 
Unknown Risks to the Developing Embryo or Fetus (an unborn baby)
The study drug, vaccine and antibiotics might involve risks to an embryo or fetus, which are 
currently unknown.  
CSMC IRB No: STUDY00000039 / MOD00005112
CSMC Date Effective: 1/31/2022


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Page 8 of 23 
Collection of Pregnancy Outcomes 
We will collect information on the outcome of your pregnancy including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, abnormalities, or 
complications, and the health status of your child. By signing this consent, you are agreeing to have 
this information about you and your child collected from your medical records and by telephone 
calls at 1-2 weeks and 6-8 weeks after delivery.  However, you are always free to withdraw your 
consent to participate in any research procedure. 
Follow-up Visit for Discontinuing Participants
While you are free to discontinue your participation at any time, we encourage you to complete a 
final clinical and laboratory assessment by the study team if you discontinue the study prior to 
hospital discharge.  During this visit, we will conduct tests to collect safety data, and discuss any 
information that may be important to share with your treating physician.
4.
ARE THERE BENEFITS IN TAKING PART IN THE STUDY?
If you agree to take part in this research study, there may or may not be direct medical benefit to 
you.  The possible benefits of taking part in the research study are prolongation of pregnancy 
compared to standard of care alone.  Prolongation of pregnancy may allow additional time for your 
baby to develop in the womb and reduce prematurity-related complications after delivery.  It is also 
possible that treatment with the study drug, compared to standard of care alone, will reduce your risk 
of developing serious complications such as seizure, stroke, or damage to other organ systems in 
your body. However, no benefit is guaranteed.  It is possible that your condition may remain 
unchanged or even get worse.
We hope the information learned from this research study will benefit other individuals with 
preeclampsia in the future by helping us to learn if eculizumab is an effective treatment option.  
5.
WILL I BE INFORMED OF RESEARCH RESULTS?  
Some of the research tests done in this study follow standard clinical procedures and are performed 
in certified clinical labs. These test results may be shared with you and may be placed in your 
Cedars-Sinai medical record. Other research tests done in this study are for research purposes only 
and are performed in a research only lab where the results are not intended for clinical use. These 
research-only results will not be shared with you or included in your Cedars-Sinai medical record. 
Unanticipated Incidental Findings
If, unexpectedly, we find that results of your research procedures could suggest important medical 
information and we determine there is something you or your doctors can do in response to this 
finding, we will contact you using the last contact information provided by you. If necessary, we 
may recommend additional clinical testing to confirm the research finding. The cost of any 
additional testing and any related treatment will be your responsibility.
6.
WHY WOULD MY PARTICIPATION BE STOPPED?
Your participation in this study may be stopped at any time by the researcher or the sponsor without 
your consent for any reason, including:

The study is stopped or suspended;

Funding for the study is reduced, stopped or withdrawn;
CSMC IRB No: STUDY00000039 / MOD00005112
CSMC Date Effective: 1/31/2022


CSMC Combined Main ICF, HIPAA Authorization and Optional Sub-Study Template_01.16.2019
Page 9 of 23 

If it is in your best interest;

You do not consent to continue in the study after being told of changes in the research that may 
affect you;

You do not follow the study procedures;

Febrile illness (Temperature > 100.4° F); 

Signs or symptoms of hypersensitivity or anaphylaxis to study drug;

If you are discharged prior to being given the study drug;

Significant study intervention non-compliance; 

If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in your best interest;

Disease progression which requires discontinuation of the study intervention;

If you meet an exclusion criterion (either newly developed or not previously recognized) that 
precludes further study participation; 

You are unable to receive study drug for more than 8 days from previous dose.
You may choose (or you may be required) to withdraw from certain parts of the study but invited to 
continue with other parts.  For example, you might stop taking a study drug, but continue with 
follow-up visits or allow us to continue to collect data from your medical records.  Separate written 
consent will be requested if your continued participation will involve procedures not described in 
this consent form.
7.
ARE THERE ANY OTHER OPTIONS?
Your participation is voluntary, so you have the right to decline to participate or to withdraw from 
this research study at any time without any penalty or loss of benefits to which you would be entitled 
outside of the study.  Choosing not to participate will not affect the care you receive at Cedars-Sinai 
Health System. 
If you decide not to take part in this study, you have other choices. For example:

you may choose to be treated following the usual clinical approach: expectant management, 
treatment of high blood pressures, magnesium sulfate to prevent seizure;

you may choose to take part in a different study at CSMC or elsewhere, if one is available;

you could decide not to be treated.
The researcher will discuss these options and their risks and benefits with you.
8.
WILL MY INFORMATION BE KEPT CONFIDENTIAL?
We will do our best to make sure that the personal information collected as part of this study is kept 
private.  However, we cannot guarantee total privacy.  A copy of your research consent and 
authorization forms may be filed in your electronic medical record at CSMC.  Your personal 
information may be given out if required by law.  If information from this study is published or 
presented at scientific meetings, your name and other identifiable personal information will not be 
used. Organizations that may look at and/or copy your medical records for research oversight, 
quality assurance, and data analysis include: accrediting agencies, government and regulatory groups 
(such as Food and Drug Administration (FDA), Office for Human Research Protections (OHRP), 
etc.), safety monitors, companies that sponsor the study, and authorized representatives of the 
sponsor. 
CSMC IRB No: STUDY00000039 / MOD00005112
CSMC Date Effective: 1/31/2022


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Page 10 of 23 
Attached to this consent form is an “Authorization Form” that outlines with whom your information 
may be shared for the purposes of this research and under what circumstances.  
We might share your information and/or research samples collected in this study with other 
researchers at Cedars-Sinai, other academic institutions, or third party commercial entities for future 
research without additional informed consent from you. Information that identifies you will be 
removed and will not be shared with other researchers or anyone outside of Cedars-Sinai. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law.  This Website will not include information that can identify you.  At most, the Website 
will include a summary of the results.  You can search this Website at any time.
9.
WHAT IF I BECOME ILL OR INJURED BECAUSE OF TAKING PART IN THIS 
STUDY?
Contact your study doctor at once if you feel that you are ill or have been injured because of taking 
part in this study.  If it is a medical emergency, call 911 or go to an emergency room.  Promptly 
notify your study doctor of your situation at the phone number listed on page 1 of this consent form.
Who pays for my research related illness or injury?
Cedars-Sinai has no plans to pay for costs associated with the treatment of research-related injury or 
illness.  We will make every effort to seek reimbursement from your health plan.  However, you will 
be responsible for any deductibles and co-payments required under your health plan and for any 
claims ultimately denied by your health plan.  Financial assistance may be available under Cedars-
Sinai’s Charity Care Policy and Procedure.  If you feel that you have had a research-related injury 
and need financial assistance, please contact the IRB Office at 310-423-3783.  You do not waive any 
of your legal rights by signing this form.
10.
FINANCIAL CONSIDERATIONS
Costs of Participation
You and your insurance company will not be charged for your participation in this research study.  
The Sponsor will cover the cost of all items, drugs and services required by this study, including any 
procedures required by the study that may be standard of care.
Compensation for Participating
You will not be paid for participating in the research study.  
Financial Interest in the Research
A significant financial interest is a situation in which financial considerations have the potential to 
influence a person’s professional judgment.  This study has been designed to minimize the impact of 
the investigator’s financial interest.  You are encouraged to ask the investigator to explain how the 
financial interest disclosed below will be managed.
Richard Burwick, MD, MPH receives payment from the company supporting this study.  Dr. 
Burwick is on the Speaker’s Bureau for Alexion Pharmaceuticals and he receives payments for 
educational lectures on atypical hemolytic uremic syndrome, which is treated with eculizumab.   The 
PI and institution have no other potential financial conflict of interest with respect to this study.
CSMC IRB No: STUDY00000039 / MOD00005112
CSMC Date Effective: 1/31/2022


CSMC Combined Main ICF, HIPAA Authorization and Optional Sub-Study Template_01.16.2019
Page 11 of 23 
11.
WHAT IF I HAVE QUESTIONS OR PROBLEMS?
Please contact one of the investigators listed on the first page of this form for questions or concerns 
about the research.  
If you have questions, problems, or concerns that you want to discuss with someone who is not 
associated with this study, or want to offer suggestions or feedback, please contact:
Cedars-Sinai Human Research Protection Program (HRPP)
Phone: (310) 423-3783
Email: ResearchConcerns@cshs.org
The Cedars-Sinai HRPP has been established to protect the rights and welfare of research 
participants.  You may also contact the Cedars-Sinai HRPP if you want to offer input or obtain 
information regarding the study.
12.
CONSENT PROVISIONS 
If you sign this form below, it means that:  
(1) You have taken the time to carefully read and understand the information presented in this 
informed consent form; you should discuss it with others, and if appropriate seek a second opinion 
to make an informed decision;
(2) The information concerning the research study and its involved procedures has been fully 
explained to you and your questions have been answered to your satisfaction; 
(3) You have received and understand all of the information you desire regarding your 
participation in the research study; 
(4) You have considered the potential risks, any anticipated benefits and alternatives (and their 
relative risks and benefits) of participation;
(5) You are voluntarily agreeing to participate in this research study;
(6) You understand that by consenting to participate in the research, you are not giving up any of 
your legal rights; 
(7) You understand that you have the right to be informed of significant new findings related to this 
research study which may affect your willingness to continue participating in this study; and
(8) You have been provided with a copy of the “Experimental Subject’s Bill of Rights”, if 
applicable to this research study, and have been provided with an opportunity to ask questions 
regarding the Bill of Rights.
We will give you a copy of this signed and dated consent form and the Experimental Subject’s Bill 
of Rights.
CSMC IRB No: STUDY00000039 / MOD00005112
CSMC Date Effective: 1/31/2022


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Page 12 of 23 
SIGNATURE PAGE
Consent Form for Research and 
Authorization for Use and Disclosure of Identifiable Health Information (Research)
SIGNATURE BY THE PARTICIPANT
(Adult or Pregnant Minor between 13 to <18 years old)
Main Research Study: I hereby agree to participate in the research study described to me during 
the informed consent process and in this informed consent form. I also give my permission for the 
researchers to collect my child’s health information, as described in this informed consent form. 
You will be given a signed and dated copy of this form.
Name of Participant (Print)
Signature
Date Signed
Optional Sub-study: I hereby agree that I and my child may participate in the optional sub-study 
described to me during the informed consent process and described in the attached Appendix B to 
this form.  
Name of Participant (Print)
Signature
Date Signed
Authorization for Use and Disclosure of Identifiable Health Information 
(Research): I hereby agree that my and my child’s identifiable health information 
may be used and/or disclosed in accordance with this “Authorization for Use and 
Disclosure of Identifiable Health Information (Research)” form attached as Appendix 
to this form.
Name of Participant (Print)
Signature
Date Signed
Optional Sub-Study: Authorization for Use and Disclosure of Identifiable Health Information 
(Research): I hereby agree that my and my child’s identifiable health information may be used 
and/or disclosed in accordance with this “Authorization for Use and Disclosure of Identifiable 
Health Information (Research)” form attached as Appendix to this form.
Name of Participant (Print)
Signature
Date Signed
CSMC IRB No: STUDY00000039 / MOD00005112
CSMC Date Effective: 1/31/2022


CSMC Combined Main ICF, HIPAA Authorization and Optional Sub-Study Template_01.16.2019
Page 13 of 23 
SIGNATURE BY THE INVESTIGATOR
I attest that all the elements of informed consent described in this form have been discussed fully in 
non-technical terms with the participant.  I further attest that all questions asked by the participant 
were answered to the best of my knowledge.   
Name of Investigator (Print)
Signature
Date Signed
SIGNATURE BY THE INTERPRETER/WITNESS
(Signature of an interpreter is only required when a non-English speaking subject is consented 
with the assistance of an interpreter and an IRB-approved ‘short form.’  The witness may be any 
person who is conversant in both English and the language of the Non-English speaking subject, 
such as the interpreter (the certified hospital interpreter), study staff, a family member, or other 
person.  The witness signs the consent forms to confirm that the oral interpretation occurred.)
Name of Witness (Print)
Signature
Date Signed
CSMC IRB No: STUDY00000039 / MOD00005112
CSMC Date Effective: 1/31/2022


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Page 14 of 23 
APPENDIX A: EXPERIMENTAL SUBJECT’S BILL OF RIGHTS
In accordance with California Health and Safety Code 24172, any person who is required to consent 
to participate as a subject in a research study involving a medical experiment or who is requested to 
consent on behalf of another has the right to:
1.
Be informed of the nature and purpose of the experiment.
2.
Be given an explanation of the procedures to be followed in the medical experiment, and any 
drug or device to be utilized.
3.
Be given a description of any attendant discomforts and risks to the subject reasonably to be 
expected from the experiment.
4.
Be given an explanation of any benefits to the subject reasonably to be expected from the 
experiment, if applicable.
5.
Be given a disclosure of any appropriate alternative procedures, drugs or devices that might 
be advantageous to the subject, and their relative risks and benefits.
6.
Be informed of the avenues of medical treatment, if any, available to the subject after the 
experiment if complications should arise.
7.
Be given an opportunity to ask any questions concerning the experiment or the procedure 
involved.
8.
Be instructed that consent to participate in the medical experiment may be withdrawn at any 
time and the subject may discontinue participation in the medical experiment without 
prejudice.
9.
Be given a copy of any signed and dated written consent form used in relation to the 
experiment.
10.
Be given the opportunity to decide to consent or not to consent to a medical experiment 
without the intervention of any element of force, fraud, deceit, duress, coercion, or undue 
influence on the subject’s decision.
CSMC IRB No: STUDY00000039 / MOD00005112
CSMC Date Effective: 1/31/2022


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Page 15 of 23 
AUTHORIZATION FOR USE AND DISCLOSURE OF
IDENTIFIABLE HEALTH INFORMATION FOR RESEARCH

USE AND DISCLOSURE OF HEALTH INFORMATION
If you agree to this Authorization, you give permission to the research team at Cedars-
Sinai Medical Center (“CSMC”) to use or disclose your identifiable health 
information (“private information”) for the research study titled “Complement 
Regulation to Undo Systemic Harm in Preeclampsia: the CRUSH study ” which is 
described in the Consent Form for Research (“Consent Form”) to which this 
Authorization is attached. In particular, you authorize the research team acting under 
the direction of the Principal Investigator to review your medical records and collect 
your private information from the following sources: 
☒ Laboratory tests
☒ Pathology reports
☒ Imaging reports (e.g., x-rays or scans)
☐ Photographs or videos of your image
☒ Doctor/clinic records  
☒ Hospital/medical records
☐ Mental health records
☐ Billing records
☒ Other tests or other types of medical information: Neonatal records

WHO WILL HAVE ACCESS TO YOUR PRIVATE INFORMATION?
Your private information will be used by and/or shared with the CSMC investigators 
listed in Section A of the Consent Form and their research staff.  
In addition to the research team, if applicable, the following parties may receive your 
private information and inspect your records: 

The reviewing Institutional Review Boards and CSMC offices with authority to 
oversee research compliance.

U.S. government agencies, such as the Food and Drug Administration and the 
Department of Health and Human Services. 

Researchers at other organizations who are participating in this research study.

The Study Sponsor and its business partners, for matters related to research study 
oversight, data analysis and use of research results in product development. 

Representatives from regulatory agencies in other countries may join in the review 
of your research records, including research-related medical reports and 
information, with the Sponsor and/or the FDA.
CSMC IRB No: STUDY00000039 / MOD00005112
CSMC Date Effective: 1/31/2022


CSMC Combined Main ICF, HIPAA Authorization and Optional Sub-Study Template_01.16.2019
Page 16 of 23 
CSMC is required by law to protect your private information. However, the recipients 
described above may re-disclose (or share) your information with other parties unless 
such sharing is prohibited by law.

WHEN WILL MY AUTHORIZATION EXPIRE? 
By signing this document, you authorize the use and sharing of your private 
information until the end of the research study. 

REVOKING AUTHORIZATION 
You may change your mind and revoke (take back) this Authorization at any time.  
Even if you revoke this Authorization, the research team may still use or disclose 
private information they already have obtained about you as necessary to maintain the 
integrity or reliability of the current research. To revoke this Authorization, you must 
write to the Principal Investigator of the research study. The mailing address is: 
Richard Burwick, MD, MPH.  8635 W. 3rd St.  Medical Office Tower, Suite 160W, 
Los Angeles, CA 90048.  

NOTICE OF RIGHTS AND OTHER INFORMATION
You do not have to agree to this Authorization, but if you do not agree, you may not 
participate in the research study. CSMC may not condition (withhold or refuse) 
treating you on whether you agree to this Authorization.
If you agree to this Authorization, please sign on the appropriate signature line below. 
You will receive a copy of this Authorization. 
 

OPTIONAL SUB-STUDY
In addition to the main research study, you have the option to agree to participate in 
one or more optional sub-studies as explained to you during the informed consent 
process. Your decision to take part in the optional sub-study(ies) does not impact your 
ability to participate in the main research study. 
If you agree that your identifiable health information may be used and/or disclosed for 
the optional sub-study described in the informed consent process and above, you will 
be required to sign a second time in the signature section. 
CSMC IRB No: STUDY00000039 / MOD00005112
CSMC Date Effective: 1/31/2022


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Page 17 of 23 
APPENDIX B:  OPTIONAL SUB-STUDY 
INTRODUCTION
This Appendix is provided to you as a supplement to the main study consent form. In addition to the 
main study, you are also invited to take part in this optional sub-study. You do not have to agree to 
this optional sub-study to be in the main study. Your medical care at Cedars-Sinai Medical 
Center (CSMC) will not be changed in any way as a result of your decision.
Before you make a decision, please read the rest of this Appendix and ask the researchers any 
questions to help you understand the sub-study.
This Appendix will be given with the study consent form. If you agree to participate in the optional 
sub-study, then you will be asked to sign separate sub-study signature lines in the main consent 
form. 
A. PURPOSE OF THIS OPTIONAL SUB-STUDY 
We are interested in storing specimens and data collected from you during this study for future 
research. Your samples and data could be used to research the causes of hypertensive disorders of 
pregnancy such as preeclampsia, its complications, and other conditions for which individuals with 
hypertensive disorders of pregnancy are at increased risk, and to improve treatment. 
B. STUDY PROCEDURES INVOLVED IN THIS OPTIONAL SUB-STUDY
No additional procedures will be conducted for this optional sub-study. Your samples and data will 
have been collected only for research purposes during a research-specific procedure. 
Your specimens and data will be de-identified. Any information that could identify you will be 
removed and kept separately from your specimens and medical information. The only link between 
your specimens/medical data and your identity will be a list with a unique study number that will 
link your identity so that only the research team, or other trusted researchers, can recognize you. 
C. LENGTH OF THIS OPTIONAL SUB-STUDY
In this optional sub-study, testing of your specimens may go on for a long period of time.  Therefore, 
while your direct participation in this optional sub-study will be done once you have completed the 
procedures/visits described above, your specimen(s) may be studied for many years. 
 
CSMC IRB No: STUDY00000039 / MOD00005112
CSMC Date Effective: 1/31/2022


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Page 18 of 23 
D. POSSIBLE RISKS OR DISCOMFORTS OF THIS OPTIONAL SUB-STUDY
There are no additional risks to you for participating in this optional sub-study.
E. BENEFITS OF THIS OPTIONAL SUB-STUDY
You should not expect to benefit from taking part in this optional sub-study. 
While no benefit is ever guaranteed, we hope the information learned from this optional sub-study 
will benefit other individuals with the condition being studied in the future. 
F. PAYMENT
You will not be paid for providing data and samples for this study. Once you provide the samples for 
the research, you no longer have access to them. The donated samples become the property of 
CSMC or the study sponsor. Researchers might use your samples (even if identifiers are removed) to 
develop new products, tests or discoveries. Sometimes, these inventions may result in commercial 
profit for the researchers, CSMC, and/or other organizations. If this happens, you will not receive 
any financial benefits. 
CSMC IRB No: STUDY00000039 / MOD00005112
CSMC Date Effective: 1/31/2022


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Page 19 of 23 
APPENDIX C: FLOWCHART OF PROCEDURES
Schedule of Activities
Screening
Day -7 to 
Day -1
Visit 1
Day 
1
Visit 2
Day
 4
Visit 3
Day 
8
Visit 4
Day 
11
Visit 5
Day 
15
Visit 6
Day
 18
Visit 7
Day 
22
Visit 8 
Day 
25
Visit 9
Day 
29
…
***
Eligibility checklist 
X
Informed consent
X
Medical history and 
demographics
X
Physical exam
(pre-infusion on treatment 
days)
X
X
X
X
X
X
X
Screening labs
Platelet count, ALT, AST, LDH, 
Cr, PT/PTT, INR
X
Quadrivalent meningococcal 
conjugate vaccine 
(MenACWY) *
X
X
X
Meningococcus serogroup B 
vaccine (MenB)*
X
X
X
Prophylactic Antibiotics**
X
X
X
X
X
X
X
X
X
X
Eculizumab 900 mg IV
X
X
X
X
Eculizumab 1200 mg IV 
X
X
Safety Labs:† 
CBC, CMP, LDH (pre-infusion 
on treatment days)
X
X
X
X
X
X
X
X
X
X
Lab Tests for Research† C3, 
C4, CH50, Haptoglobin
(pre-infusion on treatment 
days)
X
X
X
X
X
X
X
X
X
X
Blood collection for Research 
Labs †
X
X
X
X
X
X
X
X
X
X
Urine collection††
(pre-infusion on treatment 
days)
X
X
X
X
X
X
X
X
X
X
Medical record review
X
X
X
X
X
X
X
X
X
X
Assessment for adverse 
maternal/fetal outcomes‡
X
X
X
X
X
X
X
X
X
X
Total time
60
 min
20
 min
60 
min
20 
min
60 
min
20 
min
60 
min
20 
min
60 
min
20-60 
min
CSMC IRB No: STUDY00000039 / MOD00005112
CSMC Date Effective: 1/31/2022


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Sample and Procedure Table:
Visit days above refer to the number of days from initiation of study drug (Day 1 = first day of eculizumab), 
they do not refer to antepartum or postpartum state.   
*  For subjects without meningococcal vaccination in the prior 5 years, administer Quadrivalent 
meningococcal conjugate vaccine (MenACWY): 2 doses of Menactra or Menveo with the first dose of the 
vaccine on Day 1 (prior to the first dose of eculizumab) or up to 7 days prior to Day 1 (after informed 
Consent), and the second dose of the vaccine at least 2 months later. Also, administer Meningococcus 
serogroup B vaccine (MenB): 2 doses of Bexsero with the first dose of the vaccine on Day 1 (prior to the first 
dose of eculizumab) or up to 7 days prior to Day 1 (after informed Consent), and the second dose of the 
vaccine at least 1 month later. For subjects with prior vaccination, revaccinate in accordance with the 
recommendation of the Advisory Committee on Immunization Practices, considering the duration of 
eculizumab therapy.  The second dose of the two meningococcal vaccines may be administered up to 8 weeks 
postpartum, however in some subjects, the second dose may become due prior to delivery.
** Penicillin 500 mg PO bid, or Azithromcyin 250 mg PO daily (if allergy to penicillin), until 4 weeks after the 
last dose of eculizumab
*** Following induction dose of eculizumab (900 mg IV every 7 days x 4 weeks), eculizumab will be given at 
maintenance dose of 1200 mg IV on week 5, followed by 1200 mg every 2 weeks.  Eculizumab should be given 
until 48 hours postpartum.  Alternating study visits for specimen collection & medical record review will 
continue until hospital discharge.  Blood draws and urine samples are to be drawn the day of and prior to 
every eculizumab infusion and 3 days after every eculizumab infusion, even if patient is in the postpartum 
period.  If the patient discontinues participation in the study before hospital discharge, a final discontinuation 
visit will be performed on that day, including collection of blood and urine samples and assessment of 
maternal and fetal status.  Blood and urine collections will be discontinued upon hospital discharge
Postpartum follow up
1-2 weeks 
postpartum
6-8 weeks 
postpartum
0-8 weeks
Postpartum
Quadrivalent meningococcal conjugate 
vaccine (MenACWY), 2nd dose 
(at least 2 months from 1st dose)*
X
Meningococcus serogroup B vaccine 
(MenB) 
(at least 1 month from 1st dose)*
X
Prophylactic Antibiotics**
X
X
Medical record review
X
X
Assessment for adverse maternal 
outcomes (chart review / telephone visit)‡‡
X
X
Assessment for adverse neonatal 
outcomes (chart review / telephone visit)‡‡
X
X
Total time
20 min
20 min
20 min
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 † Safety labs (CBC, CMP, and LDH), as well as other labs specific to the research study (C3, C4, CH50, and 
haptoglobin), will be sent to the Cedars-Sinai Laboratory.  Additional research samples to be collected will 
include one 10ml purple-top tube for plasma and one 10ml red-top tube for serum. To assess peak and 
trough effects of the study drug, subjects will have blood collected three days after each study drug 
administration (peak) and just prior to the study drug infusion on each subsequent treatment day (trough).  
These additional research samples will be processed and stored in Karumanchi laboratory.   Future research 
assays, including measurements of C5a, C5b-9, CD59, sFLT1, PlGF and PK/PD assays, will be performed in the 
Karumanchi laboratory or Alexion Pharmaceuticals laboratory, and such results will not be available to the 
treatment team or study participant.  
† † Urine sample to be sent clinically for protein assessment (one of the following: urine protein/creatinine 
ratio, 24hr urine protein or urinalysis), and an additional research sample will be collected up to 20ml. Future 
research assays, including measurements of urinary C5a, C5b-9, CD59, sFLT1 and PlGF, will be performed in 
the Karumanchi laboratory, and such results will not be available to the treatment team or study participant.  
‡ In addition to the study visits designated in the table, a member of the study team will write a brief progress 
note daily assessing maternal and fetal status.  
‡‡ For postpartum visits, maternal and neonatal outcomes will be assessed by chart review and telephone call 
to the patient.  Up to three telephone calls will be made to reach the study participant, after which they will 
be deemed lost to follow up.
 
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CSMC Date Effective: 1/31/2022


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APPENDIX D:  Detailed Description of Common Medical Procedures Performed 
for Research Purposes and Associated Risks
The procedures listed below are often performed as part of routine care for a person with your 
condition.  They are being repeated or performed more frequently as part of this research.  
However, the risks associated with each procedure should be comparable to what you would 
experience even if you were undergoing the procedure outside this research study.
Study Procedure
Related Risks
Blood draw: A needle is placed in the vein in 
your arm to draw blood.
Blood drawing may cause some pain and has a 
small risk of bleeding, bruising, or infection at the 
puncture site. There is also a small risk of 
fainting.
Infusion Procedure: Infusion is the 
administration of drugs directly into your 
bloodstream using intravenous (IV) lines. The 
risks associated with IV lines are described 
separately below.
Occasionally, people have allergic reactions 
(including life-threatening reactions) when taking 
any medication.  Symptoms of any allergic 
reaction can include a rash, hives, itching, and/or 
difficulty breathing, closing of the throat, swelling 
of the lips, tongue or face, and rarely death.  If 
you experience any difficulty breathing, closing 
of the throat, swelling of the lips, tongue or face, 
or hives, you should stop taking your study drug 
and immediately seek emergency medical 
attention.
In general, allergic reactions to medicines are 
more likely to occur in people who have allergies 
to other drugs, foods, or things in the 
environment, such as dust or grass.  If you have 
allergies to other medicines, foods, or other things 
in the environment, or if you have asthma, you 
should let your researcher know.
Injection: A method for putting fluids into 
the body using a syringe and a hollow needle 
that is pierced through the skin
These reactions could include bruising, pain, 
bleeding, and rarely infection at the injection site, 
feeling lightheaded and fainting.  As with any 
injection, there may be some irritation at the 
injection site where the study drug is 
administered.
Intravenous (IV) lines: You will receive the 
study drug or other medications or contrast 
agent through an intravenous (IV) line. An IV 
line is a small tube that is attached to a 
catheter and inserted by needle into a vein 
usually in your hand or arm.  Qualified 
medical professionals will place IV lines for 
use in this study.
IV lines are usually safe and well tolerated and 
complications are rare, but can include phlebitis 
(swelling of the vein) and infection.  The IV may 
come out accidentally or blood may leak around 
the line.  If the IV is not in the vein, medication or 
fluid can enter the surrounding soft tissues, and 
can be associated with swelling, discomfort, 
bruising and irritation.  Rarely, a clot can develop 
in the IV line itself.  If this happens, the staff may 
remove the old IV line and start a new IV line.  
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There is also a small risk of feeling lightheaded 
and fainting.
Medical History Review: You will be asked 
about your medical and surgical history with 
attention to other medical conditions, 
medication use, smoking and drug habits, and 
prior infections.  
There are no physical risks associated with this 
procedure.
Urine Collection: You will be asked to 
provide a urine sample in a specimen cup.
There are no risks associated with this procedure.
Demographic Information: You will be 
asked about your age, gender, race, and 
ethnicity.
There are no physical risks associated with these 
procedures.
CSMC IRB No: STUDY00000039 / MOD00005112
CSMC Date Effective: 1/31/2022