An Open-label, Single-arm, Multicenter Pilot Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Efficacy and Safety of Pegcetacoplan in Patients With Transplant-associated Thrombotic Microangiopathy (TA-TMA) After Hematopoietic Stem Cell Transplantation (HSCT)
Phase: PHASE2
Conditions: Transplant-Associated Thrombotic Microangiopathy
Sponsor: Swedish Orphan Biovitrum

Protocol Sobi.PEGCET-201 
Version 3.0 (including Protocol Amendment 2), 17 September 2024 
 
Protocol Title: An Open-label, Single-arm, Multicenter Pilot Study to Evaluate 
the Pharmacokinetics, Pharmacodynamics, Efficacy and Safety of Pegcetacoplan 
in Patients with Transplant-associated Thrombotic Microangiopathy (TA-TMA) 
After Hematopoietic Stem Cell Transplantation (HSCT) 
 
 
National Clinical Trial number: NCT05148299 

Pegcetacoplan/TA-TMA
Clinical Study No: Sobi.PEGCET-201
Confidential
Page 1 of 89
Version 3.0 Final Date 17 Sep 2024
An Open-label, Single-arm, Multicenter Pilot Study to Evaluate the 
Pharmacokinetics, Pharmacodynamics, Efficacy and Safety of Pegcetacoplan 
in Patients with Transplant-associated Thrombotic Microangiopathy 
(TA-TMA) After Hematopoietic Stem Cell Transplantation (HSCT)
Brief Title:
A Study of Pegcetacoplan for Patients with Transplant-associated Thrombotic 
Microangiopathy After Hematopoietic Stem Cell Transplantation
Final Protocol Number: Sobi.PEGCET-201
EU CT Number: 2023-510443-37-00
EudraCT Number: 2021-003157-27
IND Number: 156294 
Type of Study: Therapeutic Exploratory
Original Protocol: 07 July 2021
Protocol version 3.0 (including Protocol Amendment 2): 17 September 2024
Sponsor: Swedish Orphan Biovitrum AB, SE-112 76 Stockholm, Sweden
Sponsor’s Medical Director 
Principal Coordinating Investigator
Medical Director
Swedish Orphan Biovitrum AB
SE-112 76 Stockholm, Sweden
Signature
Date
Signature
Date
Confidential
This protocol contains confidential information belonging to Swedish Orphan Biovitrum. Except as may be 
otherwise agreed to in writing, by accepting or reviewing these materials, you agree to hold such information in 
confidence and not to disclose it to others (except where required by applicable law) nor use it for unauthorized 
purposes. In the event of actual or suspected breach of this obligation, Swedish Orphan Biovitrum should be 
promptly notified.
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Investigator statement 
I have read the protocol entitled “An Open-label, Single-arm, Multicenter Pilot Study to Evaluate 
the Pharmacokinetics, Pharmacodynamics, Efficacy and Safety of Pegcetacoplan in Patients with 
Transplant-Associated Thrombotic Microangiopathy (TA-TMA) After Hematopoietic Stem Cell 
Transplantation (HSCT)” and the accompanying current Investigator’s Brochure. I agree to 
conduct the clinical investigation in compliance with the Final Protocol, Version 3.0, 17 
September 2024, the International Council for Harmonisation (ICH) harmonised guideline 
E6(R2): Guideline for Good Clinical Practice (GCP) [1], applicable regulatory/government 
regulations, and in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki [2]. I will not implement any changes to study procedures or conduct without prior 
approval from the sponsor and, when applicable, the Independent Ethics Committee/Institutional 
Review Board/Research Ethics Board and Regulatory Authority. I will supervise any individual 
or party to whom I delegate study-related duties and functions conducted at the study site and 
ensure qualification of individuals or parties who perform delegated tasks.  
I agree to maintain the confidentiality of this study protocol, as described on the title page. 
Further, I will not publish results of the study without authorization from Swedish Orphan 
Biovitrum AB (publ). 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 
 
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Table of contents 
1 
Synopsis ............................................................................................................................ 8 
Study schematic ........................................................................................................................... 14 
Schedule of assessments .............................................................................................................. 15 
2 
Abbreviations and definition of terms............................................................................. 22 
2.1 
List of Abbreviations and definitions ......................................................................... 22 
3 
Ethics ............................................................................................................................... 25 
3.1 
Independent ethics committee and/or institutional review board ............................... 25 
3.2 
Ethical conduct of the study ....................................................................................... 25 
3.3 
Patient information and consent ................................................................................. 25 
4 
Introduction ..................................................................................................................... 25 
4.1 
Background ................................................................................................................ 25 
4.2 
Study rationale ............................................................................................................ 26 
4.3 
Potential risks and benefits ......................................................................................... 27 
5 
Study objectives and endpoints ....................................................................................... 29 
5.1 
Primary objectives ...................................................................................................... 29 
5.1.1 
Primary PK endpoints ............................................................................................ 29 
5.1.2 
Safety endpoints..................................................................................................... 29 
5.2 
Secondary objectives .................................................................................................. 29 
5.2.1 
Secondary endpoints supporting the secondary objectives ................................... 29 
5.3 
Exploratory objectives ................................................................................................ 31 
5.3.1 
Exploratory endpoints ............................................................................................ 31 
6 
Investigational plan ......................................................................................................... 32 
6.1 
Overall study design and plan .................................................................................... 32 
6.1.1 
Screening period (up to 2 weeks) .......................................................................... 32 
6.1.1.1 Retesting and rescreening ................................................................................. 32 
6.1.1.2 Screen failures ................................................................................................... 33 
6.1.2 
Treatment period (up to 16 weeks) ........................................................................ 33 
6.1.2.1 Clinical worsening ............................................................................................ 33 
6.1.3 
Follow-up period (up to 12 weeks) ........................................................................ 34 
6.1.4 
Unscheduled visits ................................................................................................. 34 
6.1.5 
Stopping criteria..................................................................................................... 34 
6.2 
Discussion of study design ......................................................................................... 35 
6.3 
Selection of study population ..................................................................................... 35 
6.3.1 
Inclusion criteria .................................................................................................... 35 
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6.3.2 
Exclusion criteria ................................................................................................... 36 
6.3.3 
Withdrawal of patients from treatment or study .................................................... 37 
6.3.3.1 Discontinuation from treatment ........................................................................ 37 
6.3.3.2 Withdrawal from study ..................................................................................... 37 
6.3.3.3 Lost to follow-up ............................................................................................... 38 
6.3.4 
Replacement of withdrawn patients....................................................................... 38 
6.3.5 
Specific restrictions/requirements ......................................................................... 38 
6.3.5.1 Acceptable methods of contraception ............................................................... 38 
6.4 
Treatments .................................................................................................................. 39 
6.4.1 
Treatments administered ........................................................................................ 39 
6.4.1.1 Investigational medicinal products ................................................................... 39 
6.4.2 
Identity of investigational medicinal products ...................................................... 39 
6.4.2.1 IMP packaging and labeling ............................................................................. 39 
6.4.2.2 IMP storage and handling ................................................................................. 40 
6.4.3 
Method of assigning patients to treatment groups ................................................. 40 
6.4.4 
Selection of doses .................................................................................................. 40 
6.4.5 
Selection and timing of doses for each patient ...................................................... 43 
6.4.6 
Dose modification .................................................................................................. 44 
6.4.7 
Infusion supplies .................................................................................................... 44 
6.4.8 
Blinding and unblinding ........................................................................................ 44 
6.4.9 
Prior and concomitant therapy ............................................................................... 44 
6.4.9.1 Permitted concomitant therapy ......................................................................... 45 
6.4.9.2 Prohibited medications ...................................................................................... 45 
6.4.10 
Treatment compliance ........................................................................................... 45 
6.4.11 
IMP accountability................................................................................................. 45 
6.4.12 
IMP disposal .......................................................................................................... 46 
6.5 
Baseline, efficacy, safety, pharmacokinetic, pharmacodynamic and 
pharmacogenetics assessments ................................................................................... 46 
6.5.1 
Medical history ...................................................................................................... 46 
6.5.1.1 Vaccines medical history .................................................................................. 47 
6.5.2 
Demography .......................................................................................................... 47 
6.5.3 
Biopsy samples of affected organs ........................................................................ 47 
6.5.4 
Pharmacokinetic assessments ................................................................................ 47 
6.5.4.1 Pharmacokinetic parameters ............................................................................. 48 
6.5.5 
Safety assessments ................................................................................................. 48 
6.5.5.1 Adverse events .................................................................................................. 48 
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6.5.5.2 Laboratory safety assessments .......................................................................... 53 
6.5.5.3 Vital signs ......................................................................................................... 55 
6.5.5.4 Body weight and height .................................................................................... 55 
6.5.5.5 Physical examination ........................................................................................ 56 
6.5.5.6 Electrocardiograms ........................................................................................... 56 
6.5.5.7 Infusion-site reactions/pump-safety assessments ............................................. 56 
6.5.5.8 Appropriateness of safety measurements .......................................................... 57 
6.5.5.9 Safety review committee ................................................................................... 57 
6.5.6 
Pharmacodynamic assessments ............................................................................. 57 
6.5.6.1 Immunogenicity ................................................................................................ 57 
6.5.7 
Efficacy assessments ............................................................................................. 58 
6.5.7.1 Clinical response ............................................................................................... 58 
6.5.7.2 TMA response ................................................................................................... 58 
6.5.7.3 Overall survival, time to response, duration of response, TA-TMA relapse .... 58 
6.5.7.4 Transfusions ...................................................................................................... 59 
6.5.7.5 Health-related quality of life ............................................................................. 59 
6.5.7.6 Appropriateness of efficacy measurements ...................................................... 59 
6.5.8 
Other study assessments ........................................................................................ 60 
 
 
7 
Quality control and quality assurance ............................................................................. 60 
8 
Statistical plan ................................................................................................................. 61 
8.1 
Determination of sample size ..................................................................................... 61 
8.2 
Definition of study populations .................................................................................. 61 
8.2.1 
Screened set ........................................................................................................... 61 
8.2.2 
Safety set ................................................................................................................ 61 
8.2.3 
Intent-to-treat set .................................................................................................... 61 
8.2.4 
Pharmacokinetic set ............................................................................................... 62 
8.2.5 
Pharmacodynamic set ............................................................................................ 62 
8.3 
Overall statistical and analytical plan ......................................................................... 62 
8.3.1 
General statistical issues ........................................................................................ 62 
8.3.2 
Demographics and baseline characteristics ........................................................... 62 
8.3.3 
Analysis related to primary objective .................................................................... 62 
8.3.3.1 Analysis of pharmacokinetics ........................................................................... 62 
8.3.3.2 Analysis of safety and tolerability data ............................................................. 63 
8.3.4 
Analysis related to secondary objective ................................................................ 63 
8.3.4.1 Analysis of pharmacodynamics ........................................................................ 63 
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8.3.4.2 Analysis of secondary efficacy endpoints ......................................................... 64 
8.3.5 
Analysis related to exploratory objective .............................................................. 65 
8.3.6 
Interim analysis ...................................................................................................... 65 
8.3.7 
Multiple comparison/multiplicity .......................................................................... 65 
8.3.8 
Exploratory subgroup analyses .............................................................................. 65 
8.3.9 
Handling of missing data ....................................................................................... 65 
9 
Data collection, handling and record keeping ................................................................. 65 
9.1 
Data standards ............................................................................................................ 65 
9.2 
Case report form ......................................................................................................... 65 
9.3 
Source data ................................................................................................................. 66 
9.4 
Protocol deviations ..................................................................................................... 66 
9.5 
Database closure ......................................................................................................... 67 
9.6 
Record retention ......................................................................................................... 67 
10 
End of study .................................................................................................................... 67 
11 
Sponsor’s discontinuation criteria ................................................................................... 68 
12 
Dissemination and publication of results ........................................................................ 68 
13 
Confidentiality ................................................................................................................ 68 
14 
Reference list ................................................................................................................... 69 
Appendix 1 
Additional protocol signatures ............................................................................... 73 
 
 
 
 
 
 
 
 
Appendix 6 
Protocol changes to be followed during COVID-19 restrictions ........................... 82 
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Table of tables 
Table 1 
Schedule of Assessments ......................................................................... 15 
Table 2 
Investigational medicinal product ........................................................... 39 
Table 3 
Laboratory assessments ........................................................................... 54 
Table 4 
Revised COVID-19 minimum schedule of assessments ......................... 84 
Table of figures 
Figure 1 
Study schematic ....................................................................................... 14 
Figure 2 
Predicted pegcetacoplan concentration-time profile by body weight group 
compared to PNH reference .................................................................... 42 
 
Appendices 
Appendix 1 
Additional protocol signatures 
 
 
 
 
 
 
 
 
Appendix 6 
Protocol changes to be followed during COVID 19 restrictions 
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1 
Synopsis 
STUDY IDENTIFIERS 
 
Title of study: 
An Open-label, Single-arm, Multicenter Pilot Study to Evaluate the 
Pharmacokinetics, Pharmacodynamics, Efficacy and Safety of Pegcetacoplan in 
Patients with Transplant-associated Thrombotic Microangiopathy (TA-TMA) After 
Hematopoietic Stem Cell Transplantation (HSCT) 
Clinical study number: 
Sobi.PEGCET-201 
 
 
 
 
Type of study: 
Therapeutic exploratory 
STUDY OBJECTIVES 
 
Primary objective: 
To evaluate the pharmacokinetics (PK), safety and tolerability of pegcetacoplan in 
patients with TA-TMA. 
Secondary objectives: 
· 
To evaluate the pharmacodynamics (PD) of pegcetacoplan in patients with 
TA-TMA.  
· 
To evaluate the efficacy of pegcetacoplan in patients with TA-TMA. 
 
 
 
 
 
 
 
STUDY ENDPOINTS 
 
Primary PK endpoints: 
· 
Pegcetacoplan PK parameters:  
o 
AUC0-tau, Cmax, Tmax and Ctrough. 
Safety endpoints: 
· 
Occurrence of treatment-emergent adverse events. 
· 
Changes from baseline in laboratory parameters and vital signs. 
· 
Occurrence of clinically significant abnormal electrocardiogram findings. 
· 
Presence of antibodies to polyethylene glycol (PEG) and pegcetacoplan 
throughout treatment and follow-up periods. 
Secondary endpoints: 
· 
PD endpoints: 
o 
Absolute levels, change from baseline, and % change from 
baseline to Week 24 in biomarkers of complement activation: 
sC5b-9, C3a, C3, Bb, C4a, functional assays for classical and 
alternative complement pathways. 
· 
Clinical response at Week 24, defined as improvement in laboratory 
markers and improvement in clinical status as follows: 
Improvement in laboratory markers:  
o 
Lactate dehydrogenase (LDH) less than 1.5 x upper limit of 
normal (ULN) and  
o 
Platelet count ≥ 50 000/mm3 without transfusion support during 
the prior 7 days. 
AND in patients with signs or symptoms of organ dysfunction at 
baseline, in addition to the above laboratory markers, at least 1 of the 
following clinical criteria needs to be fulfilled, depending on the 
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organ/system involved at baseline (without appearance of new signs or 
symptoms of organ dysfunction in other organs not present at baseline): 
o 
Renal response – requires > 40 % reduction in creatinine, or 
normalization of creatinine, or discontinuation of renal 
replacement therapy, or ≥ 50 % reduction from baseline in 
random urine protein/creatinine ratio (rUPCR). 
o 
Pulmonary response – requires extubation and discontinuation 
of positive pressure ventilation. 
o 
Gastrointestinal (GI) response – applicable only to patients 
with biopsy-proven GI TA-TMA and requires improvement in GI 
function as determined by the Mount Sinai Acute Graft-versus-
host disease International Consortium (MAGIC) criteria (no or 
intermittent nausea, vomiting or anorexia attributed to TA-TMA 
for upper GI; stool output/day for lower GI as follows: 
< 500 mL/day or < 3 episodes/day. 
o 
Neurological response – requires improvement in reversible 
neurological conditions (e.g., cessation of seizures or controlled 
under medication, resolution of mental alteration; residual 
radiologic signs are acceptable without clinical symptomatology), 
or stabilization of irreversible neurological conditions (e.g., 
stability of neurological deficits following stroke without further 
deterioration or subsequent strokes). 
o 
Freedom from transfusion – requires absence of platelet or 
packed red blood cells (PRBC) transfusions attributed to 
TA-TMA during the prior 7 days (only applicable if patient was 
undergoing platelet or PRBC transfusion at baseline). 
o 
Cardiovascular response – requires resolution of pulmonary 
hypertension (may receive anti-pulmonary hypertension 
medications if still on maintenance therapy), or hypertension 
control on no more than 2 medications excluding diuretics 
(applicable only to patients with severe hypertension at baseline). 
o 
Serositis response – requires no evidence of clinically significant 
pericardial or pleural effusion requiring surgical therapy (e.g., 
pericardiocentesis/ thoracocentesis). 
Patients meeting intercurrent events, including use of prohibited 
medication or study withdrawal before Week 24 will be considered as 
failures/nonresponders. 
· 
TMA response at Week 24, defined as improvement in laboratory 
markers as follows: 
o 
LDH < 1.5 x ULN and  
o 
Platelet count ≥ 50 000/mm3 without transfusion support during 
the prior 7 days and 
o 
≥ 50 % reduction from baseline in rUPCR. 
· 
Overall survival at Day 100 from date of TA-TMA diagnosis. 
· 
Overall survival at Week 24 from treatment start. 
· 
Time to clinical response. 
· 
Time to TMA response. 
· 
Duration of clinical response. 
· 
Duration of TMA response. 
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· 
TA-TMA relapse at Week 24.  
· 
Clinical response at Week 12 
· 
TMA response at Week 12. 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DESIGN AND METHODS 
 
Study design: 
 
This is a prospective, open-label, multicenter, single-arm, pilot study to evaluate 
the PK, PD, efficacy and safety of pegcetacoplan in patients with TA-TMA after 
HSCT. 
The study will enroll 12 patients with TA-TMA, who will receive treatment with 
open-label pegcetacoplan at the planned dose indicated below (see Test product; 
dose and mode of administration).  
The planned study duration for each patient is up to 24 weeks. The study will 
consist of the following periods: 
1) Screening period (up to 2 weeks) 
Informed consent will be obtained at screening before any study-related procedures 
being conducted. Patients will be screened to confirm that the patient selection 
criteria for the study have been met. Key inclusion and exclusion criteria will be 
reviewed by the study medical monitor and eligibility will be confirmed prior to the 
enrollment. 
2) Treatment period (up to 16 weeks) 
 
 
  
At Week 12, if a clinical and/or TMA response according to the protocol definition 
is not reached, the investigator may decide to continue treatment, according to 
his/her judgment, for a total 16 weeks of treatment. If at Week 12 the patient has 
reached a partial clinical response (defined as improvement in signs/symptoms in 
1 or more affected organs without meeting the protocol definition of clinical 
response), 4 additional weeks of pegcetacoplan every 3 days will be administered 
to complete 16 weeks of treatment.  
At any time after the first 3 weeks of treatment, in the event of significant clinical 
worsening associated with active laboratory TMA (as defined below), the patient 
may be discontinued from study treatment and receive rescue therapy. In case of 
earlier clinical worsening, it is recommended to wait until at least 3 weeks of 
treatment are completed to allow pegcetacoplan to reach the target exposure and 
exert a clinical effect; however, if deemed by the investigator that the patient’s 
safety is at risk, the patient can be discontinued from study treatment at any time. 
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Discontinued patients will remain on study and will be followed for survival until 
the end of the study. 
Clinical worsening will be defined as active laboratory TA-TMA as per Inclusion 
Criterion #3 and 3 of the 5 organ injuries listed below: 
a. 
Kidney: requirement of renal replacement therapy after initial TA-TMA 
control, sustained (> 7 days) and attributable to TA-TMA. 
b. Lungs: requirement of sustained (> 7 days) positive pressure ventilation, 
and attributable to TA-TMA. 
c. 
Cardiovascular: uncontrolled severe hypertension with > 2 medications 
(excluding diuretics), and attributable to TA-TMA. 
d. Central nervous system (CNS): uncontrolled seizures under medication 
attributable to posterior reversible encephalopathy syndrome or to 
hypertension resulting from TA-TMA. 
e. 
GI tract: clinically significant GI bleeding requiring ≥ 20 mL/kg/day of 
PRBC transfusion daily for at least 7 days. 
Any concomitant TA-TMA directed therapy will be prohibited for the entire 
treatment period, including plasma-exchange, defibrotide and any other 
complement inhibitor. 
3) Follow-up period (up to 12 weeks) 
After completion of the treatment period, all patients will enter in the follow-up 
period until Week 24. This includes an End of treatment visit 4 weeks after the last 
IMP dose and 1 or 2 more follow-up visits every 4 weeks for patients who have 
completed 16 or 12 weeks of treatment, respectively. The main analysis will be 
performed after all patients have completed their Week 24 visit.  
 
The end of the study is defined as when all enrolled patients have completed the 
follow‑up period and performed the End of study visit at Week 24 or the Early 
Termination visit in case of early discontinuation. 
A Safety Review Committee (SRC) will assess the progress and cumulative PK and 
safety data of the study. 
Number of patients 
planned: 
12 patients. 
 
Diagnosis and main criteria 
for inclusion: 
Patients with TA-TMA after HSCT. 
Inclusion criteria: 
1. Male and female patients aged ≥ 18 years at the time of informed consent 
form (ICF) signature. 
2. Received allogeneic HSCT from a related or unrelated, human leukocyte 
antigen-matched or mismatched donor. Patients having received any of the 
following stem cell sources are eligible: granulocyte colony stimulating 
factor mobilized peripheral blood stem cells, bone marrow, umbilical cord 
blood. 
3. Diagnosis of TA-TMA established as per the laboratory markers below, 
indicating TMA:  
a. 
De novo or progressing thrombocytopenia (platelet count 
< 50 x 109/L or > 50 % decrease in platelet count from the highest 
value achieved after transplantation). AND 
b. Elevated LDH (> 1.5 x ULN).  
AND at least 2 additional laboratory/clinical criteria among the following: 
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c. 
Presence of schistocytes on the peripheral blood smear (≥ 2 per hpf) 
or histologic evidence of microangiopathy in any biopsied organ. OR 
d. De novo anemia (hemoglobin < LLN or anemia requiring PRBC 
transfusion support as per local institutional standard). OR 
e. 
Proteinuria (random urinalysis protein concentration ≥ 30 mg/dL). OR 
f. 
Elevated plasma concentration of sC5b-9 above ULN. OR 
g. Arterial hypertension, defined by systolic blood pressure (BP) 
≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg. 
4. Have a diagnosis of TA-TMA that persists despite initial management of 
any triggering condition. 
5. Have rUPCR ≥ 1 mg/mg. 
6. Women of childbearing potential, defined as any women who have 
experienced menarche and who are NOT permanently sterile or 
postmenopausal, must have a negative serum pregnancy test at screening 
and agree to use protocol-defined methods of contraception for the 
duration of the study and 8 weeks after their last IMP dose. 
Note: Postmenopausal is defined as having had 12 consecutive 
months with no menses without an alternative medical cause. 
7. Men must agree to the following for the duration of the study and 8 weeks 
after their last dose of IMP: 
a. 
Avoid fathering a child. 
b. Use protocol-defined methods of contraception. 
c. 
Refrain from donating sperm. 
8. Patient and/or legally authorized representative must be capable of giving 
signed informed consent, which includes compliance with the 
requirements and restrictions listed in the ICF. 
Exclusion criteria: 
1. Positive direct Coombs test. 
2. Known familial or acquired ADAMTS13 deficiency. 
3. Known Shiga toxin‐related hemolytic uremic syndrome. 
4. Known bone marrow or graft failure. 
5. Diagnosis of disseminated intravascular coagulation. 
6. Diagnosis of veno-occlusive disease (VOD). 
7. Active GI bleeding (hematemesis or hematochezia) at baseline.  
8. Body weight < 30 kg and > 100 kg. 
9. Uncontrolled systemic bacterial or fungal infection, presence or suspicion 
of sepsis.  
10. Previously or currently treated with a complement inhibitor (approved or 
investigational). 
11. Pregnancy or breastfeeding. 
12. Positive human immunodeficiency virus antibody at screening or 
documented in pre-HSCT medical record. 
13. Hepatitis C virus detectable by polymerase chain reaction at screening or 
documented in pre-HSCT medical record.  
14. Chronic inactive hepatitis B virus with viral loads > 1000 IU/mL 
(> 5000 copies/mL) at screening or documented in pre-HSCT medical 
record. Eligible patients who are chronic active carriers (≤ 1000 IU/mL) 
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must receive prophylactic antiviral treatment (e.g., entecavir, tenofovir, 
lamivudine) according to local country guidelines. 
15. Known or suspected hereditary fructose intolerance. 
16. Hypersensitivity to pegcetacoplan or any of its excipients. 
17. Inability to cooperate with study procedures or any condition that, in the 
opinion of the investigator, could increase the patient’s risk by 
participating in the study or confound the outcome of the study. 
Assessments: 
Refer to Table 1. 
Test product; dose and 
mode of administration: 
Pegcetacoplan is a 54-mg/mL solution for injection/infusion for 
 or s.c. use. 
Each vial contains 1080 mg pegcetacoplan in a 20-mL volume. 
Pegcetacoplan will be administered using a syringe pump. 
 
 
 
No dose modification is foreseen in this study. Treatment interruption or 
discontinuation necessary to manage toxicities will be decided upon investigator’s 
judgment and should be discussed with the study medical monitor. 
Reference product; dose 
and mode of 
administration: 
Not applicable. 
Duration of treatment(s): 
Up to maximum 16 weeks. 
Determination of sample 
size: 
This is a pilot study and the sample size is based on practical rather than statistical 
aspects.  
A total of 12 patients will be included and treated in the study. With 12 patients 
included, it is estimated that 9 patients will complete at least 4 weeks of treatment, 
which is deemed sufficient to characterize the PK of pegcetacoplan in patients with 
TA-TMA to an appropriate precision. In addition, 12 patients will provide a 72 % 
probability to observe a response rate of at least 8 responders of the 12 patients 
recruited (assuming the true response rate is 70 %).    
Statistical methods: 
All endpoints will be evaluated with descriptive statistics. PK and PD may also be 
presented graphically. 
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able to align the date of a study visit with his/her pegcetacoplan administration schedule (e.g., if the patient has to utilize the visit window in order to be able to 
attend a study visit). In such instances it is important that pegcetacoplan dosing occurs according to the dosing schedule and not the visit schedule.  
d On the days of clinic visits, if pegcetacoplan is administered at the visit site, an assessment of the pegcetacoplan infusion site will be made as a part of the AE 
assessment. If pegcetacoplan is administered at the visit, the site staff will observe the dosing and pump use safety will be assessed. The infusion site will be 
checked again within 30 minutes after each study drug administration. The infusion-site assessments will be performed by an appropriately trained staff, as 
delegated by the investigator. The infusion site and surrounding area will be inspected for redness, swelling, induration and bruising. The patient will be asked 
about the presence of pain and/or tenderness, and any issue related to pump use. Patients will be instructed to notify the investigator or other study personnel if 
an infusion-site reaction occurs after self-administration of pegcetacoplan. 
e Vital signs (body temperature, respiration rate, heart rate, systolic and diastolic blood pressure measurements) will be evaluated per institutional practices. 
When pegcetacoplan is administered at the study site, vital signs will be measured within 2 hours before dosing and venipuncture (and ECG, if applicable), and 
at 30 minutes (± 5 min) postdose. 
f  On dosing Days 1, 3 and 5, PK samples will be taken up to 30 minutes predose and at 15 minutes (± 5 min), 30 minutes (± 5 min), 1 hour (± 10 min), 4 hours 
(± 10 min), 8 hours (± 30 min), and 24 hours (± 30 min) postdose. From Day 8 and onwards, PK samples will be taken predose at all other visits.  
g  Laboratory tests: refer to Table 3. Blood and urine samples will be analyzed at a central unless a local laboratory facility is necessary, as defined in the 
laboratory manual. Urine samples will be analyzed by dipstick and microscopic analysis. The use of silica agents should be avoided in patients treated with 
pegcetacoplan. 
h Samples that are confirmed positive for anti-pegcetacoplan peptide or anti-PEG antibodies will be characterized with an antibody titer for that specific 
antibody. Any samples that are confirmed positive for anti-pegcetacoplan peptide antibody will be further characterized with a neutralizing antibody assay. If a 
clinic visit is on a dosing day, the sample should be taken predose but otherwise a sample is still required.  
i Pre-HSCT evaluations will be accepted as screening tests. 
k β-HCG for women of childbearing potential and FSH for postmenopausal women. For women of childbearing potential, a serum pregnancy test will be 
performed at screening. Urine pregnancy tests will be performed at all subsequent site visits. Patients with positive results will be excluded or discontinued from 
the study.  
m All AEs occurring upon receiving the first IMP dose up to 8 weeks after last IMP administration must be recorded in the eCRF. SAEs will be reported from 
signing of the ICF up to 8 weeks after last IMP administration. New SAEs occurring at any time after the 8-week AE follow-up period up to EOS should be 
reported only if considered causally related to previous exposure to the IMP by the investigator. 
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o An EOT/ET visit will be performed 4 weeks after the last dose of pegcetacoplan. For patients who complete 12 weeks of treatment, the EOT visit will be at
Week 16, and there will be further follow-up visits at Weeks 20 and 24. For patients who complete 16 weeks of treatment, the EOT visit will be at Week 20 and
there will be a further follow-up visit at Week 24. The main analysis will be performed after all patients have completed their Week 24 visit.
p Blood collection for safety laboratory tests at Day 1 can be omitted if screening samples were collected on Day -1.Note: On dosing days, all blood samples will 
be collected predose. The date and time of the sample and the date and time of the previous dose of pegcetacoplan must be recorded in the eCRF. 
Note: Unscheduled additional visits may be performed at the investigator’s judgment. Any of the study procedures or other assessments may be performed at 
the unscheduled visit at the discretion of the investigator. 
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IB 
Investigator’s Brochure 
ICE 
Intercurrent event 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent ethics committee 
 
 
 
 
IMP 
Investigational medicinal product 
IRB 
Independent review board 
IRT 
Interactive response technology  
ITT 
Intent-to-treat 
LDH 
Lactate dehydrogenase 
LLN 
Lower limit of normal 
MAGIC 
Mount Sinai Acute Graft-versus-host disease International 
Consortium 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NOAEL 
No-observed-adverse-effect level  
PD 
Pharmacodynamic(s) 
PEG 
Polyethylene glycol 
 
 
PK 
Pharmacokinetic(s) 
PNH 
Paroxysmal nocturnal hemoglobinuria 
PRBC 
Packed red blood cells 
rUPCR 
Random urine protein/creatinine ratio  
s.c. 
Subcutaneous(ly) 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
sC5b-9 
Terminal complement complex (soluble) 
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Sobi 
Swedish Orphan Biovitrum AB (publ) 
SOC 
System organ class 
SRC 
Safety Review Committee 
TA-TMA 
Transplant-associated thrombotic microangiopathy 
TEAE 
Treatment-emergent adverse event 
TMA 
Thrombotic microangiopathy 
Tmax 
Time of the maximum measured serum concentration 
 
 
ULN 
Upper limit of normal 
VOD 
Veno-occlusive disease  
WHO-DD 
World Health Organization-Drug Dictionary 
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3 
Ethics 
3.1 
Independent ethics committee and/or institutional review board  
It is the responsibility of the investigator to obtain approval of the study protocol, possible 
amendments and the written patient information and ICF from the IEC/IRB. The investigator 
should file all correspondence with the IEC/IRB. Copies of IEC/IRB correspondence and 
approvals should be forwarded to Swedish Orphan Biovitrum (Sobi). 
3.2 
Ethical conduct of the study 
This study will be conducted in compliance with this protocol, the ICH GCP [1], applicable 
regulatory requirements, and in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki) [2]. 
3.3 
Patient information and consent 
It is the responsibility of the investigator to give each patient (or patient’s acceptable 
representative) prior to any study-related activities, full and adequate verbal and written 
information regarding the objective and procedures of the study and the possible risks involved. 
The patients must be informed about their right to withdraw from the study at any time. The 
written patient information and/or ICF must not be changed without prior discussion with Sobi. 
Before any revisions are implemented, the revised written patient information and/or ICF must 
be approved by the IEC/IRB. 
It is the responsibility of the investigator to obtain signed informed consent (or witnessed verbal 
consent according to applicable regulations) from all patients prior to any study-related activities. 
The patients should receive a copy of the written information and the signed ICF. 
4 
Introduction 
4.1 
Background 
TA-TMA is a life-threatening complication of HSCT characterized by microangiopathic 
hemolytic anemia, thrombocytopenia, and ischemic organ damage most commonly affecting the 
kidneys, lungs, CNS and the GI tract due to platelet clumping in the microcirculation [3].  
The incidence of TA-TMA varies widely, in part, due to the lack of standard diagnostic criteria. 
The reported incidence of TA-TMA following allogeneic transplant ranged from 0 % to 64 % in 
a review of 35 published case series, though 28 different diagnostic criteria were used [4,5]. 
Since 2005, several studies have proposed different algorithms to assist in the diagnosis of 
TA-TMA using various clinical and laboratory criteria [5,6,7,8]. However, frequently, TA-TMA 
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is clinically judged at an earlier stage before all these criteria are fulfilled, and most retrospective 
studies have been based on cases diagnosed by nonharmonized diagnostic criteria [9]. 
Diagnostic misjudgment may also be caused by the co-existence of other HSCT complications, 
such as infections, GVHD and VOD/sinusoidal obstruction syndrome, usually appearing in the 
acute phase after allo-HSCT when TA-TMA is most often observed [10]. The pathophysiology 
of TA-TMA differs substantially from that of idiopathic thrombotic thrombocytopenic purpura 
as evidenced by normal levels of ADAMTS13 [11] and a normal von Willebrand factor 
multimer pattern [12]. Endothelial injury is fundamental to the pathogenesis of TA-TMA, and 
the initiation of endothelial injury can be portrayed as a “2-hit” process consisting of generation 
of risk factors that create a procoagulant state during the preconditioning and an early aplastic 
phase post HSCT (infections, chemotherapy and radiotherapy, prolonged immobilization, human 
leukocyte antigen mismatch, unrelated donor), and subsequent exposure to conditions that 
facilitate injury during the recovery phase and beyond (calcineurin and mechanistic target of 
rapamycin inhibitors, acute GVHD, infections). The endothelial injury initiates the process of 
platelet aggregation and thrombus formation in the microvessels. These microthrombi lead to 
consumptive thrombocytopenia, affected organ failure and intravascular hemolysis [13]. 
Despite the broadened understanding of its pathogenesis and significant improvement in pre- and 
posttransplant supportive care, TA-TMA is still recognized as a devastating complication after 
allogeneic HSCT, exhibiting a mortality rate of up to 60 % to 75 % [6,14].  
4.2 
Study rationale 
Significant effort was made in recent years by researchers and physicians to better understand 
the complement role in the pathophysiology of TA-TMA [3].  
In 2015, the first prospective TA-TMA monitoring study was published by Jodele et al in 
100 children and young adults demonstrating that complement activation plays a significant role 
in the pathogenesis and severity of TA-TMA. This prospective study showed that recipients with 
HSCT with both proteinuria and terminal complement activation as measured by elevated 
plasma C5b-9 level had very poor 1-year HSCT survival (< 20 %), whereas patients without 
complement activation (normal plasma C5b-9) survived without any targeted interventions [3]. 
This initial research was followed with several valuable studies dedicated to the understanding of 
the complement system in TA-TMA pathogenesis, and investigating complement system as a 
diagnostic and therapeutic target [15,16,17]. Jodele et al also examined the possibility of genetic 
predisposition to TA-TMA by analyzing 17 candidate genes known to play a role in complement 
activation by using gene expression profiling. Totally, 65 % of patients with TA-TMA had 
genetic variants in at least 1 gene compared with 9 % of patients without TA-TMA. Patients at 
risk of developing TA-TMA likely have complement genetic polymorphisms that would not be 
significant under normal life circumstances, but complement activation can be provoked under 
adequate stressors of the transplantation process like chemotherapy, radiation, infections and 
medications. The complement system is activated by the stressors in susceptible individuals 
leading to vascular endothelial injury due to an activated terminal complement complex resulting 
in end-organ injury. All these data together indicate that HSCT-associated TMA is driven by 
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complement-mediated tissue injury and that complement dysregulation is not simply a marker of 
tissue injury incurred during transplantation [18]. 
There are no universally agreed on care strategies for TA-TMA after HSCT [18]. Treatment of 
TA-TMA is mostly supportive, including withdrawal or minimization of medication insult to 
endothelium, treatment of co-existing conditions such as infections and GVHD that may 
aggravate TMA and aggressive hypertension management. However, these interventions are 
successful only in nonsevere TA-TMA cases where the end-organ damage is not yet established 
[3,13]. A few pharmacologic agents like rituximab, defibrotide and daclizumab have been 
explored in TA-TMA with limited efficacy, and there are currently no approved drugs for this 
indication. Recently, several case reports and small studies have reported successful use of the 
C5 inhibitor eculizumab in TA-TMA [8,19,20]. However, eculizumab therapy in TA-TMA has 
some challenges, including difficulty in achieving therapeutic levels in critically ill patients, 
longer periods of induction therapy needed in many patients and limited availability in many 
countries [13]. A substantial unmet medical need exists for patients with TA-TMA. 
Pegcetacoplan is formed by a pentadecapeptide (combining a bioactive cyclic tridecapeptide C3 
inhibiting moiety and a 2–amino acid linker) covalently coupled to each end of a linear 40 kDa 
PEG chain, so that there are 2 active peptide moieties per molecule of pegcetacoplan. The 
peptide portion of the drug binds to complement C3 and is a broad modulator of the complement 
cascade, a biological process that is part of innate immunity and is involved in multiple 
inflammatory processes. The PEGylation of the molecule imparts slower elimination from 
mammalian systems following administration (see the pegcetacoplan IB). Pegcetacoplan has 
already proved to be effective in several clinical trials in complement-mediated hematological 
diseases (PNH, cold agglutinin disease). Pegcetacoplan received marketing approval in the US 
and EU for the treatment of adults with PNH in 2021, and further approvals have been obtained 
in Japan, Russia, Australia, and other countries in Europe, Asia, and Latin America. Moreover, 
on 06 May 2024, the indication in the EU was expanded to allow the treatment of adult patients 
with PNH who have hemolytic anemia. 
On the basis of scientific and clinical evidence on the role of complement activation in 
TA-TMA, it can be anticipated that pegcetacoplan, which acts through modulation of the 
complement system, has the potential to prevent the C3-mediated overactivation of complement 
pathways leading to endothelial injury and may represent a valid treatment strategy for patients 
with TA-TMA.  
4.3 
Potential risks and benefits 
Cumulatively, up to 13 May 2024, approximately 659 patients have been systematically exposed 
(via
 and s.c. route) to pegcetacoplan in completed and ongoing studies across multiple 
indications (refer to the pegcetacoplan IB). The administration of pegcetacoplan was well 
tolerated and the safety data did not indicate any significant safety concern. Nonetheless, a 
number of safety monitoring practices are being employed by this protocol to ensure patient 
safety, including physical examination, vital signs monitoring, ECGs, hematology (including 
coagulation), serum chemistry, urinalysis, and prompt reporting of AEs.  
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The event of hypersensitivity was identified as having a strong causal association with systemic 
pegcetacoplan. Cumulatively, in the systemic clinical development program for pegcetacoplan, 3 
SAEs were assessed as related by investigators and the sponsor. Two SAEs of hypersensitivity 
and one SAE of hypersensitivity pneumonitis have been reported. The SAEs occurred in Study 
APL2-PNH-204 (hypersensitivity), Study APL2-ALS-206 (hypersensitivity), and Study APL2-
302 (hypersensitivity pneumonitis). 
As with other complement-inhibiting drugs, there is a potential increased risk of infections with 
encapsulated pathogens including Streptococcus pneumoniae, Neisseria meningitidis 
(serogroups A, C, W, Y, and B), and Haemophilus influenzae Type B. Cumulatively in the 
systemic clinical development program for pegcetacoplan, 4 SAEs of infections associated with 
encapsulated bacteria have been reported. The 4 SAEs are comprised of 2 events of 
pneumococcal infection (1 pneumonia and 1 upper respiratory infection/epiglottitis), 1 event of 
pneumonia pneumococcal in Study APL2-C3G-310, and 1 event of Klebsiella pneumoniae in 
Study APL2-C3G-308. Three events of pneumococcal infections occurred in participants with 
renal disease; 2 of 3 were participants who had had a kidney transplant and were on 
immunosuppressive treatment. One case of Klebsiella pneumoniae occurred in a participant with 
PNH who had a history of medullary aplasia and pancytopenia. All cases were assessed as 
unrelated to pegcetacoplan by the sponsor. These cases were observed over 913.75 patient years 
of cumulative exposure in clinical studies (data until 13 May 2024, inclusive). The serious 
infections that were observed across studies were manageable. Therefore, the sponsor believes 
that the data do not support an increased risk of serious infections attributable to pegcetacoplan 
treatment.  
However, as a precautionary measure, to reduce the risk of infection, patients taking 
pegcetacoplan should be vaccinated against N. meningitidis (Types A, C, W, Y, and B) either 
within 2 years prior to Day 1 or if clinically feasible, according to institutional guidelines for 
immune reconstitution after HSCT. Patients should be re-vaccinated against H. influenzae 
Type B and S. pneumoniae if clinically feasible, according to institutional guidelines for immune 
reconstitution after HSCT. All patients must continue to be administered coverage with 
prophylactic antibiotics and antifungals according to institutional posttransplant infection 
prophylaxis guidance, including coverage against N. meningitidis, for the entire treatment period 
and for 8 weeks following the final dose of pegcetacoplan.   
Body temperature and vital signs will be monitored at all clinic visits and relevant blood 
parameters will be monitored throughout the study to assess for signs of infection. In the event of 
a suspected infection, the principal investigator should provide guidance on appropriate action to 
be taken.  
Infusion-site/pump safety will be assessed during clinical visits, and any significant finding from 
the assessment will be reported as an AE.  
Whenever possible, the study medical monitor will be contacted before interrupting or 
discontinuing treatment with IMP.  
Taking into account the measures taken to minimize risk to participants in this study, the 
potential risks identified in association with pegcetacoplan are justified by the anticipated 
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benefits that may be afforded to patients with TA-TMA for whom no valid alternative 
therapeutic options exist. 
More detailed information about the known and expected benefits, and risks and reasonably 
expected adverse events (AEs) of pegcetacoplan may be found in the pegcetacoplan IB.  
5 
Study objectives and endpoints 
5.1 
Primary objective  
The primary objective of this study is to evaluate the PK, safety and tolerability of pegcetacoplan 
in patients with TA-TMA. 
5.1.1 
Primary PK endpoints 
The primary PK endpoints of this study are the following: 
· Pegcetacoplan PK parameters:  
o AUC0-tau, Cmax, Tmax and Ctrough. 
5.1.2 
Safety endpoints 
The safety endpoints are as follows: 
· Occurrence of TEAEs. 
· Changes from baseline in laboratory parameters and vital signs. 
· Occurrence of clinically significant abnormal ECG findings. 
· Presence of antibodies to PEG and pegcetacoplan throughout treatment and follow-up 
periods. 
5.2 
Secondary objectives  
The following are the secondary objectives of this study: 
· To evaluate the PD of pegcetacoplan in patients with TA-TMA. 
· To evaluate the efficacy  of pegcetacoplan in patients with TA-TMA.  
5.2.1 
Secondary endpoints supporting the secondary objectives 
The secondary endpoints are as follows: 
· PD endpoints: 
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o Absolute levels, change from baseline, and % change from baseline to Week 24 in 
biomarkers of complement activation: sC5b-9, C3a, C3, Bb, C4a, functional 
assays for classical and alternative complement pathways. 
· Clinical response at Week 24, defined as improvement in laboratory markers and 
improvement in clinical status as follows: 
Improvement in laboratory markers:  
o LDH < 1.5 x ULN and  
o Platelet count  ≥ 50 000/mm3 without transfusion support during the prior 7 days. 
AND in patients with signs or symptoms of organ dysfunction at baseline, in addition 
to the above laboratory markers, at least 1 of the following clinical criteria needs to be 
fulfilled, depending on the organ/system involved at baseline as described in 
Section 6.5.1 (without appearance of new signs or symptoms of organ dysfunction in 
other organs not present at baseline): 
o Renal response – requires > 40 % reduction in creatinine, or normalization of 
creatinine, or discontinuation of renal replacement therapy, or ≥ 50 % reduction 
from baseline in rUPCR. 
o Pulmonary response – requires extubation and discontinuation of positive 
pressure ventilation. 
o GI response – applicable only to patients with biopsy-proven GI TA-TMA and 
requires improvement in GI function as determined by the MAGIC criteria (no or 
intermittent nausea, vomiting or anorexia attributed to TA-TMA for upper GI; 
stool output/day for lower GI as follows: < 500 mL/day or < 3 episodes/day) [21]. 
o Neurological response – requires improvement in reversible neurological 
conditions (e.g., cessation of seizures or controlled under medication, resolution 
of mental alteration; residual radiologic signs are acceptable without clinical 
symptomatology), or stabilization of irreversible neurological conditions (e.g., 
stability of neurological deficits following stroke without further deterioration or 
subsequent strokes). 
o Freedom from transfusion – requires absence of platelet or PRBC transfusions 
attributed to TA-TMA during the prior 7 days (only applicable if patient was 
undergoing platelet or PRBC transfusion at baseline). 
o Cardiovascular response – requires resolution of pulmonary hypertension (may 
receive anti-pulmonary hypertension medications if still on maintenance therapy), 
or hypertension control on no more than 2 medications excluding diuretics 
(applicable only to patients with severe hypertension at baseline). 
o Serositis response – requires no evidence of clinically significant pericardial or 
pleural effusion requiring surgical therapy (e.g., 
pericardiocentesis/thoracocentesis). 
Patients meeting intercurrent events, including use of prohibited medication or study 
withdrawal before Week 24, will be considered as failures/nonresponders. 
· TMA response at Week 24, defined as improvement in laboratory markers as follows: 
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o LDH < 1.5 x ULN and  
o Platelet count ≥ 50 000/mm3 without transfusion support during the prior 7 days 
and 
o ≥ 50 % reduction from baseline in rUPCR. 
· Overall survival at Day 100 from date of TA-TMA diagnosis. 
· Overall survival at Week 24 from treatment start. 
· Time to clinical response. 
· Time to TMA response. 
· Duration of clinical response. 
· Duration of TMA response. 
· TA-TMA relapse at Week 24.  
· Clinical response at Week 12. 
· TMA response at Week 12. 
5.3 
 
  
 
 
 
 
 
 
5.3.1 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
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6
Investigational plan
6.1
Overall study design and plan
This is a prospective, open-label, multicenter, single-arm, pilot study to evaluate the PK, PD, 
efficacy and safety of pegcetacoplan in patients with TA-TMA after HSCT.
The study will enroll 12 patients with TA-TMA, who will receive treatment with open-label 
pegcetacoplan at the planned dose indicated in Section 6.4.1.1.
The planned study duration for each patient is up to 24 weeks. The study will consist of the 
following periods: Screening period (up to 2 weeks), Treatment period (up to 16 weeks) and
Follow-up period (up to 12 weeks).
The main analysis will be performed after all patients have completed their Week 24 visit.
An SRC will assess the progress and cumulative PK and safety data of the study.
The study design is outlined in Figure 1, and the visit schedule and planned assessments at each 
visit are detailed in Table 1.
6.1.1
Screening period (up to 2 weeks)
Informed consent will be obtained at screening before any study-related procedures being
conducted. Patients will be screened to confirm that the patient selection criteria for the study 
have been met. Key inclusion and exclusion criteria will be reviewed by the study medical 
monitor and eligibility will be confirmed prior to the enrollment.
6.1.1.1
Retesting and rescreening
Patients who fail to qualify for the study on the basis of certain laboratory parameters may be 
retested and/or rescreened at the discretion of the investigator.
Retesting
Retesting is defined as repeating laboratory tests within the same screening period. 
Patients who initially fail to qualify for the study on the basis of laboratory test results not 
meeting inclusion criteria or due to technical issues (e.g., hemolysis, clotting) may have, at the 
discretion of the investigator, any individual laboratory parameter retested 1 time within the 
2-week screening period. Retesting within the 2-week screening period does not constitute 
rescreening; however, if retesting falls outside of the 2-week screening period, it should be 
considered rescreening (see below). 
Rescreening
Rescreening is permitted for patients who consent to participate in the study but who do not 
initially meet all the requirements as outlined in the inclusion and exclusion criteria. In this case, 
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additional screening visits and/or repeat screening assessments may be conducted, as needed, to 
establish eligibility. 
Screening is limited to 3 attempts (screening and 2 additional rescreening attempts).  
In the event that rescreening occurs and the patient has not remained in the screening period, the 
individual is required to reconsent and must be assigned a new identification number. 
6.1.1.2 
Screen failures 
Screen failures are defined as patients who consent to participate in the clinical study but who do 
not meet 1 or more criterion required for participation and are not subsequently entered in the 
study. A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure subjects, to meet the Consolidated Standards of Reporting Trials publishing 
requirements, and to respond to queries from regulatory authorities. Minimal information 
includes demography and reason for screen failure. 
6.1.2 
Treatment period (up to 16 weeks) 
 
 
  
At Week 12, if a clinical and/or TMA response according to the protocol definition is not 
reached, the investigator may decide to continue treatment, according to his/her judgment, for a 
total of 16 weeks of treatment. If at Week 12 the patient has reached a partial clinical response 
(defined as improvement in signs/symptoms in 1 or more affected organs without meeting the 
protocol definition of clinical response), 4 additional weeks of pegcetacoplan every 3 days will 
be administered to complete 16 weeks of treatment.  
At any time after the first 3 weeks of treatment, in the event of significant clinical worsening 
associated with active laboratory TMA (as defined in Section 6.1.2.1), the patient may be 
discontinued from study treatment and receive rescue therapy. In case of earlier clinical 
worsening, it is recommended to wait  until at least 3 weeks of treatment are completed to allow 
pegcetacoplan to reach the target exposure and exert a clinical effect; however, if deemed by the 
investigator that the patient’s safety is at risk, the patient can be discontinued from study 
treatment at any time. Discontinued patients will remain on study and will be followed for 
survival until the end of the study. 
Any concomitant TA-TMA directed therapy will be prohibited for the entire treatment period, 
including plasma-exchange, defibrotide and any other complement inhibitor. 
6.1.2.1 
Clinical worsening 
Clinical worsening will be defined as active laboratory TA-TMA as per Inclusion Criterion #3 
(see Section 6.3.1) and 3 of the 5 organ injuries listed below: 
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a. Kidney: requirement of renal replacement therapy after initial TA-TMA control, 
sustained (> 7 days) and attributable to TA-TMA. 
b. Lungs: requirement of sustained (> 7 days) positive pressure ventilation, and attributable 
to TA-TMA. 
c. Cardiovascular: uncontrolled severe hypertension with > 2 medications (excluding 
diuretics), and attributable to TA-TMA. 
d. CNS: uncontrolled seizures under medication attributable to posterior reversible 
encephalopathy syndrome or to hypertension resulting from TA-TMA. 
e. GI tract: clinically significant GI bleeding requiring ≥ 20 mL/kg/day of PRBC 
transfusion daily for at least 7 days. 
6.1.3 
Follow-up period (up to 12 weeks) 
After completion of the treatment period, all patients will enter in the follow-up period until 
Week 24. This includes an End of treatment visit 4 weeks after the last IMP dose and 1 or 2 more 
follow-up visits every 4 weeks for patients who have completed 16 or 12 weeks of treatment, 
respectively. The main analysis will be performed after all patients have completed their Week 
24 visit. 
6.1.4 
Unscheduled visits 
Unscheduled additional visits may be performed at the investigator’s judgment. Any of the study 
procedures or other assessments may be performed at the unscheduled visit at the discretion of 
the investigator. 
6.1.5 
Stopping criteria 
In the context of this study, the term toxicity means clinically significant drug related adverse 
reaction(s). In case of serious toxicity defined as a Grade 4 to 5 SAE, an ad hoc SRC meeting 
will be held within 24 hours after Sobi awareness of the AE. The SRC will decide on the impact 
on an individual or entire study level, continue study unchanged, continue study with 
modifications, or to put the study on hold.  
Standard toxicity grading according to the NCI-CTCAE are used to grade AEs and to decide on 
suspension level:  
· The study will be halted if a patient develops a Grade 5 SAE suspected to be IMP related.  
· The treatment will be halted if 2 patients experience a similar drug-related Grade 4 SAE.  
· Study treatment will be discontinued on an individual level if assessment by an ad hoc 
SRC or the investigator conclude significant risk to the patient’s safety. 
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Grade 4 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
Death 
6.2 
Discussion of study design 
This study will be the initial exploration of pegcetacoplan in patients with TA-TMA. The 
assessments of the PK, PD, safety and efficacy following administration of 
 induction doses 
followed by s.c. maintenance doses 
 will guide decisions to further develop the drug.  
The proposed inclusion criteria of the study will ensure that only patients who have not 
responded to first-line management of TA-TMA including withdrawal or minimization of 
medication insult to endothelium such as immunosuppressants and treatment of co-existing 
conditions such as infections and GVHD are enrolled.  
Measures will be taken to minimize risk to participants in this study, including recommendation 
for vaccination against encapsulated pathogens, mandatory administration of prophylactic 
antibiotics and measurement of antibodies, apart from standard safety assessments. 
6.3 
Selection of study population 
6.3.1 
Inclusion criteria 
A patient must fulfill the following criteria in order to be included in the study: 
1. Male and female patients aged ≥ 18 years at the time of ICF signature. 
2. Received allogeneic HSCT from a related or unrelated, human leukocyte 
antigen-matched or mismatched donor. Patients having received any of the following 
stem cell sources are eligible: granulocyte colony stimulating factor mobilized peripheral 
blood stem cells, bone marrow, umbilical cord blood. 
3. Diagnosis of TA-TMA established as per the laboratory markers below, indicating TMA:  
a. De novo or progressing thrombocytopenia (platelet count < 50 x 109/L or > 50 % 
decrease in platelet count from the highest value achieved after transplantation). AND 
b. Elevated LDH (> 1.5 x ULN). 
AND at least 2 additional laboratory/clinical criteria among the following: 
c. Presence of schistocytes on the peripheral blood smear (≥ 2 per hpf) or histologic 
evidence of microangiopathy in any biopsied organ. OR 
d. De novo anemia (hemoglobin < LLN or anemia requiring PRBC transfusion support 
as per local institutional standard). OR 
e. Proteinuria (random urinalysis protein concentration ≥ 30 mg). OR 
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f. Elevated plasma concentration of sC5b-9 above ULN. OR 
g. Arterial hypertension, defined by systolic BP ≥ 140 mmHg and/or diastolic BP 
≥ 90 mmHg. 
4. Have a diagnosis of TA-TMA that persists despite initial management of any triggering 
condition. 
5. Have a rUPCR ≥ 1 mg/mg.  
6. Women of childbearing potential, defined as any women who have experienced 
menarche and who are NOT permanently sterile or postmenopausal, must have a negative 
serum pregnancy test at screening and agree to use protocol-defined methods of 
contraception for the duration of the study and 8 weeks after their last dose of IMP. 
Note: Postmenopausal is defined as having had 12 consecutive months with no 
menses without an alternative medical cause. 
7. Men must agree to the following for the duration of the study and 8 weeks after their last 
dose of IMP: 
a. Avoid fathering a child. 
b. Use protocol-defined methods of contraception. 
c. Refrain from donating sperm. 
8. Patient and/or legally authorized representative must be capable of giving signed 
informed consent, which includes compliance with the requirements and restrictions 
listed in the ICF. 
6.3.2 
Exclusion criteria 
The presence of any of the following will exclude a patient from inclusion in the study: 
1. Positive direct Coombs test. 
2. Known familial or acquired ADAMTS13 deficiency. 
3. Known Shiga toxin‐related hemolytic uremic syndrome. 
4. Known bone marrow or graft failure. 
5. Diagnosis of disseminated intravascular coagulation. 
6. Diagnosis of VOD. 
7. Active GI bleeding (hematemesis or hematochezia) at baseline.  
8. Body weight < 30 kg and > 100 kg. 
9. Uncontrolled systemic bacterial or fungal infection, presence or suspicion of sepsis.  
10. Previously or currently treated with a complement inhibitor (approved or investigational). 
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11. Pregnancy or breastfeeding. 
12. Positive human immunodeficiency virus antibody at screening or documented in 
pre-HSCT medical record. 
13. Hepatitis C virus detectable by polymerase chain reaction at screening or documented in 
pre-HSCT medical record.  
14. Chronic inactive hepatitis B virus with viral loads > 1000 IU/mL (> 5000 copies/mL) at 
screening or documented in pre-HSCT medical record. Eligible patients who are chronic 
active carriers (≤ 1000 IU/mL) must receive prophylactic antiviral treatment 
(e.g., entecavir, tenofovir, lamivudine) according to local country guidelines. 
15. Known or suspected hereditary fructose intolerance. 
16. Hypersensitivity to pegcetacoplan or any of its excipients. 
17. Inability to cooperate with study procedures or any condition that, in the opinion of the 
investigator, could increase the patient’s risk by participating in the study or confound the 
outcome of the study. 
6.3.3 
Withdrawal of patients from treatment or study 
6.3.3.1 
Discontinuation from treatment 
A patient should be discontinued from the study treatment if, in the opinion of the investigator, it 
is medically necessary, or if it is the wish of the patient. See treatment stopping criteria in 
Section 6.1.5. 
Study treatment must be discontinued if a female patient becomes pregnant. 
When a patient is discontinued from treatment, the study site must immediately notify the 
medical monitor, the date of last IMP dose, and the date and reason for treatment withdrawal 
should be clearly described in the relevant sections of the eCRF. If a patient is removed from 
treatment because of an AE, the reason for treatment withdrawal should always be stated as 
‘adverse event’ irrespective of whether this was the investigator’s or the patient’s decision. 
When patients are discontinued from treatment, every effort should be made to continue their 
participation in the study without taking study treatment. Discontinued patients will be followed 
for survival until the end of the study. Patients who stop study treatment prior to the exit visit 
should undergo all follow-up visits and procedures through study completion, unless consent has 
been withdrawn (see Table 1).  
6.3.3.2 
Withdrawal from study 
A patient may withdraw from the study at any time at his/her own request or at the request of 
their legally authorized representative, or may be withdrawn at any time at the discretion of the 
investigator for safety, behavioral, compliance, or administrative reasons. This is expected to be 
uncommon. Whenever possible and irrespective of the reason for withdrawal, the patient should 
be examined as soon as possible. Relevant samples should be obtained, and all relevant 
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assessments should be completed. The eCRF should be completed as far as possible. Date and 
reason for the study withdrawal should be clearly described in the eCRF. 
Once a patient leaves the study, he/she may not reenter the study. 
6.3.3.3 
Lost to follow-up 
A minimum of 3 documented attempts must be made to contact any patient lost to follow-up at 
any point prior to the last scheduled contact (office visit or telephone contact). At least 1 of these 
documented attempts must include a written communication sent to the patient’s last known 
address via courier or mail (with an acknowledgment of receipt request) asking that the patient 
return to the site for final safety evaluations and to return any IMP. 
Should the patient continue to be unreachable, they will be considered to have withdrawn from 
the study. 
6.3.4 
Replacement of withdrawn patients 
Withdrawn patients will not be replaced. 
6.3.5 
Specific restrictions/requirements 
6.3.5.1 
Acceptable methods of contraception 
Acceptable methods of contraception include: 
· Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
o 
Oral, intravaginal or transdermal. 
· Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o 
Oral, injectable or implantable. 
· Intrauterine device. 
· Intrauterine hormone-releasing system. 
· Bilateral tubal occlusion. 
· Vasectomized partner (provided that the partner is the sole sexual partner of the women 
of childbearing potential trial participant and the vasectomized partner has received 
medical assessment of the surgical success). 
· Sexual abstinence (defined as refraining from heterosexual intercourse during the entire 
period of risk associated with study treatments). 
· Male condom, with or without spermicide (for male study patients with female partners 
of childbearing potential only). 
Not all methods of contraception may be available in all of the countries in which the study is 
being conducted. 
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Note: Sexual abstinence is accepted only when it is the preferred and usual lifestyle of the 
patient. 
Patients must agree to use an acceptable method of contraception during the study and for 
8 weeks after their last dose of IMP.  
Male patients will be counseled to avoid donating semen during the time between the first 
screening and the final exit visit and for the 8 weeks after their last dose of IMP. 
6.4 
Treatments 
6.4.1 
Treatments administered  
6.4.1.1 
Investigational medicinal products 
All patients will receive open-label pegcetacoplan.  
Table 2 
Investigational medicinal product 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
6.4.2 
Identity of investigational medicinal products 
The IMP is pegcetacoplan, which will be provided as a sterile solution of pegcetacoplan at 
 
provided in single-use stoppered glass vials. Additional information is provided in the 
pegcetacoplan IB.  
Possible deficiencies related to the handling and quality of the IMP(s) should be reported to the 
study monitor and also directly to complaints@sobi.com. 
6.4.2.1 
IMP packaging and labeling 
The IMP is supplied in 20-cc glass vials. Please refer to the pharmacy manual for details.  
All IMP will be packaged and labeled in accordance with all applicable regulatory requirements 
and Good Manufacturing Practice guidelines. 
Changes to sponsor-supplied packaging prior to administration may not occur without full 
agreement, in advance, by the sponsor. 
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6.4.2.2 
IMP storage and handling 
The IMP should be stored refrigerated at 2 °C to 8 °C, both at home and in the clinic. 
Temperature monitoring is required at the investigator site (or documented storage location) to 
ensure that the IMP is maintained within an established temperature range.  
The investigator or appropriately qualified site staff will be responsible for the following 
activities: 
· Ensuring that the IMP is stored in a secure, limited-access location at the site. 
· Ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained. 
Limited responsibility may be delegated to the pharmacy or to another member of the study 
team, but this delegation must be documented. 
A pharmacist or appropriately qualified designated person will be responsible for the following: 
· Storing the IMP appropriately. 
· Dispensing the IMP vials to the patient and entering the unique subject identifier as 
appropriate. 
When the patient receives the IMP from the site, it should be transported in a sponsor-approved 
bag or box containing previously temperature-conditioned cold plates to ensure that the storage 
temperature (2 °C to 8 °C) is maintained. Temperature monitoring will not be required during 
transport or at the patient’s residence, but a log will be kept for every infusion to ensure that all 
IMP was kept refrigerated. 
6.4.3 
Method of assigning patients to treatment groups 
This is a single-arm, open-label study.  
All patients who meet all the inclusion criteria and none of the exclusion criteria will be enrolled 
in the study after eligibility review by the study medical monitor, and will receive a unique 
subject identifier through an IRT system. 
6.4.4 
Selection of doses 
  
 
 
 
 
 
 
 
 
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6.4.5 
Selection and timing of doses for each patient 
 
  
Pegcetacoplan 
 will also be administered by the investigator’s site staff as long as 
the patient is hospitalized. If deemed by the investigator that a patient can be discharged from 
hospital upon clinical improvement, pegcetacoplan administration will occur at home. Patients 
will self-administer s.c. IMP, after receiving appropriate training by research personnel.  
When the patient’s pegcetacoplan dosing schedule aligns with study visit days, pegcetacoplan 
should be administered at the study site and the study procedures should be completed as 
outlined in this protocol (Table 1). In some instances, however, a patient may not be able to align 
the date of a study visit with his/her pegcetacoplan administration schedule (e.g., if the patient 
has to utilize the visit window in order to be able to attend a study visit). In such instances it is 
important that pegcetacoplan dosing occurs according to the dosing schedule and not the visit 
schedule.  
Patients will be instructed to self-administer pegcetacoplan only as prescribed and to contact the 
investigator immediately for guidance in the event of any missed doses. 
Dosing diaries will be used for study treatment and are to be completed for each dose 
administered at the clinic or at home. Patients should not deviate from the every-3-days dosing 
schedule. 
The preferred site of s.c. infusion will be the abdomen. If administration into the abdomen is not 
feasible, alternative appropriate sites are acceptable (see the Pump Instructions for Use document 
for more details).  
Pegcetacoplan will be administered using a syringe pump. Details of infusion volume and time 
will be detailed in the pharmacy manual. 
During initial qualification, a research nurse or other appropriately qualified research personnel 
will administer the s.c. infusions (as needed) and will qualify and supervise the 
self-administration or caregiver administration. These qualified research personnel will be made 
available for a minimum of 6 days on treatment (2 doses) to ensure the patient has been qualified 
to conduct self-administration; the duration can be shortened if qualification happens sooner. 
During qualification, the patient or caregiver must demonstrate to the research personnel their 
ability to safely and effectively administer the IMP using the infusion pump. Following 
self-administration or caregiver administration qualification, patients or caregivers may 
self-administer the s.c. infusions without supervision. Once qualified, the patient or caregiver 
will continue to administer infusions at the clinic on those days when a clinic visit occurs and at 
an off-site location convenient to the patient on all other days. Self-administration or caregiver 
administration conducted at the clinic will be supervised to ensure that the patient or caregiver 
continues to remain compliant with the administration guidelines.  
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Missed doses will be handled on a case-by-case basis between the investigator and medical 
monitor, with the general approach being to administer a missed dose as soon as noticed, unless 
the next dose has already been administered. 
NOTE: If the patient or caregiver requires further training, the self-administration qualification 
period may be extended beyond 6 days on treatment (2 doses). Caregiver administration may be 
conducted by a member of the patient’s household, a family member, etc, who will undergo the 
same qualification criteria (qualification is not intended to be restricted to the patient).  
6.4.6 
Dose modification 
No dose modification is foreseen in this study. Treatment interruption or discontinuation 
necessary to manage toxicities will be decided upon investigator’s judgment and should be 
discussed with the study medical monitor. 
6.4.7 
Infusion supplies  
The sponsor will supply syringes, vial adapters, infusion sets, ambulatory syringe infusion 
pumps, and any other supplies needed for the safe home IMP administration as required. Refer to 
the pharmacy manual for further details. 
6.4.8 
Blinding and unblinding 
Not applicable. 
6.4.9 
Prior and concomitant therapy 
Other therapy considered necessary for the patient’s welfare may be given at the discretion of the 
investigator. All such therapy must be recorded in the eCRF. 
All medications administered and procedures performed within 12 weeks of the first IMP dose 
through the end of study visit will be recorded. Those that stop before first IMP dose will be 
regarded as prior medications and procedures. Medications administered and procedures 
performed that are ongoing at the time of first IMP dose or start after first IMP dose are regarded 
as concomitant and will be documented as such. Prior and concomitant medication information 
must be recorded on the appropriate eCRF page.  
With the exception of prohibited medications, any concomitant medications deemed necessary 
for the patient’s standard of care or wellbeing during the study or for the treatment of any AE 
may be given at the discretion of the investigator. It is the responsibility of the investigator to 
ensure that the details regarding all medications are recorded in full in the patient’s eCRF.  
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6.4.9.1 
Permitted concomitant therapy 
All medications already taken at study entry for other indications will be allowed (e.g., 
rituximab). 
All patients must continue to be administered coverage with prophylactic antibiotics and 
antifungals according to institutional posttransplant infection prophylaxis guidance, including 
coverage against N. meningitidis the entire treatment period and for 8 weeks following the final 
dose of pegcetacoplan. 
6.4.9.2 
Prohibited medications 
Other than pegcetacoplan, any therapy for TA-TMA is prohibited during patient’s participation 
in the study, including: 
· Defibrotide. 
· Any other complement inhibitor (e.g., eculizumab, ravulizumab, or narsoplimab). 
· Plasma-exchange. 
6.4.10 
Treatment compliance 
Dosing diaries will be utilized for pegcetacoplan and are to be completed for each dose 
administered at the study site or outside regular clinic visits. Patients should not deviate from 
their dosing schedule. 
When patients are dosed at the site, they will receive pegcetacoplan directly from the investigator 
or designee, under medical supervision. The date and time of each dose administered in the clinic 
will be recorded in the source documents and recorded in eCRF. The dose of pegcetacoplan and 
study patient identification will be confirmed at the time of dosing by a member of the study site 
staff other than the person administering the study intervention. 
When patients self-administer pegcetacoplan at home, compliance will be assessed at each visit. 
Patients must be instructed to bring their empty/partially used/unused IMP packaging to every 
visit in case of home administration. Compliance will be assessed during the site visits and 
documented in the source documents and eCRF. The pharmacist/designee will record details on 
the drug accountability form. Refer to the pharmacy manual for further details. 
6.4.11 
IMP accountability 
Accountability and maintenance of the IMP at the study center is the responsibility of the 
investigator. The investigator will ensure that the IMP is used only in accordance with this study 
protocol. Where allowed, the investigator may choose to delegate drug accountability 
responsibilities to a pharmacist or other appropriate individual. 
Investigators will be provided with the IMP to carry out this protocol for the agreed number of 
patients. The investigator/designee will acknowledge receipt of the IMP, and documenting 
shipment contents and conditions. Accurate records of all IMP dispensed, used/unused, returned, 
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and/or destroyed must be maintained. Accountability records will include dates, quantities, 
batch/serial numbers, expiration dates (if applicable), and participant numbers. The 
sponsor/designee will review IMP accountability at the study center on an ongoing basis during 
monitoring visits. The IMP must not be used for any purpose other than the present study. IMP 
that has been dispensed to a patient and returned unused must not be re-dispensed to a different 
patient. 
The investigator is responsible for ensuring the retrieval of all returnable study supplies from 
patients. 
6.4.12 
IMP disposal 
All unused and used IMP vials should be retained at the center until accountability and 
reconciliation has been performed by the study monitor. At the end of the treatment period, any 
unused IMP will either be destroyed at the investigator site or be returned to the 
sponsor/designee for destruction, and destruction will be documented appropriately. If no 
supplies remain, this fact will be documented appropriately. 
6.5 
Baseline, efficacy, safety, pharmacokinetic, pharmacodynamic 
and pharmacogenetics assessments 
6.5.1 
Medical history 
Medical history will be recorded at screening. Investigators should document the occurrence, 
signs, and symptoms of the patient’s preexisting conditions, including all prior significant 
illnesses, up to and including 1 year before enrollment in the study. Additional preexisting 
conditions that started before and are ongoing at the date of enrollment are to be regarded as 
current medical conditions. Medical history will include alcohol consumption and smoking 
history, if applicable.  
Information about HSCT and related complications will be also collected, including underlying 
disease diagnosis; donor type; HLA mismatch; stem cell source; type and start date of 
conditioning regimen; conditioning medications; date of transplant; transplant manipulation; 
donor chimerism; date of confirmed engraftment; GVHD date of onset; GVHD grade according 
to the International Bone Marrow Transplant Registry severity Index [22]; presence of 
infections; presence of donor specific antibodies; posttransplant treatments and date (e.g., donor 
lymphocyte infusion, stem cell boost, growth factors; infusion of antiviral T cells); GVHD 
prophylaxis. 
Information about TA-TMA will be collected including date of diagnosis (defined as the earliest 
date when all required laboratory criteria outlined in Inclusion Criterion #3 are met); diagnostic 
laboratory markers; initial management; and  presence of signs and symptoms of end organ 
injury. 
Baseline end organ injury will be evaluated as follows, with associated medications: 
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a. Kidney: doubling of serum creatinine compared with pre-HSCT level or patient receiving 
renal replacement therapy or proteinuria ≥ 30 mg/dL OR rUPCR ≥ 1 mg/mg. 
b. Lungs: hypoxemia or any need for noninvasive or invasive positive pressure ventilation. 
c. Cardiovascular: pulmonary hypertension diagnosed by a cardiologist using cardiac 
catheterization, or pulmonary hypertension criteria on echocardiography or arterial 
hypertension, defined by systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg at 
baseline or hypertension requiring > 2 medications (excluding diuretics). 
d. Serositis: clinically significant pleural effusion or pericardial effusion requiring surgical 
therapy (e.g., pericardiocentesis/ thoracocentesis). 
e. CNS: seizures attributable to posterior reversible encephalopathy syndrome. 
f. GI tract: presence of biopsy-proven GI TA-TMA. Patients with GI bleeding (hematemesis or 
hematochezia) will be excluded. 
Illnesses first occurring or detected during the study and worsening of a concomitant illness 
during the study are to be documented as AEs on the eCRF in accordance with Section 6.5.5.1.2. 
6.5.1.1 
Vaccines medical history 
Patients should be vaccinated against N. meningitidis (Types A, C, W, Y, and B) either within 
2 years prior to Day 1 or, if clinically feasible, according to institutional guidelines for immune 
reconstitution after HSCT. Patients should be re-vaccinated against H. influenzae Type B and 
S. pneumoniae, if clinically feasible, according to institutional guidelines for immune 
reconstitution after HSCT. Received vaccines with dates will be recorded in the eCRF. 
6.5.2 
Demography 
Demographic data, including age, sex, race and ethnicity, will be collected for all patients, as 
allowed, per applicable regulations and recorded in the eCRF. 
6.5.3 
Biopsy samples of affected organs 
Diagnosis of TA-TMA may be established by histologic evidence of microangiopathy in any 
biopsied organ. Biopsy of affected organs is optional. In the case that any biopsy sample results 
are available prior to screening (up to 1 month before), these results can be used to confirm 
diagnosis. 
6.5.4 
Pharmacokinetic assessments 
Blood sampling and processing blood samples for the PK assessment of pegcetacoplan will be 
collected via direct venipuncture at the time points outlined in the schedule of assessments 
(Table 1). Should the patient have a central catheter already in place, in order to minimize patient 
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discomfort, the central line can be used to collect PK samples, except for the 15 and 30 minutes 
postdose samples.
On dosing Days 1, 3 and 5, PK samples will be taken up to 30 minutes predose and at 15 minutes 
(± 5 min), 30 minutes (± 5 min), 1 hour (± 10 min), 4 hours (± 10 min), 8 hours (± 30 min),  and 
24 hours (± 30 min) postdose. From Day 8 and onwards, PK samples will be taken predose at all 
other visits.
Instructions for collection, handling, processing, storage and shipping of samples will be 
provided in a separate sample handling manual prior to study initiation.
Serum sample analysis will be performed using validated liquid chromatography tandem mass 
spectrometry methods. The methods used and the results obtained will be included in the CSR as 
an appendix.
6.5.4.1
Pharmacokinetic parameters
PK parameters for pegcetacoplan will be computed from the individual serum concentration-time 
data, using actual sample times using a non-compartmental approach. Appropriate validated PK 
software (e.g., Phoenix WinNonlin®) will be used.
The following PK parameters will be calculated:
 induction phase:
·
AUC0-tau: area under the concentration-time curve over the dosing interval.
·
Cmax: maximum observed serum concentration. 
·
Tmax: time of the maximum measured serum concentration. If the maximum value occurs 
at more than 1 time point, Tmax is defined as the first time point with this value. 
s.c. maintenance phase:
·
Ctrough: observed serum concentration predose.
6.5.5
Safety assessments
6.5.5.1
Adverse events
Definitions
Adverse event
An AE is any untoward medical occurrence in a patient or study patient administered a 
pharmaceutical product; the event does not necessarily have a causal relationship with the 
treatment or usage.
AEs include the following:
·
Abnormal test findings, as specified below.
·
Changes in physical examination findings.
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· Progression/worsening of underlying disease. 
· Signs and symptoms resulting from overdose, withdrawal of treatment, drug-drug 
interactions, abuse and misuse. 
· Increase in frequency or intensity of a preexisting episodic disease or medical condition. 
· Disease or medical condition detected or diagnosed during the course of the study even 
though it may have been present prior to the start of the study. 
· Continuous persistent disease or symptoms present at study start that worsen following 
the start of the study. 
For pregnancies and breastfeeding, see Section 6.5.5.1.5. 
Abnormal test findings 
An abnormal test finding, e.g. abnormal laboratory analysis results, vital signs or ECG, should be 
recorded as an AE in any of the following situations: 
· The investigator considers the abnormal test finding to be clinically significant. 
· The abnormal test finding leads to a medical/surgical intervention including withdrawal 
of IMP(s) or discontinuation from the study. Repeat/confirmatory testing is not 
considered a medical intervention. 
Preexisting conditions  
A preexisting condition (i.e., a disorder present before the AE reporting period started and noted 
on the pretreatment medical history/physical examination form) should not be reported as an AE 
unless the condition worsens or episodes increase in frequency during the AE reporting period.  
AEs diagnosis versus signs/symptoms 
For any AE, a diagnosis should be recorded rather than individual signs and symptoms or 
abnormal laboratory findings. However, if at the time of AE reporting a diagnosis is not 
available, each individual sign/symptom should be recorded. If a diagnosis is subsequently 
established, all previously reported AEs based on signs and symptoms should be removed and 
replaced by one AE report based on the single diagnosis, with a starting date that corresponds to 
the start date of the first symptom of the eventual diagnosis. 
Procedures 
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not be 
reported as AEs. However, the medical condition for which the procedure was performed should 
be reported if it meets the definition of an AE. For example, an acute appendicitis that begins 
during the AE reporting period should be reported as the AE and the resulting appendectomy 
entered in the comments section of the eCRF. 
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Treatment-emergent adverse event 
A treatment-emergent AE is any AE temporally associated with the use of study treatment, i.e., 
from study treatment initiation until 8 weeks after study treatment discontinuation. 
Serious adverse event 
An AE that meets one or more of the following criteria/outcomes is classified as serious: 
· Results in death. 
· Is life-threatening (i.e., at immediate risk of death). 
· Requires in-patient hospitalization or prolongation of existing hospitalization. 
· Results in persistent or significant disability/incapacity. 
· Is a congenital anomaly/birth defect (i.e., in an offspring to the study patient). 
· Is a medically important AE. 
Medically important AEs are events that may not result in death, be life-threatening, or require 
hospitalization but may be considered serious when, based upon appropriate medical judgment, 
may jeopardize the patient or patient or may require medical or surgical intervention to prevent 
one of the outcomes listed above. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse. 
Serious also includes any other event that the investigator or company judges to be serious. Any 
suspected transmission of an infectious agent via IMP shall also be considered serious. 
Hospitalization 
In general, hospitalization means that the patient has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician's office or outpatient setting. When in doubt as to 
whether hospitalization occurred or was necessary, the AE should be considered serious. 
The following situations are not considered hospitalizations (although other SAE criteria may 
still apply): 
· Outpatient procedures/ambulatory care. 
· Emergency department visits. 
Hospitalization in the absence of an AE occurring during the study should not be considered an 
SAE. This includes: 
· Pre-planned hospitalization due to a preexisting condition not associated with a 
worsening of the preexisting condition. 
· Protocol specified admission. 
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·
Elective admission, e.g. due to cosmetic surgery.
Complications that occur during hospitalization should not be considered SAEs unless the 
complication prolongs hospitalization.
Suspected unexpected serious adverse reaction 
A SUSAR is an untoward and unintended response to a study drug that is not listed in the 
reference safety information of the IB, meets at least 1 of the seriousness criteria, and is assessed 
as causally related to the IMP.
Adverse event reporting period
The AE/SAE reporting period will be as follows: 
Screening period: Any SAEs occurring between signing of the ICF and the first IMP dose should 
be reported to Sobi.
Treatment period: All AEs (including SAEs) occurring upon receiving the first IMP dose up to 
8 weeks after last IMP administration must be recorded in the AE pages of the eCRF. In 
addition, SAEs should be reported to Sobi.
Follow-up period: New SAEs occurring at any time after the 8-week AE follow-up period up to 
EOS should be reported to Sobi only if considered causally related to previous exposure to the 
IMP by the investigator. These SAEs are only entered in the drug safety database and, hence, 
will not affect study closure.
Obtaining and recording adverse event information
The investigator obtains AE information that is directly observed or solicited from the patient or 
patient relative during the course of the study. All AEs must be recorded in the eCRF using 
concise medical terminology. 
The investigator is responsible for obtaining sufficient information to determine seriousness, 
causality and outcome of each AE.
Severity assessment
The investigator will use the adjectives MILD, MODERATE, or SEVERE to describe the 
maximum severity of the AE. For the purpose of consistency, these severity grades are defined 
as follows: 
MILD
Does not interfere with patient's usual function
MODERATE
Interferes to some extent with patient's usual function
SEVERE
Interferes significantly with patient's usual function
Note the distinction between the gravity (seriousness) and the severity of an AE. Severe is a 
measure of intensity; thus, a severe event is not necessarily a serious event. For example, a 
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headache may be severe in intensity, but would not be classified as serious unless it met one of 
the criteria for serious events listed above.
Causality assessment
For each AE, the investigator must make a causality assessment to determine whether there is a 
reasonable possibility that the IMP(s) caused the AE. The AE is assessed as related or 
not related to the IMP(s). 
Serious adverse event reporting
Both serious and nonserious AEs are to be reported on the AE page of the eCRF as specified in 
the eCRF instructions.
In addition, all SAEs must be reported by the investigator to the Sobi Global Pharmacovigilance 
& Patient Safety within 24 hours of the investigator’s first knowledge of the event.
If an SAE occurs, it is to be reported by e-mail (e-mail address is indicated on the SAE form) 
using the designated Serious Adverse Event form.
The SAE collection form is not always the same as the AE eCRF form. The forms must be 
completed in a consistent manner. For example, the same AE term should be used on both forms.
All new information obtained, relevant to an SAE report, should be forwarded to Sobi Global 
Pharmacovigilance & Patient Safety within the same timeframe as the initial information.
If the patient is hospitalized in a hospital other than the study site, it is the investigator’s 
responsibility to contact this hospital to obtain all SAE-relevant information and documentation.
New SAEs occurring after the 8-week AE follow-up period must be reported to Sobi Global 
Pharmacovigilance & Patient Safety within 24 hours of the investigator’s knowledge of the 
event, only if considered causally related to previous exposure to the study treatment by the 
investigator.
The investigator shall provide Sobi Global Pharmacovigilance & Patient Safety with sufficient 
information to enable a complete medical assessment of the reported event. Best efforts shall be 
made by the investigator to provide Sobi Global Pharmacovigilance & Patient Safety with 
additional information related to any SAE as requested.
The reference safety document to assess expectedness of a suspect serious adverse reaction and 
reported by the sponsor to Health Authorities, IRBs/IECs, and investigators is the reference 
safety information section of the IB.
Exposure during pregnancy and breastfeeding
If a woman becomes pregnant while on study treatment, study treatment must be discontinued. 
The investigator must counsel the patient and discuss the risks of continuing with the pregnancy 
and the possible effects on the fetus.
Any pregnancy occurring after study initiation (i.e., signing of ICF) up to 8 weeks following 
study treatment discontinuation must be reported within 24 hours of the investigator’s 
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knowledge of the event. This includes all situations where a woman is or has been found to be 
pregnant after being exposed to IMP ‒ directly, indirectly or via her partner (paternal exposure).
All events of exposure to the IMP during pregnancy (female patient or male patient’s partner) or 
breastfeeding, whether the exposure is associated with an AE or not, shall be reported to Sobi 
Global Pharmacovigilance & Patient Safety by e-mail using the pregnancy notification form by 
e-mail (e-mail address is indicated on the pregnancy notification form). 
In all reported situations of exposure during pregnancy, Sobi will provide the investigator with a 
Pregnancy report form that shall be completed and returned by the investigator. The investigator 
is responsible for monitoring the outcome of the pregnancy and to inform Sobi Global 
Pharmacovigilance & Patient Safety of relevant information and any information requested 
related to the outcome of the pregnancy. 
Any AEs and SAEs observed during and in relation to pregnancy, delivery or breastfeeding 
should be recorded in the eCRF and, as applicable, be reported to Sobi Global 
Pharmacovigilance & Patient Safety as described previously in this section.
Follow-up of unresolved adverse events
All AEs should be followed until they are resolved or the investigator assesses them as chronic 
or stable, or the patient’s participation in the study ends, i.e., until the last scheduled visit. How 
to report changes in an ongoing AE during a patient's participation in the study is described in 
the eCRF instructions. 
In addition, all serious and nonserious AEs assessed by the investigator as related to the IMP 
should continue to be followed until they resolve or until the investigator assesses them as 
“chronic” or “stable,” even after the patient's participation in the study is over, but without 
further recordings into the eCRF.
6.5.5.2
Laboratory safety assessments
Laboratory assessment samples (Table 3) are to be obtained at designated visits as detailed in the 
schedule of assessments (Table 1). Blood collection for safety laboratory tests at Day 1 can be 
omitted if screening samples were collected on Day -1.
On dosing days, all blood samples will be collected predose.
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Table 3 
Laboratory assessments 
Hematology 
ARC 
Hemoglobin 
Hematocrit 
Platelet count  
Red blood cell count 
WBC count with differential 
Serum chemistry 
Albumin 
ALT 
ALP 
AST 
Bilirubin (total, direct, and indirect) 
BUN 
Calcium 
Chloride 
Creatinine 
Creatine kinase  
Haptoglobin 
Estimated Glomerular Filtration Rate 
(using CKD-EPI formula) 
GGT 
Glucose 
Iron 
Ferritin 
TIBC 
LDH 
Magnesium  
Phosphorus 
Potassium 
CRP 
Sodium 
Uric acid 
Urinalysis 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
pH  
Pregnancy, when applicable 
Proteinuria 
rUPCR  
Specific gravity 
Urobilinogen 
Coagulation a 
aPTT 
D-dimer  
Fibrinogen 
International normalized ratio 
Prothrombin 
 
Additional 
HBV-DNA 
HCV-RNA 
HIV 
ADAMTS13 activity test 
 
Biomarkers of complement activation: 
including but not limited to sC5b-9; C3a; 
C3; Bb; C4a; functional assays for 
classical and alternative complement 
pathways 
Antibodies to PEG and 
pegcetacoplan 
 
 
Peripheral blood smear for 
schistocytes evaluation 
Direct Coomb’s test 
Serum pregnancy test (β-hCG) 
FSH (postmenopausal women) 
Abbreviations: ALP, Alkaline phosphatase; ALT, Alanine aminotransferase; aPTT, Activated partial thromboplastin 
time; ARC, Absolute reticulocyte counts; AST, Aspartate aminotransferase; β-hCG, Human chorionic 
gonadotropin-beta; Bb, Activated factor B; BUN, Blood urea nitrogen; C3, Complement component 3; 
C3a, Complement component 3a; C4a, Complement component 4a; CKD-EPI, Chronic Kidney Disease – 
Epidemiology Collaboration; CRP, C-reactive protein; 
 
FSH, Follicle stimulating hormone; GGT, Gamma-glutamyltransferase; HBV, Hepatitis B virus; HCV, Hepatitis C 
virus; HIV, Human immunodeficiency virus; 
LDH, Lactate 
dehydrogenase; PEG, Polyethylene glycols; rUPCR, Random urine protein:creatine ratio; sC5b-9, Terminal 
complement complex; TIBC, Total iron binding capacity; 
 WBC, White blood 
cells. 
a The use of silica reagents in coagulation panels should be avoided in all patients. 
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Blood and urine samples will be analyzed at a central laboratory unless a local laboratory facility 
is necessary, as defined in the laboratory manual. Urine samples will be analyzed by dipstick and 
microscopic analysis. All laboratory reports must be reviewed, signed, and dated by the 
investigator. A legible copy of all reports must be filed with both the patient’s eCRF and medical 
record (source document) for that visit.  
In the event that a patient’s medical condition warrants rapid treatment initiation and the results 
of tests from the central laboratory cannot be awaited, results of tests performed at the site can be 
considered for screening purposes (inclusion/exclusion criteria checks), with the sponsor’s 
agreement. In such cases, the local test results will be entered in the eCRF to confirm the 
eligibility. 
Any laboratory test result considered by the investigator to be clinically significant should be 
considered an AE (clinically significant AEs include those that require an intervention), see 
Section 6.5.5.1.1 for details. Clinically significant abnormal values occurring during the study 
will be followed up until repeat test results return to normal, stabilize, or are no longer clinically 
significant. 
The use of silica reagents in coagulation panels should be avoided. The sponsor previously 
conducted an investigation into prolonged aPTTs observed in subjects treated with 
pegcetacoplan. It was confirmed that false-positive aPTT prolongation occurred when 
coagulation panels were performed using a Stago Analyzer and, specifically, silica reagents. It 
was determined that there was interference between the silica reagents and PEGylated 
pegcetacoplan, resulting in artificially prolonged aPTTs. 
If a patient has been tested for COVID-19, the results, if available, will be documented in the 
eCRF. 
6.5.5.3 
Vital signs 
Vital signs (body temperature, respiration rate, heart rate and systolic and diastolic BP 
measurements) will be evaluated per institutional practices at the visits indicated in the schedule 
of assessments (Table 1).  
When the IMP is administered at the study site, vital signs will be measured within 2 hours 
before dosing and venipuncture (and ECG, if applicable), and at 30 minutes (± 5 minutes) 
postdose.  
Vital signs measurements will be repeated if clinically significant or if machine/equipment errors 
occur. Out-of-range BP, respiratory rate, or heart rate measurements will be repeated at the 
investigator’s discretion. Any confirmed, clinically significant vital signs measurements must be 
reported as AEs (see Section 6.5.5.1.1 for details).   
6.5.5.4 
Body weight and height  
Body weight and height (both assessed without shoes on) will be recorded at screening. Body 
weight will also be recorded at each physical examination. 
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6.5.5.5 
Physical examination 
Full physical examinations will be performed by the investigator/designee at the time points 
outlined in the schedule of assessments (Table 1) and will include assessments of the following 
items: general; head, ears, eyes, nose, and throat; dentition; thyroid (endocrine); heart; chest; 
lungs; abdomen; skin; extremities; back/neck; musculoskeletal system and lymph nodes.  
If any abnormalities are reported at screening, they should be recorded as medical history. New 
or worsening of abnormalities after first IMP dose should be reported as AEs (see 
Section 6.5.5.1.1 for details). 
6.5.5.6 
Electrocardiograms 
Single 12-lead ECGs will be recorded prior to dosing at the time points outlined in the schedule 
of assessments (Table 1). The ECG will be taken after the patient has been resting in the supine 
position for 5 minutes in a quiet environment and prior to any blood sampling procedures, unless 
specified at time points after timed blood sampling procedures. 
The ECGs will be classified as normal, having a not clinically significant abnormality or having 
a clinically significant abnormality. For patients with an abnormal ECG, it is recommended that 
the ECG recording is reviewed by a cardiologist in addition to the treating investigator. 
Any significant ECG finding present prior to the start of IMP administration is to be documented 
in the medical history section of the eCRF. Any significant ECG finding with an onset time after 
IMP initiation and that was not present at screening, or worsened during the study, is to be 
reported as an AE. 
Clinically significant abnormal ECG findings should be reported as AEs (see Section 6.5.5.1.1 
for details). 
6.5.5.7 
Infusion-site reactions/pump-safety assessments 
On the days of clinic visits, if pegcetacoplan is administered at the visit site, an assessment of the 
pegcetacoplan infusion site will be made as a part of the AE assessment. If pegcetacoplan is 
administered at the visit, the site staff will observe the dosing and pump use safety will be 
assessed. The infusion site will be checked again within 30 minutes after study drug 
administration. The infusion-site assessments will be performed by an appropriately trained staff, 
as delegated by the investigator. The infusion site and surrounding area will be inspected for 
redness, swelling, induration and bruising. The patient will be asked about the presence of pain 
and/or tenderness, and any issue related to pump use. The date, time and outcome of the 
infusion-site assessment will be recorded on the source documents and eCRFs. 
Patients will be instructed to notify the investigator or other study personnel in the event that an 
infusion-site reaction occurs after self-administration of pegcetacoplan. All clinically relevant 
AEs, as determined by the investigator, from infusion site or related to pump use will be 
recorded as AEs (see Section 6.5.5.1.1 for details). 
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6.5.5.8 
Appropriateness of safety measurements 
The methods and measurements used for safety during the study are standard and are appropriate 
for the clinical evaluation of the patients with TA-TMA treated with pegcetacoplan. 
6.5.5.9 
Safety review committee  
An SRC will be established for this study. The SRC will review PK and safety data after the 
first patient has completed 4 weeks of treatment, then after the first 3 patients have completed 
12 weeks of treatment, and then every 6 months afterwards until all patients have completed the 
treatment period. Additional SRC meetings may be scheduled ad hoc as per investigator or Sobi 
SRC member requests (see stopping criteria in Section 6.1.5).  
The SRC will consist of internal Sobi staff and will include as a minimum the Safety Physician, 
Study Physician and Clinical Pharmacologist. An SRC charter will specify the operating 
procedures including SRC membership, voting members, responsibilities, data review meeting 
details and lines of communication with the study teams at Sobi and investigational sites.  
6.5.6 
Pharmacodynamic assessments 
Blood samples for PD assessment of hemolytic complement activation will be collected on study 
days designated in the schedule of assessments (Table 1). On dosing days, all blood samples will 
be collected predose. 
Biomarkers of complement activation will include but are not limited to sC5b-9, C3a, C3, Bb, 
C4a and functional assays for classical and alternative complement pathways. 
Since recently published data have also suggested a key relationship between increased 
interferon signaling, complement activation, and TA-TMA [23], 
 
 
 
 
Instructions for collection, handling, processing, storage, and shipping of samples will be 
provided in a separate laboratory sample handling manual prior to study initiation. 
6.5.6.1 
Immunogenicity 
Blood samples for antibodies will be collected on study days designated in the schedule of 
assessments throughout treatment and follow-up periods (Table 1). On dosing days, all blood 
samples will be collected predose. 
The presence of antibodies to PEG and pegcetacoplan will be analyzed after study completion. 
Samples that are confirmed positive for anti-pegcetacoplan peptide or anti-PEG antibodies will 
be characterized with an antibody titer for that specific antibody. Any samples that are confirmed 
positive for anti-pegcetacoplan peptide antibody will be further characterized with a neutralizing 
antibody assay.  
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6.5.7 
Efficacy assessments 
6.5.7.1 
Clinical response 
Clinical response is defined as an improvement in laboratory markers and, in patients with signs 
or symptoms of organ dysfunction at baseline, also as an improvement in clinical status (see 
Section 5.2.1).  
To assess laboratory improvement, LDH and platelets count will be collected at baseline and at 
each time point of clinical response evaluation.  
To assess the clinical status, the following clinical and laboratory parameters will be collected at 
baseline and at each time point of clinical response evaluation:  
· Creatinine; presence of renal replacement therapy (including start date, end date and 
reason).  
· Presence of noninvasive or invasive positive pressure ventilation or oxygen, including 
start date, stop date and reason. 
· Presence of nausea, vomiting or anorexia including attributed reason. 
· Stool output/day (reported either as number of episodes or mL). 
· Neurological status (e.g. presence of seizures, mental alteration, stability of irreversible 
neurological conditions) including attributed reason. 
· Presence of pulmonary hypertension and related medications. 
· Systolic and diastolic BP and anti-hypertensive medications excluding diuretics. 
· Presence of pericardial or pleural effusion requiring pericardiocentesis or thoracocentesis 
including attributed reason. 
6.5.7.2 
TMA response 
TMA response is defined as an improvement in TA-TMA specific markers (see Section 5.2.1). 
To assess TMA response, LDH, platelets counts and rUPCR will be collected at the time points 
outlined in the schedule of assessments (Table 1). 
6.5.7.3 
Overall survival, time to response, duration of response, TA-TMA relapse 
Overall survival will be assessed at Day 100 from the day of TA-TMA diagnosis and at Week 24 
from treatment start. The day of TA-TMA diagnosis will be defined as the earliest date when all 
required laboratory criteria outlined in Inclusion Criterion #3 are met. Date of death and reason 
for death will be collected (whether related to TA-TMA or not). 
Time to clinical/TMA response will be measured from the time of first IMP dose to the first 
documentation of attainment of a clinical or of a TMA response as defined in Section 5.2.1. 
Duration of clinical and of TMA response will be measured from the first documentation of 
attainment of a response until TA-TMA relapse. 
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TA-TMA relapse will be defined as reappearance of all laboratory markers as outlined in 
Inclusion Criterion #3 in a patient who has reached a clinical response. 
6.5.7.4 
Transfusions 
All the platelet and PRBC transfusions performed during the study period from screening until 
end of the study will be recorded, including date, number of units and whether the transfusion is 
attributed or not to TA-TMA. 
6.5.7.5 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
6.5.7.6 
Appropriateness of efficacy measurements 
The methods and measurements used for efficacy during the study (overall survival, TA-TMA 
relapse, clinical response, TMA response, time to and duration of clinical and TMA response, 
laboratory parameters, number of platelet and PRBC transfusions and health-related quality of 
life tools) will be used to determine responses to IMP and are appropriate measures to assess the 
efficacy objectives. 
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6.5.8 
Other study assessments 
6.5.8.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7 
Quality control and quality assurance 
This study will be conducted in compliance with this protocol, study-specific procedures, Sobi 
standard operating procedures, contract research organization standard operating procedures, the 
ICH Guideline for GCP [1], and applicable regulatory requirements, including EU CT 
Regulation 536/2014. 
The sponsor will systematically review the study quality management to identify, evaluate and 
control risks to study critical processes and data that would affect patient safety and reliability of 
study data. 
The sponsor will establish a systematic, prioritized, risk-based approach to monitoring and has 
chosen a combination of on-site and centralized monitoring. 
The sponsor will notify the authorities as applicable (in line with country/region requirements) 
about a serious breach of the regulations or of the version of the protocol applicable at the time 
of the breach. A ‘serious breach’ means a breach likely to affect to a significant degree the safety 
and rights of a subject or the reliability and robustness of the data generated in the clinical trial. 
In case of new waves of restricted access to trial sites due to the unforeseeable evolution of the 
COVID-19 pandemic, to ensure ongoing patients’ rights, safety and wellbeing, and control risks 
to study critical processes, the sponsor might decide to apply alternative mechanisms of 
oversight and monitoring. Among these mechanisms, remote source data verification would be 
implemented only if allowed by country regulations and within the limits established. 
Monitoring visits to the study site will be performed periodically during the study, to help ensure 
compliance with the protocol, study-specific procedures and applicable regulatory requirements. 
Source documents will be reviewed for verification of agreement with data in eCRFs. All patient 
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ICFs will be reviewed. The investigator or institution guarantees access to source documents by 
Sobi, its representatives, and appropriate regulatory agencies. 
The study site may be subject to a quality assurance audit by Sobi or its representatives, as well 
as inspection by appropriate regulatory agencies. 
It is important that the investigator(s) and the(ir) relevant personnel are available during the 
monitoring visits and possible audits and that sufficient time is devoted to the process. 
8 
Statistical plan 
A formal first version of the SAP will be developed and finalized before the first patient is 
screened. The full details of data presentations and analyses will be provided in the SAP. Any 
potential update of the SAP will include description of changes/additions. Any deviations from 
the final SAP or from what is outlined in the protocol will be discussed in the CSR. 
8.1 
Determination of sample size 
This is a pilot study and the sample size is based on practical rather than statistical aspects.  
A total of 12 patients will be included and treated in the study. With 12 patients included, it is 
estimated that 9 patients will complete at least 4 weeks of treatment, which is deemed sufficient 
to characterize the PK of pegcetacoplan in patients with TA-TMA to an appropriate precision. In 
addition, 12 patients will provide a 72 % probability to observe a response rate of at least 8 
responders of the 12 patients recruited (assuming the true response rates is 70 %).    
8.2 
Definition of study populations 
8.2.1 
Screened set 
The screened set will include all patients who provide written informed consent. This set will be 
used only for the purpose of describing patient disposition. 
8.2.2 
Safety set 
The safety set will include all patients who receive at least 1 dose of IMP. This analysis set will 
be used for all safety analyses.  
8.2.3 
Intent-to-treat set 
The ITT set will include all patients enrolled. This analysis set will be used for efficacy 
endpoints. 
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8.2.4 
Pharmacokinetic set 
The PK set will include all patients in the ITT set who receive IMP and have at least 1 evaluable 
postdose concentration measurement.  
8.2.5 
Pharmacodynamic set 
The PD set will include all patients in the ITT set who receive IMP and have at least 1 evaluable 
postdose PD measurement.  
8.3 
Overall statistical and analytical plan 
All details of the statistical analyses for primary and secondary endpoints will be described in the 
SAP. 
8.3.1 
General statistical issues 
All endpoints will be evaluated with descriptive statistics. PK and PD may also be presented 
graphically. 
Baseline will be defined as the Baseline visit. If no assessment is available at the Baseline visit, 
then the last assessment during the screening period will be used. If multiple values assessments 
are available, then the last assessment prior to first dose will be used. 
No statistical tests will be performed.  
8.3.2 
Demographics and baseline characteristics 
Demographics, baseline characteristics, concomitant medications/treatments, medical history, 
and IMP exposure will be summarized. 
The WHO-DD and MedDRA coding dictionaries will be used for the coding of concomitant 
medications/treatments and medical histories, respectively. 
8.3.3 
Analysis related to primary objective 
8.3.3.1 
Analysis of pharmacokinetics 
A primary objective is to evaluate the pegcetacoplan PK in patients with TA-TMA. The primary 
endpoints are the PK parameters computed from the individual serum concentration-time data, 
using actual sample times and a non-compartmental approach, i.e., AUC0-tau, Cmax, Tmax and 
Ctrough. For further details, see Section 6.5.4. 
PK parameters will be summarized using descriptive statistics (arithmetic means, standard 
deviation, coefficients of variation, N, minimum, maximum, median, first quartile [Q1] and third 
quartile [Q3]). In addition, geometric means with 95% CI will be calculated for AUC 
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parameters, and for Cmax. Figures will be created to display median and individual pegcetacoplan 
concentration-time curves. Additional PK analyses may be performed if deemed appropriate.  
The analysis of the PK endpoints will be performed on the PK set. 
A separate pegcetacoplan population PK Analysis Plan will be developed, and results will be 
reported separately. 
8.3.3.2 
Analysis of safety and tolerability data 
Pretreatment AEs are those occurring between ICF signature and the first IMP administration. 
TEAEs are defined as those AEs that develop or worsen after the first dose of IMP and up to 
8 weeks after the last IMP dose.  
All AEs will be coded using the MedDRA. Pretreatment AEs will be summarized in individual 
listings. TEAEs will be summarized by SOC and preferred term in frequency tables with the 
number of patients and proportion reporting the event. A similar summary will be produced for 
SAEs, AEs leading to premature discontinuation of IMP and AEs related to the IMP. The 
intensity of AEs and the relationship to the IMP will be summarized for each SOC and preferred 
term.  
The AE summaries will be presented across all patients. All AEs will be listed by patient, along 
with information regarding onset, duration, relationship to IMP, severity, action taken with IMP, 
treatment of event and outcome.  
Changes from baseline in clinical laboratory test results will be summarized, using descriptive 
statistics, by visit and nominal time postdose. Out-of-range values will be flagged in data 
listings.  
Changes from baseline in vital signs will be summarized, using descriptive statistics, visit and 
nominal time postdose.  
Changes in physical examinations will be described in a data listing. 
8.3.4 
Analysis related to secondary objectives 
8.3.4.1 
Analysis of pharmacodynamics 
A secondary objective is to evaluate the pegcetacoplan PD in patients with TM-TMA. 
The related secondary PD endpoints are the following: 
· Absolute levels, change from baseline, and % change from baseline to Week 24 in 
biomarkers of complement activation, which include but are not limited to sC5b-9, C3a, 
C3, Bb, C4a, functional assays for classical and alternative complement pathways). 
PD parameters will be summarized using descriptive statistics (N, mean, standard deviation, 
median, minimum and maximum values). 
The analysis of the PD endpoints will be performed on the PD set. 
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8.3.4.2 
Analysis of secondary efficacy endpoints 
The secondary efficacy endpoints are described in Section 5.2.1. 
A secondary endpoint is clinical response at 24 weeks. A composite estimand is used where 
patients meeting intercurrent events are considered as failures. The intercurrent events of 
interests are use of prohibited medication or study withdrawal before Week 24. Patients meeting 
these intercurrent events will be considered as failures/nonresponders.  
A 2-sided 95 % confidence interval for the proportion will be calculated using the 
Clopper-Pearson method.   
Clinical response at Week 12 as well as TMA response at Week 12 and Week 24 will be 
evaluated the same way as clinical response at Week 24. 
Another secondary endpoint is overall survival at Day 100 from diagnosis of TA-TMA. 
Pegcetacoplan withdrawn patients for which survival at Day 100 is unknown will be censored at 
the date of last contact. Kaplan-Meier curve estimates of survival at Day 100 and survival curves 
will be estimated.  
Overall survival at Week 24 from study Day 1 will be evaluated the same way as overall survival 
at Day 100 from diagnosis of TA-TMA. 
Time to clinical response will be defined as the time from study Day 1 to first occurrence of 
clinical response and will be evaluated for:  
· Patients achieving clinical response (without a preceding ICE) at any time during the 
study. 
· Patients achieving clinical response at Week 24 without meeting an ICE. 
Time to clinical response will be analyzed using Kaplan-Meier methodology. Kaplan-Meier 
curves and estimates will be presented.  
Time to TMA response will be evaluated in the same way as time to clinical response. 
Duration of clinical response is defined as the time from the first observed clinical response until 
the response criteria is no longer fulfilled or until end of study. Duration of response will be 
defined for patients with clinical response without meeting an ICE. Duration of clinical response 
will be analyzed using Kaplan-Meier methodology. Kaplan-Meier curves will also be presented. 
Duration of TMA response will be evaluated the same way as duration of clinical response. 
TA-TMA relapse at Week 24 will be defined for patients reaching clinical response at some 
point of the study. Counts and proportions of patients with and without relapse at Week 24 will 
be summarized. 
The analysis of the secondary endpoints will be performed on the ITT set. 
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8.3.5 
Analysis related to exploratory objective 
The exploratory endpoints are described in Section 5.3.1. Exploratory endpoints will be 
evaluated with descriptive statistics. 
8.3.6 
Interim analysis 
No interim analysis will be conducted. 
8.3.7 
Multiple comparison/multiplicity 
No formal statistical tests are performed in this study. 
8.3.8 
Exploratory subgroup analyses 
Subgroup analyses will be conducted on subgroups based on BATAP score [29] (categories will 
be defined based on distribution of BATAP scores). The following endpoints will be considered 
for subgroup analyses: PK parameters, clinical response and TMA response, and overall 
survival. In each defined subgroup, the analysis will be carried out using the same type of 
methodology as described for the overall analysis of the corresponding endpoint. For subgroups 
without an adequate number of patients, the analyses will not be performed. Details will be 
provided in the SAP. 
8.3.9 
Handling of missing data 
Imputation of missing data (e.g., partial or missing dates) will be described in the SAP. 
9 
Data collection, handling and record keeping 
9.1 
Data standards 
Collection of data should be performed in the Clinical Data Acquisition Standards 
Harmonization format, according to the Clinical Data Interchange Standards Consortium. The 
standards should be used to the extent possible and/or required for the specific study/project. The 
minimum requirement of the Clinical Data Interchange Standards Consortium standard is to 
collect all core variables specified as ‘Required’ in the Study Data Tabulation Model format.  
9.2 
Case report form 
An eCRF is required and should be completed for each included patient. In this study, an eCRF 
will be used, and the designated investigator site staff will only be given access to the electronic 
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data capture system upon completion of the user training. The completed original eCRFs are the 
sole property of Sobi and should not be made available in any form to third parties, except for 
authorized representatives of appropriate regulatory authorities, without written permission from 
Sobi. 
It is the responsibility of the investigator to ensure completion and to review and approve all 
eCRFs. eCRFs must be signed electronically by the investigator. These signatures serve to attest 
that the information contained on these eCRFs is correct. At all times, the investigator has final 
responsibility for the accuracy and authenticity of all clinical and laboratory data entered on the 
eCRFs. 
9.3 
Source data 
Patient source documents are the physician’s patient records maintained at the study site. In most 
cases, the source documents will be the hospital’s or the physician’s chart. In those cases, the 
information collected in the eCRFs must match those charts. In some cases, a portion of the 
source documents for a given patient may be the eCRF.  
A separate source document location agreement will be completed and signed by the principle 
investigator and the monitor before study start. 
Source data should be attributable, legible, contemporaneous, original, accurate, complete, 
consistent, enduring and available (ALCOA+). Changes to source data should be traceable, 
should not obscure the original entry, and should be explained if necessary (e.g., via an audit 
trial). 
The Sponsor or designee will perform monitoring to confirm that data entered into the eCRF by 
authorized site personnel are accurate, complete, and verifiable from source documents; that the 
safety and rights of patients are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, ICH GCP, and 
all applicable regulatory requirements. 
9.4 
Protocol deviations 
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The investigator is responsible for ensuring the 
study is conducted in accordance with the procedures and evaluations described in this protocol 
and must protect the rights, safety, and welfare of patients. The investigator should not 
implement any deviation from, or changes to, the protocol, unless it is necessary to eliminate an 
immediate hazard to study patients. 
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited.  
When a deviation from the protocol is identified, the investigator or designee must ensure the 
medical monitor is notified. The medical monitor will follow up with the investigator, as 
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applicable, to assess the deviation and the possible impact to the safety and/or efficacy of the 
patient to determine patient continuation in the study. 
The investigator and contract research organization must contact Sobi immediately if a deviation 
is discovered that significantly affects or has the potential to significantly affect human patient 
protection or the reliability of study results. 
The investigator will also assure that deviations are reported and documented in accordance with 
IEC/IRB and applicable regulatory requirements.  
9.5 
Database closure 
Prior to database closure, all tasks or criteria defined in the data management plan must be 
completed and documented. The study database must be locked and before generation of any 
results. The database lock will be approved by relevant study personnel, and all edit accesses will 
be removed. The study database can only be unlocked in cases where critical errors, affecting the 
main conclusions of the study, are discovered.  
9.6 
Record retention 
The investigator should maintain a record of the location(s) of investigator’s essential documents 
as defined in the ICH GCP Guideline [1] including source documents and should have control of 
and continuous access to all essential documents and records generated by the 
investigator/institution before, during, and after the study.  
All documents and data relating to the study will be kept securely by the investigator in a 
secure file and/or electronically. The storage system used during the study and for archiving 
(irrespective of the type of media used) should provide for document identification, version 
history, search and retrieval. The data will be available for evaluation and/or audits from Health 
Authorities, Sobi or Sobi’s representatives. 
When a copy is used to replace an original document (e.g., source documents, eCRF), the copy 
should fulfill the requirements for certified copy as defined in ICH GCP Guideline [1].  
The records should be retained by the investigator as specified in the Clinical Trial Agreement 
and in accordance with local regulations.  
If the investigator relocates, retires, or for any reason withdraws from the study, the study 
records may be transferred to an acceptable designee, such as another investigator or another 
institution. Archiving on behalf of the investigator can also be delegated to Sobi.   
10 
End of study 
The end of study is defined as when all enrolled patients have completed the follow‑up period 
and performed the End of study visit (the date of the last visit of the last patient) at Week 24, or 
the Early Termination visit in case of early discontinuation. 
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11 
Sponsor’s discontinuation criteria 
Sobi reserves the right to discontinue the study prior to inclusion of the intended number of 
patients, but intends only to exercise this right for valid scientific or administrative reasons. After 
such a decision, the investigator must contact all participating patients within 30 days. All study 
materials must be collected, and all the eCRFs must be completed to the greatest extent possible. 
12 
Dissemination and publication of results 
A CSR will be prepared once all patients have completed their Week 24 visit and the database 
has been cleaned for all visits up to and including Week 24. 
Sobi will register the study by posting study information and post study results regardless of 
outcome on a publicly accessible website in accordance with applicable laws and regulations, 
e.g., on www.clinicaltrials.gov and EudraCT/Clinical Trial Information System portal. The 
results of this study will be published within 12 months of the end of study, including a summary 
written in a manner that is understandable to laypersons.  
Sobi is committed to publishing study results in a complete, accurate, balanced, transparent and 
timely manner. Sobi follows the principles of the International Committee of Medical Journal 
Editors recommendations for the conduct, reporting, editing, and publication of scholarly work 
in medical journals including criteria for authorship [30]. 
The data from this study will be considered for reporting at a scientific meeting or for 
publication in a scientific journal. The sponsor will be responsible for these activities and will 
work with the investigators to determine how the publication is written, the number and order of 
authors, the journal or scientific meeting to which it will be submitted, and other related issues. 
The results of the study, or any part thereof, shall not be published without the prior written 
consent and approval of Sobi, such consent and approval not to be unreasonably withheld. 
13 
Confidentiality 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written consent 
is gained from the sponsor. However, authorized regulatory officials, IRB/IEC personnel, the 
sponsor and its authorized representatives are allowed full access to the records. 
The contract between Sponsor and study sites specifies responsibilities of the parties related data 
protection, including handling of personal data breaches and respective communication and 
cooperation of the parties. 
Information technology systems used to collect, process, and store study-related data are secured 
by technical and organizational security measures designed to protect such data against 
accidental or unlawful loss, alteration, or unauthorized disclosure or access. 
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All study patients must be informed that their personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the patient, who will be required to give consent for their data to be used as 
described in the ICF. The patients must be informed that their medical records may be examined 
by auditors or other authorized personnel appointed by the sponsor, by appropriate IRB/IEC 
members, and by inspectors from regulatory authorities. 
Identification of patients and CRFs shall be by unique subject identification numbers only. All 
personal identifiers according to applicable regulations (e.g., name, phone number) must be 
redacted permanently by the site personnel and replaced with the subject’s unique identification 
number in all records and data before transfer to the sponsor (or designee). 
All personal details will be treated as confidential by the investigator and sponsor’s or designated 
staff. The investigator and the contract research organization must contact Sobi immediately if a 
potential serious breach is discovered that significantly affects the safety and rights of a subject, 
the physical and mental integrity of a subject, or has the potential to significantly affect human 
subject protection and the reliability of study results. The investigator will also assure that 
deviations are reported and documented in accordance with applicable regulatory and legal 
requirements. 
 
14 
Reference list 
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microangiopathy. Thromb Haemost. 2020 Apr;120(4):638-46.   
29 
Zhao P, Wu YJ, He Y, Chong S, Qu QY, Deng RX, et al. A prognostic model (BATAP) 
with external validation for patients with transplant-associated thrombotic 
microangiopathy. Blood Adv. 2021 Dec 28;5(24):5479-5489. doi: 
10.1182/bloodadvances.2021004530.  
30 
International Committee of Medical Journal Editors. Recommendations for the conduct, 
reporting, editing, and publication of scholarly work in medical journals: updated 
December 2016 [Internet]. International Committee of Medical Journal Editors (ICMJE); 
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2016. [cited 2017 Jan 12]. Available from: http://www.icmje.org/recommendations/   
 
 
 
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Appendix 1 
Additional protocol signatures 
 
 
Sponsor’s Clinical Study Manager  
  
Clinical Study Manager 
 
 
Date 
 
 
Sponsor’s Statistician 
 
Statistical Science Director 
  
 
Date 
 
 
 
 
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Appendix 2 
 
  
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Appendix 6 
Protocol changes to be followed during 
COVID-19 restrictions 
OVERVIEW  
It is expected that all patients will be vaccinated against coronavirus SARS-CoV-2 prior to the 
HSCT and routinely tested for COVID-19 as per standard of care. 
In response to the COVID-19 crisis, to ensure the safety of study patients and investigative sites 
as well as proper conduct of the study, TEMPORARY changes to the protocol may be 
implemented. These changes should be followed only during COVID-19 restrictions. These 
changes will be reported as COVID-19-related protocol deviations. 
In case of new waves of restricted access to trial sites due to the unforeseeable evolution of the 
COVID-19 pandemic, to ensure ongoing patients’ rights, safety and wellbeing, and control risks 
to study critical processes, the sponsor might decide to apply alternative mechanisms of 
oversight and monitoring. Among these mechanisms, remote source data verification would be 
implemented only if allowed by country regulations and within the limits established. 
MINIMUM SCHEDULE OF ACTIVITIES 
Where feasible, sites could continue to follow the full schedule of activities The minimum 
assessment tables, only to be followed during this COVID-19 effort and if determined necessary 
to use on the basis of the investigator’s clinical judgment, are provided below to reduce the time 
required for each study visit. Assessments not performed (even those that have been removed in 
the minimum assessment table) should be documented and captured in the eCRFs. 
Patients who have been discharged and are not able to come into the clinic for a study visit 
because of COVID-19-related restrictions, should be contacted via the phone for the collection 
of AEs (including SAEs) and concomitant medications. All SAEs are still required to be 
reported within 24 hours of site awareness, even if reported via phone call. All 
communications via phone call should also be documented in the source documentation and in 
the respective eCRF page. In addition, these patients should be instructed to self-monitor their 
symptoms at home and report any changes in symptoms or their overall health via phone 
call. The site must inform the sponsor of any patients lost to follow-up.  
It is critical that local, country, and regional governance regarding COVID-19 is followed along 
with your best clinical judgment when managing this situation.   
MINIMUM STUDY REQUIREMENTS 
The following are the minimum study requirements for Study Sobi.PEGCET-201 during the 
COVID-19 pandemic and should be used as guidance when the full protocol requirements cannot 
be conducted.  
1. Obtain key safety laboratory assessments. 
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a. All laboratory assessments should be drawn at the frequency required by 
the minimized schedule of events (Table 4). 
i. Includes (at minimum): hematology with differential, chemistry including 
LDH and creatinine.  
b. In the event that the clinical investigative site is closed or patients are 
unable/unwilling to travel, patients should be referred to a certified local 
laboratory that can perform the required safety testing (see schedule of events 
below). The investigator should collect the local laboratory reports, which must 
be redacted (e.g., name and other local requirements) and added to the study 
records.  
2. Perform minimal medical safety assessments.  
a. If the patient is unable to have an in-person assessment, the investigator (or 
delegated site staff) should have a telephone contact at a frequency noted in the 
protocol (at minimum) to solicit AEs (including SAEs), concomitant medications 
and transfusions. The appropriate forms in the eCRF should be completed.  
3. Document appropriate contact with the patient. 
a. Earnest and reasonable attempts must be made to solicit AEs and concomitant 
medications. The CRA/medical monitor must be notified of any patients lost to 
follow-up.  
b. All communication with the patient (including failed attempts at contact) must be 
documented in the study records.  
 
The modified schedule of activities is shown in Table 4. 
 
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g  Laboratory tests: refer to Table 3. Blood and urine samples will be analyzed at a central unless a local laboratory facility is necessary, as defined in the laboratory 
manual. Urine samples will be analyzed by dipstick and microscopic analysis. The use of silica agents should be avoided in patients treated with pegcetacoplan. 
h Samples that are confirmed positive for anti-pegcetacoplan peptide or anti-PEG antibodies will be characterized with an antibody titer for that specific antibody. Any 
samples that are confirmed positive for anti-pegcetacoplan peptide antibody will be further characterized with a neutralizing antibody assay. If a clinic visit is on a 
dosing day, the sample should be taken predose but otherwise a sample is still required.  
i Pre-HSCT evaluations will be accepted as screening tests. 
k β-HCG for women of childbearing potential and FSH for postmenopausal women. For women of childbearing potential, a serum pregnancy test will be performed at 
screening. Urine pregnancy tests will be performed at all subsequent site visits. Patients with positive results will be excluded or discontinued from the study.  
m All AEs occurring upon receiving the first IMP dose up to 8 weeks after last IMP administration must be recorded in the eCRF. SAEs will be reported from signing 
of the ICF up to 8 weeks after last IMP administration. New SAEs occurring at any time after the 8-week AE follow-up period up to EOS should be reported only if 
considered causally related to previous exposure to the IMP by the investigator. 
o An EOT/ET visit will be performed 4 weeks after the last dose of pegcetacoplan. For patients who complete 12 weeks of treatment, the EOT visit will be at Week 16,
and there will be further follow-up visits at Weeks 20 and 24. For patients who complete 16 weeks of treatment, the EOT visit will be at Week 20 and there will be a
further follow-up visit at Week 24. The main analysis will be performed after all patients have completed their Week 24 visit.
p Blood collection for safety laboratory tests at Day 1 can be omitted if screening samples were collected on Day -1. 
Note: On dosing days, all blood samples will be collected predose. The date and time of the sample and the date and time of the previous dose of pegcetacoplan must 
be recorded in the eCRF. 
Note: Unscheduled additional visits may be performed at the investigator’s judgment. Any of the study procedures or other assessments may be performed at the 
unscheduled visit at the discretion of the investigator. 
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