Clinical trial NCT05067127
Conditions: C3G IC-MPGN C3 Glomerulopathy C3 Glomerulonephritis Complement 3 Glomerulopathy Complement 3 Glomerulopathy (C3G) Complement 3 Glomerulonephritis Dense Deposit Disease DDD Membranoproliferative Glomerulonephritis Membranoproliferative Glomerulonephritis (MPGN) Immune Complex Membranoproliferative Glomerulonephritis (IC-MPGN)
Sponsor: Apellis Pharmaceuticals, Inc.
Start date: 2021-11-12; Completion date: 2025-01-14
Enrollment: 124 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 3 study to assess the efficacy and safety of twice-weekly subcutaneous (SC) doses of pegcetacoplan compared to placebo in patients with C3 glomerulopathy (C3G) or immune-complex membranoproliferative glomerulonephritis (IC-MPGN) on the basis of a reduction in proteinuria.

Detailed description:

Arms: arm 1: Subcutaneous infusion of 20mL (1080 mg), twice weekly (for adults or adolescents \>50kg), and the three other weight-based doses either of 10mL (540mg), 12mL (648mg), or 15mL (810mg) arm 2: Subcutaneous infusion of either 10mL, 12mL, 15mL, or 20mL, twice weekly
Interventions: intervention 1: Pegcetacoplan intervention 2: Placebo
Intervention descriptions: intervention 1: Complement (C3) Inhibitor intervention 2: Sterile solution of equal volume to active arm

Protocol documents:
Prot_000.pdf: 
Apellis Pharmaceuticals, Inc
Page 1 of 117
Confidential
PEGCETACOPLAN (APL-2) 
APL2‑C3G-310
A PHASE 3, RANDOMIZED, PLACEBO-CONTROLLED, 
DOUBLE-BLINDED, MULTICENTER STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF 
PEGCETACOPLAN IN PATIENTS WITH C3 
GLOMERULOPATHY OR IMMUNE-COMPLEX 
MEMBRANOPROLIFERATIVE 
GLOMERULONEPHRITIS
Regulatory Agency Identifier 
Number(s)
IND: 136409 
EudraCT: 2020-003767-25
Phase: 3
Version: Amendment 4
Approval Date: 25 April 2024 
Confidentiality Statement
This document is confidential. It contains proprietary information of Apellis Pharmaceuticals, Inc. Any viewing or 
disclosure of such information that is not authorized in writing by Apellis Pharmaceuticals, Inc, is strictly prohibited. 
Such information may be used solely for the purpose of reviewing or performing this study.


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INVESTIGATOR’S AGREEMENT 
I have read the Study APL2‑C3G-310 protocol and agree to conduct the study as outlined. I agree to 
maintain the confidentiality of all information received or developed in connection with this protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Protocol Amendment 4 
Overall Rationale for the Amendment: 
The protocol was amended to revise the order of the key secondary endpoints in response to updated 
knowledge from the nephrology field. Intercurrent event (ICE) strategies for the statistical analysis of 
the endpoints were updated to align with comments from the FDA. The strategy for closing 
enrollment was clarified. Additional revisions were made to clarify study procedures and activities in 
response to feedback from investigators and/or to align with current company practices. 
Minor formatting and stylistic revisions were made to align with current templates, and any identified 
typographical errors were corrected; these are not identified individually in the descriptions below. 
Description of change 
Section(s) affected 
Rationale for change 
Study endpoint changes 
 
Order of key secondary endpoints 
revised; change in eGFR at 26 weeks now 
the last key secondary endpoint 
Synopsis 
Section 5.2.1  
Section 12.3.2.1  
Based on emerging data and recent expert 
discussions, histopathologic changes are 
expected to occur before improvements in 
eGFR are observed. The order of the key 
secondary endpoints was amended to 
prioritize the histopathologic endpoints 
over the eGFR endpoint. 
Removed exploratory endpoint evaluating 
normalization of hematuria 
Section 5.2.1 
No post-baseline hematuria evaluations 
will be conducted. 
Removed exploratory endpoint of 
evaluation of changes in drusen at 26 weeks 
Section 5.2.1 
If conducted, ophthalmologic evaluations 
are at baseline and between weeks 42 
and 52 only. 
Study assessment changes 
 
Revised description of the window for 
conducting the optional activities 
(ophthalmologic evaluations and 
measured GFR) 
Schedule of 
Activities 
(Table 2), 
footnotes t and u 
Section 10.6  
Section 10.7  
Description revised to align with study 
visit schedule. 
Safety reporting changes 
 
Moved definition of TEAEs and the 
period for recording and reporting TEAEs 
Section 11.2.1.1  
Section 11.2.2  
Section 12.4  
Moved so provided with other definitions 
related to safety reporting. 
Statistical analysis changes 
 
Updated strategies for addressing ICEs  
Section 12.3 
and subsections 
Updated to align with FDA comments.  
Revised description of the data review for 
the analysis set 
Section 12.2.7  
Revised for clarity. 


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Description of change 
Section(s) affected 
Rationale for change 
Clarified the analysis set for the 
evaluation of endpoints related to renal 
biopsy observations 
Section 12.3.2 
Revised for clarity. 
Study conduct changes 
 
Added description of the activities at the 
closure of enrollment 
Section 6.2  
As the study was approaching target 
enrollment, the sponsor announced the 
planned closure of enrollment. 
Sites continued patient screening 
activities and all eligible participants were 
enrolled, resulting in a final enrollment of 
124 participants. Added a description to 
clarify activities at the closure of enrollment. 
Revised description of antidrug antibody 
assessments 
Section 11.1.13  
Revised to align with current Apellis 
practice. 
Document organization changes 
 
Added an Appendix containing country-
specific modifications to the protocol. 
Country-specific modifications are noted 
for Canada, Czech Republic, France, 
Germany, Netherlands, Israel, Japan, 
and Switzerland.  
Appendix 2 
Added to align with current Apellis practice. 
 


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1. 
SYNOPSIS 
Name of Sponsor/Company: 
Apellis Pharmaceuticals, Inc 
Name of Active Substance: 
Pegcetacoplan (APL-2) 
Protocol Number: APL2‑C3G-310 
Title of Study:  
A Phase 3, Randomized, Placebo-Controlled, Double-Blinded, Multicenter Study to Evaluate the Efficacy and 
Safety of Pegcetacoplan in Patients with C3 Glomerulopathy or Immune-Complex Membranoproliferative 
Glomerulonephritis 
Objectives:  
Primary: 
To assess the efficacy of twice-weekly subcutaneous (SC) doses of pegcetacoplan compared with that of placebo 
in patients with primary C3 glomerulopathy (C3G) or immune-complex membranoproliferative 
glomerulonephritis (IC-MPGN) on the basis of a reduction in proteinuria.  
Secondary: 
• 
To assess the effect of pegcetacoplan on estimated glomerular filtration rate (eGFR) 
• 
To assess the effect of pegcetacoplan on additional C3G/IC-MPGN disease–related parameters 
• 
To evaluate the safety of pegcetacoplan over 52 weeks of treatment  
Endpoints:  
Primary: 
The log-transformed ratio of uPCR at week 26 compared to baseline  
Key Secondary Endpoints: 
Key secondary endpoints (to be evaluated at week 26) 
• 
The proportion of participants who meet the criteria for achieving a composite renal endpoint (a stable or 
improved eGFR compared to the baseline visit (≤15% reduction in eGFR), and a ≥50% reduction in 
uPCR compared to the baseline visit.) 
• 
The proportion of participants with a reduction of at least 50% from baseline in uPCR  
• 
For participants with evaluable renal biopsies, the change from baseline in the activity score of the C3G 
histologic index score 
• 
The proportion of participants with evaluable renal biopsies showing decreases in C3c staining on renal 
biopsy from baseline  
• 
Change from baseline in eGFR 
Additional Secondary Endpoints (to be evaluated at week 26): 
• 
The proportion of participants achieving proteinuria <1 g/day 
• 
For participants with serum albumin levels below the lower limit of normal (LLN) at baseline, 
the proportion of participants with normalization of serum albumin levels 
• 
For participants with serum C3 levels below the LLN at baseline, the proportion of participants with 
serum C3 levels above the LLN 
• 
The change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue Scale 
score 
• 
The change from baseline in Kidney Disease Quality of Life score 
The primary, key secondary, and additional secondary endpoints will also be evaluated at week 52 as exploratory 
endpoints. 


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Safety Endpoints: 
• 
Incidence and severity of treatment-emergent adverse events (TEAEs)  
• 
Change from baseline in vital signs measurements, clinical laboratory tests, and electrocardiogram 
results 
• 
Number and incidence of rejection episodes (posttransplant participants only) 
• 
Number and incidence of graft loss (posttransplant participants only) 
• 
Incidence of death, stratified by transplant history 
Study Design: 
Methodology:  
This is a phase 3, randomized, placebo-controlled, double-blinded, multicenter study to evaluate the safety and 
efficacy of twice-weekly SC infusions of pegcetacoplan in patients diagnosed with primary C3G or IC-MPGN. 
The planned duration of participation in the study for each participant is a maximum of approximately 70 weeks. 
The study will consist of 4 parts: 
• 
Part 1: 10-week screening period 
• 
Part 2: 26-week randomized controlled period (RCP) 
• 
Part 3: 26-week open-label period 
• 
Part 4: 8-week follow-up period (only for participants who do not roll into a long-term extension study) 
Informed consent (and assent if applicable) will be obtained prior to the conduct of any study-related procedures. 
Part 1: Screening Period (10 Weeks) 
• 
Participants will be screened to confirm that eligibility criteria are met. 
• 
One 24-hour urine sample and 3 sets of triplicate first-morning spot urine (FMU) samples (first-morning 
void collected on 3 consecutive days) will be collected to determine eligibility and establish a 
baseline uPCR. 
• 
For adult participants, a renal biopsy will be performed to confirm diagnosis and eligibility and to serve 
as the baseline renal biopsy. A historic renal biopsy done within 28 weeks of randomization may be used 
for eligibility confirmation and serve as the baseline biopsy if it is confirmed as adequate by central 
pathology review. Biopsies will not be required for adolescent participants if they have an adequate 
previous renal biopsy to establish the diagnosis, even if the previous biopsy is more than 28 weeks prior 
to randomization.  
• 
Retrospective data for a period of up to 3 years prior to study entry will be collected to calculate 
historical eGFR (using the Chronic Kidney Disease–Epidemiology Collaboration creatinine equation for 
adults and the Bedside Schwartz equation for adolescents). 
• 
Vaccinations against Streptococcus pneumoniae, Neisseria meningitidis (types A, C, W, Y, and B), 
and Haemophilus influenzae (type B) are mandatory unless documented evidence exists that participants 
have received the recommended vaccinations or are nonresponders to vaccination. If required, 
vaccination series should be initiated at least 14 days prior to randomization.  
Part 2: Randomized Controlled Period (26 Weeks) 
Approximately 80 to 100 participants who meet all of the inclusion criteria and none of the exclusion criteria will 
be randomly assigned in a 1:1 ratio to either the pegcetacoplan treatment arm or the placebo treatment arm. 
To achieve balance between the arms, 2 stratification factors will be applied to the randomization. The first 
stratification factor examines participants with posttransplant recurrence versus nontransplant participants; 
the second stratification factor examines participants with baseline renal biopsies (either collected during 
screening or a historic biopsy collected within 28 weeks prior to randomization) versus participants without 
baseline renal biopsies.  
• 
Pegcetacoplan group: Participants will receive SC pegcetacoplan twice weekly.  
• 
Placebo group: Participants will receive SC placebo twice weekly. 
• 
Every effort will be made to minimize changes to medications related to C3G/IC-MPGN disease. 


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• 
Triplicate first-morning spot urines will be collected at each visit, and an additional triplicate 
first-morning sample will be collected during week 25. 
• 
Safety and efficacy will be assessed. 
• 
At the end of the RCP, there will be a renal biopsy, which is required for adult participants to advance to 
the open-label period (Part 3). Participants younger than 18 years are not required to provide renal 
biopsies and may advance to the open-label period upon completion of all assessments for weeks 24 
through 26 other than the renal biopsy. 
Part 3: Open-Label Period (26 Weeks) 
• 
All participants will be treated with pegcetacoplan twice weekly to assess durability of response and 
long-term safety and efficacy. Open-label dosing will begin at the first visit after the week 26 renal 
biopsy for adults and any adolescents providing renal biopsies. Open-label dosing for adolescents not 
providing renal biopsies should start at the week 26 visit. 
• 
At the end of the open-label period, there will be an optional renal biopsy.  
Part 4: Follow-up Period (8 Weeks) 
• 
Participants who would benefit from continuing to receive pegcetacoplan, as per the investigator’s 
opinion, may roll over into a long-term extension study after completion of the open-label period. 
• 
Participants who do not enter a long-term extension study will discontinue pegcetacoplan treatment 
and complete the 8-week follow-up period.  
Number of Participants (Planned) and Sample Size Justification:  
Approximately 80 to 100 participants, including patients with disease in native kidney or post-transplant, will be 
randomized 1:1 to pegcetacoplan or placebo with 40 to 50 participants per arm.  
Based on preliminary data from Study APL2-201, a reduction of 60% in uPCR in the pegcetacoplan group at 
week 26 is assumed vs a reduction of 20% in uPCR in the placebo arm, which corresponds to mean log ratio to 
baseline of −0.92 vs −0.22 respectively, and a standard deviation of 0.88 (on log-scale). Based on this assumption, 
a sample size of 70 participants in total provides at least 90% power at 1-sided significance level of 0.025. 
Considering a 10% attrition to account for potential missing assessments and impact by COVID-19, it is expected 
that at least 78 participants with native kidney disease should be enrolled.  
A minimum of 63 participants with C3G in native kidneys will be enrolled, which is approximately 80% of the 
enrolled participants with native kidney disease. 
Diagnosis:  
Patients with a diagnosis of primary C3G or IC-MPGN, including those with posttransplant recurrence 
Main Criteria for Inclusion:  
Inclusion Criteria 
1. 
Aged at least 18 years; where approved, adolescents (aged 12-17 years) weighing at least 30 kg may also 
be enrolled. 
2. 
A diagnosis of primary C3G or IC-MPGN (with or without previous renal transplant). 
3. 
Evidence of active renal disease, based on one or more of the following: 
a. 
In adults or adolescents with a baseline renal biopsy (either one collected during screening or a 
historic biopsy collected within 28 weeks prior to randomization), at least 2+ C3c staining on the 
baseline renal biopsy. 
b. 
In adolescents not providing a baseline renal biopsy, at least one of the following: 
− 
Plasma sC5b-9 level above the upper limit of normal during screening 
− 
Serum C3 below the LLN during screening 
− 
Presence of an active urine sediment during screening, as evidenced by hematuria with at least 
5 red blood cells per high-power field and/or red blood cell casts on routine local or central 
microscopic analysis of urine 
− 
Presence of C3 nephritic factor within 6 months of screening, based on central laboratory 
results or medical history 


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4. 
No more than 50% global glomerulosclerosis or interstitial fibrosis on the baseline biopsy for adult 
participants or adolescent participants providing a baseline biopsy. 
5. 
At least 1 g/day of proteinuria on a screening 24-hour urine collection and a uPCR of at least 1000 mg/g 
in at least 2 first-morning spot urine samples collected during screening. 
6. 
eGFR ≥30 mL/min/1.73 m2 calculated by the Chronic Kidney Disease–Epidemiology Collaboration 
creatinine equation for adults or the Bedside Schwartz equation for adolescents. 
7. 
Stable regimen for C3G/IC-MPGN treatment, as described below: 
a. 
Angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, and/or sodium-glucose 
cotransporter-2 inhibitor therapy that is stable and optimized, in the opinion of the investigator, 
for at least 12 weeks prior to randomization 
b. 
Stable doses of other medications that can affect proteinuria (eg, steroids, mycophenolate mofetil, 
and/or other allowed immunosuppressants that the participant is receiving for treatment of C3G 
or IC-MPGN) for at least 12 weeks prior to randomization. 
c. 
If a participant is on prednisone (or other systemic corticosteroid) for C3G or IC-MPGN treatment, 
the dosage is stable and no higher than 20 mg/day (or equivalent dosage of a corticosteroid other 
than prednisone) for at least 12 weeks prior to randomization. 
8. 
Have received vaccinations against S pneumoniae, N meningitidis (types A, C, W, Y, and B), 
and H influenzae (type B) as per ACIP recommendations for adults or children with complement 
deficiencies. Vaccination series should be initiated at least 14 days prior to randomization. Vaccination 
is mandatory unless documented evidence exists that participants are nonresponders to vaccination.  
9. 
Female participants of childbearing potential, defined as any women who have experienced menarche 
and who are not permanently sterile or postmenopausal, must have negative blood pregnancy tests at 
screening (and negative urine pregnancy tests on day 1) and must agree to use protocol-defined methods 
of contraception from screening through at least 90 days after receiving the last dose of pegcetacoplan.  
10. Male participants must agree to use protocol-defined methods of contraception and agree to refrain from 
donating semen from screening through at least 90 days after receiving the last dose of pegcetacoplan. 
11. Participants above the legal age of consent, in accordance with local regulations, must be willing and 
able to provide informed consent. The legally authorized representative of participants under the legal 
age of consent must be willing and able to provide informed consent; where appropriate, participants 
under the legal age of consent must also give their assent to participation in the study. 
12. Willing and able to self-administer pegcetacoplan or have an identified caregiver who can perform 
the administration.  
Exclusion Criteria 
1. 
Previous exposure to pegcetacoplan. 
2. 
Evidence of improving renal disease in the 8 weeks prior to screening or during the screening period 
according to available data; improving renal disease is defined as >30% increase in eGFR or >50% 
decrease in proteinuria. 
3. 
From a renal transplant participant, evidence of rejection that requires treatment in the baseline renal 
biopsy collected during screening. 
4. 
C3G/IC-MPGN secondary to another condition (eg, infection, malignancy, monoclonal gammopathy, 
a systemic autoimmune disease such as systemic lupus erythematosus, chronic antibody-mediated 
rejection, or a medication), in the opinion of the investigator. 
5. 
Current or prior diagnosis of HIV, hepatitis B, or hepatitis C infection or positive serology during 
screening that is indicative of infection with any of these viruses.  
6. 
Body weight greater than 100 kg at screening. 
7. 
Hypersensitivity to pegcetacoplan or to any of the excipients. 
8. 
History of meningococcal disease. 
9. 
Malignancy, except for the following: 
a. 
Cured basal or squamous cell skin cancer 
b. 
Curatively treated in situ disease 


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c. 
Malignancy-free and off treatment for ≥5 years 
10. Severe infection (eg, requiring IV antibiotic therapy) within 14 days prior to the first dose of 
pegcetacoplan. 
11. An absolute neutrophil count <1000 cells/mm3 at screening. 
12. Significant other renal disease that would, in the opinion of the investigator, confound interpretation of 
study results. 
13. Participation in any other investigational drug trial or exposure to other investigational agent, device, 
or procedure within 30 days or 5 half-lives from the last dose of investigational agent (whichever is 
longer) prior to screening period. 
14. Use of rituximab, belimumab, or any approved or investigational anticomplement therapy other than 
pegcetacoplan within 5 half-lives of that product prior to the screening period. 
15. Female participants who are pregnant or who are currently breastfeeding and are unwilling to 
discontinue for the duration of the study and for at least 90 days after the final dose of study drug. 
16. Inability to cooperate or any condition that, in the opinion of the investigator, creates an undue risk for 
the participant by participating in the study or is likely to confound interpretation of the study results. 
17. Evidence of ongoing drug or alcohol abuse or dependence, in the opinion of the investigator. 
18. Presence or suspicion of severe infection during the screening period (including but not limited to 
recurrent or chronic infections) that, in the opinion of the investigator, may place the participant at 
unacceptable risk by study participation. 
19. Known or suspected hereditary fructose intolerance. 
Investigational Product, Dosage and Mode of Administration:  
Pegcetacoplan will be provided as a sterile solution in single-use glass vials. Each vial contains an isotonic sterile 
solution of pegcetacoplan 1080 mg/20 mL (54 mg/mL) in 10 mM acetate buffer, pH 5.0, containing 4.1% 
sorbitol. Placebo will be provided as a sterile solution of 10 mM acetate buffer, pH 5.0, containing 4.1% sorbitol 
supplied in single-use glass vials.  
All participants will receive SC infusions of pegcetacoplan or matching volumes of placebo twice weekly. 
All adult participants (regardless of weight), and adolescent participants who weigh at least 50 kg, will receive 
20-mL SC infusions. Adolescent participants who weigh at least 35 kg but less than 50 kg will receive a reduced 
infusion volume (12 mL for the first infusion and 15 mL for each infusion thereafter). Adolescent participants 
who weigh at least 30 kg but less than 35 kg will receive a further reduced infusion volume (10 mL for the first 
2 infusions and 12 mL twice weekly thereafter), as presented below. Study drug will be self-administered by the 
participant or administered by their caregiver, after receiving appropriate training and sign-off by a research nurse 
or other qualified personnel in their first treatment week.  
Planned Dosing Regimens 
Weight 
First dose 
(infusion volume) 
Second dose 
(infusion volume) 
Maintenance dose 
(infusion volume) 
All adult 
participants, 
adolescent 
participants 
≥50 kg 
1080 mg (20 mL) 
1080 mg (20 mL) 
1080 mg twice weekly (20 mL) 
Adolescent 
participants 
35 to <50 kg 
648 mg (12 mL) 
810 mg (15 mL) 
810 mg twice weekly (15 mL) 
Adolescent 
participants 
30 to <35 kg 
540 mg (10 mL) 
540 mg (10 mL) 
648 mg twice weekly (12 mL) 
 
 


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Duration of Participation:  
Total participation will be 70 weeks (screening: 10 weeks; RCP: 26 weeks; open-label period: 26 weeks; 
follow-up: 8 weeks). Depending on treatment assignment, treatment with pegcetacoplan will be for a maximum of 
52 weeks (RCP: 26 weeks; open-label period: 26 weeks).  
Statistical Methodology: 
Efficacy: 
Primary Efficacy: 
The targeted treatment regimen to be used for this study is pegcetacoplan or placebo plus stable regimen for 
C3G/IC-MPGN treatment. The primary estimand on the treatment effect of pegcetacoplan is for the participant 
population as defined through the study inclusion/exclusion criteria, with the primary endpoint based on the 
log-transformed ratio of uPCR (sampled from first-morning urine collections) at week 26 compared to baseline 
using an equal-weighted average over weeks 24, 25, and 26. Intercurrent events (ICEs) will be addressed as 
defined in Table 8.  
The primary endpoint will be analyzed using a mixed effect model for repeated measures (MMRM). The model 
will include fixed categorical effects for treatment group, visit, stratification factors, disease type (C3G vs 
IC-MPGN), and the visit-by-treatment group interaction, as well as the continuous, fixed covariate of baseline 
log-transformed uPCR. Initially, an unstructured covariance matrix will be investigated. If this analysis fails to 
converge, other covariance structures will be used; details will be provided in the statistical analysis plan. 
The difference between treatment groups will be estimated with its 95% CI and corresponding P value.  
Key Secondary Efficacy: 
To preserve the overall type I error among the primary endpoint and key and additional secondary endpoints, 
a fixed-sequence testing strategy will be used; hence, statistical significance of the first secondary endpoint will be 
evaluated only if statistical significance is achieved with the primary analysis of the primary endpoint. 
The remaining secondary endpoints will also adhere to this testing strategy, and their order will match the order in 
which they are presented in Section 5.2.1.  
• 
The numbers and proportion of participants who meet the criteria for achieving a composite renal 
endpoint at week 26 will be tabulated by treatment group and analyzed using a logistic regression model 
with treatment group as the independent variable and adjusted for baseline eGFR values, baseline 
log-transformed uPCR values, disease type, and stratification factors. The P value and odds ratio of 
being a responder for the pegcetacoplan group to being a responder for the placebo group and associated 
95% CI will be provided. 
• 
The numbers and proportion of participants who achieve uPCR response at week 26 (defined as a 
reduction from baseline in uPCR of at least 50% sampled from triplicate first-morning urine collections) 
will be tabulated by treatment group and compared using a logistic regression model similar to that for 
the composite renal endpoint. The odds ratio of being a responder for the pegcetacoplan group to being a 
responder for the placebo group with associated 95% CI and P value will be provided.  
• 
For participants with evaluable renal biopsies, evaluation of the change from baseline to week 26 in the 
activity score in the C3G histologic index will use analysis of covariance (ANCOVA) model with 
treatment as a fixed effect, adjusted for baseline C3G histologic index activity score, disease type, 
and stratification factors. P value and least-square (LS) means will be presented for each treatment 
group, along with the between-treatment difference and 95% confidence interval. 
• 
For participants with evaluable renal biopsies, the numbers and proportion of participants showing 
decreases in C3c staining on renal biopsy from baseline to week 26 will be tabulated by treatment group 
and compared using a logistic regression model similar to that for the composite renal endpoint. 
The odds ratio of being a responder for the pegcetacoplan group to being a responder for the placebo 
group and associated 95% CI and P value will be provided. 
• 
Change from baseline in eGFR at week 26 will be analyzed using a MMRM model similar to that for 
the primary endpoint. The difference between treatment groups will be estimated with its 95% CI and 
corresponding P value. 


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Safety: 
Adverse events (AEs) will be coded using the current version of the Medical Dictionary for Drug Regulatory 
Activities. TEAEs will be summarized by System Organ Class, Preferred Term, and treatment group for the 
number of participants and proportion reporting the event. A similar summary will be produced for serious 
adverse events, AEs leading to termination of study drug, severe AEs, and AEs related to the investigational 
product. The intensity of AEs and the relationship to investigational product will be summarized for each 
System Organ Class and Preferred Term by treatment group.  
AEs leading to withdrawal will be summarized for each body system and Preferred Term by treatment group. 
Laboratory assessments, antidrug antibody results, chest radiography, and electrocardiogram results will be 
summarized by treatment group using appropriate descriptive statistics.  
Interim Analyses: 
No interim analyses are planned. 
 


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2. 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
SIGNATURE PAGE .......................................................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................................................4 
1. 
SYNOPSIS ........................................................................................................................6 
2. 
TABLE OF CONTENTS ................................................................................................13 
LIST OF TABLES .........................................................................................................................18 
LIST OF FIGURES .......................................................................................................................18 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................................19 
4. 
INTRODUCTION ...........................................................................................................21 
4.1. 
C3G and IC-MPGN and Unmet Medical Need ..........................................................21 
4.2. 
Study Rationale ...........................................................................................................21 
4.2.1. 
Justification of Study Population ...............................................................22 
4.2.2. 
Justification of Study Design .....................................................................22 
4.2.3. 
Justification of Dose ..................................................................................23 
4.3. 
Summary of Clinical Experience With Pegcetacoplan ...............................................23 
4.4. 
Clinical Risks/Benefits of Pegcetacoplan ...................................................................24 
4.4.1. 
COVID-19 Risk Mitigation Measures .......................................................25 
5. 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................26 
5.1. 
Study Objectives .........................................................................................................26 
5.1.1. 
Primary Objective ......................................................................................26 
5.1.2. 
Secondary Objectives .................................................................................26 
5.1.3. 
Exploratory Objectives ..............................................................................26 
5.2. 
Study Endpoints ..........................................................................................................26 
5.2.1. 
Efficacy Endpoints .....................................................................................26 
5.2.2. 
Safety Endpoints ........................................................................................28 
5.2.3. 
Pharmacokinetic, Pharmacodynamic, and Immunogenicity 
Endpoints ...................................................................................................28 
6. 
INVESTIGATIONAL PLAN .........................................................................................30 
6.1. 
Overall Study Design ..................................................................................................30 
6.1.1. 
Part 1: Screening Period (10 Weeks) .........................................................33 
6.1.1.1. 
Rescreening ..........................................................................................34 


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6.1.2. 
Part 2: Randomized Controlled Period (26 Weeks) ......................................34 
6.1.3. 
Part 3: Open-Label Period (26 Weeks) ........................................................34 
6.1.4. 
Part 4: Follow-up Period (8 Weeks) ..........................................................35 
6.2. 
Number of Participants ...............................................................................................40 
6.3. 
Treatment Assignment .................................................................................................40 
6.4. 
End of Study ................................................................................................................40 
7. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS .........................................41 
7.1. 
Inclusion Criteria ........................................................................................................41 
7.1.1. 
Acceptable Methods of Contraception .......................................................42 
7.2. 
Exclusion Criteria .......................................................................................................43 
7.3. 
Discontinuations and Participants Lost to Follow-up .................................................44 
7.3.1. 
Early Treatment Discontinuation and Study Withdrawal ..........................44 
7.3.2. 
Reasons for Discontinuation of Treatment or Withdrawal From 
the Study ....................................................................................................44 
7.3.3. 
Lost to Follow-up Prior to Last Scheduled Visit .......................................45 
7.3.4. 
Replacement of Participants ......................................................................45 
8. 
TREATMENT OF PARTICIPANTS ..............................................................................46 
8.1. 
Study Interventions .....................................................................................................46 
8.2. 
Vaccinations ...............................................................................................................46 
8.2.1. 
Empiric Antibiotic Treatment for Possible Infection .................................47 
8.3. 
Concomitant Medications ...........................................................................................47 
8.3.1. 
Treatment Regimens for C3G or IC-MPGN ..............................................48 
8.3.1.1. 
Posttransplant Immunosuppression .....................................................48 
8.3.2. 
Rescue Therapy ..........................................................................................48 
8.3.3. 
Prohibited Medications ..............................................................................48 
8.4. 
Treatment Compliance ................................................................................................49 
8.5. 
Measures to Minimize Bias: Study Treatment Assignment .......................................49 
8.5.1. 
Randomization ...........................................................................................49 
8.5.2. 
Blinding......................................................................................................49 
8.5.2.1. 
Study Drug Unblinding ........................................................................49 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ................................................51 
9.1. 
Study Drug ..................................................................................................................51 
9.2. 
Study Drug Packaging and Labeling ..........................................................................51 


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9.2.1. 
Packaging ...................................................................................................51 
9.2.2. 
Labeling .....................................................................................................51 
9.3. 
Study Drug Storage .....................................................................................................51 
9.4. 
Infusion Supplies ........................................................................................................52 
9.5. 
Study Drug Administration .........................................................................................52 
9.6. 
Study Drug Accountability .........................................................................................53 
9.7. 
Study Drug Handling and Disposal ............................................................................53 
10. 
ASSESSMENT OF EFFICACY .....................................................................................54 
10.1. 
Retrospective Data Collection for eGFR and Measured Glomerular Filtration 
Rate ............................................................................................................................54 
10.2. 
24-Hour Urine Collection ...........................................................................................54 
10.3. 
Triplicate FMU Collections ........................................................................................55 
10.4. 
Random Spot Urine Collection ...................................................................................55 
10.5. 
Renal Biopsy ...............................................................................................................56 
10.5.1. 
Renal Biopsies in Adults ............................................................................56 
10.5.2. 
Renal Biopsies in Adolescents ...................................................................56 
10.6. 
Ophthalmologic Evaluation ........................................................................................57 
10.7. 
Measured GFR ............................................................................................................57 
10.8. 
Health-Related Quality of Life Assessments ..............................................................58 
10.8.1. 
Functional Assessment of Illness Therapy–Fatigue Scale .........................58 
10.8.2. 
5-Level EuroQol-5 Dimension ..................................................................58 
10.8.3. 
Kidney Disease Quality of Life .................................................................58 
10.8.4. 
Patient Global Impression of Change ........................................................58 
10.8.5. 
Work Productivity and Activity Impairment Questionnaire: 
Specific Health Problem ............................................................................58 
11. 
ASSESSMENT OF SAFETY .........................................................................................59 
11.1. 
Safety Parameters .......................................................................................................59 
11.1.1. 
Demographic/Medical History...................................................................59 
11.1.2. 
Vital Signs ..................................................................................................59 
11.1.3. 
Weight and Height .....................................................................................60 
11.1.4. 
Physical Examination.................................................................................60 
11.1.5. 
Menses .......................................................................................................60 
11.1.6. 
Electrocardiograms ....................................................................................60 


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11.1.7. 
Chest Radiography .....................................................................................60 
11.1.8. 
Infusion Site/Pump Safety Assessment .....................................................61 
11.1.9. 
Laboratory Assessments ............................................................................61 
11.1.9.1. 
Pregnancy Screen .................................................................................62 
11.1.10. 
Pharmacokinetic Assessment .....................................................................63 
11.1.11. 
Pharmacodynamic Assessment ..................................................................63 
11.1.12. 
Blood Volume for Study Assessments ......................................................63 
11.1.13. 
Antidrug Antibody Assessment .................................................................64 
11.1.14. 
COVID-19 Assessments .............................................................................65 
11.2. 
Adverse and Serious Adverse Events ...........................................................................65 
11.2.1. 
Definitions ..................................................................................................65 
11.2.1.1. 
Adverse Events .....................................................................................65 
11.2.1.2. 
Serious Adverse Events .........................................................................65 
11.2.1.3. 
Unexpected AEs ...................................................................................66 
11.2.2. 
Recording and Reporting AEs ...................................................................66 
11.2.2.1. 
Relationship to Study Drug ..................................................................66 
11.2.2.2. 
Severity of Events ................................................................................67 
11.2.3. 
Reporting AEs ............................................................................................67 
11.2.4. 
Pregnancy ...................................................................................................67 
11.2.5. 
AEs of Special Interest...............................................................................68 
11.2.6. 
Abuse, Misuse, Overdose, and Medication Errors ....................................68 
12. 
STATISTICS ...................................................................................................................69 
12.1. 
Determination of Sample Size ....................................................................................69 
12.2. 
Analysis Set ................................................................................................................69 
12.2.1. 
Screened Set ...............................................................................................69 
12.2.2. 
Safety Set ...................................................................................................69 
12.2.3. 
Intent-to-Treat Set ......................................................................................69 
12.2.4. 
Per-Protocol Set .........................................................................................69 
12.2.5. 
Pharmacokinetic Set ...................................................................................70 
12.2.6. 
Pharmacodynamic Set ................................................................................70 
12.2.7. 
Data Review for Analysis Set ....................................................................70 
12.3. 
Efficacy Analysis ........................................................................................................70 
12.3.1. 
Analysis of Primary Efficacy Endpoint .....................................................70 


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12.3.2. 
Analysis of Secondary Efficacy Endpoints ................................................71 
12.3.2.1. 
Key Secondary Efficacy Endpoints: ....................................................71 
12.3.2.2. 
Additional Secondary Efficacy Endpoints: ..........................................73 
12.3.3. 
Analysis of Exploratory Endpoints ............................................................74 
12.4. 
Safety Analysis ...........................................................................................................74 
12.5. 
Pharmacokinetic Analysis ..........................................................................................75 
12.6. 
Pharmacodynamic Analysis .........................................................................................76 
12.7. 
Other Analyses ............................................................................................................76 
12.8. 
Interim Analysis ...........................................................................................................76 
12.9. 
Data Monitoring Committee ........................................................................................76 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .............................................77 
13.1. 
Study Monitoring ........................................................................................................77 
13.2. 
Audits and Inspections ................................................................................................77 
13.3. 
Institutional Review Board .........................................................................................78 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE ..............................................79 
15. 
ETHICS ...........................................................................................................................80 
15.1. 
Ethics Review .............................................................................................................80 
15.2. 
Ethical Conduct of the Study ......................................................................................80 
15.3. 
Written Informed Consent ..........................................................................................80 
16. 
DATA HANDLING AND RECORDKEEPING ............................................................82 
16.1. 
Inspection of Records .................................................................................................82 
16.2. 
Retention of Records ..................................................................................................82 
17. 
PUBLICATION POLICY ...............................................................................................83 
18. 
LIST OF REFERENCES ................................................................................................84 
19. 
APPENDICES .................................................................................................................86 
Appendix 1. 
Protocol Amendment History ....................................................................87 
Appendix 2. 
Country-Specific Protocol Modifications ..................................................97 
Appendix 3. 
COVID-19 Study Continuity Plan ...........................................................108 
 


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LIST OF TABLES 
Table 1: 
Efficacy Endpoints ......................................................................................................27 
Table 2: 
Schedule of Activities .................................................................................................36 
Table 3: 
Planned Dosing Regimens (Pegcetacoplan and Placebo) ...........................................46 
Table 4: 
Laboratory Assessments .............................................................................................61 
Table 5: 
Approximate Blood Volume Collected ......................................................................64 
Table 6: 
Definitions of Adverse Event Relatedness .................................................................66 
Table 7: 
Severity of Events .......................................................................................................67 
Table 8: 
Intercurrent Events During the Randomized Treatment Phase and Strategies 
Addressing Intercurrent Events for the Primary Efficacy Endpoint ...........................71 
Table 9: 
Intercurrent Events During the Randomized Treatment Phase and Strategies 
Addressing Intercurrent Events for the Composite Renal Endpoint ..........................72 
 
LIST OF FIGURES 
Figure 1: 
Study APL2‑C3G-310 Design ....................................................................................32 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Abbreviation 
Definition 
ACIP 
Advisory Committee on Immunization Practices 
ADA 
antidrug antibodies 
AE 
adverse event 
AH50 
50% alternative hemolytic complement pathway activity 
AP 
alternative pathway 
C3G 
C3 glomerulopathy 
C3GN 
C3 glomerulonephritis 
CH50 
50% classical hemolytic complement pathway activity 
CKD-EPI 
Chronic Kidney Disease–Epidemiology Collaboration 
CRF 
case report form 
DDD 
dense deposit disease 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
eGFR 
estimated glomerular filtration rate 
ESRD 
end-stage renal disease 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy–Fatigue  
FDA 
Food and Drug Administration 
FMU 
first-morning spot urine 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
HHCP 
home health care provider 
HRQoL 
health-related quality of life 
IB 
investigator’s brochure 
IC-MPGN 
immune-complex membranoproliferative glomerulonephritis 
ICE 
intercurrent event 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
independent ethics committee 
IND 
Investigational New Drug 
IRB 
institutional review board 
ITT 
intent-to-treat 
KDQOL 
Kidney Disease Quality of Life 


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Abbreviation 
Definition 
LLN 
lower limit of normal 
MAR 
missing at random 
MMRM 
mixed effect model for repeated measures 
PD 
pharmacodynamic 
PEG 
polyethylene glycol 
PK 
pharmacokinetic 
PNH 
paroxysmal nocturnal hemoglobinuria 
PP 
per-protocol 
RCP 
randomized controlled period 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD-OCT 
spectral domain optical coherence tomography 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
uACR 
urine albumin-to-creatinine ratio 
uBCR 
urinary β2-microglobulin–to-creatinine ratio 
uPCR 
urine protein-to-creatinine ratio 
WOCBP 
women of childbearing potential 
WPAI 
Work Productivity and Activity Impairment 
 


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4. 
INTRODUCTION 
Two similar diseases, C3 glomerulopathy (C3G) and immune-complex membranoproliferative 
glomerulonephritis (IC-MPGN), will be studied in this protocol. This study will include patients 
with native kidney disease or with posttransplant disease recurrence and will exclude patients 
whose C3G or IC-MPGN is secondary to an underlying condition (eg, infection, monoclonal 
gammopathy, malignancy, or medication). 
4.1. 
C3G and IC-MPGN and Unmet Medical Need 
C3G is a disease in which the complement system, specifically the alternative pathway (AP), 
is indiscriminately overactive, leading to excessive deposition of C3 breakdown products in the 
glomeruli of the kidney, and damage to the renal parenchyma. The underlying AP hyperactivity 
can be due to various factors, most commonly, an acquired autoantibody which stabilizes the 
AP C3 or C5 convertase (C3 or C5 nephritic factor). AP hyperactivity leads to uncontrolled 
C3 activation, resulting in an excess of C3 breakdown products that are deposited in the 
glomerular basement membrane and mesangium. This stimulates a brisk inflammatory response, 
disrupting the normal glomerular architecture. 
There are 2 subtypes of C3G: dense deposit disease (DDD) and C3 glomerulonephritis (C3GN), 
which are distinguishable only by renal biopsy. The clinical presentation, features, and disease 
course are similar between the 2 subtypes, but with some distinctions. DDD tends to present 
earlier in life than C3GN (median ages of diagnosis for DDD and C3GN are 12 and 26 years old, 
respectively), and DDD is also associated with extrarenal manifestations, such as acquired partial 
lipodystrophy and macular degeneration. The incidence of C3GN is about 3-fold greater than 
that of DDD (Medjeral-Thomas et al. 2014; Servais et al. 2012; Lu et al. 2012). 
Although IC-MPGN is typically considered a distinct pathologic entity from C3G, the underlying 
pathophysiology and clinical course of the 2 primary diseases are remarkably similar  
(Noris et al. 2019; Holle et al. 2018). As in C3G, patients with primary IC-MPGN often have 
evidence of AP hyperactivity, including the presence of genetic or acquired causes of AP 
dysregulation. In these patients, uncontrolled C3 activation and glomerular deposition of C3 
breakdown products is also observed, similar to C3G. The only pathologic distinction from C3G is 
that the glomerular C3 deposition in IC-MPGN is accompanied by immunoglobulin deposition. 
The common clinical manifestations of primary IC-MPGN are the same as those of C3G and other 
glomerulonephritides – proteinuria, hematuria, hypertension, and reduced glomerular filtration rate. 
4.2. 
Study Rationale 
There are no therapies approved to prevent or reverse disease progression in C3G or IC-MPGN. 
Similar to other glomerular diseases, disease management includes nonspecific measures to 
manage proteinuria, hypertension, hyperlipidemia, edema, and other facets of glomerular and 
chronic kidney disease. Despite these various measures, the prognosis of C3G and IC-MPGN is 
poor as patients steadily progress to end-stage renal disease (ESRD) (Smith et al. 2019; 
Regunathan-Shenk et al. 2019; Medjeral-Thomas et al. 2014; Zhang et al. 2014; 
Pickering et al. 2013; Lu et al. 2012; Okpechi et al. 2014). 


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Renal transplantation is an option for patients who reach ESRD, but the incidence of disease 
recurrence is high, with up to 50% of patients losing their renal allografts because of disease 
recurrence (Medjeral-Thomas et al. 2014; Zhang et al. 2014; Pickering et al. 2013; Lu et al. 2012). 
Therefore, a therapy that can protect the kidneys, native or transplanted, from ongoing damage due to 
complement hyperactivity is an unmet need. 
As an inhibitor of C3 and its fragment, C3b, pegcetacoplan has the potential to address the 
underlying disease pathophysiology of complement hyperactivity in C3G and IC-MPGN. 
Specifically, by inhibiting C3, it is expected that pegcetacoplan will halt the inappropriate and 
excessive C3 activation that characterizes these diseases. Additionally, by inhibiting C3b, 
pegcetacoplan inhibits the activity of the AP C3 convertase (whether it is stabilized by nephritic 
factors or not) through a second complementary mechanism of action in addition to the inhibition 
of C3 as a substrate in the complement cascade. These 2 complementary mechanisms are 
expected to prevent further deposition of C3 breakdown products in the glomeruli, affording the 
opportunity for the kidney to recover by clearing existing deposits and resolving inflammation. 
This renal recovery would be expected, initially, to yield a reduction in proteinuria, and 
ultimately, to result in prolonged renal survival. Therefore, pegcetacoplan is a potentially 
life-altering therapy for C3G and IC-MPGN. 
4.2.1. 
Justification of Study Population 
Based on the mechanism of action of pegcetacoplan, Apellis aims to study patients with glomerular 
disease driven by complement over-activation and as such, will include patients with either C3G or 
IC-MPGN, as both are characterized by complement dysregulation leading to excessive deposition of 
C3 breakdown products in glomeruli (Iatropoulos et al. 2018; Cook 2018; Servais et al. 2012). 
Because the same underlying pathophysiology of complement dysregulation that leads to 
C3G/IC-MPGN in the native kidney also leads to disease recurrence posttransplant, and the clinical 
course for both is characterized by significant proteinuria and risk of progression to ESRD, the trial 
includes patients with posttransplant disease recurrence, in addition to nontransplant patients. 
Finally, the trial includes adolescents (ages 12–17), as the disease features in adolescents are similar 
to those of adults.  
4.2.2. 
Justification of Study Design 
A randomized, placebo-controlled, double-blinded trial design was selected in order to evaluate 
the treatment effect of pegcetacoplan on proteinuria and renal function in patients with C3G or 
IC-MPGN in a robust and minimally biased fashion. The placebo control enables identification 
of potential study effects that are not related to the study drug and provides data on the course of 
the disease in the absence of study treatment. Given that participants must have had stable or 
worsening disease for the preceding 3 months prior to study entry, a spontaneous disease 
remission is unlikely to occur during the study. However, participants may have improved 
(or worsened) compliance with nonstudy medications related to study participation. These types 
of study effects are expected to occur in the first 2 to 3 months of the study, so any 
placebo-related effect should be evident and stable by week 26.  


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To minimize unnecessary exposure for participants to placebo infusions, the study will include a 
26-week placebo-controlled period, after which the placebo group will be transitioned to 
pegcetacoplan treatment. In this way, all participants will have the opportunity to receive 
pegcetacoplan in a reasonable time frame while still establishing the placebo response rate. 
4.2.3. 
Justification of Dose 
The dosing regimen for adults will be 1080 mg administered subcutaneously (SC) twice weekly. 
This dosing regimen is intended to result in systemic exposures of pegcetacoplan similar to those 
seen in the ongoing phase 2 study in patients with complement-mediated glomerulopathies, 
Study APL2-201, and the phase 3 studies in patients with paroxysmal nocturnal hemoglobinuria 
(PNH), Study APL2-302 and Study APL2-308, in which pegcetacoplan has been generally safe 
and well tolerated.  
The dosing regimens for adolescents are intended to yield similar exposures as 1080 mg twice 
weekly in adults. Modeling-based simulations were performed for adolescents on the basis of an 
adult population PK model incorporating pegcetacoplan serum concentration-time data from 
10 clinical studies (five phase 1 studies in healthy volunteers, one special population study in adults 
with severe renal impairment, three phase 1b/2a studies in adult PNH patients, and one phase 3 study 
[Study APL2-302; data up to week 16] in adult PNH patients). The results of these model analyses 
were used to select the dosing regimens for adolescents, as summarized below:  
• In adolescents aged 12 to 17 years with body weights of at least 50 kg, a dose 
regimen of 1080 mg twice weekly is expected to result in exposure similar to that 
seen in adults at the same dosage. 
• In adolescents aged 12 to 17 years with body weights of 35 to 49 kg, a 648-mg initial 
dose followed by 810 mg twice weekly is anticipated to result in exposures at 
weeks 1, 2, and 16 (steady-state) that are similar to those of the adult dosage of 
1080 mg twice weekly. 
• In adolescents aged 12 to 17 years with body weights of 30 to 34 kg, the first 2 doses 
will be 540 mg, and following doses will be 648 mg twice weekly. This regimen is 
anticipated to result in exposures at weeks 1, 2, and 16 (steady-state) that are similar 
to those of the adult dosage of 1080 mg twice weekly. 
Modeling of exposure in high body weight participants (those weighing >100 kg) results in 
predicted exposures at least 15% lower than those for a reference 70-kg participant; participants 
with body weights of >100 kg will therefore be excluded from the study. 
4.3. 
Summary of Clinical Experience With Pegcetacoplan 
Pegcetacoplan is being studied in APL2-201, an ongoing phase 2 study that includes patients 
with 1 of 4 glomerular diseases: C3G, immunoglobulin (Ig) A nephropathy, primary 
membranous nephropathy, or lupus nephritis. Preliminary data from the 8 C3G participants in 
this study indicate that pegcetacoplan is able to target the complement hyperactivity of C3G, 
as well as reduce proteinuria in patients with C3G. 


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Clinical data is also available from 5 studies with pegcetacoplan in patients with PNH 
(phase 1b: Studies APL-CP0514 and APL2-CP-PNH-204; phase 2a: Study APL2-202; 
phase 3: Studies APL2-302 and APL2-308). Results from these studies indicate that pegcetacoplan is 
effective in providing broad control of intravascular and extravascular hemolysis, as evidenced by 
the following: increased and stable hemoglobin levels, normalization of lactate dehydrogenase levels, 
normalization of absolute reticulocyte count, normalization of total bilirubin levels, reduction in C3 
fragment opsonization, and increased numbers of PNH red blood cells.  
Pegcetacoplan at doses of 360 mg/d and 1080 mg twice weekly has been generally well tolerated 
when administered via SC infusion, including to patients with C3G and other glomerular diseases.  
Refer to the latest version of the pegcetacoplan investigator’s brochure (IB) for the overall 
risk/benefit assessment and the most current information regarding the drug metabolism, 
pharmacokinetic (PK), efficacy, and safety of pegcetacoplan. 
4.4. 
Clinical Risks/Benefits of Pegcetacoplan 
Pegcetacoplan has the potential to address the underlying disease pathophysiology of 
complement hyperactivity in C3G and IC-MPGN, and, therefore, to provide benefit in these 
diseases with a high unmet medical need.  
The safety of SC pegcetacoplan administration has been studied in multiple phase 2 and 3 studies for 
C3G, PNH, and autoimmune hemolytic anemia, with an acceptable safety profile to date. 
Nonetheless, a number of safety monitoring practices are being employed by this protocol to ensure 
participant safety, including physical examination, vital signs monitoring, electrocardiograms 
(ECGs), hematology (including coagulation), serum chemistry, urinalysis at specified intervals, 
as well as prompt reporting of adverse events (AEs). 
Infusion site/pump safety will be assessed during clinical visits, and any significant finding from 
the assessment will be recorded as an AE (see Section 11.2.2). The volume of blood planned for 
collection from each participant over the course of the study will be minimized to limit the 
impact on the overall health of these anemic participants.  
Systemic complement inhibition might predispose individuals to infections caused by encapsulated 
organisms, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus 
influenzae. Vaccinations against these organisms according to the most current Advisory Committee 
on Immunization Practices (ACIP) recommendations for patients with complement deficiencies will 
be required to minimize potential risk of infection. Vaccinations will be initiated at least 14 days 
prior to receiving the first dose of pegcetacoplan; therefore, prophylactic antibiotic use is not 
required. Body temperature and vital signs will be monitored periodically, and relevant blood 
parameters monitored regularly throughout the study to assess for signs of infection. Participants will 
be counseled regarding this potential risk for infection and given a participant safety wallet card in 
the event of an emergency. The investigator should be contacted immediately in the event of a 
suspected infection for guidance on appropriate action to be taken. 


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4.4.1. 
COVID-19 Risk Mitigation Measures 
Apellis is not currently aware of any evidence associating pegcetacoplan use with specific risks or 
complications of COVID-19. Apellis recognizes the need to consider the public health risks of the 
COVID-19 pandemic within the context of conducting a clinical trial. Because these risks may 
change as the pandemic evolves and may vary on the basis of geographic location, Apellis will 
continue to evaluate the risk/benefit around study conduct on an ongoing and 
participant-by-participant basis. 
In the event that an investigative site is closed or a participant is unable or unwilling to travel 
because of the COVID-19 pandemic, and if in the opinion of the investigator it is in the 
participant’s best interest to continue in the study, the following mitigation measures may be 
implemented for the study and used if deemed necessary and authorized by the sponsor, 
including but not limited to:  
• Collection of AEs or serious adverse events (SAEs) should be done over the phone 
and documented in the source documents. 
• A minimized schedule of activities is presented in Table A1 of Appendix 3.  
• Any activities not performed because of COVID-19–related restrictions will be 
identified in the participant source document.  
• Any change in COVID-19 status (serology or antigen), if available, will be captured 
in the participant's source document.  
• Where applicable, relevant study documentation will be updated and communicated 
to health authorities and/or institutional review boards (IRBs) or independent ethics 
committees (IECs) as required.  
Apellis is currently not aware of any contraindications to vaccination (of any modality) 
and concurrent treatment with pegcetacoplan. In the absence of data, Apellis currently 
recommends that the decision to vaccinate study participants against COVID-19 should be made 
by the investigator and the participant, with consideration of local and national vaccination 
recommendations and a benefit-risk assessment. Vaccination against COVID-19 is not 
mandatory for continued study participation. 
These measures are described in more detail Appendix 3.  


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5. 
STUDY OBJECTIVES AND ENDPOINTS 
5.1. 
Study Objectives 
5.1.1. 
Primary Objective 
The primary objective of this study is to assess the efficacy of twice-weekly SC doses of 
pegcetacoplan compared with that of placebo in patients with primary C3G or IC-MPGN on the 
basis of a reduction in proteinuria. 
5.1.2. 
Secondary Objectives 
The secondary objectives of the study are as follows: 
• To assess the effect of pegcetacoplan on estimated glomerular filtration rate (eGFR) 
• To assess the effect of pegcetacoplan on additional C3G/IC-MPGN disease–related 
parameters 
• To evaluate the safety of pegcetacoplan over 52 weeks of treatment 
5.1.3. 
Exploratory Objectives 
The exploratory objectives are to characterize the additional clinical, laboratory, and histologic 
findings of C3G/IC-MPGN in response to pegcetacoplan. 
5.2. 
Study Endpoints 
5.2.1. 
Efficacy Endpoints 
Table 1 lists the efficacy endpoints and the time points at which they will be evaluated. 
The primary and secondary endpoints will be evaluated at week 26. The primary and secondary 
endpoints will also be evaluated at week 52 as exploratory endpoints. The table also lists 
additional exploratory endpoints which will be evaluated at both week 26 and week 52. 


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Table 1: 
Efficacy Endpoints 
Study endpoints 
Week 26 
Week 52 
Primary efficacy endpoint 
 
 
The log-transformed ratio of uPCR at week 26 compared to baseline 
X 
 
Key secondary efficacy endpoints 
 
 
The proportion of participants who meet the criteria for achieving a composite renal 
endpoint (a stable or improved eGFR compared to the baseline visit (≤15% reduction 
in eGFR), and a ≥50% reduction in uPCR compared to the baseline visit.) 
X 
 
The proportion of participants with a reduction of at least 50% from baseline in uPCR  
X 
 
For participants with evaluable renal biopsies, the change from baseline in the activity 
score of the C3G histologic index score (Bomback et al. 2018) 
X 
 
The proportion of participants with evaluable renal biopsies showing decreases in C3c 
staining on renal biopsy from baseline  
X 
 
Change from baseline in eGFR 
X 
 
Additional secondary efficacy endpoints 
 
 
The proportion of participants achieving proteinuria <1 g/day 
X 
 
For participants with serum albumin levels below the LLN at baseline, the proportion 
of participants with normalization of serum albumin levels 
X 
 
For participants with serum C3 levels below the LLN at baseline, the proportion of 
participants with serum C3 levels above the LLN 
X 
 
The change from baseline in the FACIT-Fatigue Scale score 
X 
 
The change from baseline in the KDQOL score 
X 
 
Exploratory efficacy endpoints 
 
 
The log-transformed ratio of uPCR at week 52 compared to baseline 
 
X 
The proportion of participants who meet the criteria for achieving a composite renal 
endpoint 
 
X 
The proportion of participants with a reduction from baseline in uPCR of at least 50% 
 
X 
Change from baseline in eGFR 
 
X 
For participants with evaluable renal biopsies, the change from baseline in the activity 
score of the C3G histologic index (Bomback et al. 2018) 
 
X 
The proportion of participants with evaluable renal biopsies showing decreases in C3c 
staining on renal biopsy from baseline  
 
X 
The proportion of participants achieving proteinuria <1 g/day 
 
X 
For participants with serum albumin levels below the LLN at baseline, the proportion 
of participants with normalization of serum albumin levels 
 
X 
For participants with serum C3 levels below the LLN at baseline, the proportion of 
participants with serum C3 levels above the LLN 
 
X 
The change from baseline in the FACIT-Fatigue Scale score 
 
X 
The change from baseline in the KDQOL score 
 
X 
The change from baseline in uPCR using the 24-hour urine collections 
X1 
X1 
The annual rate of change from up to 3 years prior to screening in eGFR 
X 
X 


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Table 1: 
Efficacy Endpoints 
Study endpoints 
Week 26 
Week 52 
The proportion of participants with reductions from baseline in proteinuria of 
at least 30% 
X 
X 
The proportion of participants with normalization of proteinuria 
X 
X 
The time to 50% reduction in uPCR with a stable or improved eGFR 
n/a 
n/a 
The time to normalization for the following parameters for participants in whom the 
parameter is abnormal at baseline: 
• 
serum C3 
• 
uPCR 
• 
serum albumin 
• 
blood pressure 
n/a 
n/a 
The change in glomerular macrophage count, as determined by CD68 staining 
X 
X 
The change from baseline in PGIC score 
X 
X 
The change from baseline in EQ-5D-5L score 
X 
X 
The change from baseline in WPAI score 
X 
X 
Change in drusen from baseline: 
• 
change in maximum drusen size 
• 
change in number of intermediate or large drusen 
 
X 
Abbreviations: C3G = C3 glomerulopathy; eGFR = estimated glomerular filtration rate; FACIT-Fatigue = Functional Assessment of 
Chronic Illness Therapy–Fatigue; KDQOL = Kidney Disease Quality of Life; LLN = lower limit of normal; PEG = polyethylene 
glycol; PGIC = Patient Global Impression of Change; uPCR = urine protein-to-creatinine ratio; WPAI = Work Productivity and 
Activity Impairment. 
1. 24-hour urine collections are at week 24 and week 48. 
5.2.2. 
Safety Endpoints 
The safety endpoints are as follows: 
• The incidence and severity of treatment-emergent adverse events (TEAEs) 
• The change from baseline in:  
− vital signs measurements 
− clinical laboratory tests 
− ECG results 
• The number and incidence of rejection episodes (posttransplant participants only) 
• The number and incidence of graft loss (posttransplant participants only) 
• The incidence of death, stratified by transplant history 
5.2.3. 
Pharmacokinetic, Pharmacodynamic, and Immunogenicity Endpoints 
The PK endpoint is:  
• Pegcetacoplan serum concentrations over time 


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The pharmacodynamic (PD) endpoints are: 
• Changes from baseline in complement levels at week 26 and week 52: 
− CH50 (50% classical hemolytic complement pathway activity) 
− AH50 (50% alternative hemolytic complement pathway activity) 
− sC5b-9 
Additional complement components may be measured, as noted in Table 4 and Section 11.1.11, 
and evaluated as exploratory endpoints.  
The immunogenicity endpoint is:  
• The incidence of antidrug antibodies (ie, antibodies against the peptide and 
polyethylene glycol [PEG] domains of pegcetacoplan) 
 


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6. 
INVESTIGATIONAL PLAN 
This phase 3 randomized, placebo-controlled, double-blinded, multicenter clinical study is designed 
to evaluate the safety and efficacy of twice-weekly SC infusions of pegcetacoplan in patients with 
primary C3G or IC-MPGN. There will be approximately 80 to 100 participants enrolled in this study, 
at least 78 of whom will have native kidney disease and up to 22 of whom may have posttransplant 
recurrence of C3G or IC-MPGN. At least 63 participants with C3G in native kidney will be enrolled. 
The enrollment of participants with C3G or IC-MPGN will be monitored to ensure balance between 
the groups. At least 10 adolescent participants (aged 12-17 years) will be enrolled; adolescent 
participants may be either patients with native kidney disease or posttransplant disease recurrence. 
Participants initially screened as adolescents will follow adolescent procedures and requirements 
through the duration of their participation in study, even if they pass their 18th birthday while 
enrolled in the study.  
The planned length of participation in the study for each participant is a maximum of 
approximately 70 weeks. This study will consist of 4 parts: 
• Part 1: 10-week screening period 
• Part 2: 26-week randomized controlled period (RCP) 
• Part 3: 26-week open-label period 
• Part 4: 8-week follow-up period (only for participants who do not roll into a long-term 
extension study) 
Informed consent (and assent, when applicable) will be obtained prior to any study-related 
procedures being conducted. The screening period will start once informed consent has 
been obtained.  
See Figure 1 for the study schematic, and Table 2 for the schedule of activities. 
6.1. 
Overall Study Design 
This is a placebo-controlled, double-blinded, phase 3 study in patients with clinical and 
pathologic evidence of primary C3G or IC-MPGN. Participants will be randomly assigned 1:1 
to either the pegcetacoplan group (pegcetacoplan treatment throughout the RCP and open-label 
period) or the placebo group (placebo treatment during the RCP and pegcetacoplan treatment 
during the open-label period). The visit schedule will be the same, regardless of randomization.  
The study includes renal biopsies, one during screening and a second at the end of the RCP 
(week 26). An optional third biopsy may be collected at the end of the open-label period 
(week 52). The biopsy requirements are discussed in Section 10.5, including additional 
information on biopsies for participants under the age of 18.  
After completion of the RCP and open-label period, any participant who, in the opinion of the 
investigator, is experiencing clinical benefit from pegcetacoplan administration will be invited 
to participate in a planned long-term extension study to continue to receive treatment with 
pegcetacoplan until it is commercially available for the treatment of C3G and/or IC-MPGN 
and accessible in their countries, or the development program for C3G and/or IC-MPGN is 
terminated, in compliance with all applicable national and local laws and regulations. 


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Participants who do not continue on pegcetacoplan in a planned long-term extension study will 
enter the 8-week follow-up period of this study.  
See Figure 1 for the study schematic. 
 




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6.1.1. 
Part 1: Screening Period (10 Weeks) 
Participants will be screened to confirm that the selection criteria for the study have been met. 
The screening period will occur in 2 stages, and all assessments described in the schedule of 
activities (Table 2) at screening visit 1 should occur before those in screening visit 2. This ensures 
that the more invasive procedures (vaccinations and renal biopsy) do not occur unless the participants 
meet all other eligibility criteria.  
• One 24-hour urine sample and 3 sets of triplicate first-morning spot urine (FMU) samples 
(first-morning void collected on 3 consecutive days) will be collected to determine eligibility 
and establish a baseline uPCR. Collection of urine samples is discussed in more detail in 
Section 10.2 and Section 10.3. Calculation of baseline uPCR is discussed in Section 12.3.1 
and Section 12.3.2.  
• For adult participants, a renal biopsy will be performed to confirm diagnosis and eligibility 
and to serve as the baseline renal biopsy. The baseline renal biopsy may be conducted at any 
time during screening once eligibility is confirmed by the assessments from screening visit 1. 
All biopsies will be evaluated by the central pathology laboratory. Renal biopsies are 
discussed in more detail in Section 10.5. 
o A historic renal biopsy done within 28 weeks of randomization may be used for 
eligibility confirmation and serve as the baseline biopsy if it is confirmed as adequate 
by the central pathology laboratory on the basis of review of the biopsy report as well 
as slides and/or images.  
o Participants under the age of 18 are not required to provide a biopsy if they have an 
adequate previous renal biopsy to establish the diagnosis, even if the previous biopsy 
is more than 28 weeks prior to randomization.  
• Retrospective data for a period of up to 3 years prior to study entry will be collected to 
calculate historical eGFR using the Chronic Kidney Disease–Epidemiology Collaboration 
[CKD-EPI] creatinine equation for adults and the Bedside Schwartz equation 
(eGFR = 0.413 × [height (in centimeters)] / serum creatinine) for adolescents. 
Retrospective data for eGFR are discussed in more detail in Section 10.1. 
• The participant’s medical history and screening data will be reviewed by the investigator, 
in collaboration with the medical monitor, to confirm the diagnosis of primary C3G or 
IC-MPGN. The investigator and medical monitor will consider all available historical, 
laboratory, and pathology data. For an adolescent in whom a renal biopsy within 28 weeks of 
day 1 is not available, the investigator and medical monitor will consider alternative evidence 
for active renal disease as described in Section 7.1.  
• Vaccinations against S pneumoniae, N meningitidis (types A, C, W, Y, and B), 
and H influenzae (type B) are mandatory unless documented evidence exists that participants 
are nonresponders to vaccination. If required, vaccination series should be initiated at least 
14 days prior to randomization. Vaccinations are discussed in more detail in Section 8.2. 


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Individuals who consent to participate in the study but who do not initially meet all the 
requirements as outlined in the inclusion and exclusion criteria are not able to be enrolled; 
however, these individuals may be held in the screening period until such time that they meet 
inclusion requirements and are able to be enrolled. In this case, additional screening visits and/or 
repeat screening assessments may be conducted, as needed, to establish eligibility. The medical 
monitor will contact the investigator to identify screening activities related to the confirmation of 
participant eligibility that must be repeated.  
6.1.1.1. 
Rescreening 
In the event that rescreening occurs and the participant has not remained in the screening period 
(ie, is a screening failure), the individual is required to reconsent and must be assigned a new 
identification number. For rescreened participants, the historic biopsy (within 28 weeks before 
randomization), chest radiography, vaccination, ophthalmologic evaluations, and measured GFR in 
the previous screening period may be considered as validated testing for rescreening.  
6.1.2. 
Part 2: Randomized Controlled Period (26 Weeks) 
Approximately 80 to 100 participants who meet all of the inclusion criteria and none of the exclusion 
criteria will be randomly assigned in a 1:1 ratio to receive either pegcetacoplan or placebo. 
Randomization will be performed as described in Section 8.5.1.  
• Pegcetacoplan group: Participants will receive SC pegcetacoplan twice weekly.  
• Placebo group: Participants will receive SC placebo infusions twice weekly.  
• Every effort will be made in both groups to minimize changes to medications related to 
C3G/IC-MPGN disease.  
• Triplicate FMU samples will be collected at each visit, and an additional triplicate FMU 
uPCR sample will be collected during week 25.  
• Safety and efficacy will be assessed.  
• At the end of the RCP, there will be a renal biopsy, which is required for participants aged 
18 years and older to advance to the open-label period (Part 3). Participants younger than 
18 years are not required to provide renal biopsies and may advance to the open-label period 
upon completion of all assessments for weeks 24 through 26 other than the renal biopsy. 
Biopsy requirements are discussed in more detail in Section 10.5. 
6.1.3. 
Part 3: Open-Label Period (26 Weeks) 
At the end of the RCP, participants from both groups will proceed to the 26-week open-label period, 
in which all participants will be treated with pegcetacoplan twice weekly. Open-label dosing will 
begin at the first visit after the week 26 renal biopsy for adults and any adolescents providing renal 
biopsies. Open-label dosing for adolescents not providing renal biopsies should start at the week 26 
visit. At the end of the open-label period, there will be an optional renal biopsy. Participants younger 
than 18 years who did not have a baseline biopsy within 28 weeks of day 1 will not have a biopsy at 
the end of the open-label period. Upon completion of the open-label period, participants will enter 
the follow-up period (Part 4) unless they enter a long-term extension study.  


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6.1.4. 
Part 4: Follow-up Period (8 Weeks) 
After completion of the open-label period, participants who would benefit from continuing to 
receive pegcetacoplan, in the investigator’s opinion, may roll over into a long-term extension 
study. Participants who do not enter a long-term extension study will discontinue pegcetacoplan 
treatment and complete the 8-week follow-up period. In addition, any participant who discontinues 
study drug during the RCP or open-label period should complete follow-up activities, as described in 
Section 7.3.1. 
 






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Table 2: 
Schedule of Activities 
Abbreviations: Ab = antibodies; ADA = antidrug antibodies; AE = adverse events; AH50 = 50% alternative hemolytic complement pathway activity; ANA = antinuclear 
antibodies; ANCA = antineutrophil cytoplasmic antibodies; β-HCG = beta human chorionic gonadotropin; CH50 = 50% classical hemolytic complement pathway activity; 
ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; EQ-5D-5L = 5-Level EuroQol-5 Dimension; FACIT-Fatigue = Functional Assessment of Chronic 
Illness Therapy–Fatigue Scale; FMU = first-morning spot urine; FSH = follicle-stimulating hormone; GFR = glomerular filtration rate; HIV = human immunodeficiency virus; 
HRQoL = health-related quality of life; KDQOL = Kidney Disease Quality of Life; N/A = not applicable; PGIC = Patient Global Impression of Change; PK = pharmacokinetic; 
SC = subcutaneous; SD-OCT = spectral domain optical coherence tomography; SPEP = serum protein electrophoresis; uPCR = urine protein-to-creatinine ratio; 
WPAI = Work Productivity and Activity Impairment. 
NOTE: When multiple assessments/procedures occur at the same visit, order should be: vital signs, ECGs, blood collection/sampling, study drug dosing.  
a. 
All visit 2 assessments need not occur in a single visit and visit 2 can be split into multiple visits (eg, visit 2a, visit 2b). 
b. 
Vaccinations, baseline renal biopsy, and screening chest radiography can occur any time during screening after confirmation of eligibility based on visit 1 data. 
c. 
For transplant participants only. Must be documented prior to assignment to study treatment.  
d. 
Vaccine series should be initiated at least 14 days prior to randomization; additional vaccines may be required at visit 6. Please see Section 8.2 for more details on vaccination 
requirements. Vaccination serum samples will be collected on the day of vaccination before receiving vaccinations on that visit. These samples will be analyzed to evaluate response 
to vaccinations in the event that the participant has a positive infection for Streptococcus pneumoniae, Neisseria meningitidis, or Haemophilus influenzae.  
e. 
A full physical examination is required at visits 1, 3 (week 1), 10 (week 26), and 16 (week 52). A full physical examination should also be conducted on the first day of open-label 
dosing, if that is not at the week 26 visit. Brief physical examinations, including weight (kg) and assessment of edema, will be conducted at all other visits noted. A symptom-driven 
physical examination may be performed at any time, at the investigator’s discretion. Body height (cm) will be measured only during screening for adults but will be measured at 
screening and every 12 weeks throughout the study for adolescents; weight (kg) will be measured throughout study, during brief and full physical examinations for all participants. 
Both body weight and height will be assessed without shoes on; height will be measured using a calibrated stadiometer. Edema should be assessed at every visit. 
f. 
Renal biopsies will not be required for participants younger than 18 years provided that they have adequate previous renal biopsies to establish the diagnosis as per the central 
pathology laboratory. 
g. 
The week 26 renal biopsy need not occur on the same day as all other assessments for that visit. However, the week 26 triplicate FMU uPCR collections must occur before the renal 
biopsy. In addition, the week 26 biopsy must occur before the first visit of the open-label period at week 28. Participants younger than 18 years are not required to provide renal 
biopsies and may advance to the open-label period upon completion of all assessments for weeks 24 through 26 other than the renal biopsy.  
h. 
The week 52 renal biopsy is optional for all participants. If performed it should be after collection of the week 48 24-hour urine and FMU samples, and not more than 8 weeks after 
the week 52 visit. In the event that a participant has a renal biopsy as part of their clinical management within this window, it may serve as the week 52 biopsy provided that it 
includes the required components for this study. 
i. 
Study drug will be self-administered by the participant or administered by their caregiver, after receiving appropriate training and sign-off by a research nurse (or other qualified 
personnel) in their first treatment week, as described in Section 9.5. Once qualified, the participant or caregiver should administer study drug at site visits (as done at home) on those 
days when a clinic visit occurs on a dosing day. If a home nurse is administering study drug on nonvisit days, the site staff may administer study drug on days of site visits. 
j. 
Between site visits, participants will be instructed to report any infusion site reactions to the study staff. Pump use safety will be reviewed by licensed health care professionals 
(eg, investigator or nurse) for each study drug administration at clinic visits and during at-home qualification.  
k. 
Vital signs should be measured a maximum of 2 hours before study drug infusion. On day 1 and on the first day of open-label dosing (week 26 or week 28, depending on whether a 
week 26 renal biopsy is required and when it is performed), vital signs should also be measured approximately 30 minutes to 1 hour after the first infusion of study drug dosing, 
timed from the completion of the study drug administration. Blood pressure and heart rate should be evaluated after the participant has been resting in a seated position for at least 
5 minutes, except when they are supine or semireclined because of study procedures and/or AEs, or if deemed necessary by the investigator. 
l. 
FACIT-Fatigue, EQ-5D-5L, KDQOL, PGIC, and WPAI. 
m. 
The screening 24-hour urine collection may be done any time between screening visit 1 and screening visit 2. After week 1, collections should be within ±1 week of the visit 
(except for the week 24 collection, which cannot be earlier than week 24). Courier arrangements can be made to pick up the collection container from the participant, or the 
participant may return the container directly to the site. 


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Table 2: 
Schedule of Activities 
n. 
Triplicate FMU samples will be collected by the participant at home on 3 consecutive days throughout the duration of the study. These should be the first urinary output of the day. 
An additional triplicate FMU uPCR sample will be collected at week 25. Samples should be collected within ±1 week of the clinic visit (except for weeks 24 through 26, 
when sample collection should be within ±3 days of the clinic visit). Courier arrangements can be made to pick up the collection containers from the participants, or the participant 
may return the containers directly to the site. At every visit, enough uPCR collection containers should be dispensed to the participant to enable all at-home uPCR collections until 
the next clinic visit. 
o. 
The day 1 triplicate FMU uPCR samples should be collected before the first dose of study drug (eg, day –2, day –1, and before dosing on day 1).  
p. 
Serum complement profile includes AH50, CH50, and C3NeF; C3NeF will only be assayed in samples collected at the baseline (screening) visits. Plasma complement profile 
includes C3a, C3b/iC3b, C5a, and sC5b-9. See laboratory assessments (Table 4) for more details. 
q. 
The day 1 samples should be collected before dosing with study drug. Participants who discontinue dosing will have ADA samples collected at 2 and 8 weeks after the last treatment. 
Participants who have a treatment-emergent or treatment-boosted ADA response at any time will have ADA samples collected approximately every 6 months until the antibody 
levels revert to baseline. 
r. 
eGFR will be calculated using the Chronic Kidney Disease–Epidemiology Collaboration creatinine equation for adults or the Bedside Schwartz equation for adolescents. For each 
participant, eGFR will be calculated using the same formula for the duration of the study; the choice of formula will be determined by the participant’s age at study entry.  
s. 
Serum FSH (to be measured in female participants only), hepatitis B panel, hepatitis C panel, HIV antibodies, SPEP (adult participants only), ANA, and ANCA (see Table 4 
and laboratory manual for more details). 
t. 
Ophthalmologic evaluations are optional and will be performed at selected sites. If evaluations are performed, each participant should have a baseline ophthalmologic evaluation, 
including a basic ophthalmologic examination, SD-OCT, and color fundus photography, at an approved ophthalmologic clinical site at any time during the screening period. 
For participants who have drusen before pegcetacoplan administration, a follow-up ophthalmologic evaluation, including an SD-OCT and color fundus photography, should occur at 
a convenient time between weeks 42 and 52. 
u. 
Measured GFR is an optional assessment that, if performed, should occur at 3 time points: once on day 1 or within 10 weeks before day 1, again at week 26, and a third time between 
week 42 and week 52, inclusive. Measured GFR should only be done at sites where it is routinely performed, as per the site’s standard protocol. 
 


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6.2. 
Number of Participants 
Approximately 80 to 100 patients with clinical and pathologic evidence of C3G or IC-MPGN will be 
randomized into this study, at least 78 of whom will have native kidney disease and up to 22 of 
whom may have posttransplant recurrence of C3G or IC-MPGN. At least 63 participants with C3G 
in native kidneys will be enrolled. At least 10 adolescent participants (aged 12-17 years) will be 
enrolled; adolescent participants may be patients with either native kidney disease or posttransplant 
disease recurrence. When the study is approaching the target enrollment, the sponsor will notify sites 
and investigators of the anticipated enrollment closure. Potentially eligible participants who have 
started screening may complete screening activities and enroll in the study if they meet eligibility 
criteria, even if this results in enrollment of more than the planned maximum of 100 participants.  
6.3. 
Treatment Assignment 
All participants who meet all the inclusion criteria and none of the exclusion criteria will be enrolled 
in the study, until such time that the intended enrollment has been met. After confirmation of study 
eligibility, participants will be randomized in a ratio of 1:1 to receive pegcetacoplan or placebo as 
described in Section 8.5.1.  
Following completion of the RCP, all participants will receive pegcetacoplan starting on the first visit 
of the open-label period, after which they will enter the follow-up period, unless they enroll in a 
long-term extension study. 
6.4. 
End of Study 
Participants will be considered to have completed the study when they have completed the exit visit 
activities described in the schedule of activities (Table 2), when they have enrolled in a subsequent 
study of pegcetacoplan, or when they have discontinued study treatment and completed the activities 
described in Section 7.3.1. 
The end of the study will be the last participant’s last visit or the last participant’s last scheduled 
visit/assessment as indicated in the schedule of activities (Table 2) or as requested by the sponsor. 
 


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7. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
7.1. 
Inclusion Criteria 
1. Aged at least 18 years; where approved, adolescents (aged 12-17 years) weighing at least 
30 kg may also be enrolled. 
2. A diagnosis of primary C3G or IC-MPGN (with or without previous renal transplant). 
3. Evidence of active renal disease, based on one or more of the following: 
a. In adults or adolescents with a baseline renal biopsy (either one collected during 
screening or a historic biopsy collected within 28 weeks prior to randomization), at least 
2+ C3c staining on the baseline renal biopsy 
b. In adolescents not providing a baseline renal biopsy, at least one of the following: 
− Plasma sC5b-9 level above the upper limit of normal during screening 
− Serum C3 below the lower limit of normal (LLN) during screening 
− Presence of an active urine sediment during screening, as evidenced by hematuria 
with at least 5 red blood cells per high-power field and/or red blood cell casts on 
routine local or central microscopic analysis of urine 
− Presence of C3 nephritic factor within 6 months of screening, based on central 
laboratory results or medical history 
4. No more than 50% global glomerulosclerosis or interstitial fibrosis on the baseline biopsy for 
adult participants or adolescent participants providing a baseline biopsy. 
5. At least 1 g/day of proteinuria on a screening 24-hour urine collection and a uPCR of at least 
1000 mg/g in at least 2 FMU samples collected during screening. 
6. eGFR ≥30 mL/min/1.73 m2 calculated by the CKD-EPI creatinine equation for adults or the 
Bedside Schwartz equation for adolescents. 
7. Stable regimen for C3G/IC-MPGN treatment, as described below: 
a. Angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, and/or 
sodium-glucose cotransporter-2 inhibitor therapy that is stable and optimized, in the 
opinion of the investigator, for at least 12 weeks prior to randomization 
b. Stable doses of other medications that can affect proteinuria (eg, steroids, mycophenolate 
mofetil, and/or other allowed immunosuppressants that the participant is receiving for 
treatment of C3G or IC-MPGN) for at least 12 weeks prior to randomization. 
c. If a participant is on prednisone (or other systemic corticosteroid) for C3G or IC-MPGN 
treatment, the dosage is stable and no higher than 20 mg/day (or equivalent dosage of a 
corticosteroid other than prednisone) for at least 12 weeks prior to randomization. 
8. Have received vaccinations against S pneumoniae, N meningitidis (types A, C, W, Y, and B), 
and H influenzae (type B) as per ACIP recommendations for adults or children with 
complement deficiencies. Vaccination series should be initiated at least 14 days prior to 
randomization. Vaccination is mandatory unless documented evidence exists that participants 
are nonresponders to vaccination.  


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9. Female participants of childbearing potential, defined as any women who have 
experienced menarche and who are not permanently sterile or postmenopausal, must have 
negative blood pregnancy tests at screening (and negative urine pregnancy tests on day 1) 
and must agree to use protocol-defined methods of contraception from screening through 
at least 90 days after receiving the last dose of pegcetacoplan. 
10. Male participants must agree to use protocol-defined methods of contraception and 
agree to refrain from donating semen from screening through at least 90 days after 
receiving the last dose of pegcetacoplan. 
11. Participants above the legal age of consent, in accordance with local regulations, must 
be willing and able to provide informed consent. The legally authorized representative 
of participants under the legal age of consent must be willing and able to provide 
informed consent; where appropriate, participants under the legal age of consent must 
also give their assent to participation in the study. 
12. Willing and able to self-administer pegcetacoplan or have an identified caregiver who 
can perform the administration.  
7.1.1. 
Acceptable Methods of Contraception 
Women of childbearing potential (WOCBP) and male participants with female partners of 
childbearing potential will be instructed to practice an acceptable method of birth control throughout 
the duration of the study and for 90 days following the end of study drug administration.  
A woman is considered to be of childbearing potential following menarche and until becoming 
postmenopausal, unless she is permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause.  
Approved 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 partner is the sole sexual partner of the WOCBP 
trial participant and that 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 participants with female 
partners of childbearing potential only) 


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Not all methods of contraception may be available in all of the countries in which this study is 
being conducted. 
Note: Sexual abstinence is only accepted when it is the preferred and usual lifestyle of the participant. 
7.2. 
Exclusion Criteria 
1. Previous exposure to pegcetacoplan. 
2. Evidence of improving renal disease in the 8 weeks prior to screening or during the screening 
period according to available data; improving renal disease is defined as >30% increase in 
eGFR or >50% decrease in proteinuria. 
3. From a renal transplant participant, evidence of rejection that requires treatment in the 
baseline renal biopsy collected during screening. 
4. C3G/IC-MPGN secondary to another condition (eg, infection, malignancy, monoclonal 
gammopathy, a systemic autoimmune disease such as systemic lupus erythematosus, 
chronic antibody-mediated rejection, or a medication), in the opinion of the investigator.  
5. Current or prior diagnosis of HIV, hepatitis B, or hepatitis C infection or positive 
serology during screening that is indicative of infection with any of these viruses.  
6. Body weight greater than 100 kg at screening.  
7. Hypersensitivity to pegcetacoplan or to any of the excipients. 
8. History of meningococcal disease. 
9. Malignancy, except for the following: 
a. Cured basal or squamous cell skin cancer 
b. Curatively treated in situ disease 
c. Malignancy-free and off treatment for ≥5 years 
10. Severe infection (eg, requiring IV antibiotic therapy) within 14 days prior to the first 
dose of pegcetacoplan. 
11. An absolute neutrophil count <1000 cells/mm3 at screening. 
12. Significant other renal disease that would, in the opinion of the investigator, confound 
interpretation of study results. 
13. Participation in any other investigational drug trial or exposure to other investigational 
agent, device, or procedure within 30 days or 5 half-lives from the last dose of 
investigational agent (whichever is longer) prior to screening period. 
14. Use of rituximab, belimumab, or any approved or investigational anticomplement 
therapy other than pegcetacoplan within 5 half-lives of that product prior to the 
screening period. 
15. Female participants who are pregnant or who are currently breastfeeding and are 
unwilling to discontinue for the duration of the study and for at least 90 days after the 
final dose of study drug. 


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16. Inability to cooperate or any condition that, in the opinion of the investigator, creates an 
undue risk for the participant by participating in the study or is likely to confound 
interpretation of the study results. 
17. Evidence of ongoing drug or alcohol abuse or dependence, in the opinion of the 
investigator. 
18. Presence or suspicion of severe infection during the screening period (including but not 
limited to recurrent or chronic infections) that, in the opinion of the investigator, may 
place the participant at unacceptable risk by study participation. 
19. Known or suspected hereditary fructose intolerance. 
7.3. 
Discontinuations and Participants Lost to Follow-up  
7.3.1. 
Early Treatment Discontinuation and Study Withdrawal 
A participant may discontinue study treatment or withdraw from the study at any time, for any 
reason, without prejudice to his/her future medical care. The investigator or sponsor may 
discontinue study treatment or withdraw the participant from the study at any time (eg, in the 
interest of the participant’s safety). If a participant discontinues study treatment or is withdrawn 
from the study for any reason, the study site must immediately notify the medical monitor.  
Once withdrawn from the study, the participant may not reenter the study. 
Participants who discontinue study treatment prior to the end of the RCP should be encouraged 
to complete the remaining visits for the RCP. If discontinuing study treatment after week 18, 
participants should also complete the activities described for the exit visit in the schedule of 
activities (Table 2) approximately 8 weeks after their last dose of study drug. If the participant is 
unwilling or unable to complete the exit visit activities, they should be encouraged to complete 
the other follow-up visits and procedures described in the schedule of activities (Table 2). 
Participants who discontinue study treatment during the open-label period should enter the 
follow-up period of the study, including all follow-up visits and procedures through study 
completion, unless unwilling, unable, or consent has been withdrawn. Participants who wish to 
fully withdraw from the study during the open-label period but prior to the week 52 visit and are 
unwilling or unable to complete the follow-up visits and procedures should complete the 
activities described for the exit visit in the schedule of activities (Table 2) at their last visit.  
7.3.2. 
Reasons for Discontinuation of Treatment or Withdrawal From the Study  
The date of and reason for treatment discontinuation must be determined by the investigator and 
recorded in the participant’s medical record. If it is determined that there was more than one reason 
for the discontinuation, each reason should be recorded in the source document and the most 
clinically relevant reason, as determined by the investigator, should be noted. Treatment will be 
discontinued if any of the following occur: 
• Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent 
illness, or other medical condition (including infections) or circumstance that 
indicates to the investigator that continued participation is not in the best interest of 
the participant.  


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• Participant withdrawal of consent: at any time, a participant’s participation in the 
study may be terminated at his or her request or on the basis of the investigator’s 
clinical judgment. The reason for participant withdrawal will be noted in the 
participant’s source document.  
• Participant fails to adhere to the protocol requirements (eg, drug noncompliance, 
failure to return for defined number of visits, failure to meet randomization criteria), 
such that continued participation in the study is not in the best interest of the 
participant (in the opinion of the investigator) or compromises the ability of the 
sponsor to appropriately analyze the data from the study.  
• Participant is lost to follow-up: the participant stopped coming for visits, and study 
personnel were unable to contact the participant.  
• Termination of the study by the sponsor or regulatory authorities.  
• Pregnancy, as indicated in Section 11.2.4.  
Any participant who discontinues treatment early, or is withdrawn from the study early, because 
of a TEAE, whether serious or nonserious, will be followed until the TEAE resolves (returns to 
normal or baseline values) or stabilizes, or until it is judged by the investigator to no longer be 
clinically significant. 
Participants for whom study treatment is discontinued should be encouraged to complete 
additional activities as described in Section 7.3.1, unless unwilling, unable, or consent has been 
withdrawn. If consent is withdrawn, no further study evaluations are to be performed and no 
attempts are to be made to collect additional data. 
Additionally, the sponsor may stop the study at any time for safety, regulatory, legal, or other 
reasons aligned with Good Clinical Practice (GCP). This study may be terminated at the 
discretion of the sponsor or any regulatory agency. An investigator may elect to discontinue or 
stop the study at his/her study site for any reason, including safety or low enrollment. 
7.3.3. 
Lost to Follow-up Prior to Last Scheduled Visit 
A minimum of 3 documented attempts must be made to contact any participants lost to follow-up 
at any time 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 participant’s last 
known address via courier or mail (with an acknowledgment of receipt request) asking that 
he/she return to the site for final safety evaluations and to return any study drug. 
Should the participant continue to be unreachable, he/she will be considered to have withdrawn 
from the study. 
7.3.4. 
Replacement of Participants 
Participants who discontinue the study will not be replaced.  


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8. 
TREATMENT OF PARTICIPANTS 
8.1. 
Study Interventions 
All participants will receive SC infusions of pegcetacoplan or matching volumes of placebo 
twice weekly. The planned dosing regimens for pegcetacoplan and the matching volume of 
placebo are presented in Table 3. All adult participants (regardless of weight), and adolescent 
participants who weigh at least 50 kg, will receive 20-mL SC infusions. Adolescent participants 
who weigh at least 35 kg but less than 50 kg will receive a reduced infusion volume (12 mL for 
the first infusion and 15 mL for each infusion thereafter). Adolescent participants who weigh at 
least 30 kg but less than 35 kg will receive a further reduced infusion volume (10 mL for the first 
2 infusions and 12 mL twice weekly thereafter). As described in Section 11.1.3, participant 
weight will be assessed at each visit; if an adolescent participant’s weight has changed, the dose 
and infusion volume should be adjusted accordingly. 
Table 3: Planned Dosing Regimens (Pegcetacoplan and Placebo) 
Weight 
First dose 
(infusion volume) 
Second dose 
(infusion volume) 
Maintenance dosing regimen 
(infusion volume) 
All adult participants, 
adolescent participants 
≥50 kg 
1080 mg (20 mL) 
1080 mg (20 mL) 
1080 mg twice weekly (20 mL) 
Adolescent participants 
35 to <50 kg 
648 mg (12 mL) 
810 mg (15 mL) 
810 mg twice weekly (15 mL) 
Adolescent participants 
30 to <35 kg 
540 mg (10 mL) 
540 mg (10 mL) 
648 mg twice weekly (12 mL) 
Participants and/or their caregivers will be trained to administer the infusions, as described in 
Section 9.5.  
If a participant misses any regularly scheduled doses for any reason, all efforts should be made to 
restart dosing as soon as possible to reach and maintain therapeutic steady-state concentrations of 
pegcetacoplan. A single missed dose should be administered as soon as possible, regardless of 
whether the missed dose is administered on a regularly scheduled dosing day. Dosing should 
then continue twice weekly at the prescribed dose level (see Table 3 above) according to the 
original dosing schedule, even if this results in an interval of less than 3 days between 2 doses. 
If multiple doses are missed, dosing should resume as soon as possible at the prescribed dose 
level (see Table 3 above) according to the original dosing schedule. The medical monitor should 
be notified of any gaps in dosing.  
8.2. 
Vaccinations 
To receive study drug, participants will be required to be vaccinated as follows on the basis of 
ACIP recommendations for adults or children with complement deficiencies (available at 
https://www.cdc.gov/vaccines/schedules/hcp/index.html) or other similar local guidelines.  
• N meningitidis types A, C, W, and Y: First dose at least 14 days prior to 
randomization with a second dose 2 months later, and then boosters every 5 years.  


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• N meningitidis type B: First dose at least 14 days prior to randomization with a 
second dose after at least 1 month. First booster dose 1 year later, and then additional 
booster doses every 2 to 3 years. 
• S pneumoniae: pneumococcal conjugate vaccine (PCV13, PCV15, or PCV20, depending 
on participant age and vaccine availability) and/or pneumococcal polysaccharide vaccine 
23 (PPSV23). Adults who have not previously received any pneumococcal vaccine may 
receive PCV20, if the site is able to procure it, and a subsequent dose of PPSV23 would 
not be required. Multiple scenarios exist depending on previous vaccination history and 
investigators should consult ACIP guidelines for adults or children with complement 
deficiencies or other similar local guidelines. 
• H influenzae type B: Documentation of childhood vaccination or one dose at least 
14 days prior to randomization. 
Vaccination is mandatory, unless documented evidence exists that participants have received the 
recommended vaccinations or are nonresponders to vaccination. For participants who do not 
have this documented evidence, the required missing vaccination(s) will be administered as 
needed to bring participants up to date. The investigator will discuss with the medical monitor 
any individual participant circumstances relevant to the vaccination requirements that would 
make the above schedule not possible or reasonable, of if the investigator has any questions or 
concerns about the vaccination requirements. If local or national guidelines for immunizations 
differ from the ACIP recommendations, the differences should be discussed with the medical 
monitor to determine an appropriate course of vaccinations. On an ongoing basis, including upon 
entry into a long-term extension, participants should be reevaluated for the need for any 
additional vaccinations or boosters on the basis of ACIP recommendations.  
Vaccination serum samples will be collected on the day of vaccination before receiving 
vaccinations on that visit. These samples will be analyzed to evaluate response to vaccinations if 
the participant tests positive for infection with S pneumoniae, N meningitidis, or H influenzae.  
8.2.1. 
Empiric Antibiotic Treatment for Possible Infection 
Body temperature, vital signs, and relevant blood parameters will be monitored regularly 
throughout the study to assess for signs of infection. The investigator should be contacted 
immediately in the event of a suspected infection for guidance on appropriate action to be taken. 
Action to be taken may include empiric administration of a broad-spectrum antibiotic to cover 
possible serious infections, such as meningococcus. 
8.3. 
Concomitant Medications 
All medications administered (including over the counter or prescription medicines, vitamins, and/or 
herbal supplements) and all procedures performed within 12 weeks of screening will be collected as 
prior medications and procedures. Medications administered and procedures performed from the 
time of informed consent through the final visit (the week 60 exit visit, an exit visit following early 
discontinuation as described in Section 7.3.1, or the final visit before transition to the long-term 
extension study, as applicable) are regarded as concomitant and will be documented.  


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8.3.1. 
Treatment Regimens for C3G or IC-MPGN 
Participants should be on stable doses of all medications relevant to their renal disease for at least 
12 weeks prior to randomization, as described in Section 7.1. During the screening period and 
the RCP, changes to the baseline treatment regimens for C3G/IC-MPGN (including medications, 
dietary restrictions, and lifestyle modifications) should be minimized to the extent possible and 
made only when required for the well-being of the participant (with the exception of 
posttransplant immunosuppression—see below). During the open-label period, if the investigator 
plans to make changes to the baseline treatment regimen, these should be approved by the 
sponsor before implementation. 
8.3.1.1. 
Posttransplant Immunosuppression  
If the participant is in a posttransplant time frame in which immunosuppression or other 
transplant-related medication adjustments are anticipated, these adjustments should still occur, 
adhering to the center’s standard protocol for posttransplant care. For all posttransplant 
participants, the plan for posttransplant immunosuppression for the duration of the study should 
be documented prior to randomization. Any deviation during the study from the prespecified 
plan should be documented with a justification for the change.  
Posttransplant participants with evidence of rejection on the baseline biopsy collected during 
screening that requires treatment will need to undergo their antirejection treatment, and then can 
be reconsidered for pegcetacoplan dosing, but will need to meet all other study eligibility criteria, 
including a repeat biopsy to serve as the baseline (refer to Section 10.5 for further details). 
Participants with evidence of subclinical rejection on the biopsy collected during screening may 
proceed with pegcetacoplan treatment, at the discretion of the investigator, provided no treatment 
is initiated for the rejection. 
8.3.2. 
Rescue Therapy 
In the event of an increase in serum creatinine to at least 2× the baseline level that in the opinion 
of the investigator is due to the underlying C3G/IC-MPGN disease, rescue therapy may be 
considered, such as high-dose corticosteroids and/or C5 inhibitor treatment. 
If the participant receives rescue therapy that is not a prohibited concomitant medication, then they 
will be allowed to remain on study drug. If a participant receives rescue therapy that is a prohibited 
concomitant medication, they will be discontinued from study drug, as described in Section 8.3.3. 
8.3.3. 
Prohibited Medications 
The use of rituximab, belimumab, or any approved or investigational anticomplement therapy other 
than pegcetacoplan (including, but not limited to, eculizumab and/or ravulizumab) is prohibited 
within 5 half-lives of that product prior to screening and for the duration of the study.  
If a participant receives a prohibited concomitant medication, they will be discontinued from 
study drug and the procedures described in Section 7.3 should be followed. 
Analysis of results from participants receiving prohibited medications is described in Table 8 
and Table 9.  


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8.4. 
Treatment Compliance 
Participants must be instructed to bring their empty/unused study drug packaging and diaries to 
every visit. The pharmacist/nominated person will record drug accountability information in the 
interactive response technology. 
8.5. 
Measures to Minimize Bias: Study Treatment Assignment 
8.5.1. 
Randomization 
Participants will be randomized to receive pegcetacoplan or placebo in a ratio of 1:1 via a 
computer-generated randomization schedule. The randomization will be performed centrally. 
To achieve balance between the arms, 2 stratification factors will be applied to the randomization. 
The first stratification factor examines participants with posttransplant recurrence versus 
nontransplant participants; at least 78 participants with C3G or IC-MPGN in a native kidney will be 
enrolled. This is followed by the second stratification factor, which examines participants with 
baseline renal biopsies (either collected during screening or a historic biopsy collected within 
28 weeks prior to randomization) versus participants without baseline renal biopsies. 
The stratification will ensure balance between treatment groups for the stratification factors.  
8.5.2. 
Blinding 
Dosing will be double-blinded in the RCP; the open-label period is not blinded. All central 
evaluations (including evaluation of renal biopsies by the central pathologist) will be blinded to 
treatment assignment.  
Participants, the sponsor, investigators, and all study site personnel conducting study-related 
activities (including carrying out study procedures, evaluating participants, and entering and/or 
evaluating study data) will remain blinded to treatment allocations during the RCP at least until all 
participants have completed the week 26 assessments and the RCP portion of the database has been 
locked. Although treatment in the open-label period is not blinded, investigators, study site 
personnel, and participants will remain blinded to the RCP treatment assignment until the blind has 
been broken. Only the drug supply distributor/logistics personnel who are not site personnel will be 
unblinded to study treatment. These individuals are not allowed to discuss treatment and/or 
participant outcome with blinded study staff, including the evaluating physician. Active and placebo 
product labels will not include any information which would unblind the treatment assignment 
during the RCP, as described in Section 9.2.2.  
8.5.2.1. 
Study Drug Unblinding  
Except as noted below, investigators shall not break the study blind. If knowledge of the participant’s 
treatment assignment is necessary for clinical management, the investigator should first attempt to 
contact the medical monitor or designee to discuss the need for unblinding to occur. The medical 
monitor or designee will be available at all times for such discussions. If the investigator is unable to 
reach the medical monitor or designee, or in the case of a medical emergency, the investigator should 
use their best judgment based on the nature and urgency of the clinical situation, and if necessary 
may proceed with unblinding without having successfully contacted the medical monitor or designee. 
If a participant’s treatment assignment is unblinded under these circumstances, the medical monitor 
and study coordinator must be notified within 24 hours.  


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Information describing the unblinding (eg, date and time of the call to the medical monitor by the 
investigator, reason for unblinding, and date and time of unblinding) must be clearly recorded in the 
participant’s study file. In addition, the investigator should consider whether the clinical event 
prompting unblinding should be considered an AE or an SAE according to the definitions in 
Section 11.2.1; if so, such events must be recorded and reported as described in Section 11.2.2 
and Section 11.2.3. 


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9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Study Drug 
The investigational product is pegcetacoplan (APL-2). The study drug may be pegcetacoplan or 
placebo during the RCP, depending on the treatment assignment. The study drug will be 
pegcetacoplan during the OLP.  
Pegcetacoplan will be provided as a sterile solution in single-use glass vials. Each vial contains an 
isotonic sterile solution of pegcetacoplan 1080 mg/20 mL (54 mg/mL) in 10 mM acetate buffer, 
pH 5.0, containing 4.1% sorbitol. Additional information is provided in the pegcetacoplan IB.  
Placebo will be provided as a sterile solution of 10 mM acetate buffer, pH 5.0, containing 4.1% 
sorbitol supplied in single-use glass vials. 
9.2. 
Study Drug Packaging and Labeling 
9.2.1. 
Packaging 
Both pegcetacoplan and placebo will be supplied in 20-mL glass vials. Please refer to the pharmacy 
manual for details.  
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement, 
in advance, by the sponsor. 
9.2.2. 
Labeling 
Labels containing study information and pack identification are applied to the investigational 
product container. 
All investigational product (pegcetacoplan drug product or placebo) is labeled with a minimum 
of the following items: protocol number, dosage form (including product name and quantity in 
pack), route of administration, directions for use, storage conditions, batch number and/or 
packaging reference, statements required per local regulations (eg, “For clinical trial use only”), 
and name and address of the sponsor. 
Space is allocated on the label so that the site representative can record a unique participant 
identifier and date dispensed by the site to the participant. 
Additional labels may, on a case-by-case basis, be applied to the investigational product to 
satisfy national, local, or institutional requirements but must not contradict the clinical study 
label, obscure the clinical study label, unblind the treatment assignment during the RCP, 
or identify the participant by name. 
Additional labels may not be added without the sponsor’s prior full agreement. 
9.3. 
Study Drug Storage 
The study drug should be stored refrigerated at 2-8 °C, both at home and in the clinic. Temperature 
monitoring is required at the investigator site (or documented storage location) to ensure that the 
study drug is maintained within an established temperature range.  


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The investigator or appropriately qualified site staff will be responsible for the following: 
• ensuring that the study drug is stored in a secure, limited-access location at the site 
o limited responsibility may be delegated to the pharmacy or member of the study 
team, but this delegation must be documented 
• ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained 
A pharmacist or appropriately qualified designated person will be responsible for the following: 
• storing the study drug appropriately 
• dispensing the vials of study drug to the participant 
• entering the unique participant identifier on the study drug bottle/carton labels as they are 
distributed 
When the participant receives the study drug 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 (2-8 °C) is maintained. Temperature monitoring will not be required 
during transport or at the participant’s residence, but a log will be kept for every infusion to ensure 
that all study drug was kept refrigerated. 
With sponsor prior approval, investigational product and/or ancillary supplies may be shipped from 
the study site to a participant’s designated location. Such shipments will only be implemented at sites 
where this activity is approved by the IRB/IEC and health authority (if required). Participant consent 
will be required prior to any participant information being provided to a courier. The responsibility to 
return both empty vials and any unused investigational product as described in Section 8.4 shall 
remain unchanged. 
9.4. 
Infusion Supplies 
The sponsor will supply syringes, vial adapters, infusion sets, and ambulatory syringe infusion 
pumps, as required. Refer to the pharmacy manual for further details. 
9.5. 
Study Drug Administration 
Study drug will be administered as an SC infusion. The infusion volume depends on the dose 
received, as described in Section 8.1.  
The preferred site of infusion will be the anterior abdominal wall. If administration into the 
abdomen is not feasible, alternative appropriate sites are acceptable. Alternative sites include the 
anterior aspects of the thighs or upper arms (see Study Medication Administration Instructions—
Participant’s Guide for more details). It is advisable to change infusion site after each drug 
administration in order to avoid skin irritation. Research nurses or other appropriately qualified 
research personnel will administer the SC infusions (as needed) and will qualify and supervise 
the self-administration. Study drug administration may also be conducted by a caregiver or a 
member of the participant’s household, etc, who will undergo the same training (training is not 
intended to be restricted to the participant).  


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These qualified personnel will be made available for a minimum of 6 days on treatment (2 doses) 
to ensure the participant or caregiver has been qualified to conduct administration, but duration 
could be shortened if qualification happens sooner or extended if the participant or caregiver 
requires further training. During qualification, the participant or caregiver must demonstrate to 
the research personnel their ability to safely and effectively administer study drug using the 
infusion pump. Following administration qualification, the participant or caregiver may 
administer the SC infusions without supervision. Once qualified, the participant or caregiver will 
continue to administer infusions at the clinic on those days when a clinic visit occurs on a dosing 
day and at an off-site location convenient to the participant on all other days. Self-administration 
or caregiver administration conducted at the clinic will be supervised to ensure that the 
participant or caregiver continues to remain compliant with the administration guidelines.  
9.6. 
Study Drug Accountability 
Accountability for the study drug at the study center is the responsibility of the investigator. 
The investigator will ensure that the study drug is used only in accordance with this protocol. 
Where allowed, the investigator may choose to delegate drug accountability responsibilities to a 
pharmacist or other appropriate individual. 
Investigators will be provided with sufficient amounts of the study drug to carry out this protocol for 
the agreed number of participants. The investigator or designee will acknowledge receipt of the 
investigational product and placebo, documenting shipment content and condition. Accurate records 
of all study drug dispensed, used, returned, and/or destroyed must be maintained. Accountability 
records will include dates, quantities, batch/serial numbers, expiration dates (if applicable), 
and participant numbers. The sponsor or its designee will review study drug accountability at the 
study center on an ongoing basis during monitoring visits. 
Study drug must not be used for any purpose other than the present study. Study drug that has been 
dispensed to a participant and returned unused must not be redispensed to a different participant. 
The investigator is responsible for ensuring the retrieval of all returnable study supplies from 
participants. 
9.7. 
Study Drug Handling and Disposal 
All unused and used study drug vials should be retained at the center until they are inventoried by the 
study monitor. All used, unused, or expired study drug vials will be returned to the sponsor or its 
designee for destruction and destruction will be documented, or if authorized, disposed of at the 
study center per the center’s standard operating procedures and documented.  


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10. 
ASSESSMENT OF EFFICACY 
10.1. 
Retrospective Data Collection for eGFR and Measured Glomerular 
Filtration Rate 
Retrospective data will be collected on glomerular filtration rate (GFR) to calculate historical 
eGFR for up to 3 years prior to study entry, depending on the date of diagnosis (for renal 
transplant recipients, this refers to diagnosis of recurrent disease, not diagnosis of the original 
disease in native kidneys). Three years of retrospective data will be collected to calculate eGFR 
for those diagnosed at least 3 years prior to randomization. Retrospective data for the period 
between randomization and diagnosis will be collected for those diagnosed less than 3 years 
prior to randomization. For historical eGFR calculations, data will be collected to enable 
calculation of eGFR by CKD-EPI (with serum creatinine) in adults and by the Bedside Schwartz 
equation in adolescents. Specifically, age, sex, race, height (adolescents only), serum creatinine, 
serum blood urea nitrogen (adolescents only), and serum cystatin C (if available) will be 
collected. For each participant, eGFR will be calculated using the same formula for the duration 
of the study; the choice of formula will be determined by the participant’s age at study entry. 
If a participant has historical data on measured GFR, then this data, including the method used to 
measure GFR, should also be collected (in addition to the data required to calculate eGFR in that 
participant) for the same timeframe. 
10.2. 
24-Hour Urine Collection 
A 24-hour urine collection is defined as collection of all urine produced over a 24-hour period. 
As 24-hour urine collections will be done at home, participants will be provided with containers 
for the collection as well as an instruction sheet that details the collection procedure. The 24-hour 
urine collection should begin following the first urinary output for the day, and then continue for 
a 24-hour period. Samples should be collected within ±1 week of the clinic visit (except for the 
week 24 collection, which cannot be earlier than week 24).  
In brief, the first urine (on the day of collection) must be discarded (as this is urine made prior to 
the start of the collection date/time). The time and date of this discarded void must be recorded, 
as it represents the start of the collection. The participant should then collect all urine over the 
next 24 hours. At the 24-hour time point, the participant should empty their bladder and collect 
this urine as the final void of the 24-hour urine collection. The date and time of this last collected 
void should be recorded, as it represents the end of the 24-hour urine collection. 
There will be six 24-hour urine collections, at the visits outlined in the schedule of activities 
(Table 2):  
• screening (between week –8 and week –4 and before the renal biopsy)  
• week 12  
• week 24 (before the week 26 renal biopsy) 
• week 36  
• week 48 (before the week 52 renal biopsy, if performed)  
• week 60 


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If menses are occurring at the scheduled time of a 24-hour urine collection, then the collection 
should be delayed until completion of menses, with this information recorded in the participant’s 
source document. Urine must be stored at 2 to 8 °C (ie, in refrigerator). Courier arrangements 
can be made by the site to pick up the collection container from the participant’s home and return 
it to the site, or the participant may return it directly to the site. Total urine volume, total protein 
concentration, total albumin concentration, total β-2 microglobulin, and total creatinine 
concentration will be measured on the 24-hour urine collections, with calculation of total protein 
excretion, total albumin excretion, total creatinine excretion, total β-2 microglobulin excretion, 
uPCR, urinary albumin-to-creatinine ratio (uACR), and urinary β2-microglobulin–to-creatinine 
ratio (uBCR) based on the 24-hour collection.  
10.3. 
Triplicate FMU Collections 
Triplicate FMU collection is defined as a collection of first-morning urine on 3 consecutive 
mornings, with each morning urine sample collected into a separate container. Samples should 
be collected within ±1 week of the clinic visit (except for weeks 24 to 26, when sample 
collection should be within ±3 days of the clinic visit).  
It is important that each of these collections represent the first urinary output upon awakening, 
after an extended period of rest. The date and time of each collected sample should be recorded. 
In the event that a participant has an atypical sleep/wake schedule, the appropriate timing for 
these spot urine collections may not be morning. In this case, the timing of the collection should 
be adjusted to ensure collection of the first urinary output after an extended period of rest 
(eg, at least 6 hours), and the alternate timing should be documented in the source document. 
If menses are repeatedly occurring at the scheduled times of a triplicate FMU collection, 
the collection dates should be adjusted to avoid collection during menses to the extent possible, 
with this information recorded in the participant’s source document. 
After FMU collection, the urine samples must be stored at 2-8 °C (ie, in a refrigerator). 
Courier arrangements can be made by the site to pick up the collection containers from the 
participants, or the participant may return them directly to the site. Urine protein, albumin, β-2 
microglobulin, and creatinine concentrations should be measured on all spot urine samples, 
with calculation of uPCR, uACR, and uBCR values. 
Triplicate FMU collections should be before each clinic visit (ie, approximately every 4 weeks), 
with an additional triplicate to be collected at week 25. At each scheduled clinic visit, the site 
will dispense the number of spot urine containers needed before the next scheduled visit 
(dispense 3 containers at each visit except week 24, when 6 containers should be dispensed); 
participants will return the triplicate spot urine collections at their next visit.  
10.4. 
Random Spot Urine Collection 
At each clinic visit, participants will be asked to submit a urine sample. As this sample will not 
necessarily reflect a specific time of day, it is considered a “random” spot urine sample, so as to 
distinguish it from the first-morning spot collections. After collection, the urine samples must be 
stored at 2 to 8 °C (ie, in a refrigerator). Urine protein, albumin, β-2 microglobulin, and creatinine 
concentrations should be measured on all spot urine samples, with calculation of uPCR, uACR, 
and uBCR values. 


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10.5. 
Renal Biopsy 
The renal biopsy procedure should be performed according to the local standard practices at the 
site, including use of anesthesia/sedation, pre-procedure evaluation (eg, laboratory testing prior 
to renal biopsy), and post-procedure observation and monitoring. The renal biopsy must include 
adequate material for light microscopy (7 or more glomeruli), immunofluorescence microscopy 
(3 or more glomeruli) and electron microscopy (2 or more glomeruli). Renal biopsy samples 
should be handled and processed as per the pathology manual. All renal pathology will be 
reviewed by the central pathology laboratory, which will be blinded to treatment assignment. 
If a coagulation panel is performed for any reason, including as a prebiopsy assessment, the use 
of silica reagents for this test should be avoided in participants participating in this study because 
of the potential for interference with pegcetacoplan. 
10.5.1. 
Renal Biopsies in Adults 
For adult participants, a percutaneous biopsy will be performed at the visits indicated in the 
schedule of activities (Table 2).  
A renal biopsy will be performed during screening to confirm diagnosis and eligibility, and to 
serve as the baseline renal biopsy. Once participant eligibility has been confirmed on the basis of 
the assessments from screening visit 1 and the initial 24-hour urine collection is complete as 
described in Section 10.2, the baseline renal biopsy may be conducted at any time during 
screening. A prior renal biopsy done within 28 weeks of randomization may be used for 
eligibility confirmation and serve as the baseline biopsy, if confirmed as adequate per central 
pathology review. Copies of prior renal biopsy reports will be requested for review by the central 
pathology laboratory. If a prior renal biopsy is used to establish eligibility and/or will serve as 
the baseline biopsy, images and/or slides from that biopsy will also be required. Tissue blocks 
and/or unstained slides may also be requested for staining at the central pathology laboratory. 
Follow-up renal biopsies will be performed at week 26 and week 52. The week 26 biopsy is 
required for participants aged 18 years and older. The week 26 renal biopsy need not occur on 
the same day as all other assessments for that visit. However, the week 26 biopsy must occur 
after the week 26 triplicate FMU collections and before the first visit of the open-label period at 
week 28. The week 52 biopsy is optional. If performed it should be after collection of the 
week 48 24-hour urine and not more than 8 weeks after the week 52 visit. 
In the event that a participant has a renal biopsy as part of their clinical management, biopsy 
samples should be reviewed by the central pathology laboratory and the results should be entered 
into the study database, if possible. If this biopsy includes the required components for this study 
and is collected within the window defined above, it may serve as the week 52 biopsy. 
10.5.2. 
Renal Biopsies in Adolescents 
Participants younger than 18 years will be requested to provide renal biopsies in countries and at sites 
where permitted but are not required to do so, and refusal of a participant younger than 18 years to 
provide any or all renal biopsies will not be considered noncompliance. Renal biopsies will not be 
collected for research purposes from adolescent participants in the US or from adolescent participants 
at sites where not permitted by national or local regulations. 


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An adequate prior renal biopsy will be used to establish the diagnosis and eligibility for adolescent 
participants who do not provide a baseline renal biopsy during screening, even if the prior biopsy was 
performed more than 28 weeks prior to randomization. Copies of prior renal biopsy reports will be 
requested for review by the central pathology laboratory. If a prior renal biopsy is used to establish 
eligibility and/or will serve as the baseline biopsy, images and/or slides from that biopsy will also be 
required. If the historical biopsy was performed more than 28 weeks prior to randomization, 
then eligibility will be determined on the basis of alternative evidence of active renal disease as 
described in Section 7.1.  
Participants younger than 18 years may advance to the open-label period upon completion of all 
week 24 though week 26 assessments other than the renal biopsy. Participants younger than 18 years 
who did not have a baseline biopsy within 28 weeks of day 1 will not have week 26 or week 52 
biopsies under any circumstances. Participants under the age of 18 who had a baseline biopsy within 
28 weeks of day 1 will be requested to provide week 26 and week 52 renal biopsies, in countries and 
at sites where allowed. When collected, renal biopsies in adolescent participants should be collected 
within the windows defined in Section 10.5.1 for biopsies in adult participants.  
In the event that a participant younger than 18 years has a renal biopsy as part of their clinical 
management, biopsy samples should be reviewed by the central pathology laboratory and the results 
should be entered into the study database, if possible. If this biopsy includes the required components 
for this study and is collected within the windows defined in Section 10.5.1 for biopsies in adult 
participants, it may serve as one of the study biopsies. 
10.6. 
Ophthalmologic Evaluation 
Ophthalmologic evaluation is an optional assessment and will be performed at selected sites. 
If performed, participants should have a baseline ophthalmologic evaluation, including a 
basic ophthalmologic examination, spectral domain optical coherence tomography 
(SD-OCT), and color fundus photography, at an approved ophthalmologic clinical site at any 
time during the screening period. For those participants with drusen prior to pegcetacoplan 
administration, a followup- ophthalmologic evaluation, including a basic ophthalmologic 
examination, SD-OCT, and color fundus photography, is requested to occur at a convenient 
time between week 42 and week 52 of the study. The SD-OCT and color fundus photography 
will be acquired using a standardized protocol, performed by reading center certified imagers 
on registered equipment, and will be transmitted to a central reading center for evaluation. 
The basic ophthalmologic examination should include best-corrected visual acuity, 
intraocular pressure, and a dilated fundus examination with comment on presence or absence 
of pigment, drusen, hemorrhage, atrophy, or other evidence of macular degeneration. 
10.7. 
Measured GFR 
Measured GFR is an optional assessment that may be done by a site that routinely performs this 
assessment. In this case, the site should follow its standard procedure for measured GFR 
(and document the procedure within the participant’s source document) once prior to the first 
pegcetacoplan dose (but no more than 10 weeks prior to the first dose), again at week 26, and a third 
time between week 42 and week 52, inclusive. In the event that retrospective measured GFR data are 
available, these should be collected for the same time frame as retrospective data for calculation of 
eGFR (see Section 10.1). 


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10.8. 
Health-Related Quality of Life Assessments 
Health-related quality of life (HRQoL) assessments will be completed during clinic visits as 
outlined in the schedule of activities (Table 2). 
10.8.1. 
Functional Assessment of Illness Therapy–Fatigue Scale  
The FACIT-Fatigue scale is a 13 item Likert scaled instrument that is self-administered by 
participants. Participants are presented with 13 statements and asked to indicate their responses 
as it applies to the past 7 days. The 5 possible responses are “Not at all” (0), “A little bit” (1), 
“Somewhat” (2), “Quite a bit” (3) and “Very much” (4). With 13 statements the total score has a 
range of 0 to 52. Before calculating the total score, some responses are reversed to ensure that 
the higher score corresponds to a higher quality of life.  
10.8.2. 
5-Level EuroQol-5 Dimension 
The EQ-5D-5L assessment is a standardized measure of health status developed to assess 
HRQoL by the EuroQoL Group. The questionnaire consists of a descriptive system and a visual 
analog scale. The descriptive system contains 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression) with 5 levels in each dimension.  
10.8.3. 
Kidney Disease Quality of Life  
The KDQOL survey is a kidney disease-specific measure of HRQoL developed by the RAND 
Corporation, which is self-administered by participants. It includes a generic chronic disease 
core, and additional items relevant to patients with kidney disease, such as symptoms, burden of 
illness, social interaction, staff encouragement, and patient satisfaction. Scores are reported 
separately for each of 5 subscales.  
10.8.4. 
Patient Global Impression of Change 
The Patient Global Impression of Change is a 1-item questionnaire that measures the 
participant’s impression of the change in their health and assesses whether there has been an 
improvement or decline in clinical status since the start of the study.  
10.8.5. 
Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem 
The Work Productivity and Activity Impairment Questionnaire: Specific Health Problem 
(WPAI:SHP) is a patient-reported quantitative assessment of the amount of absenteeism, 
presenteeism, and daily activity impairment attributable to a specific health problem for working 
patients. It includes 6 questions assessing health-related work productivity loss over the previous 
7 days.  


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11. 
ASSESSMENT OF SAFETY 
11.1. 
Safety Parameters 
11.1.1. 
Demographic/Medical History 
Medical history will be recorded at screening. Investigators should document the occurrence, signs, 
and symptoms of the participant’s preexisting conditions, including all prior significant illnesses, 
up to and including 1 year before screening. Additional preexisting conditions, present at the time 
when informed consent is given, up to the time of first dosing, are to be regarded as concomitant. 
Medical history will include alcohol consumption and smoking history, if applicable. 
A detailed medical history with regard to disease indication (C3G or IC-MPGN) will be 
requested, and will include prior surgeries, renal biopsies, hospitalizations, dialysis, 
transplantation, laboratory data, and extrarenal manifestations of the disease. Available disease 
medical history for the 3 years preceding screening will be requested. Submission of additional 
historical data is encouraged, when available. Copies of prior renal biopsy reports will be 
requested for review by the central pathology laboratory. If a prior renal biopsy is used for 
eligibility and/or will serve as the baseline biopsy, images and/or slides from that biopsy will 
also be required. Tissue blocks or unstained slides may also be requested for staining at the 
central pathology laboratory. 
Illnesses first occurring or detected during the study and/or worsening of a concomitant illness 
during the study are to be documented as AEs in accordance with Section 11.2.2. 
Additionally, demographic data will be collected for all participants, as allowed per applicable 
regulations.  
11.1.2. 
Vital Signs 
Vital signs (body temperature, respiration rate, heart rate, and systolic and diastolic blood 
pressure measurements) will be evaluated at the visits indicated in the schedule of activities 
(Table 2). All vital signs will be measured after the participant has been resting in a sitting 
position for at least 5 minutes, except when they are supine or semireclined because of study 
procedures and/or AEs, or if deemed necessary by the investigator. Blood pressure 
measurements are to be taken in the same arm for the duration of the study.  
Vital signs measurements will be repeated, if clinically significant or if machine/equipment 
errors occur. Out-of-range blood pressure, respiratory rate, or heart rate measurements will be 
repeated, at the investigator’s discretion. Any confirmed, clinically significant vital signs 
measurements must be recorded as AEs. 
When pegcetacoplan is administered at the study site, vital signs will be measured within 2 hours 
prior to infusion. Following the infusions on day 1 and on the first day of open-label dosing 
(week 26 or week 28, depending on whether a week 26 renal biopsy is required and when it is 
performed), vital signs will also be measured approximately 30 minutes to 1 hour after dosing.  


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11.1.3. 
Weight and Height 
Body weight will be recorded at each visit. Height will be recorded at screening for adults and 
every 12 weeks throughout the study for adolescents. Height will be measured using a calibrated 
stadiometer. Both body weight and height will be assessed without shoes on.  
11.1.4. 
Physical Examination 
All full physical examinations, performed by the investigator or designee, will include, at a 
minimum, assessment of the following: general, head, ears, eyes, nose, throat, dentition, thyroid 
(endocrine), heart, chest, lungs, abdomen, skin, extremities, back/neck, musculoskeletal, 
and lymph nodes.  
Brief physical examinations will include general appearance, heart, lungs, abdomen, extremities, 
and are to be performed at all visits where a full physical examination does not occur.  
Edema will be assessed at each visit.  
Additional symptom-driven physical examinations may be performed at any time, as deemed 
necessary by the investigator.  
See the schedule of activities (Table 2) for the details regarding which type of physical 
examination should be given at each visit. 
11.1.5. 
Menses 
For WOCBP, the start and stop date of each menstrual period will be recorded in the 
participant’s source document for the duration of the study. 
11.1.6. 
Electrocardiograms 
All 12-lead ECGs will be measured once, prior to dosing, at the visits outlined in the schedule of 
activities (Table 2). The ECG will be taken following resting in the supine position for 
10 minutes in a quiet environment and prior to any blood sampling procedures. 
The ECGs will be classified as normal, having a not clinically significant abnormality, or having 
a clinically significant abnormality. In addition, ECG parameters of ventricular rate, PR interval, 
QRS duration, and QT internal (uncorrected and corrected using Fridericia’s method [QTcF]) 
will be reviewed for eligibility and ongoing safety. 
11.1.7. 
Chest Radiography 
Chest radiography will be performed prior to dosing at the visits outlined in the schedule of 
activities (Table 2). Posterior-anterior and lateral views of the chest will be recorded via chest 
radiography; both views are required. The actual chest radiography technical procedure should 
be performed according to the site’s standard protocol. The radiographs will be classified as 
normal, having a not clinically significant abnormality, or having a clinically significant 
abnormality per radiology report, and this classification should be included in the source 
documentation.  


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11.1.8. 
Infusion Site/Pump Safety Assessment 
On the days of clinic visits, pump use safety will be reviewed after study drug administration. 
This technique evaluation will be performed by a physician or other licensed health care provider 
(eg, study nurse), as delegated by the investigator. The participant will be asked about any issues 
related to pump use. 
Participants will be instructed to notify the investigator or other study personnel if an infusion 
site reaction occurs after self-administration or caregiver administration of study drug. 
All clinically significant findings related to infusion procedures will be recorded as AEs. 
11.1.9. 
Laboratory Assessments 
Laboratory assessment samples (Table 4) are to be obtained at designated visits as detailed in the 
schedule of activities (Table 2). 
Table 4: Laboratory Assessments 
Hematology 
Serum chemistry 
Urine studies 
Hb 
Hematocrit 
Platelet count 
RBC count 
Reticulocytes 
WBC count with 
differential 
Albumin 
ALT 
ALP 
AST 
Bicarbonate 
Bilirubin (total, direct, and indirect) 
BUN 
C3 
C4 
Calcium 
Chloride 
Creatinine 
Creatine kinase  
Cystatin C 
Estimated GFR (using CKD-EPI formula for 
adults; Bedside Schwartz for adolescents) 
GGT 
Glucose 
HDL 
LDH 
LDL 
Phosphorus 
Potassium 
Sodium 
Triglycerides 
Total cholesterol 
Total protein 
Uric acid 
Urinalysis 
• Blood 
• Bilirubin 
• Glucose 
• Ketones 
• Leukocyte esterase 
• Nitrite 
• pH 
• Pregnancy, when applicable 
• Protein 
• Specific gravity 
• Urobilinogen 
• Microscopic examination of urine sediment, 
including for presence of RBCs, WBCs, and casts, 
will be performed on all urinalyses 
 
Spot Urines (First-Morning and Random) 
• ACR  
• BCR 
• PCR 
• Total albumin concentration 
• Total β-2 microglobulin concentration 
• Total creatinine concentration 
• Total protein concentration 
 
24-Hour Urine 
• ACR 
• BCR  
• PCR 
• Total albumin concentration 
• Total β-2 microglobulin concentration 
• Total creatinine concentration 
• Total protein concentration 
• Total volume 


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Table 4: Laboratory Assessments 
Hematology 
Serum chemistry 
Urine studies 
Coagulationa 
Additional 
PT 
aPTT 
INR 
FSH (postmenopausal women)b 
Hepatitis B panelb,c 
Hepatitis C panelb,d 
HIV antibodiesb 
SPEP2 
ANA (with reflex anti-dsDNA)b 
ANCA (with reflex anti-MPO and anti-PR3)b 
Serum pregnancy testb 
Complement tests (serum/plasma)e 
Anti-drug antibodies  
Vaccination responsef 
Abbreviations: ACR = albumin-to-creatinine ratio; ALP = alkaline phosphatase; ALT = alanine aminotransferase; 
ANA = antinuclear antibodies; ANCA = antineutrophil cytoplasmic antibodies; aPTT = activated partial thromboplastin time; 
AST = aspartate aminotransferase; BCR = β-2 microglobulin:creatinine ratio; BUN = blood urea nitrogen; CKD-EPI = Chronic 
Kidney Disease–Epidemiology Collaboration; ds DNA = double stranded DNA; FSH = follicle-stimulating hormone; 
GFR = glomerular filtration rate; GGT = γ-glutamyltransferase; Hb = hemoglobin; HBcAb = hepatitis B core antibody; 
HbsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HDL = high-density lipoprotein; Hib = Haemophilus influenzae type B 
vaccine; HIV = human immunodeficiency virus; INR = international normalized ratio; LDH = lactate dehydrogenase; 
LDL = low-density lipoprotein; MPO = myeloperoxidase; PCR = protein-to-creatinine ratio; PCV13 = pneumococcal conjugate 
vaccine; PPSV23 = pneumococcal polysaccharide vaccine 23; PR3 = proteinase 3; PT = prothrombin time; RBC = red blood cell; 
SPEP = serum protein electrophoresis; WBC = white blood cell. 
a. 
The use of silica reagents in coagulation panels should be avoided in participants participating in this study because of the 
potential for interference with pegcetacoplan. 
b. 
Screening only. SPEP will be evaluated only in adult participants.  
c. 
HbsAg and HbcAb. 
d. 
Hepatitis C antibody with reflex HCV RNA polymerase chain reaction. 
e. 
Complement tests (serum/plasma): AH50, CH50, C3a, C3b/iC3b, C5a, sC5b-9, C3NeF, and potentially additional complement 
components. C3NeF will only be assayed in samples collected at the baseline (screening) visits.  
f. 
Serum samples will be collected to evaluate response to vaccinations to N. meningitidis (types A, C, W, Y, and B), PCV13 
or PPSV23, and Hib. Samples will only be analyzed in the event that the participant has a positive infection for Streptococcus 
pneumoniae, Neisseria meningitidis, or Haemophilus influenzae. 
Blood and urine samples will be analyzed at a central or local laboratory facility, as defined in 
the laboratory manual. Urine samples will be analyzed by dipstick and a microscopic analysis. 
All laboratory reports must be reviewed, signed, and dated by the investigator. A legible copy of 
all reports must be filed with the participant’s medical record (source document) for that visit. 
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). 
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. 
11.1.9.1. Pregnancy Screen 
For WOCBP, a serum pregnancy test will be performed at screening. Participants with a positive 
result will be excluded or discontinued from the study as described in Section 7.3. A urine 
pregnancy test will also be performed starting at baseline and then at all visits through the end of 
the study, including the follow-up visits. Male participants will be counseled to avoid donating 
semen during the time between the first screening and the final week 60 exit visit and for the 
90 days after their last dose of study drug. 


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11.1.10. 
Pharmacokinetic Assessment 
Blood samples for PK assessment of pegcetacoplan will be collected before dosing via direct 
venipuncture at the visits delineated in the schedule of activities (Table 2). 
Instructions for collection, handling, processing, storage, and shipping of samples will be 
provided in a separate laboratory reference manual prior to study initiation. 
The concentration of study drug will be determined from the serum samples using a validated 
analytical method. Details of the method validation and sample analysis will be included in the 
final clinical study report. 
11.1.11. 
Pharmacodynamic Assessment 
Blood samples for assessment of the effects of pegcetacoplan on the complement profile (CH50 and 
AH50, sC5b-9, and potentially additional complement components) will be collected before dosing 
via direct venipuncture at the visits delineated in the schedule of activities (Table 2). 
Instructions for collection, handling, processing, storage, and shipping of samples will be 
provided in a separate laboratory reference manual prior to study initiation. 
PD assessment results will be included in the final clinical study report. 
11.1.12. 
Blood Volume for Study Assessments 
Table 5 presents the approximate blood volume to be collected for this study. See the laboratory 
manual for additional details regarding the blood volume required throughout the study. 
The maximum volume of blood drawn at any single visit is 24.7 mL for adult participants and 
22.2 mL for adolescent participants and occurs at the first screening visit. For the remainder of the 
study, the maximum volume of blood drawn at any single visit is 18.2 mL for both adult and 
adolescent participants. For an adolescent participant at the minimum permitted body weight of 
30 kg, the 22.2-mL and 18.2-mL volumes would be 0.74 and 0.61 mL of blood per kg of body 
weight, respectively. Over a 4-week period, the maximum blood volume to be drawn is 
approximately 55 mL for adult participants and 52.5 mL for adolescent participants. This would 
occur only if the first screening visit was 4 weeks before the start of the RCP. For an adolescent 
participant at the minimum permitted body weight of 30 kg, this would be a maximum of 
1.75 mL/kg in a 4-week period. 


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Table 5: 
Approximate Blood Volume Collected 
Sample type 
Approximate 
volume per 
visit 
Collections 
during 
screening 
Collections 
during main 
period 
Collections 
during 
follow-up 
Approximate 
volume over 
course of study 
Serum chemistry (with 
serum complement profile) 
5 mL 
2 
12 
3 
85 mL 
Serum chemistry (without 
serum complement profile) 
3.5 mL 
0 
2 
0 
7 mL 
Plasma complement profile 
1 mL 
1 
9 
2 
12 mL 
Hematology 
1 mL 
2 
14 
3 
19 mL 
Serum coagulation 
2.7 mL 
2 
14 
3 
51.3 mL 
Additional screening tests 
15 mLa 
1 
0 
0 
15 mLa 
PK samples 
2.5 mL 
0 
8 
1 
22.5 mL 
PK and immunogenicity 
(antidrug antibodies) 
combined 
8.5 mL 
0 
6 
2 
68 mL 
Vaccination response 
samples 
3.5 mL 
1 
1 
0 
7 mL 
Approximate blood volume per visit 
12-25 mL 
10-18 mL 
11-18 mL 
 
Total approximate blood volume for study 
287 mL 
Abbreviation: PK = pharmacokinetic. 
a 12.5 mL for adolescent participants. 
11.1.13. 
Antidrug Antibody Assessment 
Blood samples for assessment of antidrug antibodies (ADAs) will be collected at the visits indicated 
in the schedule of activities (Table 2). Samples will be assayed for both antibodies against 
polyethylene glycol (PEG) (anti-PEG antibodies) and antibodies against the peptide moiety of 
pegcetacoplan (anti–pegcetacoplan peptide antibodies).  
The proposed ADA sampling schedule was established to capture the ADA signal at baseline, any 
potential early onset antibody formation, and the dynamic profile (transient or persistent) of antibody 
formation while minimizing pegcetacoplan level in the sample.  
Participants who have a treatment-emergent or treatment-boosted antidrug antibody response at any 
time will have ADA samples collected approximately every 6 months until resolution (participants 
with a treatment-boosted response will be followed until the titer returns to within four-fold of 
baseline and participants with a treatment-emergent response will be followed until there is a 
negative sample). Antibody titers will be determined for any samples that are confirmed to be 
positive for anti–pegcetacoplan peptide or anti-PEG antibodies, and any samples that are confirmed 
to be positive for anti–pegcetacoplan peptide antibodies will be further characterized with a 
neutralizing antibody assay.  


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11.1.14. 
COVID-19 Assessments 
If a participant has been tested for COVID-19, the results, if available, will be documented in the 
participant’s source document. 
11.2. 
Adverse and Serious Adverse Events 
11.2.1. 
Definitions 
11.2.1.1. 
Adverse Events 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or 
not it is considered drug-related. An AE can, therefore, be any unfavorable and unintended sign, 
including a clinically significant abnormal laboratory finding, symptom, or disease temporally 
associated with the use of an investigational product, whether or not it is considered related to the 
investigational product. TEAEs are defined as AEs that develop or worsen after the first dose of 
study medication. 
AEs can be reported spontaneously by the participant and/or in response to an open question from the 
study personnel or revealed by observation and will be recorded during the study at the 
investigational site. All identified AEs must be recorded and described in the participant’s source 
document. Fluctuating or nonsignificant changes in laboratory values do not necessarily qualify for 
AE reporting. If these changes in laboratory values are assessed as clinically significant and/or lead 
to discontinuation of administration of investigational product, they should be reported as an AE. 
If these laboratory values are linked to a diagnosis, only the diagnosis should be reported as an AE.  
11.2.1.2. 
Serious Adverse Events 
An SAE is any AE or suspected adverse reaction that, in the view of the investigator, results in death, 
is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, 
results in a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or is a congenital anomaly or birth defect. Important medical events that may 
not result in death, be life-threatening, or require hospitalization may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the participant or may require 
medical or surgical intervention to prevent one of the outcomes listed in the above definition. 
Examples of important medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
Life-threatening is defined as an AE or suspected adverse reaction, which, in the view of either 
the investigator or sponsor, places the participant at immediate risk of death as it occurred. 
It does not include an AE or suspected adverse reaction that, had it occurred in a more severe 
form, might have caused death. 
All SAEs (irrespective of causality) must be reported to Apellis Safety immediately, no later than 
24 hours of the investigator or their representative becoming aware of the event, as described in 
Section 11.2.3.  


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11.2.1.3. Unexpected AEs 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the reference 
safety information section of the IB that is in effect at the time of event onset. 
11.2.2. 
Recording and Reporting AEs 
All AEs and SAEs will be collected from the signing of the informed consent form (ICF) until 
the exit visit.  
SAEs will be followed until satisfactory resolution, until baseline level is reached, or until the 
SAE is considered by the investigator to be chronic or the patient is stable, as appropriate. 
All SAEs that are suspected of being related to study treatment must be reported immediately to 
the sponsor if the investigator becomes aware of them, regardless of the time since the 
completion of the clinical trial. 
Any events that occur prior to the start of dosing will be categorized as pretreatment events; events 
occurring after the start of dosing and up to 56 days beyond the last dose of study medication will be 
recorded as TEAEs.  
For each AE, the investigator will evaluate and report the onset date (and time, if applicable), 
resolution date (and time, if applicable), intensity, causality, action taken, seriousness criteria met 
(if applicable), and whether or not the participant discontinued the study as a result of the event. AEs 
characterized as intermittent require documentation of the start and stop of each incidence. 
If possible, the outcome of any AE resulting in permanent discontinuation or that was present at the 
end of the study should be reported. AEs resulting in interruption or discontinuation of study drug or 
that are present at the exit visit should receive follow-up as appropriate.  
11.2.2.1. Relationship to Study Drug 
The investigator will review each event and assess its relationship to study drug treatment 
(not related, unlikely related, possibly related, or definitely related). The date and time of onset, 
time relationship to drug dosing, duration, severity, action taken, and outcome 
(recovered/resolved, recovered/resolved with sequelae, recovering/resolving, not recovered/not 
resolved, fatal, or unknown) of each event will be noted. 
Table 6 should be considered when evaluating the relationship of AEs/SAEs to study treatment. 
Table 6: Definitions of Adverse Event Relatedness 
Classification 
Definition 
Definitely related 
Strong evidence of a causal relationship; the influence of other factors is unlikely 
Possibly related 
Some evidence of a causal relationship, but other factors may have caused or contributed 
to the event (eg, another illness or concomitant treatment) 
Unlikely related 
A causal relationship is not a reasonable possibility, but it cannot be completely ruled out 
with the available evidence. 
Not related 
No evidence of a causal relationship 


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11.2.2.2. Severity of Events 
The investigator will review each event and assess its severity. Note that severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 11.2.1.2. An AE can be of 
severe intensity but not be considered serious.  
Table 7 presents the definitions that should be considered when evaluating the severity of AEs 
and SAEs.  
Table 7: Severity of Events 
Severity  
Definition/description 
Mild 
Event results in mild or transient discomfort, not requiring intervention or treatment; does not limit or 
interfere with daily activities (eg, insomnia, mild headache) 
Moderate 
Event is sufficiently discomforting so as to limit or interfere with daily activities; may require 
interventional treatment (eg, febrile illness requiring oral medication) 
Severe 
Event results in significant symptoms that prevents normal daily activities; may require 
hospitalization or invasive intervention (eg, anemia resulting in blood transfusion) 
11.2.3. 
Reporting AEs 
All SAEs must be reported to Apellis Safety by completing the SAE form within 24 hours of the 
investigator or their representative becoming aware of the event, whether or not the event is 
deemed treatment related. Completed SAE forms should be emailed to Safety@Apellis.com. 
The sponsor has the responsibility to inform concerned health authorities, IRBs, IECs, and 
investigators about suspected unexpected serious adverse reactions (SUSARs) in line with GCP 
guidance and applicable regulatory requirements. 
If applicable, specific SAEs should be reported to the concerned IRB or IEC in compliance with 
local requirements. 
11.2.4. 
Pregnancy 
Although pregnancy is not an AE, all pregnancies and suspected pregnancies (including a 
positive pregnancy test regardless of the pregnant person’s age or disease state) occurring with a 
female participant or the female partner of a male participant must be followed to conclusion to 
determine their outcome and are considered immediately reportable events.  
Any pregnancy, suspected pregnancy, or positive pregnancy test must be reported to Apellis Safety 
within 24 hours of the investigator or their representative becoming aware of the event, using the 
pregnancy report form. The pregnancy report form must be signed and dated by the investigator and 
submitted via email to Safety@Apellis.com. 
The investigator should make every effort to obtain the consent from the pregnant woman to 
follow the status of the pregnancy until completion. The outcome of the pregnancy 
(eg, delivery, termination) and, as applicable, the neonatal outcome should be reported within 
24 hours of awareness. In the event of an abnormal outcome (outcome other than live, healthy birth), 
an SAE report form must be reported within 24 hours of investigator awareness, as described in 
Section 11.2.3.  


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11.2.5. 
AEs of Special Interest 
The following events are classified as AEs of special interest: 
• Thrombocytopenia 
• Severe infection (see Section 11.2.2.2 for a discussion of severity grading) 
• Hypersensitivity, including pneumonitis 
• Severe acute kidney injury (see Section 11.2.2.2 for a discussion of severity grading) 
An AE of special interest can be serious or nonserious but must be reported to the 
sponsor/Apellis Safety in the same manner as an SAE, as described in Section 11.2.3. 
11.2.6. 
Abuse, Misuse, Overdose, and Medication Errors  
Occurrences of events of abuse or misuse of the medicinal product, overdose, and medication 
error must be reported to Apellis Safety.  
Abuse of a medicinal product: Persistent or sporadic intentional, excessive use of medicinal 
products that is accompanied by harmful physical or psychological effects.  
Misuse: Intentional and inappropriate use of a medicinal product not in accordance with the 
prescribed or authorized dose, route of administration, and/or intended indication(s) or not within 
the legal status of its supply.  
Overdose: Any dose administered to or taken by a participant (accidentally or intentionally) 
that exceeds the highest daily dose or is at a higher frequency than that described in the protocol.  
Medication Error: An error made in prescribing, dispensing, administration, and/or use of the 
study drug. Medication errors are reportable to the sponsor as defined below.  
• The dispensing, administration, and/or use of unassigned study drug 
• The administration and/or use of an expired study drug 
All AEs or SAEs associated with abuse or misuse of the medicinal product, overdose, or medication 
error must be reported appropriately. The investigator, in consultation with the sponsor, will decide 
whether a dose is to be considered an overdose. In the event of an overdose, the actual dose 
administered must be recorded in the participant’s source document.  


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12. 
STATISTICS 
A formal statistical analysis plan (SAP) will be developed and finalized prior to locking the 
database. The full details of data presentations and analyses will be provided in the SAP. 
Additional statistical analyses other than those described in this section may be performed if 
deemed appropriate and included in the SAP. Any deviations from the final SAP or from what is 
outlined in the protocol will be discussed in the final study report.  
12.1. 
Determination of Sample Size 
Approximately 80 to 100 participants, including patients with native kidney disease or 
post-transplant, will be randomized 1:1 to pegcetacoplan or placebo with 40 to 50 participants 
per arm.  
Based on preliminary data from Study APL2-201, a reduction of 60% in uPCR in the pegcetacoplan 
group at week 26 is assumed vs a reduction of 20% in uPCR in the placebo arm, which corresponds 
to mean log ratio to baseline of −0.92 vs −0.22 respectively, and a standard deviation of 0.88 
(on log-scale). Based on this assumption, a sample size of 70 participants in total provides at least 
90% power at 1-sided significance level of 0.025. Considering a 10% attrition to account for 
potential missing assessments and impact by COVID-19, it is expected that at least 78 participants 
with native kidney disease should be enrolled.  
A minimum of 63 participants with C3G in native kidneys will be enrolled, which is 
approximately 80% of the enrolled participants with native kidney disease. 
12.2. 
Analysis Set 
12.2.1. 
Screened Set 
The screened set will include all participants who provide written informed consent. This set will 
be used only for the purpose of describing participant disposition. 
12.2.2. 
Safety Set 
The safety set will include all participants who receive at least 1 dose of study drug in the RCP. 
Participants will be analyzed according to the treatment they received. 
12.2.3. 
Intent-to-Treat Set 
The intent-to-treat (ITT) set will include all randomized participants. Participants will be 
analyzed according to their assigned treatment, regardless of the treatment actually received. 
All efficacy analyses will be performed with the ITT set. 
12.2.4. 
Per-Protocol Set 
The per-protocol (PP) set will include all participants in the ITT set who have not violated any 
inclusion or exclusion criteria and/or deviated from the protocol in a way that could influence 
their efficacy assessment. Decisions concerning the exclusion of participants from the PP 
analysis set will be made and documented prior to database lock. 


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12.2.5. 
Pharmacokinetic Set 
The PK set will include all participants in the ITT set who receive pegcetacoplan and have at 
least 1 evaluable postdose PK measurement.  
12.2.6. 
Pharmacodynamic Set 
The PD set will include all participants in the ITT set who receive pegcetacoplan and have at 
least 1 evaluable postdose PD measurement.  
12.2.7. 
Data Review for Analysis Set 
After all the data have been verified, coded, and entered into the database, a review will be 
performed to check the quality of the data, identify any outliers, and make decisions on how to 
deal with any data issues (eg, missing values, withdrawals, protocol deviations). After this 
review, resolution of all issues, and documentation of all decisions, the database will be locked. 
12.3. 
Efficacy Analysis 
12.3.1. 
Analysis of Primary Efficacy Endpoint 
The targeted treatment regimen to be used for this study is pegcetacoplan or placebo plus stable 
regimen for C3G/IC-MPGN treatment. The primary estimand on the treatment effect of 
pegcetacoplan is for the participant population as defined through the study inclusion/exclusion 
criteria, with the primary endpoint based on the log-transformed ratio of uPCR (sampled from 
first-morning urine collections) at week 26 compared to baseline using an equal-weighted 
average over weeks 24, 25, and 26.  
Population level summary is the treatment difference in the mean change from baseline in 
log-transformed ratio to baseline in uPCR of pegcetacoplan over placebo.  
A hypothetical strategy will be used for addressing the intercurrent events (ICEs) that are listed in 
ICE categories 1 and 2 in Table 8. In the hypothetical strategy, uPCR data collected at visits after the 
occurrence of ICEs will be set as missing and will be imputed using different approaches as 
described in Table 8. A treatment policy strategy will be used for ICEs of premature discontinuation 
of treatment (ICE category 3). In the treatment policy strategy, any measured value will be used as is.  
The primary endpoint will be analyzed using a mixed effect model for repeated measures (MMRM). 
The model will include fixed categorical effects for treatment group, visit, disease type 
(C3G vs IC-MPGN), stratification factors, and the visit-by-treatment group interaction, as well as the 
continuous, fixed covariate of baseline log-transformed uPCR. Initially, an unstructured covariance 
matrix will be investigated. If this analysis fails to converge, other covariance structures will be used; 
details will be provided in the statistical analysis plan. The difference between treatment groups 
using a composite contrast of equal-weighted average over weeks 24, 25, and 26 will be estimated 
with its 95% CI and corresponding P value. The model will be applied to each multiply imputed data 
set, and results from each imputed data set will be combined using Rubin’s rule (Rubin 1976).  
The primary efficacy analysis will be conducted using the ITT set. Supplemental analysis based 
on alternative estimands, analysis using the PP set, and sensitivity analyses for assessing the 
robustness of the primary analysis results will be performed and prespecified in the SAP.  


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Subgroup analyses will also be conducted to describe findings within both stratification factors in 
addition to other important prognostic factors such as disease type, age, sex, baseline uPCR, etc.  
Table 8: 
Intercurrent Events During the Randomized Treatment Phase and 
Strategies Addressing Intercurrent Events for the Primary Efficacy 
Endpoint 
ICEs 
Strategies for addressing ICEs 
ICE Category 1 
Use of prohibited concomitant medication in 
the protocol (Section 8.3.3)  
Use of rescue therapies defined in the protocol 
(Section 8.3.2) 
Hypothetical strategy will be used where all measurements 
after events under any ICE in this category will be set to 
missing. Missing data resulting from these ICEs will be 
imputed using reference-based imputation. 
ICE Category 2  
Start renal replacement therapy (dialysis) 
Hypothetical strategy will be used where all measurements 
after the ICEs will be set as missing. Missing data resulting 
from these ICEs will be imputed based on the worst 
change of all participants across visits plus a random error. 
ICE Category 3  
Permanent discontinuation of study treatment. 
Treatment policy strategy will be used whereby any measured 
value will be used as is. Missing data resulting from the ICEs 
will be imputed using reference-based imputation. 
Abbreviations: ICE = intercurrent event. 
12.3.2. 
Analysis of Secondary Efficacy Endpoints 
To preserve the overall type I error among the primary endpoint and key and additional secondary 
endpoints, a fixed-sequence testing strategy will be used; hence, statistical significance of the first 
secondary endpoint will be evaluated only if statistical significance is achieved with the primary 
analysis of the primary endpoint. The remaining secondary endpoints will also adhere to this testing 
strategy, and their order will match the order in which they are presented in Section 5.2.1.  
12.3.2.1. Key Secondary Efficacy Endpoints: 
• The numbers and proportion of participants who meet the criteria for achieving a composite 
renal endpoint at week 26 will be tabulated by treatment group and analyzed using a logistic 
regression model with treatment group as the independent variable and adjusted for baseline 
eGFR values, baseline log-transformed uPCR values, disease type, and stratification factors. 
The P value and odds ratio of being a responder for the pegcetacoplan group to being a 
responder for the placebo group with associated 95% CI will be provided.  
A participant meets the requirements of the composite renal endpoint if he/she satisfies: 
(1) a stable or improved eGFR compared to baseline (≤15% reduction in eGFR), 
and (2) a ≥50% reduction in uPCR compared to baseline. 
A composite strategy will be used for addressing the ICEs listed in Table 9. In the composite 
strategy, the composite renal endpoint status at or after the occurrence of any of these ICEs 
below will be regarded as non-responder.  


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Table 9: 
Intercurrent Events During the Randomized Treatment Phase and 
Strategies Addressing Intercurrent Events for the Composite Renal 
Endpoint 
ICEs 
Strategies for addressing ICEs 
Use of prohibited concomitant medication in 
the protocol (Section 8.3.3)  
Start renal replacement therapy (dialysis) 
Use of rescue therapies defined in the protocol 
(Section 8.3.2) 
Permanent discontinuation of study treatment  
Composite strategy. The composite renal endpoint status at 
or after the initiation of any of ICEs will be regarded as 
non-responder.  
Abbreviations: ICE = intercurrent event. 
• The numbers and proportion of participants who achieve uPCR response at week 26 will 
be tabulated by treatment group and compared using a logistic regression model with 
treatment group as the independent variable and adjusted for baseline uPCR values, 
disease type, and stratification factors. The P value and odds ratio of being a responder 
for the pegcetacoplan group to being a responder for the placebo group with associated 
95% CI will be provided. ICEs will be handled as described in Table 9. 
The uPCR response, defined as a reduction of at least 50% from baseline in uPCR at 
week 26, will be calculated using the following steps: 
1. Baseline uPCR value will be calculated as the average of the uPCR measurements 
from at least 6 of the 9 FMU samples collected between the start of screening and 
day 1, inclusive. The uPCR values used to calculate baseline should include those 
from the samples collected on day –2, day –1, and before dosing on day 1.  
2. Week 26 uPCR value will be calculated as the average of the uPCR 
measurements from at least 6 of the 9 FMU samples collected in week 24, 
week 25, and week 26. 
3. Each participant will be categorized as either a success or a failure according to 
whether the change from baseline in uPCR calculated from steps 1 and 2 is a 
reduction of at least 50%. 
For participants with evaluable renal biopsies, evaluation of the change from baseline to 
week 26 in the C3G histologic index activity score will use an analysis of covariance 
(ANCOVA) model with treatment as a fixed effect, adjusted for baseline C3G histologic 
index activity score, disease type, and stratification factors. Least-square (LS) means will be 
presented for each treatment group, along with the between-treatment difference, 
95% confidence interval, and P value. The strategies to handle intercurrent events are the 
same as those for the primary endpoint. This endpoint will be evaluated based on adult 
participants only because neither the week 26 renal biopsy nor an on-study baseline renal 
biopsy are required for adolescent participants. All data, including any data from adolescent 
participants, will be included in a summary table.  


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For participants with evaluable renal biopsies, the numbers and proportion of participants 
showing decreases in C3c staining intensity of at least 2 orders of magnitude from baseline to 
the week 26 renal biopsy will be tabulated by treatment group and compared using a logistic 
regression model with treatment group as the independent variable and adjusted for baseline 
C3c staining, disease type, and stratification factors. The odds ratio of being a responder for 
the pegcetacoplan group to being a responder for the placebo group and associated 95% CI 
and P value will be provided. ICE will be handled the same as Table 9. This endpoint will be 
evaluated based on adult participants only because neither the week 26 renal biopsy nor an 
on-study baseline renal biopsy are required for adolescent participants.  
• Change from baseline in eGFR at week 26 will be tabulated by treatment group and analyzed 
using a MMRM model. The model will include fixed categorical effects for treatment group, 
visit, disease type, stratification factors, and the visit-by-treatment group interaction, as well 
as the continuous, fixed covariate of baseline eGFR values. Initially, an unstructured 
covariance matrix will be investigated, if this analysis fails to converge, other covariance 
structures will be used, details will be provided in the statistical analysis plan. The difference 
between treatment groups will be estimated with its 95% CI and corresponding P value. 
The strategies to handle intercurrent events are similar to those for the primary endpoint. 
12.3.2.2. Additional Secondary Efficacy Endpoints: 
• The proportion of participants achieving proteinuria <1 g/d at week 26 will be analyzed 
using the same approach as the first key secondary endpoint. 
• For participants with serum albumin levels below the LLN at baseline, the number and 
proportion of participants with normalization of serum albumin at week 26 will be 
calculated using the following steps: 
1. Baseline serum albumin value will be calculated as the average of up to 2 serum albumin 
measurements preceding and including day 1. Participants will be included in the 
denominator of this calculation only if the baseline albumin value is below the LLN.  
2. Week 26 serum albumin values will be calculated as the average of up to 2 serum 
albumin measurements preceding and including week 26. 
3. Each participant will be categorized as either a success or a failure according to the 
week 26 serum albumin values as calculated in Step 2. Values greater than or equal to 
the LLN will be categorized as a success; values less than the LLN will be 
categorized as a failure.  
For participants with serum albumin levels below the LLN at baseline, the numbers and 
proportion of participants with normalization of serum albumin at week 26 will be 
tabulated by treatment group and compared using a logistic regression model with 
treatment group as an independent variable and adjusted for baseline albumin value, 
disease type, and stratification factors. The P value and odds ratio of showing serum 
albumin above the LLN at week 26 for the pegcetacoplan group vs. the placebo group 
and associated 95% CI will be provided. The strategies to handle intercurrent events are 
the same as those for the first key secondary endpoint. 


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• For participants with low serum C3 levels at baseline, the number and proportion of 
participants with normalization of serum C3 levels at week 26 will be calculated using 
the following steps: 
1. 
Baseline serum C3 value will be calculated as the average of up to 2 serum C3 
measurements preceding and including day 1. Participants will only be included 
in the denominator of this calculation if the baseline C3 value is below the LLN.  
2. 
Week 26 serum C3 value will be calculated as the average of up to 2 serum C3 
measurements preceding and including week 26. 
3. 
Each participant will be categorized as either a success or a failure based on the 
week 26 serum C3 value as calculated in Step 2. Values greater than or equal to 
the LLN will be categorized as a success; values less than the LLN will be 
categorized as a failure.  
For participants with low serum C3 levels at baseline, the numbers and proportion of 
participants with normalization of serum C3 levels at week 26 will be tabulated by 
treatment group and compared using a logistic regression model adjusting for baseline 
serum C3 level, disease type, and stratification factors. The odds ratio of showing a 
serum C3 level above the LLN at week 26 for the pegcetacoplan group vs. the placebo 
group and associated 95% CI and P value will be provided. The strategies to handle 
intercurrent events are the same as those for the first key secondary endpoint. 
• The change from baseline in FACIT-Fatigue score at week 26 will be analyzed using 
analysis of covariance (ANCOVA) model with treatment as a fixed effect, adjusted for 
baseline FACIT-Fatigue score, disease type, and stratification factors. LS means will be 
presented for each treatment group, along with the between-treatment difference and 95% 
confidence interval. The strategies to handle intercurrent events are the same as those for 
the primary endpoint.  
• The change from baseline in KDQOL score at week 26 will be analyzed using analysis of 
covariance (ANCOVA) model with treatment as a fixed effect, adjusted for baseline 
KDQOL score, disease type, and stratification factors. LS means will be presented for each 
treatment group, along with the between-treatment difference and 95% confidence interval. 
The strategies to handle intercurrent events are the same as those for the primary endpoint. 
12.3.3. 
Analysis of Exploratory Endpoints 
Details regarding the analysis of exploratory endpoints will be presented in the SAP.  
12.4. 
Safety Analysis 
All safety analyses will be summarized for the safety set. 
AEs will be coded using the current version of the Medical Dictionary for Regulatory Activities 
at the time of analysis. TEAEs will be summarized by System Organ Class, Preferred Term, 
and treatment group for the number of participants and proportion reporting the event. A similar 
summary will be produced for SAEs, AEs leading to discontinuation of study drug, severe AEs, 
and AEs related to the investigational product.  


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The intensity of AEs and the relationship to investigational product will be summarized for each 
System Organ Class and Preferred Term by treatment group.  
Withdrawals due to AEs will be summarized for each body system and Preferred Term by 
treatment group. 
The AE summaries will be presented across all participants. All AEs will be listed by participant 
along with information regarding onset, duration, relationship to study drug, severity, action 
taken with study drug, treatment of event, and outcome. In addition, the number and incidence of 
rejection episodes and graft loss as well as the incidence of death stratified by transplant history 
will be tabulated.  
In participants who are post transplant, the number and incidence of rejection episodes at 
week 26, will be tabulated by treatment group and compared between treatment groups using 
Fisher’s exact test or a stratified Cochran-Mantel-Haenszel χ-square test as appropriate. 
The number and incidence of rejection episodes at week 52 will be tabulated.  
In participants who are post transplant, the number and incidence of graft loss at week 26 will be 
tabulated by treatment group, and the results for treatment groups will be compared using 
Fisher’s exact test or a stratified Cochran-Mantel-Haenszel χ-square test as appropriate. 
The number and incidence of graft loss at week 52 will be tabulated.  
Changes from baseline in clinical laboratory test results will be summarized, using descriptive 
statistics, by visit and nominal time postdose. Baseline will be taken as the measurement closest 
to but before randomization. Out-of-range values will be flagged in data listings.  
ADA results, ECG results, and changes from baseline in vital sign measurements will be 
summarized by treatment group, using appropriate descriptive statistics. Baseline will be taken as 
the measurement closest to but before randomization. 
Values of potential clinical significance (eg, increase in QTcF ≥30 milliseconds from baseline) 
will be flagged in listings and summarized by treatment. 
ECG parameters will be analyzed using concentration effect models. 
Changes in physical examination results will be described in a data listing. 
12.5. 
Pharmacokinetic Analysis 
The PK concentrations will be evaluated using the PK set. 
Concentrations will be summarized, using descriptive statistics, over time, in the randomized 
treatment group (pegcetacoplan group). 
Individual participant concentration-time data will be plotted against actual sampling time. 
Median profiles of the concentration-time data, using nominal sampling times, will also be presented. 
Both linear-linear and linear-log plots will be presented.  
Population PK and exposure-response modeling of the safety and efficacy data will be described in a 
pegcetacoplan population PK/PD analysis plan. The methods will be based on the FDA guidances 
for both exposure-response and population PK (FDA Guidance for Industry: Population 
Pharmacokinetics; FDA Guidance for Industry: Exposure-Response Relationships). 


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12.6. 
Pharmacodynamic Analysis 
The PD endpoints will be evaluated using the PD set. 
Absolute values, changes from baseline, and percentage changes from baseline will be summarized 
using descriptive statistics, over time by treatment group. 
Individual participant time profiles will be plotted against actual sampling time. Median profiles, 
over time, using nominal sampling time, will also be presented. 
The PD endpoints will be compared between treatment groups using mixed effect repeated 
measures analyses. 
12.7. 
Other Analyses 
Demographics, baseline characteristics, concomitant medication, medical history, and study 
medication exposure will be summarized by treatment group. 
World Health Organization and Medical Dictionary for Regulatory Activities coding dictionaries will 
be used for the concomitant medications and medical histories, respectively.  
12.8. 
Interim Analysis  
An analysis will be conducted for administrative purposes or regulatory submissions when all 
participants have completed the randomized controlled period and the data is cleaned. No type I 
error adjustment is necessary. 
12.9. 
Data Monitoring Committee 
A formal independent data monitoring committee (DMC) will be used for this study. Representatives 
of Apellis Pharmaceuticals, Inc, will not participate in the review of unblinded data, but if requested 
by the DMC may participate in the review of blinded data or attend portions of DMC meetings at 
which blinded data are presented and discussed to facilitate or answer questions. In addition, external 
medical and scientific experts may be invited to participate in the reviews, as needed. 
DMC meetings will be held according to the schedule in the DMC charter. The remit, roles, 
and responsibilities of the DMC will be specified in a DMC charter. 


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13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
13.1. 
Study Monitoring 
Before an investigational site can enter a participant into the study, a representative of 
Apellis Pharmaceuticals, Inc, will visit the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Apellis Pharmaceuticals, Inc, or its 
representatives. This will be documented in a clinical study agreement between 
Apellis Pharmaceuticals, Inc, and the investigator. 
During the study, a monitor from Apellis Pharmaceuticals, Inc, or representative will have 
regular contacts with the investigational site, for but not limited to the following: 
• Provide information and support to the investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that study drug accountability checks 
are being performed 
• Perform source data verification. This includes a comparison of the data in the case report 
forms with the participant’s medical records at the hospital or practice, and other records 
relevant to the study. This will require direct access to all original records for each 
participant (eg, clinic charts). 
• Record and report any protocol deviations not previously sent to Apellis Pharmaceuticals, Inc 
• Confirm AEs and SAEs have been properly documented on CRFs and confirm any SAEs 
have been forwarded to Apellis Pharmaceuticals, Inc, and those SAEs that met criteria for 
reporting have been forwarded to the IRB 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
13.2. 
Audits and Inspections 
Authorized representatives of Apellis Pharmaceuticals, Inc, a regulatory authority, an Independent 
Ethics Committee, or an IRB may visit the site to perform audits or inspections, including source 
data verification. The purpose of an Apellis Pharmaceuticals, Inc, audit or inspection is to 
systematically and independently examine all study-related activities and documents to determine 
whether these activities were conducted, and data were recorded, analyzed, and accurately reported 
according to the protocol, GCP guidelines of the International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH), and any applicable regulatory 
requirements. The investigator should contact Apellis Pharmaceuticals, Inc, immediately if contacted 
by a regulatory agency about an inspection. 


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13.3. 
Institutional Review Board 
The principal investigator must obtain IRB approval for the investigation. Initial IRB approval 
and all materials approved by the IRB for this study, including the informed consent and assent 
forms and any recruitment materials, must be maintained by the investigator and made available 
for inspection. 
 


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14. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, 
Apellis Pharmaceuticals, Inc, may conduct a quality assurance audit. Please see Section 13.2 
for more details regarding the audit process. 
 


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15. 
ETHICS 
15.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate. The investigator must submit written 
approval to Apellis Pharmaceuticals, Inc, before he or she can enroll any participant into the study. 
The principal investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit participants for the study. The protocol must be reapproved by the 
IRB or IEC upon receipt of amendments and annually, as local regulations require. 
The principal investigator is also responsible for providing the IRB with reports of any reportable 
serious adverse drug reactions from any other study conducted with the investigational product. 
Apellis Pharmaceuticals, Inc, will provide this information to the principal investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
15.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with the GCP guideline of the ICH, applicable 
regulatory requirements, and the Apellis Pharmaceuticals, Inc, policy on bioethics. 
15.3. 
Written Informed Consent 
The principal investigator(s) at each center will ensure that written informed consent is obtained 
for each participant before any study procedures are conducted. The informed consent process 
must at a minimum include the following: 
• The investigator or his/her representative will explain the nature of the study to the 
participant and/or his or her legally authorized representative, including full and 
adequate oral and written information about the nature, purpose, and possible risks 
and benefits of the study, and answer all questions regarding the study. 
Participants and/or their legally authorized representatives or guardians should have 
the opportunity to consider the information provided before providing their consent. 
• Participants must be informed that their participation is voluntary and that they are 
free to discontinue from the study at any time. Each participant or their legally 
authorized representative will be required to sign a statement of informed consent that 
meets the requirements of Chapter 50 of Title 21 of the US Code of Federal 
Regulations, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act requirements, where applicable, and the requirements of the 
IRB/IEC or study center. Where appropriate, the participant must also give assent to 
participation in the study in accordance with local regulations. 


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• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
• If the ICF is revised, participants must be reconsented to the most current version of 
the ICF(s) during their participation in the study.  
• If informed consent is initially provided by a participant’s legally authorized 
representative and the participant acquires the ability to provide informed consent 
during their participation in the study (eg, by reaching the age of majority), informed 
consent must be obtained from the participant before additional study-related 
activities are conducted. 
The principal investigator(s) must maintain the original, signed ICF. A copy of the ICF must be 
given to the participant. 


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16. 
DATA HANDLING AND RECORDKEEPING 
16.1. 
Inspection of Records 
Apellis Pharmaceuticals, Inc, will be allowed to conduct site visits to the investigation facilities 
for the purpose of monitoring any aspect of the study. The investigator agrees to allow the 
monitor to inspect the drug storage area, study drug stocks, drug accountability records, 
participant charts and study source documents, and other records relative to study conduct. 
16.2. 
Retention of Records 
The principal investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval, or if not approved 2 years following the 
discontinuance of the test article for investigation. If it becomes necessary for 
Apellis Pharmaceuticals, Inc, or the regulatory authority to review any documentation relating to 
the study, the investigator must permit access to such records. 
 


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17. 
PUBLICATION POLICY 
Both the use of data and the publication policy are detailed within the clinical study agreement. 
Intellectual property rights (and related matters), generated by the investigator and others performing 
the clinical study, will be participant to the terms of a clinical study agreement that will be agreed 
between the institution and the sponsor or its designee. With respect to such rights, the sponsor or its 
designee will solely own all rights and interests in any materials, data, and intellectual property rights 
developed by investigators and others performing the clinical study described in this protocol, 
participant to the terms of any such agreement. To facilitate such ownership, investigators will be 
required to assign all such inventions, either to their institution or directly to the sponsor or its 
designee, as will be set forth in the clinical study agreement. 
 


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18. 
LIST OF REFERENCES 
Bomback AS, Santoriello D, Avasare RS, et al. C3 glomerulonephritis and dense deposit disease 
share a similar disease course in a large United States cohort of patients with C3 glomerulopathy. 
Kidney Int. 2018 Apr;93(4):977-985. doi: 10.1016/j.kint.2017.10.022 
Cook HT. Evolving complexity of complement-related diseases: C3 glomerulopathy and atypical 
haemolytic uremic syndrome. Curr Opin Nephrol Hypertens. 2018 May;27(3):165-170.  
doi: 10.1097/MNH.0000000000000412 
Holle J, Berenberg-Goßler L, Wu K, et al. Outcome of membranoproliferative 
glomerulonephritis and C3-glomerulopathy in children and adolescents. Pediatr Nephrol. 
2018 Dec;33(12):2289-2298. doi: 10.1007/s00467-018-4034-z 
Iatropoulos P, Daina E, Curreri M, et al. Cluster analysis identifies distinct pathogenetic patterns in 
C3 glomerulopathies/immune complex-mediated membranoproliferative GN. J Am Soc Nephrol. 
2018 Jan;29(1):283-294. doi: 10.1681/ASN.2017030258 
Lu DF, Moon M, Lanning LD, et al. Clinical features and outcomes of 98 children and adults 
with dense deposit disease. Pediatr Nephrol. 2012 May;27(5):773-81.  
doi: 10.1007/s00467-011-2059-7 
Mallinckrodt CH, Lane PW, Schnell D, et al. Recommendations for the primary analysis of 
continuous endpoints in longitudinal clinical trials. Drug Inf J. 2008 Jul;42(4):303-319. 
Medjeral-Thomas NR, O’Shaughnessy MM, O’Regan JA, et al. C3 glomerulopathy: 
clinicopathologic features and predictors of outcome. Clin J Am Soc Nephrol. 2014 Jan;9(1):46-53. 
doi: 10.2215/CJN.04700513 
Noris M, Donadelli R, Remuzzi G. Autoimmune abnormalities of the alternative complement 
pathway in membranoproliferative glomerulonephritis and C3 glomerulopathy. Pediatr Nephrol. 
2019 Aug;34(8):1311-1323. doi: 10.1007/s00467-018-3989-0 
Okpechi IG, Dlamini TA, Duffield M, et al. Outcome of patients with primary immune-complex 
type mesangiocapillary glomerulonephritis (MCGN) in Cape Town South Africa. pLoS One. 
2014 Nov 20;9(11):e113302. doi: 10.1371/journal.pone.0113302 
Pickering MC, D’Agati VD, Nester CM, et al. C3 glomerulopathy: consensus report. Kidney Int. 
2013 Dec;84(6):1079-89. doi: 10.1038/ki.2013.377 
Regunathan-Shenk R, Avasare RS, Ahn W, et al. Kidney transplantation in C3 glomerulopathy: 
a case series. Am J Kidney Dis. 2019 Mar;73(3):316-323. doi: 10.1053/j.ajkd.2018.09.002 
Rubin DB. Inference and missing data. Biometrika. 1976 Dec;63(3):581-592. 
https://doi.org/10.1093/biomet/63.3.581 
Servais A, Noël LH, Roumenina LT, et al. Acquired and genetic complement abnormalities play 
a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int. 
2012 Aug;82(4):454-64. doi: 10.1038/ki.2012.63 
Smith RJH, Appel GB, Blom AM, et al. C3 glomerulopathy—understanding a rare 
complement-driven renal disease. Nat Rev Nephrol. 2019 Mar;15(3):129-143.  
doi: 10.1038/s41581-018-0107-2 


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Zhang Y, Nester CM, Martin B, et al. Defining the complement biomarker profile of C3 
glomerulopathy. Clin J Am Soc Nephrol. 2014 Nov 7;9(11):1876-1882.  
doi: 10.2215/CJN.01820214 


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19. 
APPENDICES 


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Appendix 1. 
Protocol Amendment History 
A.1.1. 
Protocol Amendment History 
DOCUMENT HISTORY 
Document 
Date 
Country-specific modifications to 
Protocol Amendment 3 
 
 
Amendment 3.1 DEU 
02 November 2023 
 
Amendment 3.1 CHE 
12 September 2023 
 
Amendment 3.1 FRA, NLD 
31 July 2023 
 
Addendum 3.1 ISR 
06 April 2023 
 
Addendum 3.1 JPN 
06 April 2023 
 
Addendum 3.1 CZE 
06 April 2023 
 
Addendum 3.1 CAN 
06 April 2023 
Amendment 3 
03 March 2023 
Amendment 2 
14 August 2021 
Amendment 1 
12 March 2021 
Original Protocol 
26 September 2019 
Country-specific protocol modifications are only listed for the most recent global amendment. Any outstanding 
country-specific modifications are evaluated at each global amendment and incorporated into the global 
amendment as appropriate.  


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Amendment 3: Summary of Changes From the Previous Version 
Overall Rationale for the Amendment: 
The protocol was amended to revise and reorganize the study endpoints in response to feedback and 
comments from the FDA. Strategies for the statistical analysis of the endpoints were updated to align 
with the revised endpoints. Additional revisions were made to clarify study procedures and activities 
in response to feedback from investigators and/or to align with current company practices. 
Minor formatting and stylistic revisions were made to align with current templates, and any identified 
typographical errors were corrected; these are not identified individually in the descriptions below. 
Description of change 
Section(s) affected 
Rationale for change 
Study design and rationale changes 
 
Updated summary of clinical 
experience to include Study APL2-308 
Section 4.3 
Updated to reflect current clinical 
experience with pegcetacoplan 
Increased duration of screening period 
from 8 to 10 weeks with a 
corresponding increase of total duration 
of study participation to 70 weeks 
Synopsis, Section 6, 
Section 6.1.1, 
Figure 1 
Updated to allow extra time for the 
transfer, processing, and reading of biopsy 
materials within the screening period 
Increased the minimum number of 
adolescent participants from 8 to 10 
Section 6, 
Section 6.2 
Increased to align with the current 
pediatric investigational plan, and 
clarified that participants initially 
screened as adolescents will follow 
adolescent procedures and requirements 
through the duration of the study. 
Revised study scheme diagram 
Figure 1 
Reflects revised screening period 
Study endpoint changes 
 
Changed primary efficacy endpoint from 
the proportion of subjects with a 
reduction from baseline in uPCR of at 
least 50% to the log-transformed ratio of 
uPCR at week 26 compared to baseline 
Synopsis, 
Section 5.2.1, 
Section 12.3.1 
Dichotomization of continuous outcomes 
in clinical trials can result in loss of 
statistical power. Revised in response to 
FDA suggestion to assess the primary 
endpoint as a continuous variable 
Changed key secondary efficacy 
endpoint to the proportion of 
participants who meet the criteria for 
achieving a composite renal endpoint 
(a stable or improved eGFR compared 
to the baseline visit (≤15% reduction in 
eGFR), and a ≥50% reduction in uPCR 
compared to the baseline visit.) 
Synopsis, 
Section 5.2.1, 
Section 12.3.2 
Revised to provide analysis of the 
population with reduced proteinuria who 
maintain a stable eGFR. Revised in 
response to FDA suggestion to redefine 
the criteria for a stable or improved 
eGFR; combined eGFR and uPCR 
responses in a new composite endpoint 
Escalated change in eGFR to a key 
secondary endpoint 
Synopsis, 
Section 5.2.1, 
Section 12.3.2 
Reorganized secondary endpoints following 
the change to the primary endpoint 
Added the proportion of participants with 
a reduction of at least 50% from baseline 
in uPCR as a key secondary endpoint 
Synopsis, 
Section 5.2.1, 
Section 12.3.2 
Reorganized secondary endpoints following 
the change to the primary endpoint 


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Description of change 
Section(s) affected 
Rationale for change 
Removed change from baseline in 
uPCR as an additional secondary 
efficacy endpoint 
Synopsis, 
Section 5.2.1, 
Section 12.3.2 
Reorganized secondary endpoints following 
the change to the primary endpoint 
Revised and reorganized exploratory 
endpoints to align with changes to 
primary and secondary endpoints 
Section 5.2.1 
Reorganized exploratory endpoints 
following the change to the primary and 
secondary endpoints 
Reorganized pharmacokinetic, 
pharmacodynamic, 
and immunogenicity endpoints to 
appear in a single heading 
Section 5.2.3 
Organizational change in presentation of 
endpoints 
Participant selection changes 
 
Clarified that biopsy-based inclusion 
criteria apply to both baseline biopsies 
collected as part of the study and 
historical biopsies collected within 
28 weeks of randomization and used as 
baseline biopsies 
Synopsis, 
Section 7.1 
Clarified to provide additional guidance 
for investigators 
Added sodium-glucose cotransporter-2 
inhibitors to the description of stable 
treatment regimens for C3G/IC-MPGN 
Synopsis, 
Section 7.1 
Added to reflect recognition of treatment 
with sodium-glucose cotransporter-2 
inhibitors as standard of care treatment for 
chronic kidney disease 
Updated the time requirements for 
stable dosing regimens to remove 
reference to baseline renal biopsy; 
timing of stable treatment requirements 
is now based solely on randomization 
Synopsis, 
Section 7.1 
Clarified to provide additional guidance 
for investigators and for consistency with 
stable treatment requirement period 
Added recent severe infection as an 
exclusion criterion 
Synopsis, 
Section 7.2 
Incorporated changes requested by health 
authorities 
Study intervention changes 
 
Clarified when open-label dosing will 
begin 
Synopsis, 
Section 6.1.3, 
Table 2  
(Schedule of 
Activities), 
Section 11.1.2 
Clarified that open-label dosing will begin 
at the first visit after the week 26 renal 
biopsy for adults and any adolescents 
providing renal biopsies. Open-label 
dosing for adolescents not providing renal 
biopsies should start at the week 26 visit. 
Clarified procedures and requirements for 
the transition to open-label dosing to 
provide additional guidance for 
investigators 
Updated vaccination guidance to 
recognize the potential use of local 
guidelines as an alternative to ACIP 
guidelines 
Section 8.2 
Added to recognize that vaccination 
requirements and practices may differ 
between countries 
Updated discussion of vaccination 
against S pneumoniae to reflect recent 
changes to ACIP guidelines  
Section 8.2 
Revised to reflect current ACIP guidelines 


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Description of change 
Section(s) affected 
Rationale for change 
Study assessment changes 
 
Removed testing of C3Nef from 
samples collected after screening 
Table 2  
(Schedule of 
Activities),  
Table 4  
(Laboratory 
Assessments) 
Revised protocol to incorporate guidance 
in a previous protocol clarification letter, 
as the evidence suggests C3 inhibition 
does not change C3NF 
Clarified the timing of the collection of 
baseline and week 26 renal biopsies 
and the requirements for using a prior 
biopsy as the baseline biopsy 
Section 6.1.1, 
Section 10.5 
Clarified the windows for collection of 
the baseline and 26-week renal biopsies. 
Clarified requirements for chest 
radiography, moved baseline 
radiography to visit 2 
Section 11.1.7, 
Table 2  
(Schedule of 
Activities) 
Clarified requirements for chest radiography 
to provide additional guidance for 
investigators. Moved collection of the 
baseline chest radiography to follow the 
initial screening visit for consistency with 
other invasive procedures (eg, vaccination, 
renal biopsy) 
Safety reporting changes 
 
Updated discussion of assessment of 
severity of adverse events 
Section 11.2.2.2 
Updated to align with current company 
practices 
Updated description of procedures for 
reporting SAEs to Apellis 
Section 11.2.3 
Updated to align with current company 
practices 
Updated description of procedures for 
monitoring and reporting pregnancies 
to Apellis 
Section 11.2.4 
Updated to align with current company 
practices 
Statistical analysis changes 
 
Updated discussion of the 
determination of sample size  
Synopsis, Section 6, 
Section 6.2, 
Section 12.1 
Updated to provide additional background, 
and to reflect determination of the sample 
size based on the revised primary endpoint. 
Changing the primary endpoint led to an 
increase in the number of participants with 
native kidney disease to 78. Also provided 
enrolment targets for participants with 
posttransplant recurrence and for 
participants with C3G in native kidneys. 
Updated the discussion of the efficacy 
analyses  
Synopsis, 
Section 12.3 
Updated to reflect the revised the primary, 
key secondary, and additional secondary 
endpoints 
Study conduct changes 
 
Clarified screening procedures, 
including rescreening activities 
Section 6.1.1, 
Section 6.1.1.1 
Clarified procedures based on feedback 
from investigational sites 
Clarified discussion of study treatment 
discontinuation, study withdrawal, and 
the activities to be undertaken in these 
situations 
Section 7.3 
Updated to align with current company 
practices 


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Description of change 
Section(s) affected 
Rationale for change 
Provided guidance for the resumption 
of dosing if regularly scheduled doses 
are missed 
Section 8.1 
Updated to provide additional guidance 
for investigators  
Clarified discussion of study treatment 
blinding requirements 
Section 8.5.2 
Updated to align with current company 
practices 
Added the potential to ship 
investigational product and/or ancillary 
study supplies directly to the 
participant, where permitted 
Section 9.3 
Updated to align with current company 
practices 
Clarified guidance regarding infusion 
sites 
Section 9.5 
Updated to align with current company 
practices 
Document organization changes 
 
Updated Responsible Medical Director 
Signature Page 
Updated to reflect organizational change 
in study management 
Changed wording from “subjects” to 
“participants” 
Global 
Updated to align with current company 
practices 


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Amendment 2: Summary of Changes From the Previous Version 
Overall Rationale for the Amendment: 
The protocol was amended to address comments from the FDA. Additional revisions were made 
for clarification of study activities or to align with current company practices. 
Minor formatting and stylistic revisions were made to align with current templates, and any 
identified typographical errors were corrected; these are not identified individually in the 
descriptions below. 
Description of change 
Section(s) affected by change 
Study design and rationale changes 
Changed planned enrollment from 90 to 80-100 subjects 
Synopsis, Section 6, Section 6.1.2, 
Section 6.2, Section 12.1 
Clarified vaccination strategy and prophylactic antibiotic use in 
Risk/Benefit discussion 
Section 4.4 
Changed primary and key secondary objectives to align with 
endpoint changes 
Synopsis, Section 5.1 
Changed from 10 posttransplant minimum to 77 native kidney 
minimum 
Section 6, Section 6.2, Section 8.5.1, 
Section 12.1 
Added 8-adolescent minimum 
Section 6, Section 6.2 
Revised study scheme diagram 
Section 6.1 (Figure 1) 
Study endpoint changes 
Changed primary efficacy endpoint to remove eGFR 
component 
Synopsis, Section 5.2, Section 12.3.1 
Removed proportion of subjects with uPCR reductions of at 
least 50% as a secondary efficacy endpoint 
Synopsis, Section 5.2, Section 12.3.2 
Changed primary and key secondary efficacy endpoints from 
week 52 to week 26 
Synopsis, Section 5.2, Section 12.3.1, 
Section 12.3.2 
Revised and reorganized secondary and exploratory endpoints 
(including timing of evaluations) 
Synopsis, Section 5.2, Section 12.3.1, 
Section 12.3.2 
Subject selection changes 
Increased minimum body weight to 30 kg 
Synopsis, Section 7.1, Section 8.1 
Updated inclusion criteria to define evidence of active renal 
disease and remove central medical review 
Synopsis, Section 7.1 
Updated inclusion criteria to define acceptable stable regimens 
for treatment of C3G/IC-MPGN 
Synopsis, Section 7.1 
Revised replacement of subjects section to clarify that subjects 
who discontinue will not be replaced 
Section 7.3.4 
Study intervention changes 
Clarified wording of renal biopsies in adolescents section to 
explicitly note that biopsies will not be collected for research 
purposes from adolescent subjects in the US 
Section 10.5.2 


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Description of change 
Section(s) affected by change 
Created separate subsection in Concomitant Medications 
describing permitted prior medications 
Section 8.3 
Added section discussing possible rescue treatment for 
C3G/IC-MPGN 
Section 8.3.2 
Study assessment changes 
Added specification of use of Bedside Schwartz equation in 
adolescents where missing 
Synopsis, Section 6.1.1 
Added chest radiography to schedule of activities and 
discussion of safety procedures 
Table 2, Section 11.1.7, Table A1 
Removed fibrinogen and added prothrombin time to 
coagulation section of laboratory assessments table 
Section 11.1.9 (Table 4) 
Safety reporting changes 
Added section describing AEs of special interest 
Section 11.2.5 
Statistical analysis changes 
Removed discussion of extrapolating placebo response rate 
from week 26 to week 52 
Synopsis, Section 4.2.2, Section 12.3.1 
Removed potential sample size revision 
Synopsis, Section 6, Section 6.2, 
Section 12.8 
Changed baseline, week 26, and week 52 uPCR calculations to the 
average of 6 to 9 samples from the average of 9 samples 
Section 6.1.1, Section 12.3.1, Section 
12.3.2 
Added discussion of primary and alternate estimands 
Section 12.3.1 
Added discussion of intercurrent events and how they will be 
handled in assessment of the primary endpoint 
Section 12.3.1 
Updated descriptions of calculations of responder analysis for 
uPCR and eGFR endpoints 
Section 12.3.1, Section 12.3.2 
Revised and clarified descriptions of analysis of secondary 
endpoints 
Section 12.3.2 
Removed interim analyses (interim analysis 1 for sample size 
readjustment and interim analysis 2 for early efficacy assessment) 
Synopsis, Section 12.8 
Study conduct changes 
Added section describing maximum blood collection volumes 
Section 11.1.12 
Removed central medical review for confirmation of diagnosis 
and eligibility 
Synopsis, Section 6.1.1, Section 7.1, 
Section 10.5.2, Section 11.1.2 
Clarified that Apellis representatives will not review 
unblinded data 
Section 12.9 
COVID-19 continuity changes 
Added COVID-19 vaccine to COVID-19 risk mitigation 
section and COVID-19 Appendix 
Section 4.4.1, Appendix 2 
Document organization changes 
Added appendix listing prior revision history of the document 
Appendix 1 


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Amendment 1: Summary of Changes From the Previous Version 
Overall Rationale for the Amendment: 
The protocol was amended to revise the study design and endpoints following discussions with 
regulatory authorities and internal evaluation of the study, and to provide guidance to investigators in 
the case of COVID-19–related restrictions. Additional revisions were made for clarification of study 
activities, or to align with current company practices. 
Minor formatting and stylistic revisions were made to align with current templates, and any 
identified typographical errors were corrected; these are not identified individually in the 
descriptions below. 
Description of change 
Section(s) affected by change 
Study design and rationale changes 
Updated study design so that the randomized controlled 
period is double-blinded and added justification of study 
design section. 
Synopsis, Section 4.2.2, Section 6, 
Section 6.1, Section 8.5.2 
Shortened the follow-up period for subjects who do not 
continue receiving pegcetacoplan from 24 to 8 weeks. 
Synopsis, Section 6, Section 6.1, 
Section 6.1.4  
Added requirement that the study will enroll at least 
10 subjects with posttransplant recurrence of C3G or 
IC-MPGN. 
Synopsis, Section 6, Section 6.2, 
Section 8.5.1 
Added an interim analysis of efficacy when all subjects 
have completed the 26-week randomized controlled period.  
Synopsis, Section 12.8 
Added an optional renal biopsy at week 52 to support 
evaluation of the revised primary endpoint.  
Synopsis, Section 6.1, Section 6.1.3,  
Table 1 (Schedule of Activities), Section 10.5 
Study endpoint changes 
Revised the primary endpoint from the change from 
baseline in urine protein-to-creatinine ratio (uPCR) at week 
26 to the proportion of subjects with a reduction in uPCR of 
at least 50% and an estimated glomerular filtration rate 
(eGFR) that is stable or improved from baseline at week 52. 
Synopsis, Section 5.2.1  
Extensively revised secondary efficacy endpoints, 
exploratory endpoints, and safety endpoints. 
Synopsis, Section 5.2.2, Section 5.2.3, 
Section 5.2.4  
Subject selection changes 
Amended inclusion criteria to allow enrollment of 
adolescents of 20 kg or more, rather than 42 kg or more. 
Synopsis, Section 7.1  
Amended inclusion criteria to include a definition of 
women of childbearing potential and provided a definition 
of childbearing potential. 
Synopsis, Section 7.1, Section 7.1.1  
Added inclusion criterion that subjects must be willing and 
able to self-administer pegcetacoplan or have an identified 
caregiver who can perform the administration.  
Synopsis, Section 7.1 
Added exclusion criterion requiring an absolute neutrophil 
count of at least 1000 cells/mm3 at screening. 
Synopsis, Section 7.2 


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Description of change 
Section(s) affected by change 
Added exclusion criterion for subjects with hypersensitivity 
to pegcetacoplan or excipients.  
Synopsis, Section 7.2 
Added exclusion criterion for subjects with a history of 
meningococcal disease.  
Synopsis, Section 7.2 
Added exclusion criterion excluding subjects with known or 
suspected hereditary fructose intolerance. 
Synopsis, Section 7.2 
Removed exclusion criterion for subjects with liver 
dysfunction.  
Synopsis, Section 7.2 
Replaced inclusion criterion for body mass index ≤35 kg/m2 
with exclusion criterion for weight >100 kg. 
Synopsis, Section 7.1, Section 7.2 
Study intervention changes 
Revised dosing recommendations, adding regimens for 
adolescent subjects ≥50 kg, 35 to <50 kg, and 20 to <35 kg. 
Synopsis, Section 4.2.3, Section 8.1 
Revised wording of vaccination requirements to cite 
Advisory Committee on Immunization Practices guidelines 
and align with current company practices. 
Section 8.2 
Added description of blinding and unblinding procedures. 
Section 8.5.2 
Study assessment changes 
Clarified instructions for triplicate first-morning spot urine 
collection.  
Section 10.3 
Provided additional guidance on the collection of renal 
biopsy samples, including clarification of the biopsy 
requirements for adolescent subjects. 
Section 10.5 
Added color fundus photography to the optional 
ophthalmologic evaluation; clarified that the evaluation 
should also include a basic ophthalmologic examination.  
Table 1 (Schedule of Activities), Section 10.6  
Safety reporting changes 
Update wording describing monitoring and reporting of 
AEs and SAEs to align with current company practices, 
including: 
 
• 
Updated wording defining terms 
Section 11.2.1 
• 
Updated description of evaluation and recording of 
adverse events 
Section 11.2.2 
• 
Clarified SAE reporting responsibilities and procedures 
Section 11.2.3 
• 
Clarified pregnancy reporting responsibilities and 
procedures 
Section 11.2.4 
• 
Added guidance on the definition and reporting of 
abuse, misuse, overdose, and medication errors 
Section 11.2.5  


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Description of change 
Section(s) affected by change 
Statistical analyses changes 
Updated descriptions of statistical analyses to align with 
revised endpoints.  
Synopsis, Section 12.3, Section 12.4  
Revised description of sample size evaluation and added a 
description of the interim analysis of efficacy.  
Synopsis, Section 12.1, Section 12.8 
Study conduct changes 
Updated and clarified procedures for obtaining informed 
consent. 
Section 15.3  
COVID-19 continuity changes 
Added wording describing risks related COVID-19 and 
activities to mitigate these risks. 
Section 4.4.1, Appendix 1 
 


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Appendix 2. 
Country-Specific Protocol Modifications 
Country-specific modifications to this protocol are listed below. 
Additions to the protocol are marked by underlined text, and deletions of existing protocol text 
are marked by strikethrough text. 
Canada 
Rationale for Modifications 
These modifications to the APL2-C3G-310 protocol are being implemented in Canada to support 
the Investigational Testing Authorization for the Crono Super PID infusion pump and CRN 
Crono 20-mL syringe reservoir. 
Summary of Changes 
Changes in the sections noted below will be enacted by this addendum. 
9.4  
Infusion Supplies 
The sponsor will provide infusion supplies supply syringes, vial adapters, infusion sets, and 
ambulatory syringe infusion pumps, as required. Refer to the pharmacy manual for further details. 
The Crono Super PID infusion pump and the CRN Crono 20-mL syringe reservoir, which will be 
used during the clinical study to deliver each dose of the isotonic sterile solution of pegcetacoplan 
1080 mg/20 mL (54 mg/mL) transferred from the vial to the syringe, do not have a medical device 
license authorizing their commercial sale in Canada and are therefore considered investigational 
medical devices. The infusion pump and reservoir will be used in conjunction with the Neria multi 
infusion set (MDL #88990; Unomedical Devices SA de CV, Aaholmvej 1-3, Osted, 4320 Lejre, 
Denmark) and the vial adaptor (MDL #70132; West Pharmaceutical Services IL, Ltd, 4 Hasheizaf St, 
Ra’Anana, Israel, 4366411), which are approved for use in Canada. 
9.4.1. Investigational Medical Devices: Crono Super PID Infusion Pump and CRN Crono 
20-mL Reservoir 
9.4.1.1. 
Descriptions of the Investigational Medical Devices 
The Crono Super PID infusion pump is an electromechanical, software-controlled, reusable 
infusion pump manufactured by Canè SpA Medical Technology (Via Cuorgnè 42/a, 10098 
Rivoli, Cascine Vica [TO], Italy) that is supplied to the participant and used throughout the 
duration of the study. The CRN Crono 20-mL syringe reservoirs are sterile, nonpyrogenic, 
single-use syringes specifically for use with the Crono pumps and are supplied in individual 
sterile packaging. A new syringe reservoir is filled from the drug vial with the transfer set, 
used for one dose of pegcetacoplan, and then disposed of. During the study, infusion site/pump 
safety will be assessed during clinical visits, and any significant finding from the assessment 
will be recorded.  


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9.4.1.2. 
Justification for the Use of the Investigational Medical Devices 
Apellis assessed the potential hazards associated with the delivery of the drug product in relation 
to the uses for which the pump carries a CE mark in the EU. The hazards evaluated were related 
to the required critical performance attributes, the user profile, and the use environment relevant 
to use with the drug product in the clinical trial. This assessment included testing to confirm 
performance to the required delivery requirements and the delivery process and evaluation of the 
user population in comparison with those for which these devices are already CE-marked for use.  
The assessment concluded that the Crono Super PID infusion pump could meet the delivery 
requirements of Study APL2-C3G-310, does not present any unique usability issues to the user 
groups in Study APL2-C3G-310, and does not introduce any additional or residual risks. 
The use of the investigational devices in human participants is justified on the basis of the design 
and intended uses of the device constituent parts (Canè Crono Super PID Infusion Pump and 
CRN Crono 20-mL syringe reservoir), which are appropriate. 
9.4.1.3. 
Anticipated Exposure to the Investigational Medical Devices 
The anticipated exposure to the investigational device is approximately 30 minutes per infusion 
twice weekly.  
9.4.1.4. 
Anticipated Adverse Device Effects 
The anticipated adverse device effects are discussed in Section 9.4.2.  
9.4.1.5. 
Number of Investigational Devices to be Used 
The sponsor plans to open 3 sites in Canada and expects to assign to treatment 2 participants 
across the sites in Canada. Each participant assigned to treatment will receive a primary pump, 
a backup pump, and enough infusion sets for 52 weeks of biweekly infusions. Sites will be 
provided with additional pumps and infusion supplies (approximately 20% overage, rounded up). 
Actual need will depend on enrollment, but 14 Super PID pumps and approximately 360 syringe 
reservoirs are planned for the study sites in Canada.  
9.4.2. Risks of Investigational Medical Devices  
The use of this delivery system with this drug in this clinical trial does not create any risks 
additional to the residual risk inherent with the current use of these devices. There is a possibility 
that participants could experience redness, swelling, and pain or tenderness at the site of 
infusion. There is also a slight possibility of infection. In addition, because pegcetacoplan is to be 
administered by SC infusion, participants may feel some discomfort from the infusion. None of 
these risks are affected by the use of these specific devices.  
9.4.3. Reporting of Incidents Related to Investigational Medical Devices  
All incidents related to investigational medical devices must be reported to Apellis immediately, 
within 24 hours of the investigator or their representative becoming aware of the event. The site 
must complete the complaints form and email it to complaints@apellis.com immediately, within 
24 hours of becoming aware of the event. 


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The sponsor is responsible for submitting reports of incidents related to an investigational 
medical device to Health Canada and the device manufacturer within 72 hours of becoming 
aware of the issue. The device manufacturer will then further assess the incident according to the 
timelines in the guidance and report their findings accordingly.  
9.4.4. Investigational Medical Device Accountability 
Accountability for the investigational medical devices at the study center is the responsibility of 
the investigator. The investigator will ensure that the investigational medical devices are used 
only in accordance with this protocol. Where allowed, the investigator may choose to delegate 
accountability responsibilities to a pharmacist or other appropriate individual. 
Investigators will be provided with sufficient amounts of the investigational medical devices to 
carry out this protocol for the agreed number of participants. The investigator or designee will 
acknowledge receipt of the investigational medical devices, documenting shipment content and 
condition. Accurate records of all the investigational medical devices provided, used, returned, 
and/or destroyed must be maintained. Accountability records will include dates, quantities, 
batch/serial numbers, expiration dates (if applicable), and participant numbers. The sponsor or its 
designee will review the investigational medical device accountability at the study center on an 
ongoing basis during monitoring visits. 
The investigational medical devices must not be used for any purpose other than the present 
study. The investigational medical devices that have been provided to a participant and returned 
unused must not be provided to a different participant. 
9.4.5. Investigational Medical Device Handling 
All used and unused investigational medical devices should be retained at the study center until 
they are inventoried by the study monitor. All used, unused, or expired investigational medical 
devices will be returned to the sponsor or its designee for disposition. Disposition will be 
documented, or if authorized disposed of at the study center according to the center’s standard 
operating procedures and documented. 
Czech Republic 
Rationale for Modifications 
These modifications to the APL2-C3G-310 protocol are being implemented in the Czech Republic, 
as requested by the State Institute for Drug Control. 
Summary of Changes 
Enrollment of Adolescent Participants 
As described in Section 7.1, Inclusion Criteria, adolescents (aged 12-17 years) may be enrolled 
where approved. The enrollment of adolescent participants is not approved in the Czech Republic, 
and therefore only adult participants, aged 18 years or older, will be enrolled in this country. 


Pe gcetac o pla n ( A P L -2)  
A P L 2‑ C 3 G -3 1 0  Pr ot oc ol A me n d me nt 4  
2 5 A pril  2 0 2 4  
A pellis P har mace uticals, I nc 
Pa ge 1 0 0  of 1 1 7  
C o nfi de ntial  
Fr a nce, Net herl a n ds, Ger m a n y  
R ati o n ale f or M o dific ati o ns  
T hese m o dificati o ns t o t he A P L 2- C 3 G - 3 1 0 pr ot oc ol are bei n g i m ple me nte d t o te m p oraril y all o w 
partici pa nts i n St u d y  A P L 2 -C 3 G - 3 1 0 i n Fra nce, t he Net herla n ds, or Ger ma n y t o c o nti n ue t o 
recei ve pe gcetac o pla n after t he c o m pleti o n of t he 5 2 wee ks of treat me nt defi ne d i n Pr ot oc ol 
A P L 2 -C 3 G - 3 1 0 if t he y are eli gi ble a n d i nte n d t o e nter St u d y 
, t he l o n g-ter m 
e xte nsi o n st u d y, b ut t hat st u d y is n ot yet f ull y a p pr o ve d a n d acti ve.  
S u m m ar y of C h a n ges  
C ha n ges i n t he secti o ns n ote d bel o w will be e nacte d b y t his a d de n d u m. 
Secti o n 6. 1. 3, P art 3: O pe n -L a bel Peri o d ( 2 6 Wee ks)  
At t he e n d of t he R C P, partici pa nts fr o m b ot h gr o u ps will pr ocee d t o t he 2 6 -wee k o pe n -la bel peri o d, 
i n w hic h all partici pa nts will be treate d wit h pe gcetac o pla n t wice wee kl y. O pe n-la bel d osi n g will 
be gi n at t he first visit after t he wee k  2 6 re nal bi o ps y f or a d ults a n d a n y a d olesce nts pr o vi di n g re nal 
bi o psies. O pe n -la bel d osi n g f or a d olesce nts n ot pr o vi di n g re nal bi o psies s h o ul d start at t he wee k 2 6 
visit. At t he e n d of t he o pe n -la bel peri o d, t here will be a n o pti o nal re nal bi o ps y. Partici pa nts y o u n ger 
t ha n 1 8 years w h o di d n ot ha ve a baseli ne bi o ps y wit hi n 2 8  wee ks of da y  1 will n ot ha ve a bi o ps y at 
t he e n d of t he o pe n-la bel peri o d. U p o n c o m pleti o n of t he o pe n-la bel peri o d, partici pa nts will e nter 
t he f oll o w-u p peri o d ( Part 4) u nless t he y e nter a l o n g -ter m e xte nsi o n st u d y.  
Partici pa nts w h o ha ve c o m plete d t he pla n ne d 5 2 wee ks st u d y partici pati o n a n d are eli gi ble a n d 
i nte n d t o e nter St u d y 
, t he l o n g-ter m e xte nsi o n st u d y, ma y c o nti n ue t o recei ve 
pe gcetac o pla n i n t his st u d y if i m me diate tra nsiti o n t o t he l o n g -ter m e xte nsi o n st u d y is n ot 
p ossi ble beca use t hat st u d y is n ot yet f ull y a p pr o ve d a n d acti ve. If t his occ urs, partici pa nts 
s h o ul d c o nti n ue st u d y visits e ver y 6 wee ks, a n d i n vesti gat ors s h o ul d c ollect at least t he 
i nf or mati o n defi ne d f or t he wee k 4 2 visit i n t he s c he d ule of acti vities, e xcl u di n g a n y o pti o nal 
assess me nts. T his e xte nsi o n peri o d ma y c o nti n ue f or u p t o a p pr o xi matel y 3 m o nt hs.  
Isr ael 
R ati o n ale f or M o dific ati o ns  
T hese m o dificati o ns t o t he A P L 2- C 3 G -3 1 0 pr ot oc ol are bei n g i m ple me nte d i n Israel t o satisf y 
re q uire me nts of t he Mi nistr y of Healt h ( M O H) a n d t o clarif y t hat o nl y a d olesce nt st u d y s u bjects 
will be e nr olle d i n Israel.  
S u m m ar y of C h a n ges  
E nr oll me nt of P artici p a nts  
T o c o m pl y wit h t he Mi nistr y of Healt h re q uire me nt t hat i n -st u d y re nal bi o psies m ust be o pti o nal, 
o nl y a d olesce nt partici pa nts will be e nr olle d at st u d y sites i n Israel. E nr olle d partici pa nts m ust 
f oll o w t he pr oce d ures descri be d i n t he pr ot oc ol, i ncl u di n g a n y s pecific n otati o ns or 
c o nsi derati o ns f or a d olesce nt partici pa nts.  
C CI
C CI


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Because only adolescent participants will be enrolled, the following portions of the protocol are 
modified as indicated: 
Synopsis and Section 7.1, Inclusion Criteria 
1. Aged at least 18 years; where approved, aAdolescents (aged 12-17 years) weighing at 
least 30 kg may also be enrolled. 
Section 10.5.1, Renal Biopsies in Adults, is no longer applicable and should be disregarded. 
Japan 
Rationale for Modifications 
These modifications to the APL2-C3G-310 protocol are being implemented in Japan to satisfy 
requirements of the Pharmaceuticals and Medical Devices Agency and to clarify study procedures in 
Japan by considering Japanese regulatory rules and the actual situation of general medical practice.  
Contraception Exceptions 
The protocol includes implantable or injectable contraceptives and removable birth control devices as 
acceptable methods of contraception. These methods of contraception are not approved in Japan and 
therefore will not be allowed for Japanese participants included in this study. 
Vaccinations 
Meningitis caused by Neisseria meningitidis type B is not endemic to Japan, and the number of 
patients with meningitis caused by N meningitidis type B in Japan has been decreasing in recent 
years. Given this, the meningococcal B vaccine is not approved in Japan. Participants enrolled in 
Japan for this clinical trial must have received the meningococcal conjugate vaccine for 
N meningitidis A, C, W, and Y and do not need to have received the meningococcal B vaccine.  
The schedule of vaccinations is consistent with the United States Centers for Disease Control and 
Prevention rationale as well as the Japanese Respiratory Society/Japanese Association for 
Infectious Diseases recommendation “Considerations of Pneumococcal Vaccination for Adults 
Aged 65 and Over.” 
All other vaccinations defined in the protocol are marketed in Japan and should be administered 
as described in Section 8.2 of the global protocol. Investigators must follow the instructions in 
the package inserts of these vaccine products when planning vaccination schedules. 
Summary of Changes 
Changes in the sections noted below will be enacted by this addendum. 
Contraception Exceptions 
Section 7.1.1, Acceptable Methods of Contraception, is modified as below: 
7.1.1. Acceptable Methods of Contraception  
Women of childbearing potential (WOCBP) and male participants with female partners of 
childbearing potential will be instructed to practice an acceptable method of birth control throughout 
the duration of the study and for 90 days following the end of study drug administration.  


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A woman is considered to be of childbearing potential following menarche and until becoming 
postmenopausal, unless she is permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause.  
Approved methods of contraception include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
− oral, intravaginal, or transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
− oral, injectable, or implantable 
• Intrauterine device 
• Intrauterine hormone releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner (provided that partner is the sole sexual partner of the WOCBP 
trial participant and that 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 participants with female 
partners of childbearing potential only) 
Not all methods of contraception may be available in all of the countries in which this study is 
being conducted. 
Note: Sexual abstinence is only accepted when it is the preferred and usual lifestyle of the participant. 
Vaccinations 
Vaccinations are discussed in multiple locations in the global protocol. The affected sections are 
modified as below: 
Study Design: Protocol Synopsis and Section 6.1.1 
Part 1: Screening Period; last bullet 
• Vaccinations against S pneumoniae, N meningitidis (types A, C, W, and Y, and B), 
and H influenzae (type B) are mandatory unless documented evidence exists that 
participants are nonresponders to vaccination. If required, vaccination series should 
be initiated at least 14 days prior to randomization. Vaccinations are discussed in 
more detail in Section 8.2. 


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Inclusion Criteria: Protocol Synopsis and Section 7.1 
Inclusion Criterion 8 
8. Have received vaccinations against S pneumoniae, N meningitidis (types A, C, W, and Y, 
and B), and H influenzae (type B) as per ACIP recommendations for adults or children 
with complement deficiencies. Vaccination series should be initiated at least 14 days 
prior to randomization. Vaccination is mandatory unless documented evidence exists that 
participants are nonresponders to vaccination.  
Vaccinations: Section 8.2 
8.2. Vaccinations 
To receive study drug, participants will be required to be vaccinated as follows on the basis of 
ACIP recommendations for adults or children with complement deficiencies (available at 
https://www.cdc.gov/vaccines/schedules/hcp/index.html) or other similar local guidelines.  
• N meningitidis types A, C, W, and Y: First dose at least 14 days prior to 
randomization with a second dose 2 months later, and then boosters every 5 years.  
• N meningitidis type B: First dose at least 14 days prior to randomization with a 
second dose after at least 1 month. First booster dose 1 year later, and then additional 
booster doses every 2 to 3 years. 
• S pneumoniae: pneumococcal conjugate vaccine (PCV13, PCV15, or PCV20, depending 
on participant age and vaccine availability) and/or pneumococcal polysaccharide vaccine 
23 (PPSV23). Adults who have not previously received any pneumococcal vaccine may 
receive PCV20, if the site is able to procure it, and a subsequent dose of PPSV23 would 
not be required. Multiple scenarios exist depending on previous vaccination history and 
investigators should consult ACIP guidelines for adults or children with complement 
deficiencies or other similar local guidelines. 
• H influenzae type B: Documentation of childhood vaccination or one dose at least 
14 days prior to randomization. 
Vaccination is mandatory, unless documented evidence exists that participants have received the 
recommended vaccinations or are nonresponders to vaccination. For participants who do not 
have this documented evidence, the required missing vaccination(s) will be administered as 
needed to bring participants up to date. The investigator will discuss with the medical monitor 
any individual participant circumstances relevant to the vaccination requirements that would 
make the above schedule not possible or reasonable, or if the investigator has any questions or 
concerns about the vaccination requirements. If local or national guidelines for immunizations 
differ from the ACIP recommendations, the differences should be discussed with the medical 
monitor to determine an appropriate course of vaccinations. On an ongoing basis, including upon 
entry into a long-term extension, participants should be reevaluated for the need for any 
additional vaccinations or boosters on the basis of ACIP recommendations.  
Vaccination serum samples will be collected on the day of vaccination before receiving vaccinations 
on that visit. These samples will be analyzed to evaluate response to vaccinations if the participant 
tests positive for infection with S pneumoniae, N meningitidis, or H influenzae.  


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Laboratory Assessments: Section 11.1.9 
Table 4: Laboratory Assessments, Footnote f 
f. 
Serum samples will be collected to evaluate response to vaccinations to N meningitidis 
(types A, C, W, and Y, and B), PCV13, PCV20, or PPSV23, and Hib. Samples will only 
be analyzed in the event that the participant has a positive infection for Streptococcus 
pneumoniae, Neisseria meningitidis, or Haemophilus influenzae. 
Switzerland 
Rationale for Modifications 
These modifications to the APL2-C3G-310 protocol are being implemented in Switzerland to 
support the Investigational Testing Authorization for the Crono Super PID infusion pump 
(version 2).  
Summary of Changes 
Changes in the sections noted below will be enacted by this addendum. 
Section 9.4, Infusion Supplies 
The sponsor will provide infusion supplies supply syringes, vial adapters, infusion sets, and 
ambulatory syringe infusion pumps, as required. Refer to the pharmacy manual for further details. 
This clinical study is a combined trial with medical devices. The Crono Super PID infusion 
pump (version 2) is an electromechanical, software-controlled, reusable infusion pump 
manufactured by CANÈ S.p.A. Medical Technology (Via Cuorgnè 42/a, 10098 RIVOLI - 
Cascine [TO] – Italy) that is supplied to the participant and used throughout the duration of the 
study. The CRN Crono 20 mL syringe reservoirs are sterile, nonpyrogenic, single-use syringes, 
specifically for use with Crono infusion pumps. Since the initiation of this clinical study, CANÈ 
S.p.A. Medical Technology has modified the intended use of the Crono Super PID infusion 
pump, and it is no longer licensed for administration of immunoglobulins and drugs in general, 
but only for the administration of immunoglobulins. Given this change, the use of the Crono 
Super PID infusion pump in this study is considered to be investigational.  
The infusion pump and syringe reservoirs will be used in conjunction with the Neria multi-infusion 
set (Unomedical Devices S.A de C.V, Aaholmvej 1-3, Osted, 4320 Lejre Denmark). And the vial 
adaptor (West Pharma. Services IL, Ltd., 4 Hasheizaf St., Ra'Anana, Israel, 4366411), which are 
conformité européenne (CE)-marked and approved for use in Switzerland. 
9.4.1 Investigational Medical Devices: Crono Super PID Infusion Pump and CRN Crono 
20 mL Syringe Reservoir 
9.4.1.1 Justification for the Use of the Investigational Medical Devices 
The Crono Super PID infusion pump was selected for use in this trial as it is the only available 
subcutaneous infusion pump that enables blinded administration of pegcetacoplan or the placebo 
used in this study by allowing the same delivery time despite their differing viscosities.  


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Apellis assessed the potential hazards associated with the delivery of the drug product in relation 
to the uses for which the pump carries a CE mark in the European Union. The hazards evaluated 
were related to the required Critical Performance Attributes, the user profile, and use 
environment relevant to use with the drug product in the clinical trial. This assessment included 
testing to confirm performance to the required delivery requirements and the delivery process 
and evaluation of the user population compared with those for which these devices are already 
CE-marked for use.  
The assessment concluded that the Crono Super PID infusion pump could meet the delivery 
requirements of Study APL2‑C3G‑310, does not present any unique usability issues to the user 
groups in Study APL2‑C3G‑310, and does not introduce any additional or residual risks. 
The use of the investigational devices in human participants is justified based on the design and 
intended uses of the device constituent parts (Crono Super PID infusion pump and CRN Crono 
20 mL syringe reservoir), which are appropriate. 
9.4.1.2 Risks of Investigational Medical Devices  
The use of this delivery system with this drug in this clinical trial does not create any risks 
additional to the residual risk inherent with the current use of these devices. There is a possibility 
that participants could experience redness, swelling, and pain or tenderness at the site of 
infusion. There is also a slight possibility of infection. In addition, as pegcetacoplan is to be 
administered by subcutaneous infusion, participants may feel some discomfort from the infusion. 
None of these risks are affected by the use of these specific devices.  
9.4.2 Reporting of Device Deficiencies and Adverse Events Related to Investigational 
Medical Devices  
All device deficiencies and serious adverse events where a relationship with the use of 
investigational medical devices cannot be ruled out must be reported to Apellis immediately, 
within 24 hours of the investigator or their representative becoming aware of the event. The site 
must complete the complaints form and email it to Complaints@Apellis.com immediately, 
within 24 hours of becoming aware of the event. 
The sponsor is responsible for submitting reports of device deficiencies and serious adverse 
events related to the use of investigational medical devices, as described in according to Art. 33 
para. 1 of the ClinO-MD, to SwissMedic and the device manufacturer within 72 hours of 
becoming aware of the issue. The device manufacturer will then further assess the incident per 
the timelines in the guidance and report their findings accordingly.  
9.4.2.1 Definitions for Reporting of Safety Events Related to Investigational Medical 
Devices  
For the purpose of reporting safety events related to investigational medical devices, 
the following definitions will apply: 
Investigational Device 
A device that is assessed in a clinical investigation.  


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Adverse Event 
Any untoward medical occurrence, unintended disease or injury, or any untoward clinical signs, 
including an abnormal laboratory finding, in participants, users or other persons, in the context of 
a clinical investigation, whether or not related to the investigational device. Note that this 
definition includes events that are anticipated as well as unanticipated events. This definition also 
includes events occurring in the context of a clinical investigation related to the investigational 
device, the comparator, or the procedures involved. 
Adverse Device Effect 
Any adverse event related to the use of an investigational medical device or a comparator. 
Anticipated Serious Adverse Device Effect 
Any serious adverse device effect which by its nature, incidence, severity, or outcome has been 
identified in the last risk assessment document upon serious adverse device effect occurred. 
Causality Assessment 
Safety events related to investigational medical devices should be classified as not related, possibly 
related, probably related, or definitely related to the use of the investigational medical device, 
according to the definitions in section 9 of the EU guidance (Safety Reporting in Clinical 
Investigations of Medical Devices Under the Regulatory [EU] 2017/745, MDCG2020-10/1, 2020). 
Device Deficiency 
Any inadequacy in the identity, quality, durability, reliability, safety, or performance of an 
investigational device, including malfunction, use errors, or inadequacy in information supplied 
by the manufacturer.  
Incident 
Any malfunction or deterioration in the characteristics or performance of a device made 
available on the market, including use-error due to ergonomic features, as well as any 
inadequacy in the information supplied by the manufacturer and any undesirable side-effect. 
Reportable Serious Adverse Device Effect 
Serious adverse event that is either possibly, probably, or definitely related to the use of the 
investigational medical devices. This includes relationship to the device or the procedure. 
Serious Adverse Device Effect 
Any adverse device effect that has resulted in any of the consequences characteristic of a serious 
adverse event. 


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Serious Incident 
Any incident that directly or indirectly led, might have led, or might lead to any of the following:  
• the death of a participant, user, or other person 
• the temporary or permanent serious deterioration of a participant’s, user’s, or other 
person's state of health 
• a serious public health threat 
 


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Appendix 3. 
COVID-19 Study Continuity Plan 
A.3.1. 
Protocol Changes to be Followed During COVID-19 Restrictions 
A.3.1.1. 
Overview 
As a response to the COVID-19 global public health emergency, Apellis will implement the 
measures outlined in this addendum to safeguard the rights, welfare, and safety of 
Study APL2‑C3G-310 participants and investigative site staff when and if deemed necessary. 
These measures are based on guidance issued by global regulatory health authorities regarding 
the impact of COVID-19 on the management of clinical trials and can only be implemented at 
each clinical investigative site after written approval from the sponsor. 
A.3.1.2. 
Minimum Study Requirements 
A.3.1.2.1. 
Safety Assessments 
When feasible, the full list of protocol assessments should be conducted; however, the following 
are the minimum study safety requirements for Study APL2‑C3G-310: 
1. Maintain dosing schedules and management per protocol guidelines 
2. Obtain key safety laboratory assessments: 
a. All laboratory assessments will be drawn at the frequency required by the minimized 
Schedule of Events (see Table A1), at a minimum. Collection of more than the 
minimum activities described in Table A1 should continue to the extent possible, 
and investigators should resume following the full schedule of activities as 
soon as possible.  
b. In the event that the clinical investigative site is closed and/or participants are 
unable or unwilling to travel, participants will be referred to a certified local 
laboratory that can perform the required safety testing specified in Table A1. 
Alternatively, a home health care provider may be sent to the participant’s home 
to draw samples for the minimum laboratory tests required for safety testing 
(see Section A.3.1.5), which may then be sent to the central laboratory or to a 
local laboratory. Use of the central laboratory is preferable whenever feasible. 
In the event that a local laboratory is used, the investigator will collect the local 
laboratory reports, which must be redacted in accordance with local privacy 
requirements. The laboratory results, reference ranges, units of measure, 
and format of laboratory values are to be filed with the study records. 
3. Perform minimal medical safety assessments: 
a. If the participant is unable to have an in-person assessment, the investigator 
(or delegated site staff) will have a telephone and/or video contact at the frequency 
noted in the protocol (at minimum) to solicit adverse events (including serious 
adverse events) and concomitant medications. The appropriate forms in the electronic 
case report form will be completed. 


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b. Serious adverse event reporting requirements are unchanged, and all serious 
adverse events are still required to be reported to Apellis within 24 hours of 
the investigator or their representative becoming aware of the event(s).  
4. Document appropriate contact with the participant: 
a. At least 3 documented attempts, including a certified letter with return receipt, 
must be made to solicit adverse events and concomitant medications before 
considering the visit missed. If contact with the participant still cannot be 
established for the following visit after another 3 documented attempts, 
participant is considered lost to follow-up. The clinical research associate and 
medical monitor must be notified of any participants lost to follow-up. 
b. All communication with the participant (including failed attempts at contact) 
must be documented in the study records. 
A.3.1.2.2. 
Efficacy Assessments 
The participants must be able to complete the following assessments to continue in the trial: 
• Renal biopsies during screening and at week 26 (adult participants only) 
• Triplicate first-morning urine collection during screening and at weeks 26 and 52 
• Serum chemistry and hematology during screening and at weeks 26 and 52 
A.3.1.3. 
Screening 
A.3.1.3.1. 
Study Screening 
A participant cannot be considered for screening using the minimum study requirements. 
The screening and baseline assessments must remain unchanged and must be completed in their 
entirety. The sponsor may decide to pause screening at any point because of the COVID-19 
pandemic, at which point sites will be notified and should not attempt to screen new participants. 
For sites continuing at full capacity (and not using the minimum study requirements), 
the investigator should assess and appropriately document the risk/benefit of participants 
continuing to come to the clinic for visits. These sites may continue to screen new participants 
using the protocol-outlined procedures.  
A.3.1.3.2. 
Institutional Screening for Public Health or Clinical Purposes 
A.3.1.3.2.1. 
Mandatory Clinical Screening Procedures 
According to local guidance, if an institution implements mandatory public health screening 
procedures related to a public health emergency (eg, COVID-19, measles, etc) for all individuals 
coming into that institution, inclusive of research participants, IRB approval is not required 
before screening procedures are implemented. Additionally, because these screening procedures 
are not research procedures, the institution does not require IRB approval to share results with a 
public health authority or research participants, although adherence to other permissions or 
notice restrictions remain under applicable law and/or policy (see Section A.3.1.12). 


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A.3.1.3.2.2. 
Excluded Public Health Surveillance Activities 
Some types of public health surveillance activities, including collection and testing of 
information or biospecimens, conducted, supported, requested, ordered, required, or authorized 
by a public health authority, may be conducted per local, regional, and national regulation and 
guidance as applicable (see Section A.3.1.12).  
If a public health authority authorizes general screening for COVID-19 for public health 
surveillance purposes and requests that test results be shared as necessary with a public health 
authority to allow the public health authority to identify, monitor, assess, or investigate the 
COVID-19 outbreak, an investigator may incorporate these activities into an existing research 
visit without prior IRB review and approval. 
Note, however, that US Food and Drug Administration regulations may apply if the screening 
procedure involves use of an investigational in vitro diagnostic device. 
A.3.1.4. 
Participants Testing Positive for COVID-19 
The following are considerations and changes that might need to be made for participants who 
test positive for COVID-19. 
If a research participant tests positive for COVID-19 
1. Follow the clinical recommendations of the study site and public health authorities to 
manage the infection. 
2. Follow the notification requirements of the study site and public health authorities. 
Investigators should inform the participant of the required reporting of 
results. Note: The results of the COVID-19 test should be recorded in the COVID-19 
electronic case report form and documented as an adverse event if the result is positive.  
3. Determine whether a positive test result meets criteria for withdrawal from the study, or for 
reporting as a serious adverse event by contacting the sponsor and notifying IRBs/ethics 
committees and/or health authorities as required per local guidelines. 
A.3.1.5. 
COVID-19 Vaccination 
In the absence of data, Apellis currently recommends that the decision to vaccinate study participants 
against COVID-19 should be made by the investigator and the participant, with consideration of 
local and national vaccination recommendations and a benefit-risk assessment. Vaccination is not 
mandatory for continued study participation. 
Apellis is currently not aware of any contraindications to vaccination (of any modality) 
and concurrent treatment with pegcetacoplan. Precaution should be taken when vaccinating 
participants with any concurrent illnesses that may affect the efficacy or safety of vaccination 
(eg, complement-activating condition) and as indicated by the labeled prescribing information.  
All vaccinations (including boosters) should be recorded as concomitant medications. 
The information should include the type of COVID-19 vaccination administered. Any untoward 
medical events related to vaccination should be captured in the participants source document and 
should include the timing in relation to the vaccine. Any questions should be directed to the medical 
monitor or study team. 


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A.3.1.6. 
Home Health Care Provider 
In the event that the clinical investigative site is closed and/or participants are unable or unwilling to 
travel, home health care providers (HHCPs) may be used to perform study activities, such as the 
below, with participants’ consent: 
• Blood draw 
• Investigational product administration 
• Investigational product accountability 
• Study assessments 
HHCPs will be required to follow all safety precautions set by the local guidance/regulations prior to 
and after contact with participant(s). HHCPs will summarize the activities completed, including any 
reported AEs, at the visit in a home visit report, which will be provided to the clinical investigative 
site for review and to file in the study records. 
A.3.1.7. 
Monitoring 
Remote monitoring measures may be implemented with participants’ consent in accordance with 
local and institutional guidelines. Methods to review and perform remote monitoring will be outlined 
in the sponsor’s clinical monitoring plan.  
A.3.1.8. 
Investigational Product 
To ensure that participants can continue treatment during the COVID-19 public health emergency 
and the associated changes with these clinical trials, additional study drug may need to be dispensed 
to participants or shipped to their homes. Additional dispensation of study drug and/or direct 
shipment of study drug to participants’ homes will only be implemented if permitted by local 
regulations, in conjunction with participant consent and corresponding ethics committee and 
competent authority approval, as required. Participants are to return all study drug to the investigator 
site once on-site visits are permitted to enable full study drug accountability.  
A.3.1.9. 
Regulatory Considerations 
Actions taken as a result of the COVID-19 public health emergency (protocol deviations, urgent 
safety measures, etc) that fall outside of standard clinical trial conduct guidance and regulations 
should be documented as appropriate in the study file. Ensure compliance with all local, regional, 
and national regulation and guidance, as applicable. 
A.3.1.10. Statistical Considerations 
In accordance with the local, regional, and national guidelines, the SAP for the study might need to 
be updated on the basis of the guidance provided by regulatory authorities related to the COVID-19 
public health emergency.  


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A.3.1.11. Schedule of Activities—Minimum Study Requirements 
For all screening visits, day 1, and week 26, the visits must occur in clinic, and all assessments on 
those days are required. Every effort should be made to conduct a full and in-person visit at week 52, 
but if COVID-19 restrictions make that impossible, the visit may be conducted virtually or by an 
HHCP after consultation with the medical monitor. The remainder of the required visits can be done 
virtually or by an HHCP, and for these visits, the required assessments are indicated. Visits and/or 
assessments not required as part of the minimum activities are shown in strikethrough text in 
Table A1. 
 






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Table A1: 
Revised COVID-19 Minimum Schedule of Activities 
Abbreviations: Ab = antibodies; ADA = antidrug antibodies; AE = adverse events; AH50 = 50% alternative hemolytic complement pathway activity; ANA = antinuclear antibodies; 
ANCA = antineutrophil cytoplasmic antibodies; β-HCG = beta human chorionic gonadotropin; CH50 = 50% classical hemolytic complement pathway activity; 
ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; EQ-5D-5L = 5-Level EuroQol-5 Dimension; FACIT-Fatigue = Functional Assessment of Chronic Illness 
Therapy- Fatigue Scale; FMU = first-morning spot urine; FSH = follicle-stimulating hormone; GFR = glomerular filtration rate; HIV = human immunodeficiency virus; 
HRQoL = health-related quality of life; KDQOL = Kidney Disease Quality of Life; N/A = not applicable; PGIC = Patient Global Impression of Change; PK = pharmacokinetic; 
SC = subcutaneous; SD-OCT = spectral domain optical coherence tomography; SPEP = serum protein electrophoresis; uPCR = urine protein-to-creatinine ratio; 
WPAI = Work Productivity and Activity Impairment. 
NOTE: When multiple assessments/procedures occur at the same visit, order should be: vital signs, ECGs, blood collection/sampling, study drug dosing.  
a) 
All visit 2 assessments need not occur in a single visit and visit 2 can be split into multiple visits (eg, visit 2a, visit 2b). 
b) 
Vaccinations, baseline renal biopsy, and screening chest radiography can occur any time during screening after confirmation of eligibility based on visit 1 data. 
c) 
For transplant participants only. Must be documented prior to randomization.  
d) 
Vaccine series should be initiated at least 14 days prior to randomization; additional vaccines may be required at visit 6. Please see Section 8.2 for more details on 
vaccination requirements. Vaccination serum samples will be collected on the day of vaccination prior to receiving vaccinations on that visit. These samples will be 
analyzed to evaluate response to vaccinations in the event that the participant has a positive infection for Streptococcus pneumoniae, Neisseria meningitidis, 
or Haemophilus influenzae.  
e) 
A full physical examination is required at visits 1, 3 (week 1), 10 (week 26), and 16 (week 52). A full physical examination should also be conducted on the first day of 
open-label dosing, if that not at the week 26 visit. Brief physical examinations, including weight (kg) and assessment of edema, will be conducted at all other visits noted. 
A symptom-driven physical examination may be performed at any time, at the investigator’s discretion. Body height (cm) will be measured only during screening for 
adults but will be measured at screening as well as every 12 weeks throughout the study for adolescents; weight (kg) will be measured throughout study, during brief and 
full physical examinations for all participants. Both body weight and height will be assessed without shoes on; height will be measured using a calibrated stadiometer. 
Edema should be assessed at every visit. 
f) 
Renal biopsies will not be required for participants under the age of 18, provided they have an adequate prior renal biopsy to establish the diagnosis as per the central 
pathology laboratory. 
g) 
The week 26 renal biopsy need not occur on the same day as all other assessments for that visit. However, the week 26 triplicate uPCR collections must occur prior to the 
renal biopsy. In addition, the week 26 biopsy must occur prior to the first visit of the open-label period at week 28. Participants younger than 18 years are not required to 
provide renal biopsies and may advance to the open-label period upon completion of all assessments for weeks 24 through 26 other than the renal biopsy. 
h) 
The week 52 renal biopsy is optional for all participants. If performed it should be after collection of the week 48 24-hour urine and FMU samples and not more than 
8 weeks after the week 52 visit, In the event that a participant has a renal biopsy as part of their clinical management within this window, it may serve as the week 52 
biopsy provided that it includes the required components for this study.  
i) 
Study drug will be self-administered by the participant or administered by their caregiver, after receiving appropriate training and sign-off by a research nurse (or other 
qualified personnel) in their first treatment week, as described in Section 9.5. Once qualified, the participant or caregiver should administer study drug at site visits 
(as done at home) on those days when a clinic visit occurs on a dosing day. In the event that a home nurse is administering study drug on nonvisit days, then the site staff 
may administer study drug on days of site visits. 
j) 
Between site visits, participants will be instructed to report any infusion site reaction to the study staff. Pump use safety will be reviewed by licensed health care 
professionals (ie, investigator or nurse) for each study drug administration at clinic visits and during at-home qualification.  
k) 
Vital signs should be measured a maximum of 2 hours before study drug infusion. On day 1 and on the first day of open-label dosing (week 26 or week 28, depending on 
whether a week 26 renal biopsy is required and when it is performed), vital signs should also be measured approximately 30 minutes to 1 hour after the first infusion of 
study drug dosing, timed from the completion of the study drug administration. Blood pressure and heart rate should be evaluated after the participant has been resting in 
a seated position for at least 5 minutes, except when they are supine or semireclined because of study procedures and/or AEs, or if deemed necessary by the investigator. 
l) 
FACIT-Fatigue, EQ-5D-5L, KDQOL, PGIC, and WPAI.  


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Table A1: 
Revised COVID-19 Minimum Schedule of Activities 
m) 
The screening 24-hour urine collection may be done any time between screening visit 1 and screening visit 2. After week 1 collections should be within ±1 week of the 
visit (except for the week 24 collection, which cannot be earlier than week 24). Courier arrangements can be made to pick up the collection container from the 
participant, or the participant may return the container directly to the site. 
n) 
Triplicate FMU samples will be collected by the participant at home on 3 consecutive days throughout the duration of the study. These should be the first urinary output 
of the day. An additional triplicate FMU uPCR sample will be collected at week 25. Samples should be collected within ±1 week of the clinic visit (except for weeks 24 
through 26, when sample collection should be within ±3 days of the clinic visit). Courier arrangements can be made by the site to pick up the collection containers from 
the participants, or the participant may return them directly to the site. At every visit, enough uPCR collection containers need to be dispensed to the participant to enable 
all at-home uPCR collections until the next clinic visit. 
o) 
The day 1 triplicate FMU uPCR samples should be collected before the first dose of study drug (eg, day –2, day –1, and before dosing on day 1). 
p) 
Serum complement profile includes AH50, CH50, and C3NeF; C3NeF will only be assayed in samples collected at the baseline (screening) visits. Plasma complement 
profile includes C3a, C3b/iC3b, C5a, and sC5b-9. See laboratory assessments (Table 4) for more details. 
q) 
The day 1 samples should be collected before dosing with study drug. Participants who discontinue dosing will have ADA samples collected at 2 and 8 weeks after the 
last treatment. Participants who have a treatment-emergent or treatment-boosted antidrug antibody response at any time will have ADA samples collected approximately 
every 6 months until the antibody levels revert to baseline. 
r) 
eGFR will be calculated using the Chronic Kidney Disease–Epidemiology Collaboration creatinine equation for adults or the Bedside Schwartz equation for adolescents. 
For each participant, eGFR will be calculated using the same formula for the duration of the study; the choice of formula will be determined by the participant’s age at 
study entry.  
s) 
Serum FSH (to be measured in female participants only), hepatitis B panel, hepatitis C panel, HIV antibodies, SPEP (adult participants only), ANA, and ANCA 
(see Table 4 and laboratory manual for more details). 
t) 
Ophthalmologic evaluations are optional and will be performed at selected sites. If evaluations are performed, each participants should have a baseline ophthalmologic 
evaluation, including a basic ophthalmologic examination, SD-OCT, and color fundus photography, at an approved ophthalmologic clinical site at any time during the 
screening period. For participants with drusen prior to pegcetacoplan administration, a follow-up ophthalmologic evaluation, including an SD-OCT and color fundus 
photography, should occur at a convenient time between weeks 42 and 52. 
u) 
Measured GFR is an optional assessment that, if performed, should occur at 3 time points: once on day 1 or within 10 weeks before day 1, again at week 26, and a third 
time between week 42 and week 52, inclusive. Measured GFR should only be done at sites where it is routinely performed, as per the site’s standard protocol. 
 


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A.3.1.12. Regulatory Guidances  
European Medicines Agency. Guidance on the management of clinical trials during the COVID-19 
(Coronavirus) pandemic. Published 28 April 2020. Accessed 24 August 2020. 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/
guidanceclinicaltrials_covid19_en.pdf 
Food and Drug Administration, US Department of Health and Human Services. 
Statistical considerations for clinical trials during the COVID-19 public health emergency: 
guidance for industry. Published 16 June 2020.  
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/statistical-
considerations-clinical-trials-during-covid-19-public-health-emergency-guidance-industry 
Office for Human Research Protections, US Department of Health and Human Services. 
OHRP guidance on coronavirus. Published 2020. Updated 08 April 2020. Accessed 24 June 2020. 
https://www.hhs.gov/ohrp/regulations-and-policy/guidance/ohrp-guidance-on-covid-19/index.html 
Office for Human Research Protections, US Department of Health and Human Services. 
Unanticipated problems involving risks & adverse events guidance. Published 2007. 
Updated 21 March 2016. Accessed 24 June 2020.  
https://www.hhs.gov/ohrp/regulations-and-policy/guidance/reviewing-unanticipated-
problems/index.html 

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Pegcetacoplan (APL-2) 
APL2-C3G-310 Statistical Analysis Plan Version 2.0 
27 June 2024 
Table 3: 
Criteria for Potentially Clinically Significant Vital Signs 
VS parameter 
Criteria 
HR 
100 BPM 
<40 BPM 
SBP 
130 mm Hg  
160 mm Hg 
180 mm Hg 
 
<90 mm Hg  
20 mm Hg decrease from baseline 
DBP 
90 mm Hg 
15 mm Hg increase from baseline 
<40 mm Hg  
15 mm Hg decrease from baseline 
Temp 
 
All vital sign values and change from baseline values will be listed. In the listing, potentially 
clinically significant vital sign values will be flagged. 
7.4. 
Electrocardiogram (ECG) 
Observed and change from baseline in ECGs (heart rate, PR interval, QRS duration, QT interval, 
and QTc interval which is corrected by Fridericia’s method) will be summarized by treatment 
group and overall at each analysis visit. 
Additionally, the number and percentage of participants with post-baseline potentially clinically 
significant (PCS) ECG values will be tabulated. ECGs are potentially clinically significant 
(PCS) if they meet the PCS criteria listed in the table below: 
Table 4: 
Criteria for Potentially Clinically Significant ECGs 
ECG parameter 
Criteria 
HR 
<40 bpm 
100 bpm 
PR 
200 msec 
QRS 
120 msec 
QTcF 
 
 
0 msec 
QTcF increase from baseline 
30 msec 
60 msec 
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J R Stat Soc B
Analysis of Longitudinal Data
J Am Stat Assoc
J Stat Comput Simul.
J Multivar Anal.
Clinical Trials with Missing Data: A Guide for Practitioners
J Am Soc Nephrol
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* The SAS codes in this section are shown as examples 
* Some modifications (such as variables used in the model statement) 
* may require further changes to reflect the methods specified in the 
* SAP and analysis data structure 
 
*---------------------------------------------------- 
* Read Analysis data 
*---------------------------------------------------- 
* In this example, repeated measures are available at 
* avisitn = 0 (baseline), 4 (Week 4), 8 (Week 8), 12 (Week 12), 16 (Week 16), 
*   20 (Week 20), 24 (Week 24), 25 (Week 25), and 26 (Week 26) 
*----------------------------------------------------; 
 
data upcr; 
 set adam.adeff; 
 if paramcd = 'LNUPRCRF' and basetype = 'NORMAL' and 
 avisitn in (0, 4, 8, 12, 16, 20, 24, 25, 26) and  
 ANL01FL = 'Y'; 
 
 * avisitc will be used in PROC TRANSPOSE;            
 if avisitn = 0 then avisitc = '00'; * Baseline; 
 if avisitn = 4 then avisitc = '04'; * Week 4; 
 if avisitn = 8 then avisitc = '08'; * Week 8; 
 if avisitn = 12 then avisitc = '12'; * Week 12; 
 if avisitn = 16 then avisitc = '16'; * Week 16; 
 if avisitn = 20 then avisitc = '20'; * Week 20; 
 if avisitn = 24 then avisitc = '24'; * Week 24; 
 if avisitn = 25 then avisitc = '25'; * Week 25; 
 if avisitn = 26 then avisitc = '26'; * Week 26; 
run; 
 
********************************; 
*** ANALYSIS using MMRM assuming MAR (e.g., Section 6.4.2(1) )***; 
********************************; 
 
proc sql; 
 
select avg(base) into: abs 
 
from upcr_t; * upcr_t is the upcr dataset but in long format; 
run; 
 
%put abs=&abs;   * this will be used for the “estimate” statement, similarly 
to obtain the empirical weight for each stratification factor and disease 
type and baseline immune use, namely stra1_wt, stra1_wt_rev, stra2_wt, 
stra2_wt_rev, distype_wt, distype_wt_rev, immunobl_wt, immunobl_wt_rev to be 
used in next procedure; 
 
 
proc mixed data=upcr method=reml covtest empirical; 
where avisitn NE 0; * exclude rows for baseline; 
* stra1 (stratification factor 1) 
* 0 = post-transplant recurrence 
* 1 = non-transplant 
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* stra2 (stratification factor 2) 
* 0 = Without Baseline Renal Biopsy 
* 1 = With Baseline Renal Biopsy 
* distype (disease type) 
* 0 = IC-MPGN 
* 1 = C3G 
* immunobl (baseline immunosuppressants use) 
* 0 = No 
* 1 = Yes 
class trtpn avisitn usubjid stra1 stra2 distype; 
model chg = trtpn stra1 stra2 distype immunobl avisitn trtpn*avisitn 
base/cl; 
  repeated avisitn / subject=usubjid type=un r; 
  lsmeans trtpn*avisitn/pdiff cl e om alpha=.05; 
  ods output diffs= diff1 LSMeans= LSMean1; 
 
estimate 'PEG Week 24-25-26 Avg LSMean' intercept 1 stra1 &stra1_wt_rev 
&stra1_wt stra2 &stra2_wt_rev &stra2_wt distype &distype_wt_rev 
&distype_wt immunobl &immunobl_wt_rev &immunobl_wt trtpn 1 0  
BASE &abs   
avisitn 0 0 0 0 0 0.333 0.333 0.334  
trtpn*avisitn 0 0 0 0 0 0.333 0.333 0.334  
               0 0 0 0 0 0 0 0 /cl ; 
estimate 'PEG vs PBO Difference Week 24-25-26 Avg' trtpn 1 -1  
trtpn*avisitn 0 0 0 0 0 0.333 0.333 0.334 
               0 0 0 0 0 -0.333 -0.333 -0.334 /cl ; 
ods output estimates = est; 
run; 
 
data lsmeans1; 
 set lsmeans; 
 geo_estimate = exp(estimate);    * = LS Geometric mean; 
 geo lower = exp(lower);          * = lower bound of the 95%CI for the 
LS Geometric mean; 
 geo upper = exp(upper);          * = upper bound of the 95%CI for the 
LS Geometric mean; 
run; 
 
data diffs1; 
 set diffs; 
 geo_estimate = exp(estimate);    * = LS Geometric mean ratio; 
 geo lower = exp(lower);          * = lower bound of the 95%CI for the 
LS Geometric mean ratio; 
 geo upper = exp(upper);          * = upper bound of the 95%CI for the 
LS Geometric mean ratio; 
run; 
 
data est1; 
 set est; 
 geo_estimate = exp(estimate);    * for composite results; 
 geo_lower = exp(lower);           
 geo_upper = exp(upper);           
run; 
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********************************; 
*** MAIN ANALYSIS (e.g., Section 6.4.1 )***; 
********************************; 
 
********************************; 
*** RESHAPE DATA FOR PROC MI ***; 
********************************; 
 
proc sort data= upcr; 
 by usubjid stra1 stra2 distype immunobl trtpn base avisitc;  
run; 
 
proc transpose data= upcr out= upcr_t(drop= _NAME_ _LABEL_) prefix=V; 
 by usubjid stra1 stra2 distype immunobl trtpn base;  
 id avisitc; 
 var aval; 
run; 
 
* Examine the missing patterns of the data; 
proc mi data=upcr_t nimpute=0;  
 var stra1 stra2 distype immunobl trtpn v00 – v26;  
 ods output missPattern=pattern;  
run; 
 
*****************************************; 
*** MCMC (impute nonmonotone missing) ***; 
*****************************************; 
 
* Below statements invoke MCMC procedure and specify IMPUTE=MONOTONE  
 to turn the arbitrary missing patterns to monotone missing patterns 
 under missing at random (MAR) assumption;  
 
proc mi data=upcr_t out=upcr_t_mono seed= 
 nimpute=100;  
 mcmc chain=multiple impute= monotone disp
t 
     initial=em(itprint);  
 var stra1 stra2 distype immunobl trtpn v00 – v26;  
run; 
 
* Examine the missing patterns of the data; 
proc mi data=upcr_t_mono nimpute=0;  
 var stra1 stra2 distype immunobl trtpn v00 – v26;  
 ods output missPattern=pattern;  
run; 
 
********************************************************************; 
*** Control-based pattern imputation(impute monotone missing) ***; 
********************************************************************; 
data upcr_t_mono2; 
 
set upcr_t_mono; 
 
**Identify the subjects in the active groups we want to keep  
  imputed as MAR; 
 
if ICEDT1>. or ICEDT2>. or ICEDT3>. then MAR = 'N'; 
 
else MAR = 'Y'; 
 
if trt01 = 2 then MAR = 'N'; 
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run; 
 
**First impute general MAR based on regression method for all subjects to get 
the true MAR; 
proc mi data=upcr_t_mono2 out=upcr_step1 nimpute=1 seed=
; 
 by _Imputation_; 
 class trtpn; 
 monotone reg(v00 – v26/details); 
 var stra1 stra2 distype immunobl trtpn v00 – v26;  
run; 
 
**Identify and keep the data from the subjects in the active group that 
should remain as a MAR; 
data upcr_step2; 
 
set upcr_step1; 
 
if Mar = "Y"; 
 
run; 
 
**Update the dataset and keep the MAR imputed data for the subjects in the 
active group that should remain as a MAR, all others remain to be imputed 
with control based imputation; 
data upcr_t_mono3; 
 
update upcr_t_mono2 upcr_step2; 
 
by _Imputation_ subjid; 
 
run; 
 
**Fill out the remaining missing where missing data should be imputed based 
on the controls; 
proc mi data=upcr_t_mono3 out=upcr_t_cbp nimpute=1 seed=
;  
 by _imputation_;  
 class trtpn;  
 var stra1 stra2 distype immunobl v00 – v26;  
 monotone reg(/details);  
 mnar model(v04 – v26 / modelobs= (trtpn='2'));  
run; 
 
**if there are ICEs of renal transplant/dialysis (ICEDT2>.) then need to 
impute based on worst change; 
 
** first, transpose the above upcr_t_cbp back to long format upcr_cbp(omit 
the details), then, collect details on worst percentage across all visits 
based on original data (e.g., name the variable as worstpchg), also, identify 
for those subjects who had ICEDT2>., their first visit that should be imputed 
based on worst percent change (e.g., name the variable as startavisit), plus, 
for all 100 imputations, calculate the average log(uPCR) for each avisit 
(e.g., name the variable as visit_avg), then; 
 
data upcr_cbp_worst; 
 
merge upcr_cbp worstpchg startavisit visit_avg; 
 
by subjid; 
 
if avisitn>startavisit>. then aval = base*(1+ worstpchg/100) + (aval-
visit_avg); 
 
**Note, the “base*(1+ worstpchg/100)” part is worst change, the “(aval-
visit_avg)” is random error; 
 
run; 
  
** lastly, transpose it back to the wide format; 
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proc transpose data= upcr_cbp_worst out= upcr_t_cbp_worst (drop= _NAME_ 
_LABEL_) prefix=V; 
 by usubjid stra1 stra2 distype immunobl trtpn base;  
 id avisitc; 
 var aval; 
run; 
 
 
 
********************************************************************; 
*** Delta-Adjusted Pattern Imputation (tipping point analysis) ***; 
********************************************************************; 
**First identify the subjects in the active treatment groups that we want to 
apply the shift parameter if they have monotone missing data; 
data upcr_t_mono2; 
 
set upcr_t_mono; 
 
 
**ICEDT1=. is just an example of a reason that we do not want to  
  apply the shift parameter. The actual reasons are in the text; 
 
if ICEDT1=. then flag = 1; 
 
else flag = 0; 
 
 
 
if trtpn = 1 and flag = 0 then adjustthis = 1; 
 
else adjustthis = 0; 
run; 
 
proc mi data=upcr_t_mono2 out=upcr_t_tip nimpute=1 seed=
;  
 by _imputation_;  
 class trtpn adjustthis;  
 var stra1 stra2 distype immunobl trtpn v00 -- v12;  
 monotone reg(/details); 
 mnar adjust(v04 / shift=0.04 adjustobs=(adjustthis = '1' )) 
  adjust(v08 / shift=0.04 adjustobs=(adjustthis = '1' )) 
  adjust(v12 / shift=0.04 adjustobs=(adjustthis = '1' )) 
  adjust(v16 / shift=0.04 adjustobs=(adjustthis = '1' )) 
  adjust(v20 / shift=0.04 adjustobs=(adjustthis = '1' )) 
  adjust(v24 / shift=0.04 adjustobs=(adjustthis = '1' )) 
  adjust(v25 / shift=0.01 adjustobs=(adjustthis = '1' )) 
  adjust(v26 / shift=0.01 adjustobs=(adjustthis = '1' ));  
run; 
 
 
 
 
*****************************************************; 
*** SAS macro to run MIANALYZE on outputs from MMRM *; 
*****************************************************; 
 
%macro mi_results(in, lsm, dif); ** Note this macro is for individual visits 
such as W4, W8,…,W24,W25,W26, see next macro for composite contrast of W24-
W25-W26 average; 
 
 
proc transpose data= &in  
    out= upcr_mi (rename= (_NAME_ = AVISITN COL1 = AVAL)); 
 by _imputation_ usubjid trtpn base stra1 stra2 distype immunobl; 
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 var V00 – V26; 
run; 
 
data upcr_mi; 
 set upcr_mi; 
 label AVISITN = 'AVISITN'; 
chg = aval - base; 
* baseline record is not used in MMRM; 
 if AVISITN = 'V00' then delete;  
run; 
 
proc sort; by _imputation_; run; 
 
proc mixed data=upcr_mi method=reml covtest empirical; 
 by _imputation_; 
 class trtpn avisitn usubjid stra1 stra2 distype immunobl; 
 model chg=trtpn stra1 stra2 distype immunobl avisitn trtpn*avisitn base /cl; 
 repeated avisitn / subject=usubjid type=UN; 
 lsmeans trtpn*avisitn / pdiff cl om alpha=.05; 
 ods output diffs= diffs lsmeans= lsmeans; 
run; 
 
* In the final step, the analysis results obtained from PROC MIXED 
procedure are combined into a single estimation with standard error 
using PROC MIANALYZE; 
 
proc sort data=lsmeans; 
 by avisitn trtpn _imputation_; 
run; 
proc mianalyze parms=lsmeans;  
 by avisitn trtpn; 
 modeleffects trtpn*avisitn;  
 ods output ParameterEstimates=&lsm;  
run; 
 
proc sort data=diffs (where= (_trtpn= 2 and (avisitn = _avisitn))); 
 by avisitn trtpn _trtpn _imputation_; 
run; 
 
proc mianalyze parms=diffs;  
 by avisitn trtpn _trtpn;  
 modeleffects trtpn*avisitn;  
 ods output ParameterEstimates=&dif;  
run; 
 
proc sql; *** LSMEANS using Multiple Imputation; 
select Parm as Effect, AVISITN, TRTPN, Estimate, StdErr, DF,  
  tValue, Probt, LCLMean as L95, UCLMean as U95 
 from &lsm; 
 
select Parm as Effect, AVISITN, TRTPN, _TRTPN, Estimate, StdErr, DF, 
  tValue, Probt, LCLMean as L95, UCLMean as U95 
 from &dif; 
quit; 
%mend; 
 
%mi_results(in= upcr_t_cbp, lsm= lsm_cbp, dif=dif_cbp ); 
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%mi_results(in= upcr_t_cbp_worst, lsm= lsm_cbp, dif=dif_cbp ); 
 
 
%macro mi_results(in, lsm, dif); ** Note this macro is for composite contrast 
of W24-W25-W26 average; 
 
proc sql; 
 
select avg(base) into: abs 
 
from &in 
 
group by _imputation_; 
run; 
%put abs=&abs;   * this will be used for the “estimate” statement, similarly 
to obtain the empirical weight for each stratification factor and disease 
type, namely stra1_wt, stra1_wt_rev, stra2_wt, stra2_wt_rev, distype_wt, 
distype_wt_rev, immunobl_wt, immunobl_wt_rev to be used in next procedure; 
 
 
proc transpose data= &in  
    out= upcr_mi (rename= (_NAME_ = AVISITN COL1 = AVAL)); 
 by _imputation_ usubjid trtpn base stra1 stra2 distype immunobl; 
 var V00 – V26; 
run; 
 
data upcr_mi; 
 set upcr_mi; 
 label AVISITN = 'AVISITN'; 
chg = aval - base; 
* baseline record is not used in MMRM; 
 if AVISITN = 'V00' then delete;  
run; 
 
proc sort; by _imputation_; run; 
 
proc mixed data=upcr_mi method=reml covtest empirical; 
 by _imputation_; 
 class trtpn avisitn usubjid stra1 stra2 distype immunobl; 
 model chg=trtpn stra1 stra2 distype immunobl avisitn trtpn*avisitn base /cl; 
 repeated avisitn / subject=usubjid type=UN; 
 lsmeans trtpn*avisitn / pdiff cl alpha=.05 om; 
estimate 'PEG Week 24-25-26 Avg LSMean' intercept 1 stra1 &stra1_wt_rev 
&stra1_wt stra2 &stra2_wt_rev &stra2_wt distype &distype_wt_rev &distype_wt 
immunobl & immunobl_wt_rev & immunobl_wt trtpn 1 0  
BASE &abs 
avisitn 0 0 0 0 0 0.333 0.333 0.334  
trtpn*avisitn 0 0 0 0 0 0.333 0.333 0.334  
               0 0 0 0 0 0 0 0 /cl ; 
estimate 'PEG vs PBO Difference Week 24-25-26 Avg' trtpn 1 -1  
trtpn*avisitn 0 0 0 0 0 0.333 0.333 0.334 
               0 0 0 0 0 -0.333 -0.333 -0.334 /cl ; 
  ods output estimates = est; 
run; 
 
proc mianalyze data=est(where=(label='PEG Week 24-25-26 Avg LSMean'));  
  modeleffects estimate; 
  stderr stderr;  
  ods output ParameterEstimates=&lsm;  
run; 
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proc mianalyze data=est(where=(label='PEG vs PBO Difference Week 24-25-26 
Avg'));  
  modeleffects estimate; 
  stderr stderr;  
  ods output ParameterEstimates=&dif;  
run; 
 
proc sql; *** LSMEANS using Multiple Imputation; 
  select Parm as Effect, Estimate, StdErr, DF,  
       tValue, Probt, LCLMean as L95, UCLMean as U95 
    from &lsm; 
 
  select Parm as Effect,  Estimate, StdErr, DF, 
       tValue, Probt, LCLMean as L95, UCLMean as U95 
    from &dif; 
quit; 
%mend; 
 
%mi_results(in= upcr_t_cbp, lsm= lsm_cbp, dif=dif_cbp ); 
%mi_results(in= upcr_t_cbp_worst, lsm= lsm_cbp, dif=dif_cbp ); 
 
 
 
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********************************; 
*** Rate of Change analyses ***;  
 
* In this example, repeated measures are available at 
* avisitn = 0 (baseline), 4 (Week 4), 8 (Week 8), 12 (Week 12) 
*   16 (Week 16), 20 (Week 20), 24 (Week 24), 25 (Week 25) and 26 (Week 26) 
* 
* AVAL is the actual average of triplicate FMU uPCR at the corresponding 
visit. 
* t is equivalent to AVISITN 
* 
* The data is read in from the control base imputation upcr_t_cbp, then 
calling another macro to generate the “Week 0 to 26” slope for each arm as 
well as the difference in slope between two arms 
********************************; 
 
********************************; 
*This is the example if not based on multiple imputation  
********************************; 
 
proc mixed data=upcr method=reml covtest empirical; 
 
class subjid trtpn stra1 stra2 distype immunobl t; 
 
model aval = trtpn stra1 stra2 distype immunobl avisitn trtpn*avisitn  
/cl solution; 
  
repeated t /type=un sub=subjid r ; 
 
 
**Week 0 to 26; 
  estimate 'PEG Week 0 to 26 slope' trtpn*avisitn 26 0   avisitn 26 /cl; 
  estimate 'PBO Week 0 to 26 slope' trtpn*avisitn 0 26   avisitn 26 /cl; 
 
  estimate 'Week 0 to Week 26 Difference in slope PEG - PBO'   trtpn*avisitn 
26 -26 /cl; 
run; 
 
 
*****************************************************; 
*** SAS macro to run MIANALYZE on outputs from multiple imputation dataset *; 
*****************************************************; 
 
%macro mi_results(in, lsm, dif);  
 
proc transpose data= &in  
    out= upcr_mi (rename= (_NAME_ = AVISITN COL1 = AVAL)); 
 by _imputation_ usubjid trtpn base stra1 stra2 distype immunobl; 
 var V00 – V26; 
run; 
 
data upcr_mi; 
  set upcr_mi; 
  label AVISITN = 'AVISITN'; 
 if avisitn = 'W00' then t = 0; 
 else if avisitn = 'W04' then t = 4; 
 else if avisitn = 'W08' then t = 8; 
 else if avisitn = 'W12' then t = 12; 
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 else if avisitn = 'W16' then t = 16; 
 else if avisitn = 'W20' then t = 20; 
 else if avisitn = 'W24' then t = 24; 
 else if avisitn = 'W25' then t = 25; 
 else if avisitn = 'W26' then t = 26; 
  drop avisitn base; 
run; 
 
data upcr_mi; 
 set upcr_mi; 
 avisitn = t; 
run; 
 
proc sort; by _imputation_; run; 
 
proc mixed data=upcr_mi method=reml covtest empirical; 
 by _imputation_; 
 class trtpn usubjid stra1 stra2 distype immunobl t; 
 model aval=trtpn stra1 stra2 distype immunobl avisitn trtpn*avisitn /cl; 
 repeated t / subject=usubjid type=UN r; 
 
  **Week 0 to 26; 
  estimate 'PEG Week 0 to 26 slope' trtpn*avisitn 26 0   avisitn 26 /cl; 
  estimate 'PBO Week 0 to 26 slope' trtpn *avisitn 0 26   avisitn 26 /cl; 
 
  estimate 'Week 0 to 26 Difference in slope PEG - PBO'   trtpn *avisitn 26 -
26 /cl; 
 
ods output estimates = est; 
run; 
 
 
proc mianalyze data=est(where=(label='PEG Week 0 to 26 slope')); * change 
label for the other estimate; 
  modeleffects estimate; 
  stderr stderr;  
  ods output ParameterEstimates=&lsm;  
run; 
 
proc mianalyze data=est(where=(label='Week 0 to 26 Difference in slope PEG - 
PBO'));  
  modeleffects estimate; 
  stderr stderr;  
  ods output ParameterEstimates=&dif;  
run; 
 
proc sql; 
select Parm as Effect, Estimate, StdErr, DF,  
       tValue, Probt, LCLMean as L95, UCLMean as U95 
    from &lsm; 
 
select Parm as Effect,  Estimate, StdErr, DF, 
       tValue, Probt, LCLMean as L95, UCLMean as U95 
    from &dif; 
quit; 
%mend; 
 
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%mi_results(in= upcr_t_cbp, lsm= lsm_cbp, dif=dif_cbp ); 
%mi_results(in= upcr_t_cbp_worst, lsm= lsm_cbp, dif=dif_cbp ); 
 
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*---------------------------------------------------- 
* logistic regression, take example of FMU uPCR of at least 50% reduction 
from baseline 
*---------------------------------------------------- 
 
* first select out the binary variable of the endpoint (avalc) 
data upcr50; 
 set ADAM.ADEFF; 
 if paramcd = 'UPRTRD50'; 
 if ittfl='Y'; 
 if avisit = 'Week 26'; 
 if anl01fl='Y'; 
 keep subjid trt01p aval avalc param paramcd stragr1 stragr2p 
disesbio; 
run; 
 
 
* then obtain the baseline variable (log-transformation) FMU uPCR value 
data fmuupcr; 
 set adam.adeff; 
 if paramcd='LNUPRCRF'; 
 if ittfl='Y'; 
 if basetype='NORMAL'; 
 if avisit='Baseline'; 
 logbase = aval; 
 keep subjid logbase; 
run; 
 
* then merge together to obtain all necessary variables 
data upcr50; 
 merge upcr50 fmuupcr; 
 by subjid; 
run; 
 
proc sort data=upcr50; by trt01p;run; 
 
** Descriptive summary of the data; 
proc freq data=upcr50; 
  by trt01p; 
  tables avalc/nocol nopercent nocum; 
run; 
 
 
** logistic regression that produces Proportion (SE), CI, odd ratio 
and CI, and p-value; 
proc logistic data=upcr50; 
 class trt01p(ref='Placebo') stragr1 stragr2p disesbio/param=glm; 
 model avalc(event='Y') = trt01p logbase stragr1 stragr2p disesbio / 
clodds=wald orpvalue; 
 oddsratio trt01p; 
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 lsmeans trt01p / ilink e cl; 
 store LogFit; 
 ods output coef=Coeffs; 
run; 
 
** calling macro to produce difference in proportion and CI of it; 
%NLMeans(instore=LogFit, coef=Coeffs, link=logit, title=Differences of 
Proportion) 
 
 
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*---------------------------------------------------- 
* Read Analysis data 
*---------------------------------------------------- 
* Example used here is the key secondary endpoint of activity score of the 
C3G Histologic Index at Week 26. 
* Note the main analysis should be performed based on multiple imputation 
dataset with ICE addressed (see sample code under 1.2.2), here is only an 
illustration of the key code using data without the multiple imputation. 
*----------------------------------------------------; 
 
data activity; 
 set ADAM.ADMI; 
 if paramcd = 'C3HISACT'; 
 if ittfl='Y'; 
 if avisit = 'Week 26'; 
 if anl01fl='Y'; 
 keep usubjid trt01p chg base stragr1 stragr2p disesbio; 
run; 
 
 
proc mixed data=activity; 
 by <subgroup>; *note: to add this line if for subgroup analysis; 
 class trt01p disesbio stragr1 stragr2p; 
 model chg = trt01p base disesbio stragr1 stragr2p; 
 lsmeans trt01p /om cl pdiff; 
run; 
 
 
 
proc lifetest data=adtte; 
 time aval*cnsr(1); 
 strata stragr1 stragr2p disesbio / group=trt01p; 
run; 
proc phreg data=adtte; 
 class trt01p/ param=reference ref=last; 
 model aval*cnsr(1) = trt01p loguPCR_BL eGFR_BL/rl ties=efron; 
 strata stragr1 stragr2p disesbio; 
run; 
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Apellis Pharmaceuticals, Inc
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Apellis Pharmaceuticals, Inc
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Apellis Pharmaceuticals, Inc
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Apellis Pharmaceuticals, Inc
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Apellis Pharmaceuticals, Inc
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Apellis Pharmaceuticals, Inc
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Apellis Pharmaceuticals, Inc
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Apellis Pharmaceuticals, Inc
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Apellis Pharmaceuticals, Inc
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Apellis Pharmaceuticals, Inc
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Apellis Pharmaceuticals, Inc
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Apellis Pharmaceuticals, Inc
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Apellis Pharmaceuticals, Inc
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Apellis Pharmaceuticals, Inc
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Apellis Pharmaceuticals, Inc
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Apellis Pharmaceuticals, Inc
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Apellis Pharmaceuticals, Inc
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Apellis Pharmaceuticals, Inc
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Apellis Pharmaceuticals, Inc
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Apellis Pharmaceuticals, Inc
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Apellis Pharmaceuticals, Inc
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Stat Med
Stat Med
Apellis Pharmaceuticals, Inc
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Apellis Pharmaceuticals, Inc
Page 116 of 116
Confidential