Clinical trial NCT03459443
Conditions: C3 Glomerulonephritis C3 Glomerulopathy Immune Complex Membranoproliferative Glomerulonephritis IC-MPGN Dense Deposit Disease
Keywords: factor D fD alternative pathway complement mediated disease C3GN DDD idiopathic MPGN MPGN Type I MPGN Type II MPGN Type III Primary MPGN MCGN Mesangiocapillary Glomerulonephritis
Sponsor: Alexion Pharmaceuticals, Inc.
Start date: 2018-06-20; Completion date: 2021-03-29
Enrollment: 22 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary purpose of this study was to evaluate the efficacy of 12 months of oral ACH-0144471 (also known as danicopan and ALXN2040) in participants with C3G or IC-MPGN based on histologic scoring and proteinuria.

Detailed description:
This was an open-label study to evaluate the efficacy of treatment with danicopan in participants 12 years of age or older with biopsy-confirmed C3G or IC-MPGN who had not undergone renal transplantation. All participants were to receive active treatment with danicopan for approximately 40 months. The starting dosage was to be 100 mg TID, and after 2 weeks, the dosage was to be increased to 200 mg TID for participants with body weight ≥ 60 kg or 150 mg TID for participants with body weight \< 60 kg. Planned enrollment was approximately 20 participants.

Arms: arm 1: Danicopan was to be administered to participants with C3G or IC-MPGN at a starting dose of 100 milligrams (mg) 3 times daily (TID) for the first 2 weeks, then the dosage was to be increased to 200 mg TID for the remainder of the study.
Interventions: intervention 1: Danicopan
Intervention descriptions: intervention 1: Danicopan was to be administered as an oral tablet.

Protocol documents:
SAP_002.pdf: 
An Open-Label Phase 2 Proof-of-Concept Study in Patients 
with C3 Glomerulopathy (C3G) or Immune-Complex 
Membranoproliferative Glomerulonephritis (IC-MPGN) 
Treated with ACH-0144471 
Unique Protocol ID: 
NCT Number: 
EudraCT Number:  
Date of SAP:  
ACH471-205 
NCT03459443 
2017-002674-39 
30 October 2020 


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STATISTICAL ANALYSIS PLAN 
 
 
 
PROTOCOL NUMBER: ACH471-205 
 
 
AN OPEN-LABEL, PHASE 2, PROOF-OF-CONCEPT STUDY IN 
PATIENTS WITH  C3 GLOMERULOPATHY (C3G) OR 
IMMUNE-COMPLEX MEMBRANOPROLIFERATIVE 
GLUMERULONEPHRITIS (IC-MPGN) TREATED WITH             
ACH-0144471 
 
 
 
 
Author: 
 
Date: 30 October 2020 
Version: 2.0
PPD


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1. 
APPROVAL SIGNATURES 
 
 
 
 
 
 
 
Date dd Mmm yyyy 
 
 
 
Date dd Mmm yyyy 
 
 
 
 
 
 
 
Date dd Mmm yyyy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD


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Table of Contents 
List of Appendices .......................................................................................................................................4 
List of Abbreviations ...................................................................................................................................5 
1 
Overview ..............................................................................................................................................7 
2 
Objective ..............................................................................................................................................7 
2.1 
Primary Objectives ......................................................................................................................7 
2.2 
Secondary Objectives ..................................................................................................................7 
2.3 
Exploratory Objectives ................................................................................................................7 
3 
Endpoints ..............................................................................................................................................8 
3.1 
Efficacy Outcome Measures ........................................................................................................8 
3.1.1 Brief Description of Renal Biopsy Scoring System .................................................................8 
3.1.2 Proteinuria Definitions .............................................................................................................9 
3.1.3 Primary Efficacy Outcome Measures .....................................................................................10 
3.1.4 Secondary Efficacy Outcome Measures .................................................................................10 
3.1.5 Other Efficacy / PK / PD / Quality of Life Outcome Measures .............................................10 
3.2 
Safety Outcome Measures .........................................................................................................10 
3.3 
Pharmacokinetic (PK) Outcome Measures ................................................................................11 
4 
Study Description ...............................................................................................................................11 
4.1 
Study Design ..............................................................................................................................11 
4.2 
Treatment Assignment ...............................................................................................................12 
4.3 
Blinding and Unblinding ...........................................................................................................12 
4.4 
Protocol Amendments ................................................................................................................12 
5 
Sample Size ........................................................................................................................................13 
6 
Analysis Sets ......................................................................................................................................14 
6.1 
Full Analysis Set (FAS) .............................................................................................................14 
7 
Statistical Analyses .............................................................................................................................14 
7.1 
General Methods ........................................................................................................................14 
7.2 
Study Population ........................................................................................................................15 
7.2.1 Patient Discontinuation and Disposition ................................................................................15 
7.2.2 Demographic and Baseline Characteristics ............................................................................15 
7.2.3 Medical History ......................................................................................................................15 
7.3 
Extent of Exposure  ....................................................................................................................15 


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7.4 
Concomitant Medications ..........................................................................................................16 
7.5 
Efficacy and PD Markers Assessment .......................................................................................16 
7.5.1 Analysis of Primary Efficacy Outcome Measures .................................................................16 
7.5.2 Analysis of Secondary Efficacy Outcome Measures .............................................................16 
7.5.3 Analysis of Other Efficacy Outcome Measure and PD Markers ...........................................18 
7.6 
Patient Report Outcomes (PRO) ................................................................................................18 
7.6.1 FACIT Fatigue Scale (Version 4) ..........................................................................................18 
7.6.2 Peds-FACIT-F ........................................................................................................................19 
7.6.3 KDQOL-SF™ version 1.3 ......................................................................................................19 
7.6.4 EQ-5D-3L ...............................................................................................................................20 
7.6.5 EQ-5D-Y ................................................................................................................................21 
7.7 
Safety Assessment .....................................................................................................................21 
7.7.1 Treatment-Emergent Adverse Events (TEAE) .......................................................................22 
7.7.2 Clinical Laboratory Parameters  .............................................................................................22 
7.7.3 ECG ........................................................................................................................................23 
7.7.4 Vital Signs and Body Weights ...............................................................................................23 
7.7.5 Physical Exam ........................................................................................................................24 
7.8 
Pharmacokinetic (PK) Assessments ..........................................................................................24 
7.8.1 PK Parameters ........................................................................................................................24 
7.8.2 Pre-dose Plasma Concentration ..............................................................................................25 
8 
Changes from Protocol Specified Analysis ........................................................................................25 
9 
Document History ..............................................................................................................................25 
 
List of Appendices 
Appendix 1. 
Grading the Severity of Laboratory Values .......................................................................26 
Appendix 2. 
KDQOL-SF Scale Scoring Procedure ...............................................................................29 
Appendix 3. 
FACIT-Fatigue Scale and Calculation of Total Score .......................................................30 
 
 
 


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List of Abbreviations 
AE 
Adverse event 
AP 
Alternative Pathway (Complement) 
BLQ 
Below the lower limit of quantification 
C3G 
C3 glomerulopathy 
CKD-EPI 
Chronic kidney disease - Epidemiology collaboration 
CV% 
Coefficient of variation 
ECG 
Electrocardiogram 
EOT 
End of treatment 
EQ-5D-3L 
Three-level version of EuroQol 5 Dimensions questionnaire 
EQ-5D-Y 
Youth version of EuroQol 5 Dimensions questionnaire 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy-Fatigue scale 
FAS 
Full Analysis Set  
IC-MPGN 
Immune complex mediated membranoproliferative glomerulonephritis  
KDQOL-SF 
Kidney Disease Quality of Life short form questionnaire  
LFT 
Liver function tests 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
Peds-FACIT-F 
Pediatric Functional Assessment of Chronic Illness Therapy – Fatigue scale 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
QTcF 
QT interval corrected using Fridericia’s formula 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
TE 
Treatment emergent 


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TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit normal 
VAS 
Visual analog scale 
 
 
  


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1 Overview 
This statistical analysis plan (SAP) describes in detail the statistical procedures and presentations to be 
implemented for the data analysis of Study ACH471-205.    
2 Objective 
2.1 Primary Objectives 
The primary objective of this study is to evaluate the efficacy of 12 months of oral ALXN2040 
(formerly ACH-0144471) in patients with C3G or IC-MPGN based on: 
• Improvement in renal biopsy results 
• Improvement relative to baseline in proteinuria.  
 
2.2 Secondary Objectives 
The secondary objectives of this study are: 
• To evaluate the clinical effect of 12 months of oral ALXN2040 in patients with C3G or IC-MPGN 
based on significant improvement in slope of estimated glomerular filtration rate (eGFR) relative to 
baseline over time 
• To evaluate for improvement in eGFR following treatment with ALXN2040 
• Where available, evaluate the change in measured (m) GFR relative to baseline at end of 12 months 
of treatment with ALXN2040  
• To evaluate the safety and tolerability of ALXN2040 in patients with C3G or IC-MPGN by 
assessing serious adverse events (SAEs). 
 
2.3 Exploratory Objectives 
The exploratory objectives of this study are: 
• To evaluate whether changes in histopathology scoring correlate with observed clinical changes 
in those patients with biopsy results before and after treatment with ALXN2040 
• To explore the effect of ALXN2040 on complement biomarkers including alternative pathway 
(AP) activity in patients with C3G or IC-MPGN over a 12-month treatment period 
• To evaluate plasma concentrations of ALXN2040 in patients with C3G or IC-MPGN 
• To evaluate kidney disease and health-related quality of life instruments in patients with C3G or 
IC-MPGN over the course of ALXN2040 treatment 


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• To explore patients’ experience of their disease (C3G or IC-MPGN), its impact, and its 
management on their everyday lives, from first symptoms to definitive diagnosis and beyond 
• To explore patients’ expectations and perceptions of ALXN2040 treatment 
 
3 Endpoints 
The following sections intend to provide a list of outcome measures from data collected on efficacy, 
including pharmacodynamics (PD), safety, and pharmacokinetics (PK) to address the study objectives.   
3.1 Efficacy Outcome Measures 
3.1.1 Brief Description of Renal Biopsy Scoring System 
A new preliminary renal biopsy scoring system for C3G disease has been developed for use in this proof 
of concept (POC) study.  A single biopsy composite index consisting of three components, activity 
index, glomerular C3c staining, and glomerular macrophage infiltration, will be used as one of the 
primary efficacy outcome measures in this study.  The chronicity index for C3G disease will also be 
explored to assess the effectiveness of ALXN2040. 
Individual biopsy features as described below are classified into four quantifiable categories.  Severity 
scores of 0, 1, 2, and 3 are assigned to the corresponding four categories for each biopsy feature. Score 
of 0 indicates the normal state (0 or extremely low quantities) of a particular feature. 
The activity index includes five features of the biopsy assessment, each with a possible score of 0 to 3, 
that are combined to give an overall activity index score ranging from 0 to 15.  The corrected activity 
score was calculated by the central pathologist by assessing each of the following five features in viable 
glomeruli.  A viable glomerulus is one that does not show global sclerosis.   
• Endocapillary hypercellularity – defined as the presence of cells in capillary loops with loop 
occlusion. Each viable glomerulus is evaluated for the percentage of the tuft that has endocapillary 
hypercellularity and classified the percentages into four categories: 0, 1-25%, 26-50%, and >50%, 
corresponding to scores 0-3.  The overall score is the median of scores of all viable glomeruli 
involved.   
• Neutrophils in capillary lumens - score each viable glomerulus as 0, 1-3, 4-10, >10 corresponding to 
scores of 0-3. The overall score is the median of scores of all viable glomeruli involved. 
• Mesangial hypercellularity – defined as more than 4 cells in a mesangial area away from the hilum 
(% glomeruli). Score as percentage of viable glomeruli involved: 0, 1-25%, 26-50%, >50% 
corresponding to scores of 0-3. 
•  Necrosis - defined as disruption of the glomerular basement membrane with fibrin exudation and 
karyorrhexis. At least two of these three lesions need to be present to meet the criteria for necrosis 
(% glomeruli). Score as percentage of viable glomeruli involved: 0, 1-10%, 11-25%, >25% 
corresponding to scores of 0-3. 


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• Cellular or fibrocellular crescents (% glomeruli) –  Score as percentage of viable glomeruli involved: 
0, 1-10%, 11-25%, >25% corresponding to scores of 0-3. 
Glomerular C3c staining is scored 0-3 based on the standard semiquantitative score in which negative, 
1+, 2+ and 3+ will correspond to scores of 0-3. 
Glomerular macrophage infiltration – defined as macrophage counts per glomerulus in a CD68 
immunostain.   The counts of each glomerulus will be assigned to one of four categories, 0 cell, 1-3 
cells, 4-10 cells, >10 cells, corresponding to scores of 0-3.  The overall score is the median of scores of 
all glomeruli involved. 
The scores from the above three elements (corrected activity index, glomerular C3c staining and 
glomerular macrophage infiltration) added to together provides a single composite biopsy score, 
ranging from 0 to 21, and serves as one of the primary efficacy measures. 
Chronicity index includes assessment of four lesion types in the biopsy, each with a possible score of 0 
to 3; therefore, the total possible scores range from 0 to 12. 
• Glomerular sclerosis – defined as % of glomeruli with segmental or global sclerosis.  Scores will be 
based on percentage glomeruli affected: <10%, 10-25%, 26-50%, >50% corresponding to scores of 
0-3. 
• Fibrous crescents -- defined as % of glomeruli with fibrous crescents.  Scores will be based on 
percentage glomeruli affected: none, <25%, 26-50%, >50% corresponding to scores of 0-3. 
• Tubular atrophy – Four categories will be given to assess tubular atrophy, <5%, 6-25%, 26-50%, and 
>50%, corresponding to scores of 0, 1, 2, and 3. 
• Interstitial fibrosis -- Four categories will be given to assess interstitial fibrosis, <5%, 6-25%, 26-
50%, and >50%, corresponding score of 0, 1, 2, and 3. 
 
3.1.2 Proteinuria Definitions 
When possible, proteinuria will be evaluated in 24-hour urine collections, but if a 24-hour urine is not 
available, a calculated equivalent will be derived from albumin:creatinine and/or total protein: creatinine 
ratios, obtained from spot urine samples.  The process for deriving this calculated equivalent will be 
described in detail in the laboratory manual. 
For 24-hour urine samples, proteinuria will be assessed as the measurements of total protein (mg/day) 
and albumin (umol/day). 
For spot urine samples, proteinuria will be assessed as the ratio of total protein/creatinine and the ratio of 
albumin/creatinine. 
For comparison and quality control of protein measurements for 24-hour urine samples, ratios of  
protein/creatinine and albumin/creatinine will also be calculated for the samples. 


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3.1.3 Primary Efficacy Outcome Measures 
• Change from baseline in biopsy, based on a score incorporating changes in both the activity index 
and C3 staining at the end of 12 months of treatment 
• Number and percent of patients with reduction in proteinuria relative to baseline at the end of 12 
months of treatment 
 
3.1.4 Secondary Efficacy Outcome Measures 
• Number and proportion of patients with significant (≥25%) increase in eGFR relative to baseline at 
the end of 12 months of treatment  
• Change and percent change from baseline in proteinuria and eGFR over 12 months of treatment for 
all patients 
• Change and percent change from baseline in eGFR over 12 months of treatment for patients meeting 
eGFR inclusion criteria at study entry 
• Descriptive analysis of slope of eGFR over the treatment period of ALXN2040 therapy 
The calculation of eGFR will be based on the following formulas: 
− For patients 19 years old and older the CKD-EPI creatinine equation (2009) will be used for 
inclusion/exclusion and primary endpoint analysis.   
− For patients <19 years old the creatinine-based “Bedside Schwartz” equation (2009) will be used 
for inclusion/exclusion and primary endpoint analysis.   
3.1.5 Other Efficacy / PK / PD / Quality of Life Outcome Measures 
• Changes in the following biomarkers over 12 months of treatment: AP activity, CP activity, Factor 
D, C3, C4, Bb, sC5b-9, and other biomarker measurements available from central laboratories.  
• Changes in kidney disease and health related quality of life measurements using KDQOL-SF v1.3 
and FACIT-Fatigue scale (version 4.0) for adults and Peds-FACIT-F for adolescents at 6 months and 
12 months of treatment 
• Determination of health state values using the 3-level version of the EuroQol 5 dimensions (EQ-5D-
3L) questionnaire (for adults) or EQ-5D-Y (for adolescents) at 6 months and 12 months of treatment 
 
3.2 Safety Outcome Measures 
• Number and incidence of SAEs 
• Number and incidence of AEs leading to discontinuation of the study drug 
• Number and incidence of Grade 3 or 4 AEs (related and regardless of relationship to study drug) 
• Change from baseline on selected laboratory test results over treatment duration 


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• Number and incidence of Grade 3 or 4 laboratory abnormalities 
• Change from baseline on parameters of vital signs and weight over treatment duration 
• Treatment emergent abnormalities on selected ECG parameters 
• Change from baseline on ECG parameters over treatment duration 
 
3.3 Pharmacokinetic (PK) Outcome Measures  
• Ctrough concentrations for C3G and IC-MPGN patients receiving ALXN2040 
 
4 Study Description 
4.1 Study Design 
This is an open-label study in which all patients receive active treatment with ALXN2040 for 
approximately 40 months.  The study is planned to enroll approximately 20 patients with biopsy-
confirmed C3G or IC-MPGN, 12 years of age or older, who have not undergone renal transplant.  
Patients who completed ACH471-201 are eligible to participate, as long as they do not meet any 
exclusion criteria. 
Patients must have biopsy-confirmed diagnosis of either C3G or IC-MPGN  and significant proteinuria, 
defined as ≥500 mg/day of protein in a 24-hour urine, that is attributable to C3G or IC-MPGN in the 
opinion of the principal investigator.  Patients who completed ACH471-201 may enroll in this study 
following a washout period of at least 30 days between the last dose of ALXN2040 in study 
ACH471-201 and the renal biopsy (if collected during screening) or the 24-hour urine collection during 
screening.   
Once eligibility is confirmed, arrangements can be made for a renal biopsy, if necessary, to confirm the 
diagnosis of C3G or IC-MPGN, or to establish a baseline for patients who choose to participate in the 
renal biopsy sub-study and/or vaccinations.  Biopsies are not obtained from patients less than 18 years of 
age (unless a biopsy is determined to be clinically indicated by the treating provider), or from patients 
for whom a biopsy is contraindicated. In addition, patients must have the diagnosis of C3G or IC-MPGN 
for at least 3 months prior to dosing, unless otherwise approved by the sponsor. 
All patients should be vaccinated against Haemophilus influenzae (H. influenzae), Streptococcus 
pneumoniae (S. pneumoniae), and Neisseria meningitidis (N. meningitidis) as recommended by the 
Advisory Committee on Immunization Practices (ACIP) guidelines at least 2 weeks before the start of 
dosing with ALXN2040.  
The starting dose of ALXN2040 is 100 mg TID, a total dose of 300 mg per day.  After two weeks of 
treatment, dosing is escalated to 200 mg TID (or 150 mg TID for patients less than 60 kg).  Additional 
dosage regimens may be investigated if supported by emerging data from this and other clinical studies. 
For each patient, the medical monitor must consult with the investigator before making the decision to 
dose escalate.  Upon treatment discontinuation, regardless of the timing or reasons for discontinuation, a 


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6-day taper period is required unless the PI determines this taper period poses a risk to the patient.  The 
taper period is in place to prevent the theoretical risk of marked increase or rebound in complement 
activity. 
Safety, efficacy (including biopsy results, PD biomarkers, and kidney disease and health related quality 
of life instruments), and PK assessments are carried out at pre-specified time points throughout 
treatment and post-treatment follow up period.   
An initial data snapshot will be performed when at least 20 patients complete the Week 28 visit or 
withdraw from the study early, and a preliminary analysis will be conducted that is descriptive in nature 
including the following data: 
- 
Patient disposition 
- 
Baseline demographics and disease characteristics 
- 
Primary efficacy outcomes, including renal biopsy results and proteinuria 
- 
Key secondary efficacy outcomes, including changes in eGFR 
- 
Overall summary of treatment-emergent adverse events 
- 
Treatment-emergent adverse events by preferred term 
- 
PK/PD changes over time 
The final analysis will occur will all patients complete the follow-up period or withdraw from the study 
early and will include analysis of all safety, efficacy, and PK data.  
4.2 Treatment Assignment 
All patients receive ALXN2040 and are assigned to the same treatment group.  Patients entering 
following completion of ACH471-201 retain the same patient identification as in study ACH471-201.  
Newly enrolled patients are assigned a sequential patient identification number within each study site. 
4.3 Blinding and Unblinding 
This is an open-label study that does not require blinding or unblinding. 
4.4 Protocol Amendments 
Amendment 
No. 
Amendment 
Date 
Main Purposes of Amendment 
1 
01-DEC-2017 
• Allow investigators who wish to do so to collect measured GFR 
in addition to the existing eGFR calculations.  


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Amendment 
No. 
Amendment 
Date 
Main Purposes of Amendment 
• The contraception requirements are being modified to align with 
updated Achillion standard wording, and SAE reporting contact 
information is being updated. 
2 
23-MAR-2018 • Revise to allow vaccinations to be administered according to 
local/national guidelines 
• Remove pharmacokinetic (PK) profile at Day 3 in order to reduce 
the burden to study patients 
• Simplify the complement-based inclusion/exclusion criteria 
• Updated contact information for reporting SAEs 
3 
02-NOV-2018 
• Allows the inclusion of adolescents 
• Makes the collection of renal biopsy samples optional, and 
changes the improvement in biopsy score from a primary to an 
exploratory objective 
• Makes changes to the inclusion/exclusion criteria to better reflect 
the intended patient population and to facilitate enrollment 
• Reduces sample collection and adds flexibility to the collection 
schedule to reduce the burden on patients 
4 
30-JAN-2019 
• Version 4 was not implemented 
5 
22-JUL-2019 
• Addition of biopsy as a primary endpoint  
• Reduces sample collection and adds flexibility to the collection 
schedule to reduce the burden on patients 
• Removes the biopsy sub-study option at Week 52 
• Extends the study to Week 104 (addition of a 12-month long-
term follow-up period) 
• Reduces the number of in-clinic study visits by having the 
ability to do visits as phone calls 
6 
15-MAY-2020 • Increases duration of study treatment 
• Allows home and telephone visits, local laboratory testing, and 
study drug to be sent directly to patient’s home when clinic 
visits are not possible due to the COVID-19 global pandemic 
• Allows optional renal biopsy to be performed when possible due 
to COVID-19 global pandemic 
• Updates contraceptive language to align with most recent 
Investigator Brochure 
 
5 Sample Size 
The sample size of 20 patients was determined based on limited clinical cases of C3G and IC-MPGN.  
Note that the sample of 20 patients includes those who enrolled after completing study ACH471-201. 
 


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6 Analysis Sets 
6.1 Full Analysis Set (FAS) 
All patients receiving at least one dose of ALXN2040 will be included in the full analysis set.  Data 
from patients in FAS will be used for efficacy, safety, pharmacokinetic (PK), and pharmacodynamic 
(PD) analyses.   
7 Statistical Analyses 
Statistical analyses and data presentations are performed using the using Statistical Analysis System® 
(SAS®) Version 9.4 or higher (SAS Institute Inc., Cary, NC, USA) or other validated statistical software. 
7.1 General Methods 
Summary statistics will be provided for efficacy and safety parameters.  Data will be summarized by 
disease type (C3G or IC-MPGN) as well as overall. 
Data listing by patient identification will be provided for all data, including efficacy, safety, PD, and PK 
parameters. 
To summarize continuous data, descriptive statistics will include: number of patients, mean, standard 
deviation, median, minimum, and maximum.  For the calculation of summary statistics and analysis, 
unrounded data will be used. 
To summarize categorical data, frequency counts and percentages will be presented.  
Missing data for QoL instruments will be handled as specified in the instructions for each instrument 
(see Appendix).  All other data will be summarized for observed cases, with no imputation for missing 
data. 
Longitudinal summaries of efficacy and safety parameters use pre-defined visit Week / Day as described 
in Appendix 1, schedule of assessment, of the protocol.  Analysis visit windows around planned 
measurement times are based on the midpoint between planned study visits unless specified otherwise.  
If there are multiple measurements within the same window, use the value in the visit window closest to 
the day of the planned visit for each time point (as determined by the absolute difference in days 
between the planned visit and the collection date, and the absolute difference in days between the 
planned visit and the assay date).  
For laboratory test results, when both local and central laboratory values are collected on the same date, 
the central laboratory value will be used.  
Baseline values for efficacy / PD and safety parameters are defined as the last measurement, including 
unscheduled visits, prior to first dose of study drug.  


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7.2 Study Population 
7.2.1 Patient Discontinuation and Disposition 
The patient disposition summary table(s) will include the following:  
• Number of patients (enrolled / treated) 
• Number of patients who completed the study  
• Reasons for not completing the study 
In addition, a summary of study visits will be provided including the number of patients who complete 
each visit as planned and the number of patients who complete modified study visits.  A patient listing 
will detail the reason for modified visit as well as the assessments that were modified and the 
modification. 
7.2.2 Demographic and Baseline Characteristics  
The following demographic and baseline characteristics will be summarized by disease type and overall: 
• demographics: age, gender, race, country  
• physical measurement at baseline: height, weight, BMI 
• disease characteristics at baseline: disease diagnosis, duration of the disease, biopsy results 
• laboratory tests at baseline: 24-hour urine protein, 24-hour protein/creatinine, 24-hour 
albumin/creatinine, spot urine protein/creatinine, spot urine albumin/creatinine, serum albumin, and 
serum creatinine. 
• prior medications: use of ACE inhibitors or ARB drugs or immunosuppression (IS) medications. 
 
7.2.3 Medical History 
Medical history will be coded with the most current version of Medical Dictionary for Regulatory 
Activities (MedDRA®) and will be summarized by preferred term and system organ class by disease 
type and overall. 
7.3 Extent of Exposure  
Treatment durations will be computed for each patient as (last date of dose – first date of dose + 1).   
If patients enter the 7-day dose taper schedule, duration of tapering dosing period may also be provided 
as a separate computation.  The duration will be calculated similarly as (last date of taper dose – first 
date of taper dose +1). 
Treatment duration will be summarized by disease type and overall. 
Compliance with study drug was collected as number of tablets dispensed and number of tablets 
returned beginning in July 2019, after patients had already been enrolled and completed study visits. The 


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number of tablets taken during this time period will be derived from the number recorded as dispensed 
at the current visit minus the number recorded as returned at the next consecutive visit.  A patient listing 
of number of tablets taken by visits during this time period will be provided.  A separate patient listing 
will be provided including study drug compliance during this time period as derived by: 
 
Compliance = (# tablets taken / # tablets assigned) * 100. 
In addition, a summary of missed doses due to COVID-19 will be provided. 
7.4 Concomitant Medications 
Concomitant medications are summarized by disease type and overall. These are medications taken any 
time on or after the first dose of study drug. Medications are presented alphabetically by anatomic class, 
therapeutic class and generic name using the most recent version of WHO dictionary. 
7.5 Efficacy and PD Markers Assessment 
7.5.1 Analysis of Primary Efficacy Outcome Measures 
The analysis methods described below utilize data from patients in FAS. 
Composite Biopsy Score   
Change and percent change from baseline for the composite biopsy score at the end of 12 months of 
treatment will be computed for each patient and summarized by disease type and overall. 
Proteinuria 
Number and percent of patients with reduction in proteinuria relative to baseline at the end of 12 months 
of treatment, defined as ≥30% decrease in proteinuria (total protein/day) relative to baseline from 24-
hour urine collections. 
In addition to the primary analysis of the primary efficacy endpoints, a sensitivity analysis will be 
performed excluding patients who had modified assessments due to COVID-19 to assess the robustness 
of the results. 
 
7.5.2 Analysis of Secondary Efficacy Outcome Measures 
The secondary efficacy endpoints include: 
• Number and proportion of patients with significant (≥25%) increase in eGFR relative to baseline at 
the end of 12 months of treatment 
• Change and percent change from baseline in proteinuria and eGFR over 12 months of treatment for 
all patients 
• Change and percent change from baseline in eGFR over 12 months of treatment for patients meeting 
eGFR inclusion criterion at study entry 


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• Descriptive analysis of slope of eGFR over the treatment period of ALXN2040 
 
Change and percent change from baseline for proteinuria will be computed for each patient and 
summarized by disease type and overall at each visit based on 24 hour urine protein, 24 hour urine 
albumin, 24 hour urine protein/creatinine ratio, 24 hour urine albumin/creatinine ratio, spot urine 
protein/creatinine ratio, and spot urine albumin/creatinine ratio. 
When possible, proteinuria will be evaluated in 24-hour urine collections, but if a 24-hour urine is not 
available, a calculated equivalent will be derived from albumin:creatinine and/or total protein: creatinine 
ratios, obtained from spot urine samples. The process for deriving this calculated equivalent will be 
described in detail in the laboratory manual. 
 
The number and proportion of patients with ≥20% and ≥25% increase in eGFR relative to baseline at the 
end of 12 months of treatment will be summarized descriptively by disease type and overall.   
 
Change and percent change from baseline in eGFR will be summarized at each pre-defined time point 
by disease type and overall.  Change and percent change from baseline in eGFR will also be summarized 
separately for patients meeting eGFR inclusion criterion at study entry.   
 
The descriptive measure of slope will be estimated using a simple linear regression for each patient with 
eGFR as the dependent variable and time as the independent variable.  The mean slope (mL/min/1.73 m2 
per month) will be summarized descriptively by disease type and overall. 
Graphic presentation on eGFR measurements over time will be provided to observe the trend and profile 
of the effect of ALXN2040 on change of eGFR.  The time-measurement graph will be provided for each 
patient as well as a mean time-measurement graph for visual examination and interpretation. 
In addition, the number and percentage of patients who achieve the following response statuses will be 
summarized at each visit by disease type and overall: 
• Complete response, defined as proteinuria <500 mg/d based on 24-hour urine samples plus stable 
eGFR (ie, less than 25% decrease from baseline)   
• Partial response, defined as ≥30% decrease from baseline in proteinuria but not <500 mg/d based on 
24-hour urine samples plus stable eGFR (ie, less than 25% decrease from baseline) 
• Worsening, defined as >25% decrease from baseline in eGFR or >30% increase from baseline in 
proteinuria based on 24-hour urine samples 
The number and percentage of patients who achieve partial response based on 24-hour urine 
protein/creatinine ratio and spot urine/protein creatinine ratio, defined as ≥30% decrease from baseline 
in proteinuria plus stable eGFR (ie, less than 25% decrease from baseline), will also be summarized at 
each visit. 


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The number and percentage of patients who achieve worsening based on 24-hour urine 
protein/creatinine ratio and spot urine/protein creatinine ratio, defined as >25% decrease from baseline 
in eGFR or >30% increase from baseline in proteinuria, will also be summarized at each visit. 
7.5.3 Analysis of Other Efficacy Outcome Measure and PD Markers 
Original values and changes from baseline at each pre-defined time point will be computed for each 
patient and will be summarized by disease type and overall for the following outcome measures: 
• AP activity 
• CP activity 
• Factor D 
• C3  
• C4 
• Bb  
• sC5b-9  
 
For Wieslab test results (AP activity), only original values will be used for summary tables.  
Graphic presentations for the longitudinal data may also be provided for the above outcome measures if 
clinically deemed meaningful. 
The patient report outcomes (PRO) instruments listed in section 3.1.5 will be described in the next 
section.   
Section 7.8 below describes in detail on PK data presentation and analysis methods.  
7.6 Patient Report Outcomes (PRO) 
All adult patients enrolled in the trial will self-administer questionnaires for the FACIT-Fatigue 
(version 4), KDQOL version 1.3, and EQ-5D-3L scales, and all adolescent patients enrolled in the 
trial will self-administer questionnaires for the Peds-FACIT-F and EQ-5D-Y scales at the times 
specified in the protocol to assess their HRQOL, fatigue, and kidney-related fears and worries (e.g. 
kidney failure, dialysis, kidney transplant), and to determine health states value, over the course of 
treatment with ALXN2040. The following sections briefly describe the utility and interpretation of these 
instruments.  Details of computing and summarizing the scores and/or scales can be found in the 
respective user manuals.   
The PRO presentations utilize data from patients in FAS. 
7.6.1 FACIT Fatigue Scale (Version 4) 
There are 13 items in the FACIT Fatigue scale questionnaire.  Each item includes 5 possible responses, 
0-4, with 0 being “Not at all” and 4 being “Very much”.  Total score from these 13 items will be 
provided for each patient at each protocol pre-defined time points. 


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Negatively stated items must be reversed before being added to obtain the scale total score.  Therefore, 
the negatively stated items will be reversed by subtracting the response from “4”.  Note that all items, 
except for items #7 and #8, are negatively stated. 
The FACIT Fatigue scale and the calculation of total score are presented in Appendix 3 of this 
document.  Note that the total score range is 0 to 52, with higher total scored indicating better quality of 
life. 
Original values and change from baseline values over time will be summarized for adult patients by 
disease type and overall for each scheduled visit. Patient listings for total score and change from 
baseline in total score will be provided for protocol pre-specified time points. 
7.6.2 Peds-FACIT-F 
There are 13 items in the Peds-FACIT-F questionnaire.  Each item includes 5 possible responses, 0-4, 
with 0 being “None of the time” and 4 being “All of the time”.  Total score from these 13 items will be 
provided for each patient at each protocol pre-defined time points. 
Negatively stated items must be reversed before being added to obtain the scale total score.  Therefore, 
the negatively stated items will be reversed by subtracting the response from “4”.  Note that all items, 
except for items #2 and #3, are negatively stated. 
The Peds-FACIT-F questionnaire and the calculation of total score are presented in Appendix 3 of this 
document.  Note that the total score range is 0 to 52, with higher total scored indicating better quality of 
life. 
Original values and change from baseline values over time will be summarized for adult patients by 
disease type and overall for each scheduled visit. Patient listings for total score and change from 
baseline in total score will be provided for protocol pre-specified time points. 
7.6.3 KDQOL-SF™ version 1.3 
The kidney disease quality of life short form (KDQOL-SF™) is a widely used health-related quality of 
life (HRQOL) measure for patients with chronic kidney diseases.  The questionnaire consists of the 
generic SF-36 as well as 11 multi-item scales focused on quality of life issues specific to patients with 
kidney disease. Two of the eleven (11) subscales of the kidney disease (KD) targeted areas are for 
patients requiring kidney dialysis and, therefore, are excluded from questionnaire for this study.  The 
remaining 9 KD targeted areas are:  
• symptoms/problems 
• effects of kidney disease 
• burden of kidney disease 
• work status  
• cognitive function  


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• quality of social interaction  
• sexual function  
• sleep  
• social support 
 
The generic 36-item health survey, SF-36, consists of two component summaries with their respective 
domains. 
• Physical Component Summary (PCS) 
o Physical functioning 
o Role-physical 
o Pain 
o General health 
• Mental Component Summary (MCS) 
o Emotional well-being 
o Role-emotional 
o Social function 
o Energy/fatigue 
 
The questionnaire items included in each of SF-36 domains and KD targeted areas are listed in 
Appendix 2. 
The scoring procedure for the KDQOL-SF™ first transforms the raw pre-coded numeric values of items 
to a 0-100 possible range, with higher transformed ‘scale scores’ always reflecting better quality of life.  
Each item is put on a 0 to 100 range so that the lowest and highest possible scores are set at 0 and 100, 
respectively.  Details of transforming each item score to corresponding scale are provided in the 
KDQOL-SF user manual.  
Original values and change from baseline values over time will be summarized for adult patients by 
disease type and overall for each scheduled visit. Patient listings on score scales will be provided for 
each of KD targeted areas and SF-36 domains.   
7.6.4 EQ-5D-3L 
The self-reported questionnaire EQ-5D-3L has two parts.  The first part is a descriptive system with 5 
dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression.  Each 
dimension has three response levels, 1, 2, and 3, representing “no problems”, “some problems”, and 
“extreme problems”, respectively.  A scoring function can be used to convert the self-reported 
descriptive system to a single summary index (EQ-5D Index score) through a set of population-based 
preference weights. 


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The second part is a visual analog scale (VAS) which records patient's self-rated health status on a 
graduated (0–100) scale, with higher scores for higher heath related quality of life.  The EQ-5D, 
therefore, produces three types of data for each patient: 
• a profile indicating the extent of problems on each of the five dimensions; 
• a population preference-weighted health index score based on the descriptive system; 
• a self-reported assessment of health status based on the EQ-VAS 
 
For this study, the U.S. population weights will be used to convert the descriptive system to an EQ-5D 
index score on a scale where 1.0 = perfect health and 0 = death. 
Original values and change from baseline values over time will be summarized for adult patients by 
disease type and overall at each scheduled visit. Patient listings will be provided for the responses of 5-
dimension descriptive system, EQ-5D-VAS, and U.S. population-based EQ-5D index. 
7.6.5 EQ-5D-Y 
The EQ-5D-Y has two parts.  The first part is a descriptive system with 5 dimensions: mobility, looking 
after myself, doing usual activities, having pain / discomfort, feeling worried, sad or unhappy.  Each 
dimension has three response levels, 1, 2, and 3, representing “no problems”, “some problems”, and “a 
lot problems”, respectively.   
The second part is a visual analog scale (VAS) which records patient's self-rated health status on a 
graduated (0–100) scale, with higher scores for higher heath related quality of life.   
The number and percentage of patients reporting each level of problems will be summarized for each 
dimension for adolescent patients at each scheduled visit.  Original values and change from baseline 
values over time in the VAS score will be summarized for adolescent patients by disease type and 
overall at each scheduled visit. Patient listings will be provided for the responses of 5-dimension 
descriptive system and EQ-5D-VAS. 
7.7 Safety Assessment  
Evaluation of safety includes assessment of the following clinical parameters and will be described in 
detail in the subsequent subsections.   
1. Treatment emergent adverse events (total as well as related versus unrelated), including 
discontinuations due to adverse event 
2. Clinical laboratory parameters 
3. ECG 
4. Vital signs 
5. Physical exam 
In addition, a listing of patients with known exposure to COVID-19 will be provided. 


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7.7.1 Treatment-Emergent Adverse Events (TEAE) 
Adverse events (AEs) will be coded with the most current version of Medical Dictionary for Regulatory 
Activities (MedDRA®). 
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during treatment with 
ALXN2040, having been absent pre-treatment, or worsens relative to the pre-treatment state.   
If an AE that was reported during treatment increases in severity, then that AE is given a resolution date 
and time and a new record initiated with the new severity.  If the severity of an AE remains the same or 
decreases, the AE will be kept open through to resolution, reflecting the maximum severity.  
AEs will be listed by patient including preferred term, verbatim term, system organ class (SOC), days 
from first dosing date, onset and resolution dates/times, duration, frequency, severity, seriousness, 
outcome, action taken, and relationship to study drugs.  
TEAEs will be summarized by preferred term and SOC for the number of patients reporting the TEAE, 
the number of TEAEs reported, and the number of events by severity and relationship to study drugs.  In 
addition, TEAEs will be summarized by decreasing order of frequency.  Summaries of TEAEs include 
both non-serious and SAEs as defined in the protocol.  Additionally, all SAEs, regardless of treatment 
emergent or not, will be listed in tabulated form.  AEs with missing severity are included only in 
summaries of all severity grades (related or regardless of relationship to study drug).  If a patient had an 
AE with different severities during treatment, then only the greatest severity is reported, unless 
otherwise specified. 
It is not anticipated to encounter AE with missing start date in this study.  Any AE with missing start 
date will be treated as TEAE.   
All events captured in the database will be listed in by-patient data listings.  However, only TEAEs will 
be summarized.  Separate patient listings will be provided for TEAEs and pre-treatment AEs.  If any 
patients report known exposure to COVID-19 during the study, a listing of all adverse events 
experienced by these patients will be provided separately.   
Should any serious adverse events (SAEs) or discontinuation of study drug due to adverse events (TEAE 
or SAE) occur, patient listings for such adverse events will be displayed in a tabulated format and 
narratives will be included in the study report.  If no such event occurs during the study, the tables 
should provide a statement clearly indicating as such, e.g. ‘No SAE reported’, ‘No TEAE led to 
discontinuation of study drug’. 
7.7.2 Clinical Laboratory Parameters  
Descriptive statistics will be provided, at a minimum, for the following laboratory test results of 
hematology, serum chemistry, urinalysis, and coagulation tests as listed in the protocol. Descriptive 
statistics may be provided for additional laboratory parameters, if clinically warranted.  


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• hematocrit (Hct), hemoglobin (Hgb), mean corpuscular volume (MCV), platelet count, and WBC 
count   
• all chemistry laboratory test results 
• pH, specific gravity 
• PT/PTT/INR 
Levels and changes from baseline in the laboratory measurements will be summarized at baseline and at 
protocol-specified visits by disease type and overall.  Baseline is the last assessment before the first dose 
of study drug, including unscheduled assessments.  
As noted in Section 7.1, when both local and central laboratory values are collected on the same date, 
the central laboratory value will be used.  Laboratory parameters are summarized based on values and 
units from laboratory reports.  Selected lab parameters may be converted to SI or US standard units, as 
clinically deemed appropriate.  Laboratory abnormalities are determined from laboratory measurements 
analyzed at the central or local laboratories and are graded using Common Terminology Criteria for 
Adverse Events (CTCAE), as presented in Appendix 1 of this document. 
For laboratory tests with CTCAE toxicity grades available, laboratory abnormalities are summarized by 
worst treatment-emergent grade [treatment emergent (TE) lab abnormalities].  For tests that have 
CTCAE toxicity grades in both high and low directions, e.g. serum glucose, etc., the summary table 
should specify separately for the TE abnormalities as being high or being low in toxicity grades.  Note 
that the post-baseline laboratory value with the highest treatment-emergent toxicity grade is reported for 
each test. 
Shift tables will be provided for liver function test (LFT) results and other selected laboratory test results 
based on CTCAE grades.  In addition, shift tables based on multiple of upper limit normal (ULN) will 
also be produced for LFT measurements.  
Laboratory abnormalities during treatment period will be further summarized by baseline toxicity grade 
(shift tables). 
Exploratory graphic presentations may be provided when data indicate that such analyses are 
appropriate and clinically meaningful. 
7.7.3 ECG 
A protocol amendment during the study changed the frequency of ECG measurements to screening only 
and therefore not all patients have multiple measurements.   
Patient listings will be provided for ECG parameters: HR, RR, PR interval, QRS interval, QT interval, 
and QTcF.  The abnormal and clinically significant findings will also be included in the listing. 
7.7.4 Vital Signs and Body Weights 
Patient listing will be provided for vital signs parameters: body temperature, systolic and diastolic blood 
pressures in triplicate, heart rate, and respiration rate.  For systolic and diastolic blood pressures, average 


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of triplicate readings will be computed for each time point.  Body weights are taken at the same time 
points as vital signs and will be included in the listing. 
Summary of changes from baseline at individual time points will be provided for each parameter of vital 
signs and body weight by disease type and overall.  Blood pressures, both systolic and diastolic, are of 
particular interest for C3G patients.  Additional analysis and presentations may be required if clinically 
deemed meaningful.   
7.7.5 Physical Exam 
Data collected from physical exams, both complete and brief, will be listed by patient and by time 
points, including unscheduled visit time points. 
7.8 Pharmacokinetic (PK) Assessments 
PK assessments will be performed on plasma concentrations from patients included in PK analysis set 
whose PK profiles can be determined. 
7.8.1 PK Parameters 
PK parameters from plasma concentrations for ALXN2040 will be calculated using a non-
compartmental approach based on the concentration versus time data. The parameters listed in the table 
below will be obtained using Phoenix WinNonlin® Version 6.4 or higher, as data permit.   
Patients for whom there is insufficient data to calculate the PK parameters will have available data 
included in the concentration tables with descriptive statistics only. 
For the calculation of the PK parameters, concentrations that are below the lower limit of quantification 
(BLQ) prior to the Tmax will be set to 0 and those thereafter as missing. Concentrations that are missing 
or not reportable will be treated as missing values. For concentration summary statistics, concentrations 
that are BLQ will be set to 0.  At least 3 time points with measurable concentration will be required for 
the calculation of AUC. 
For Day 10, the following PK parameters will be estimated: 
Parameter  
Definition/Calculation  
AUCtau 
Area under the plasma concentration-time curve from time of administration to 
the end of dosing interval, calculated by linear trapezoidal summation 
Cmax 
Maximal plasma concentration 
Ctrough 
Plasma trough (pre-dose) concentration over the dosing interval for the first 
daily dose 
Tmax 
Time to reach the maximal plasma concentration 
CL/F 
Apparent oral drug clearance during a dosing interval, calculated as 
Dose/AUCtau 
 
AUC values will be estimated using the linear trapezoidal rule. Actual sampling times relative to dosing 
will be used in the computation.  


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Unless otherwise specified below, missing sampling or concentration values should not be imputed, but 
left missing in the calculation of derived PK parameters. If the actual sampling time is missing, but a 
valid concentration value has been measured, the scheduled protocol time will be used for the 
calculation of derived PK parameters. 
On a case by case basis, it may be necessary to exclude individual PK concentration values for the 
calculation of derived PK parameters because they are erroneous, abnormal or appear implausible to the 
pharmacokineticist in charge of the analysis. Any excluded data will be flagged in the individual data 
listings. The reason for exclusion will also be documented. If the exclusion has a meaningful impact on 
the overall interpretation of the results, then it will be discussed. 
Actual post-dose time will be used in calculation of PK parameters and in the generation of individual 
concentration-time profiles. Scheduled (nominal) sampling times will be used as a replacement for 
unknown or missing actual times and will be used for the pre-dose values. Nominal sampling times will 
be used in the generation of summary concentration-time profiles and the concentration-time listings. 
7.8.2 Pre-dose Plasma Concentration 
Single trough PK samples will be taken at the time points as listed in the protocol schedule of 
assessments.  
All individual pre-dose plasma concentrations (troughs) will be listed. Descriptive statistics (number of 
non-missing observations (N), arithmetic mean, SD, median, coefficient of variation (CV%), minimum, 
maximum, geometric mean and geometric CV%) will be used to summarize these concentrations of 
ALXN2040 by disease type and overall. 
8 Changes from Protocol Specified Analysis 
Not applicable 
9 Document History 
Version No. 
Author(s) 
Descriptions 
1.0 
Original version dated 30Apr2020 
2.0 
• 
Updated to align with Protocol Amendment 6 
• 
Removed per protocol set given small sample size 
• 
Added summaries of modified study visits and missed doses due to COVID-
19 pandemic 
• 
Added summary of treatment compliance 
• 
Added sensitivity analysis for primary efficacy and safety endpoints to assess 
impact of COVID-19 pandemic 
 
PPD


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Appendix 1. 
Grading the Severity of Laboratory Values 
The Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 (v4.03: June 14, 2010) 
does not provide a separate laboratory toxicity grading table.  All the laboratory grades are part of the 
descriptions within various system organ classes (SOCs).  The following table has been created as SAS 
programming specifications for producing tables and listings for clinical study report.  The criteria for 
each grade are the same as in CTCAE descriptions. 
Grading the Severity of Laboratory Values, Unmodified from CTCAE, Version 4.0 (v4.03: June 14, 
2010) 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
LIFE-THREATING 
CHEMISTRIES 
Acidosis 
pH < normal, but 
≥7.3 
- 
pH <7.3 
Life-threatening 
consequences  
Albumin, Low 
<LLN - 3 g/dL; 
<LLN - 30 g/L 
<3 - 2 g/dL; <30 - 
20 g/L 
<2 g/dL; <20 g/L 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Alkaline Phosphatase, High 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
Alkalosis 
pH > normal, but 
≤7.5 
- 
pH >7.5 
Life-threatening 
consequences  
ALT, High 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
Amylase, High 
>ULN – 1.5 x ULN 
>1.5 – 2.0 x ULN 
>2.0 – 5.0 x ULN 
>5.0 x ULN 
AST 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
Bilirubin, High 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x ULN 
>3.0 - 10.0 x ULN 
>10.0 x ULN 
Calcium, High 
Corrected serum 
calcium of >ULN - 
11.5 mg/dL; >ULN 
- 2.9 mmol/L 
Corrected serum 
calcium of >11.5 
- 12.5 mg/dL; 
>2.9 - 3.1 
mmol/L 
Corrected serum 
calcium of >12.5 - 
13.5 mg/dL; >3.1 - 
3.4 mmol/L 
Corrected serum 
calcium of >13.5 
mg/dL; >3.4 
mmol/L 
Calcium (Ionized), High 
Ionized calcium 
>ULN - 1.5 
mmol/L 
Ionized calcium 
>1.5 - 1.6 
mmol/L 
Ionized calcium 
>1.6 - 1.8 mmol/L 
Ionized calcium 
>1.8 mmol/L 
Calcium, Low 
Corrected serum 
calcium of <LLN - 
8.0 mg/dL; <LLN - 
2.0 mmol/L 
Corrected serum 
calcium of <8.0 - 
7.0 mg/dL; <2.0 - 
1.75 mmol/L 
Corrected serum 
calcium of <7.0 - 
6.0 mg/dL; <1.75 - 
1.5 mmol/L 
Corrected serum 
calcium of <6.0 
mg/dL; <1.5 
mmol/L 
Calcium (Ionized), Low 
Ionized calcium 
<LLN - 1.0 mmol/L 
Ionized calcium 
<1.0 - 0.9 
mmol/L 
Ionized calcium 
<0.9 - 0.8 mmol/L 
Ionized calcium 
<0.8 mmol/L 
Creatine Kinase, High 
>ULN - 2.5 x ULN 
>2.5 x ULN - 5 x 
ULN 
>5 x ULN - 10 x 
ULN 
>10 x ULN 
Creatinine, High 
>1 - 1.5 x 
baseline; >ULN - 
1.5 x ULN 
>1.5 - 3.0 x 
baseline; >1.5 - 
3.0 x ULN 
>3.0 baseline; >3.0 
- 6.0 x ULN 
>6.0 x ULN 


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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
LIFE-THREATING 
eGFR or CrCl 
<LLN - 60 
ml/min/1.73 m2 
or proteinuria 2+ 
present; urine 
protein/creatinine 
>0.5 
59 - 30 
ml/min/1.73 m2 
eGFR or CrCl 29 - 
15 ml/min/1.73 
m2 
eGFR or CrCl 
<15 
ml/min/1.73 m2 
Glucose,  
   Fasting , High 
>ULN - 160 
mg/dL; >ULN - 8.9 
mmol/L 
>160 - 250 
mg/dL; >8.9 - 
13.9 mmol/L 
>250 - 500 mg/dL; 
>13.9 - 27.8 
mmol/L; 
>500 mg/dL; 
>27.8 mmol/L 
Glucose, Low  
<LLN - 55 mg/dL; 
<LLN - 3.0 mmol/L 
<55 - 40 mg/dL; 
<3.0 - 2.2 
mmol/L 
<40 - 30 mg/dL; 
<2.2 - 1.7 mmol/L 
<30 mg/dL; <1.7 
mmol/L 
GGT, High 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
Lipase, High 
>ULN – 1.5 x ULN 
>1.5 – 2.0 x ULN 
>2.0 – 5.0 x ULN 
>5.0 x ULN 
Lipid Disorders, 
    Cholesterol, High  
>ULN - 300 
mg/dL; >ULN - 
7.75 mmol/L 
>300 - 400 
mg/dL; >7.75 - 
10.34 mmol/L 
>400 - 500 mg/dL; 
>10.34 - 12.92 
mmol/L 
>500 mg/dL; 
>12.92 mmol/L 
    Triglycerides, High 
150 mg/dL - 300 
mg/dL; 1.71 
mmol/L - 3.42 
mmol/L 
>300 mg/dL - 
500 mg/dL; 
>3.42 mmol/L - 
5.7 mmol/L 
>500 mg/dL - 1000 
mg/dL; >5.7 
mmol/L - 11.4 
mmol/L 
>1000 mg/dL; 
>11.4 mmol/L 
Magnesium, High 
>ULN - 3.0 mg/dL; 
>ULN - 1.23 
mmol/L 
- 
>3.0 - 8.0 mg/dL; 
>1.23 - 3.30 
mmol/L 
>8.0 mg/dL; >3.30 
mmol/L 
Magnesium, Low 
<LLN - 1.2 mg/dL; 
<LLN - 0.5 
mmol/L 
<1.2 - 0.9 mg/dL; 
<0.5 - 0.4 
mmol/L 
<0.9 - 0.7 mg/dL; 
<0.4 - 0.3 
mmol/L 
<0.7 mg/dL; <0.3 
mmol/L 
Phosphate, Low 
<LLN - 2.5 mg/dL; 
<LLN - 0.8 
mmol/L 
<2.5 - 2.0 mg/dL; 
<0.8 - 0.6 
mmol/L 
<2.0 - 1.0 mg/dL; 
<0.6 - 0.3 
mmol/L 
<1.0 mg/dL; <0.3 
mmol/L; 
Potassium, High 
>ULN - 5.5 
mmol/L 
>5.5 - 6.0 
mmol/L 
>6.0 - 7.0 mmol/L 
>7.0 mmol/L 
Potassium, Low 
<LLN - 3.0 mmol/L 
- 
<3.0 - 2.5 mmol/L;  
<2.5 mmol/L 
SODIUM, High 
>ULN - 150 
mmol/L 
>150 - 155 
mmol/L 
>155 - 160 
mmol/L 
>160 mmol/L 
SODIUM, Low 
<LLN - 130 
mmol/L 
 -      
<130 - 120 
mmol/L 
<120 mmol/L 
URICACID 
>ULN - 10 mg/dL 
(0.59 mmol/L)  
 -      
- 
>10 mg/dL; >0.59 
mmol/L 
HEMATOLOGY 
CD4 Lymphocytes  decreased 
<LLN - 500/mm3; 
<LLN - 0.5 x 109 /L 
<500 - 200/mm3; 
<0.5 - 0.2 x 109 
/L 
<200 - 50/mm3; 
<0.2 - 0.05 x 109 /L 
<50/mm3; <0.05 x 
109 /L 


Alexion Pharmaceuticals 
ACH471-205: 15 May 2020 (Version 7) 
Statistical Analysis Plan 
30 October 2020, Version 2 
 
 
 
Confidential 
Page 28 of 32 
 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
LIFE-THREATING 
(Absolute) Lymphocyte Count, low 
<LLN - 800/mm3; 
<LLN - 0.8 x 109 /L 
<800 - 500/mm3; 
<0.8 - 0.5 x 109 
/L 
<500 - 200/mm3; 
<0.5 - 0.2 x 109 /L 
<200/mm3; <0.2 x 
109 /L 
Absolute Neutrophil Count (ANC), low 
<LLN - 1500/mm3; 
<LLN - 1.5 x 109 /L 
<1500 - 
1000/mm3; <1.5 
– 1.0 x 109 /L 
<1000 - 500/mm3; 
<1.0 - 0.5 x 109 /L 
<500/mm3; <0.5 x 
109 /L 
Fibrinogen, Decreased 
<1.0 – 0.75 x LLN 
or <25% decrease 
from baseline 
<0.75 – 0.5 x LLN 
or 25 - <50% 
decrease from 
baseline 
<0.5 – 0.25 x LLN 
or 50 - <75% 
decrease from 
baseline 
<0.25 x LLN or 
75% decrease 
from baseline or 
absolute value 
<50 mg/dL 
Hemoglobin, Low 
Hgb<LLN - 10.0 
g/dL; <LLN - 6.2 
mmol/L; <LLN - 
100 g/L 
Hgb <10.0 - 8.0 
g/dL; <6.2 - 4.9 
mmol/L; <100 - 
80g/L 
Hgb <8.0 g/dL; 
<4.9 mmol/L; 
<80 g/L; 
transfusion 
indicated 
 Life-threatening 
consequences; 
urgent 
intervention 
indicated 
INR, High 
(not on anticoagulation therapy) 
>1 - 1.5 x ULN;  
>1.5 - 2.5 x ULN;  
>2.5 x ULN; >2.5  
 -      
INR, High 
(on anticoagulation therapy) 
>1 - 1.5 times 
above baseline  
>1.5 - 2.5 times 
above baseline  
>2.5 times above 
baseline  
 -      
Platelets, Decreased 
<LLN - 
75,000/mm3; 
<LLN -75.0 x 109 
/L 
<75,000 - 
50,000/mm3; 
<75.0 -50.0 x 109 
/L 
<50,000 - 
25,000/mm3; 
<50.0 -25.0 x 109 
/L 
<25,000/mm3; 
<25.0 x 109 /L 
WBC, Decreased 
<LLN - 3000/mm3; 
<LLN - 3.0 x 109 /L 
<3000 - 
2000/mm3; <3.0 
- 2.0 x 109 /L 
<2000 - 
1000/mm3; <2.0 - 
1.0 x 109 /L 
<1000/mm3; <1.0 
x 109 /L 
APTT or PTT 
>ULN - 1.5 x ULN 
>1.5 - 2.5 x ULN 
>2.5 x ULN;  
 -      
Proteinuria 
(Dipstick) 
1+  
 
2+  
 
- 
- 
Proteinuria 
(24-hour urine) 
<1.0 g/24 hrs 
1.0 - 3.4 g/24 hrs 
>=3.5g/24 hrs 
- 
 
 
 
 
 
 


Alexion Pharmaceuticals 
ACH471-205: 15 May 2020 (Version 7) 
Statistical Analysis Plan 
30 October 2020, Version 2 
 
 
 
Confidential 
Page 29 of 32 
 
 
Appendix 2. 
KDQOL-SF Scale Scoring Procedure 
 
Scale 
Number of Items 
After Recoding, Average the 
Following Items 
 
Kidney disease targeted areas 
Symptom/problem list 
12 
14a-k  
Effects of kidney disease 
8 
15a-h 
Burden of kidney disease 
4 
12a-d 
       Work status 
2 
20,21 
       Cognitive function 
3 
13b, d, f 
     Quality of social interaction 
3 
13a,c,e 
       Sexual function 
2 
16a, b 
        Sleep 
4 
17, 18a-c 
        Social support 
2 
19a, b 
 
36-item health survey_ (SF-36) 
Physical functioning 
10 
3a-j 
           Role—physical 
4 
4a-d 
            Pain 
2 
7,8 
            General health 
5 
1, 1la-d 
Emotional well-being 
5 
9b, c, d, f, h 
           Role--emotional 
3 
5a-c 
           Social function 
2 
6, 10 
           Energy/fatigue 
4 
9a, e, g, i 
Note: The SF-36 change in health and the 0-10 overall health rating items are scored as single 
items. 
 


Alexion Pharmaceuticals 
ACH471-205: 15 May 2020 (Version 7) 
Statistical Analysis Plan 
30 October 2020, Version 2 
 
 
 
Confidential 
Page 30 of 32 
 
 
Appendix 3. 
FACIT-Fatigue Scale and Calculation of Total Score 
Below is a list of statements that other people with your illness have said are important. Please circle or mark 
one number per line to indicate your response as it applies to the past 7 days. 
Not At All 
A Little Bit 
Somewhat 
Quite a Bit 
Very Much 
1 
I feel fatigued 
0 
1 
2 
3 
4 
2 
I feel weak all over 
0 
1 
2 
3 
4 
3 
I feel listless (“washed out”) 
0 
1 
2 
3 
4 
4 
I feel tired 
0 
1 
2 
3 
4 
5 
I have trouble starting things 
0 
1 
2 
3 
4 
because I am tired 
6 
I have trouble finishing things 
0 
1 
2 
3 
4 
because I am tired 
7 
I have energy 
0 
1 
2 
3 
4 
8 
I am able to do my usual activities 
0 
1 
2 
3 
4 
9 
I need to sleep during the day 
0 
1 
2 
3 
4 
10 
I am too tired to eat 
0 
1 
2 
3 
4 
11 
I need help doing my usual activities 
0 
1 
2 
3 
4 
12 
I am frustrated by being too tired 
0 
1 
2 
3 
4 
to do the things I want to do 
13 
I have to limit my social activity 
0 
1 
2 
3 
4 
because I am tired 
 
Scoring: Items are scored as follows: 4=Not At All; 3=A Little Bit; 2=Somewhat; 1=Quite A Bit; 
0=Very Much, EXCEPT items #7 and #8 which are reversed scored. Total score range 0-52. 
Item Number 
Reverse Item? 
Item Response 
Item Score 
1 
4 
- 
= 
2 
4 
- 
= 
3 
4 
- 
= 
4 
4 
- 
= 
5 
4 
- 
= 
6 
4 
- 
= 
7 
0 
+ 
= 
8 
0 
+ 
= 
9 
4 
- 
= 
10 
4 
- 
= 
11 
4 
- 
= 
12 
4 
- 
= 
13 
4 
- 
= 
 
Sum individual item scores:   
  
 
 
 
 
 
 
 
 


Alexion Pharmaceuticals 
ACH471-205: 15 May 2020 (Version 7) 
Statistical Analysis Plan 
30 October 2020, Version 2 
 
 
 
Confidential 
Page 31 of 32 
 
 
Peds-FACIT-F and Calculation of Total Score 
Below is a list of statements that other people with your illness have said are important. Please circle or mark 
one number per line to indicate your response as it applies to the past 7 days. 
None of 
the time 
A little bit 
of the time 
Some of 
the time 
Most of the 
time 
All of the 
time 
1 
I feel tired 
0 
1 
2 
3 
4 
2 
I have energy (or strength) 
0 
1 
2 
3 
4 
3 
I could do my usual things at home 
0 
1 
2 
3 
4 
4 
I had trouble starting things because I was 
too tired 
0 
1 
2 
3 
4 
5 
I had trouble finishing things because I was 
0 
1 
2 
3 
4 
too tired 
6 
I needed to sleep during the day 
0 
1 
2 
3 
4 
7 
I got upset by being too tired to do things I 
wanted to do 
0 
1 
2 
3 
4 
8 
Being tired made it hard for me to play or go 
out with my friends as much as I’d like 
0 
1 
2 
3 
4 
9 
I needed help doing my usual things at home 
0 
1 
2 
3 
4 
10 
I feel weak 
0 
1 
2 
3 
4 
11 
I was too tired to eat 
0 
1 
2 
3 
4 
12 
Being tired made me sad 
0 
1 
2 
3 
4 
13 
Being tired made me mad (angry) 
0 
1 
2 
3 
4 
 
Scoring: Items are scored as follows: 4=Not At All; 3=A Little Bit; 2=Somewhat; 1=Quite A Bit; 
0=Very Much, EXCEPT items #2 and #3 which are reversed scored. Total score range 0-52. 
Tiredness Scale (score range: 0-44) 
Item Number 
Reverse Item? 
Item Response 
Item Score 
1 
4 
- 
= 
4 
4 
- 
= 
5 
4 
- 
= 
6 
4 
- 
= 
7 
4 
- 
= 
8 
4 
- 
= 
9 
4 
- 
= 
10 
4 
- 
= 
11 
4 
- 
= 
12 
4 
- 
= 
13 
4 
- 
= 
 
Sum individual item scores:   
  
Multiply by 11:   
 
Divide by number of items answered:    
 
 
 
 


Alexion Pharmaceuticals 
ACH471-205: 15 May 2020 (Version 7) 
Statistical Analysis Plan 
30 October 2020, Version 2 
 
 
 
Confidential 
Page 32 of 32 
 
 
Energy Scale (score range: 0-8) 
Item Number 
Reverse Item? 
Item Response 
Item Score 
2 
0 
+ 
= 
3 
0 
+ 
= 
 
Sum individual item scores:   
  
Multiply by 2:    
Divide by number of items answered:    
 
Total Score (score range: 0-52) 
Tiredness score + Enery score = Total score 
 
 
 
 
 
 
 
 
 
 
 
 
 

Prot_000.pdf: 
An Open-Label Phase 2 Proof-of-Concept Study in Patients 
with C3 Glomerulopathy (C3G) or Immune-Complex 
Membranoproliferative Glomerulonephritis (IC-MPGN) 
Treated with ACH-0144471 
Unique Protocol ID: 
NCT Number: 
EudraCT Number:  
Date of Protocol:  
ACH471-205 
NCT03459443 
2017-002674-39 
15 May 2020 


ACH 0144471 
Achillion Pharmaceuticals, Inc. (a subsidiary of 
Alexion Pharmaceuticals, Inc.). 
Clinical Protocol ACH471 205 Amendment 6 
15 May 2020 (Version 7.0) 
Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.) 
Page 1 of 91 
CLINICAL TRIAL PROTOCOL 
ACH471-205 
Study Title: 
An Open-Label Phase 2 Proof-of-Concept Study in Patients with C3 
Glomerulopathy (C3G) or Immune-Complex Membranoproliferative 
Glomerulonephritis (IC-MPGN) Treated with ACH-0144471 
Study Number: 
ACH471-205 
Study Phase: 
Phase 2 
Product Name: 
ACH-0144471 Tablets 
IND Number: 
129,916 
EudraCT 
Number: 
2017-002674-39 
WHO UTN: 
U1111-1203-9136 
Indication: 
C3 Glomerulopathy (C3G) or Immune-Complex 
Membranoproliferative Glomerulonephritis (IC-MPGN) 
Investigators: 
Sponsor: 
Achillion Pharmaceuticals, Inc. (a subsidiary of Alexion 
Pharmaceuticals, Inc.) 
Medical Monitor: 
 
 
nader.najafian@alexion.com 
Direct 
 Mobile 
 
Date 
Original Protocol: 
13 October 2017 (Version 1.0) 
Amendment 1 
01 December 2017 (Version 2.0) 
Amendment 2 
23 March 2018 (Version 3.0) 
Amendment 3 
02 November 2018 (Version 4.0) 
Amendment 4 
30 January 2019 (Version 5.0) 
Amendment 5 
22 July 2019 (Version 6.0) 
Amendment 6 
15 May 2020 (Version 7.0) 
Confidentiality Statement 
The information contained in this document, particularly unpublished data, is the property or under the control of Achillion 
Pharmaceuticals, Inc. (a subsidiary of Alexion Pharmaceuticals, Inc.), and is provided to you in confidence as an investigator, 
potential investigator, or consultant for review by you, your staff and an applicable Institutional Review Board and/or 
Independent Ethics Committee.  The information is only to be used by you and in connection with authorized clinical studies 
of the investigational drug described in the protocol.  You will not disclose any of the information to others without written 
authorization from Achillion Pharmaceuticals, except to the extent necessary to obtain informed consent from those persons to 
whom the drug may be administered. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


ACH 0144471 
Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
Clinical Protocol ACH471 205 Amendment 6 
15 May 2020 (Version 7.0) 
Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.) 
Page 2 of 91 
SPONSOR SIGNATURE(S) 
Study Title: 
An Open-Label Phase 2 Proof-of-Concept Study in Patients with C3 
Glomerulopathy (C3G) or Immune-Complex Membranoproliferative 
Glomerulonephritis (IC-MPGN) Treated with ACH-0144471 
Study Number: 
ACH471-205 
Protocol Version and 
Date 
15 May 2020 (Version 7.0) 
This clinical study protocol has been approved by the sponsor.   
Alexion Pharmaceuticals, Inc.
121 Seaport Blvd 
Boston, MA 02210 
Date 
 
 
 
22-May-2020 | 12:32:29 EDT
PPD
PPD


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Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
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(a subsidiary of Alexion Pharmaceuticals, Inc.) 
Page 3 of 91 
INVESTIGATOR’S SIGNATURE(S) 
Study Title: 
An Open-Label Phase 2 Proof-of-Concept Study in Patients with C3 
Glomerulopathy (C3G) or Immune-Complex Membranoproliferative 
Glomerulonephritis (IC-MPGN) Treated with ACH-0144471 
Study Number: 
ACH471-205 
Protocol Version and 
Date 
15 May 2020 (Version 7.0) 
I have read the protocol described above.  I agree to comply with all applicable regulations and 
to conduct the study as described in the protocol. 
 
 
<Name and Credentials/Title> 
<Affiliation/Company> 
<Address> 
<Address> 
<Phone Number> 
Date 
 
 
 
 


ACH 0144471 
Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
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Clinical Protocol ACH471 205 Amendment 6 
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Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.) 
Page 4 of 91 
SYNOPSIS 
Sponsor 
Achillion Pharmaceuticals, Inc. (a subsidiary of Alexion Pharmaceuticals, Inc.) 
121 Seaport Blvd 
Boston, MA 02210 
Phone: 
 
Name of Finished 
Product 
ACH-0144471 Tablet: 50 and 100 mg  
Name of Active 
Ingredient 
ACH-0144471 
Name of Inactive 
Ingredient 
ACH-0144471 Tablet: 
 
 
 
 
Study Title 
An Open-Label Phase 2 Proof-of-Concept Study in Patients with C3 Glomerulopathy 
(C3G) or Immune-Complex Membranoproliferative Glomerulonephritis (IC-MPGN) 
Treated with ACH-0144471 
Study Number 
ACH471-205 
Study Phase 
Phase 2 
Primary Objective 
To evaluate the efficacy of 12 months of oral ACH-0144471 in participants with C3G or 
IC-MPGN based on histologic scoring and proteinuria  
Secondary 
Objectives 
• 
To evaluate the clinical effect of 12 months of oral ACH-0144471 in 
participants with C3G or IC-MPGN based on significant improvement in 
slope of estimated glomerular filtration rate (eGFR) relative to baseline over 
time 
• 
To evaluate for improvement in eGFR following treatment with 
ACH-0144471  
• 
Where available evaluate the change in measured (m) eGFR relative to 
baseline at the end of 12 months of treatment with ACH-0144471 
• 
To evaluate the safety and tolerability of ACH-0144471 in participants with 
C3G or IC-MPGN by assessing serious adverse events (SAEs) 
PPD
PPD
PPD
CCI


ACH 0144471 
Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
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Clinical Protocol ACH471 205 Amendment 6 
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(a subsidiary of Alexion Pharmaceuticals, Inc.) 
Page 5 of 91 
Study Design 
This is an open-label study in which all participants will receive active treatment with 
ACH-0144471 for approximately 40 months.  The study will enroll approximately 
20 participants with biopsy-confirmed C3G or IC-MPGN, 12 years of age or older, who 
have not undergone renal transplant.  Participants who completed ACH471-201 are 
eligible to participate, as long as they do not meet any exclusion criteria. 
For all participants, eligibility will be confirmed based on the results from the screening 
eligibility assessments.  Once eligibility is confirmed, arrangements can be made for a 
renal biopsy (if necessary to confirm the diagnosis or to establish a baseline for adult 
participants who chose to participate in the renal biopsy sub-study) and/or vaccinations, 
as discussed below.  Biopsies will not be obtained from participants less than 18 years of 
age (unless a biopsy is determined to be clinically indicated by the treating provider), or 
from participants for whom a biopsy is contraindicated.  The initial screening visit must 
occur no more than 75 days before the first dose date.   
All participants should be vaccinated against Haemophilus influenzae (H. influenzae), 
Streptococcus pneumoniae (S. pneumoniae), and Neisseria meningitidis (N. meningitidis) 
as recommended by the Advisory Committee on Immunization Practices (ACIP) 
guidelines at least 2 weeks before the start of dosing ACH-0144471, as described in 
Section 6.4, to minimize the risk of serious infection with an encapsulated organism, 
unless otherwise recommended by local vaccination guidelines, or precluded by licenses 
or availability.  The PI may institute additional prophylactic measures, including the use 
of prophylactic antibiotics, if deemed appropriate by local clinical practice and/or 
guidelines for treatment with a complement inhibitor. 
The starting dosage will be 100 mg of ACH-0144471 TID, for a total daily dose of 
300 mg.  After 2 weeks of treatment, dosing will be escalated to 200 mg TID (or 150 mg 
TID for participants less than 60 kg). Additional dosage regimens may be investigated if 
supported by emerging data from this and other clinical studies. Upon treatment 
discontinuation, regardless of the timing or reasons for discontinuation, a 6-day taper 
period is required unless the PI determines this taper period poses a risk to the participant.  
The taper period is in place to prevent the theoretical risk of marked increase or rebound 
in complement activity, as described in Section 5.1.1. 
Renal Biopsies and Renal Biopsy Sub-Study 
Participants must have biopsy-confirmed primary C3G or IC-MPGN.  This can be a 
historical biopsy.  If no historical biopsy is available, a renal biopsy should be performed 
during the screening period, and the results must be available and reviewed before the 
first dose of ACH‑0144471. Biopsy will be obtained from participants at the 12 months 
timepoint (Week 52) if older than 18 years of age and not contraindicated. 
A sub-study is being conducted to evaluate the effects of ACH‑0144471 on renal 
pathology; participation in this study is not required.  For participants in the renal biopsy 
sub-study, biopsies will be obtained prior to dosing and after approximately 6 and/or 
24 months of dosing.    If for any reason, any additional renal biopsies are performed (e.g. 


ACH 0144471 
Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
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(a subsidiary of Alexion Pharmaceuticals, Inc.) 
Page 6 of 91 
for a clinical indication), then every effort will be made to make these biopsy samples 
and results available to the central pathology laboratory for evaluation.  
Study Visit 
Schedule 
On Day 1, the required pre-dose assessments will be obtained, followed by administration 
of the first dose of ACH-0144471.   
At each visit, safety and efficacy will be assessed.  Safety assessments may include 
physical examination, vital signs, electrocardiogram (ECG) measurements and safety 
laboratory testing.  Samples will be collected for measurement of complement 
biomarkers and PK analysis at selected visits as specified in the Schedule of Assessments 
(Appendix 1).  Quality of Life and Patient Reported Outcomes assessments will occur 
according to the Schedule of Assessments. If a participant discontinues from the study 
prior to Week 104, study participation is not necessarily immediately terminated.  
Instead, whenever possible, dosing of ACH-0144471 should be tapered over 6 days.  
Whether dosing is tapered or not, all participants should return for two follow-up visits, 2 
and 4 weeks after the last dose of ACH-0144471. 
Treatment Groups: 
There will be a single treatment group, and all participants will receive active treatment 
with ACH-0144471 
Study Population 
Participants must have biopsy-confirmed C3G or IC-MPGN, must have an eGFR 
>30 mL/min/1.73 m2, and must not have undergone renal transplant 
Number of 
Participants 
Approximately 20 
Inclusion Criteria 
Each participant must meet all of the following criteria to be enrolled in this study: 
1. Must have completed the C3G Proof of Mechanism (POM) study (ACH471-
201) (participation in the long-term follow-up portion of ACH471-201 is not 
required), followed by a washout period of at least 30 days 
OR  
Must meet all the following criteria: 
a. 
Must have biopsy-confirmed primary C3G or IC-MPGN  
b. Must have clinical evidence of ongoing disease based on significant 
proteinuria (defined as ≥500 mg/day of protein in a 24-hour urine) 
attributable to C3G disease or IC-MPGN in the opinion of the PI, and 
present prior to study entry and confirmed during Screening.  
c. 
If a pre-treatment biopsy is obtained, or if a historical biopsy is available for 
review, it must have no more than 50% global fibrosis and no more than 
50% of glomeruli with cellular crescents  
d. Must be 12 years or age or older and capable of swallowing tablets 


ACH 0144471 
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2. If on corticosteroids, anti-hypertensive medications, anti-proteinuric medications 
(e.g., ACE inhibitors or angiotensin receptor blockers [ARBs]), or 
mycophenolate mofetil (MMF), must be on a stable dose for at least 2 weeks 
prior to screening 
3. Female participants of childbearing potential must agree to use an acceptable 
method of contraception (as defined in Section 5.5.4) from the date of signing 
the informed consent to the first day of dosing (Day 1), and must agree to use a 
highly effective form of contraception (as defined in Section 5.5.4) from the first 
day of dosing to 30 days after their last dose of study drug.  Female participants 
of childbearing potential must also have a negative serum pregnancy test during 
Screening and negative urine pregnancy test on Day 1.  Female participants of 
non-childbearing potential need not employ a method of contraception.  
4. Non-sterile male participants must agree to use a highly effective form of 
contraception (as defined in Section 5.5.4) with their partner(s) of childbearing 
potential from the first day of dosing to 90 days after their last dose of study 
drug.  Male participants who are surgically sterile need not employ additional 
contraception.  Male participants must agree not to donate sperm while enrolled 
in this study and for up to 90 days after their last dose of study drug. 
5. Adult participants must be capable of providing written informed consent and 
adolescent participants must be capable of providing written assent.  All 
participants must be willing and able to comply with the requirements and 
restrictions listed in the consent form and with all procedures in the protocol, 
including, the visit schedule, the treatment plan, the schedule for laboratory 
testing, and other study procedures 
6. Must be up-to-date on routine vaccinations, or willing to be brought up-to-date, 
based on local guidelines 
7. Must have access to emergency medical care 
Exclusion Criteria 
Participants who meet any of the following criteria will be excluded from the study. 
1. Have a history of a major organ transplant (e.g., heart, lung, kidney, liver) or 
hematopoietic stem cell/marrow transplant  
2. Have a history or presence of any clinically relevant co-morbidities that would 
make the participant inappropriate for the study (for example, a comorbidity 
which is likely to result in deterioration of the participant’s condition, affect the 
participant’s safety during the study, or confound the results of the study), in the 
opinion of the PI 
3. Have an estimated GFR <30 mL/min/1.73 m2 at the time of screening or at any 
time over the preceding four weeks 
4. Is a renal transplant recipient or receiving renal replacement therapy 
5. Have other renal diseases that would interfere with interpretation of the study  
6. Have evidence of monoclonal gammopathy of unclear significance (MGUS), 
infections, malignancy, autoimmune diseases, or other conditions to which C3G 
or IC-MPGN is secondary 
7. Have been diagnosed with or show evidence of hepatobiliary cholestasis  
8. Females who are pregnant, nursing, or planning to become pregnant during the 
study or within 90 days of ACH-0144471 administration or participants with a 


ACH 0144471 
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Confidential Property of Achillion Pharmaceuticals, Inc. 
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Page 8 of 91 
female partner who is pregnant, nursing, or planning to become pregnant during 
the study or within 90 days of ACH-0144471 administration 
9. Have a history of febrile illness, a body temperature >38°C, or other evidence of 
a clinically significant active infection, within 14 days prior to ACH-0144471 
administration 
10. Have evidence of human immunodeficiency virus (HIV), hepatitis B infection, 
or active hepatitis C infection at Screening  
11. Have a history of meningococcal infection within the prior year  
12. Have a history of hypersensitivity reactions to commonly used antibacterial 
agents, including beta-lactams, penicillin, aminopenicillins, fluoroquinolones, 
cephalosporins, and carbapenems, which, in the opinion of the investigator 
and/or an appropriately qualified immunology or infectious disease expert, 
would make it difficult to properly provide either empiric antibiotic therapy or 
treat an active infection. 
13. Have participated in a clinical study in which an investigational drug was given 
within 30 days, or within 5 half-lives of the investigational drug, whichever is 
longer, prior to the first dose of ACH-0144471  
14. Have received eculizumab at any dose or interval within the past 50 days prior 
to the first dose of ACH-0144471 
15. Have received tacrolimus or cyclosporine within 2 weeks of the first dose of 
ACH-0144471 
16. Have a 12-lead ECG with a QTcF >450 msec for males or >470 msec for 
females, or have ECG findings which, in the opinion of the PI, could put the 
participant at undue risk 
17. Have received any drug known to prolong the QTc interval within 2 weeks of 
the first dose of ACH-0144471 and which, in the opinion of the PI, could put the 
participant at undue risk 
18. Have any of the following laboratory abnormalities at screening:  
 
Alanine transaminase (ALT) > upper limit of normal (ULN)  
 
Aspartate aminotransferase (AST) > ULN  
 
Absolute neutrophil counts (ANC) <1,000/μL 
 
Total bilirubin >1.5× ULN 
 
Indirect bilirubin > ULN 
 
Any laboratory abnormality that, in the opinion of the PI, would make the 
participant inappropriate for the study 
19. Are unwilling or unable to comply with the study protocol for any reason 
Study Stopping 
Rules 
The safety of dose continuation will be assessed within 24 hours if one or more of the 
following occurs: 
• 
Two or more participants experience the same or similar study drug-related 
serious adverse event 
• 
Two or more participants experience the same or similar study drug-related 
Grade 4 or higher adverse events 


ACH 0144471 
Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
Clinical Protocol ACH471 205 Amendment 6 
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Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.) 
Page 9 of 91 
• 
Two or more participants discontinue study therapy due to study drug-
related liver function test abnormalities detailed in the Stopping Rules for 
Individual Participants  
If dosing is terminated in one or more study participants, all these participants will be 
expected to complete the study by complying with the schedule for the Taper Period (if 
relevant) and Follow-Up Period.  Of note, additional visits beyond those specified in the 
protocol may be required if needed to ensure adequate safety monitoring. 
Stopping Rules for 
Individual 
Participants 
Any individual participant who meets any of the following criteria may be discontinued 
from further dosing: 
• 
The participant experiences a serious, unexpected suspected adverse reaction 
• 
The PI believes that participant continuation in the study is not advisable or the 
participant withdraws from the study or meets one of the conditions described in 
Section 6.22, including, but not limited to: 
• 
The participant becomes pregnant 
• 
Intercurrent illness that would, in the judgment of the investigator, affect 
assessments of clinical status to a significant degree 
• 
Participant requests to discontinue for any reason 
Discontinuation of treatment should also be considered if:  
• 
ALT or AST >8× ULN  
• 
ALT or AST >5× ULN for more than 2 weeks  
• 
ALT or AST >3× ULN and concomitant total bilirubin >2× ULN and/or 
International Normalized Ratio [INR]* >1.5 
• 
ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
* Participants, particularly those with nephrotic syndrome, may be receiving ongoing 
warfarin, resulting in increased INR values.  The PI should evaluate INR in the context of 
any concomitant medications to determine if any observed increases are due to an effect 
on liver function or are secondary to anticoagulation.  
Upon dosing termination, a participant will be expected to complete the study, if possible, 
by complying with the schedule for the Taper Period (if relevant) and Follow Up Period.  
Of note, additional visits beyond those specified in the protocol may be required if 
needed to ensure adequate safety monitoring. 
Duration of 
Treatment, 
Confinement, and 
Total Study 
Participation 
Screening is up to 75 days, treatment is approximately 40 months (including the taper), 
and follow-up is an additional 28 days. Therefore, the total duration of participation will 
be up to 44 months.  
Safety 
Assessments: 
Safety assessments will include assessment of AEs, clinical laboratory tests, physical 
examination findings, and vital signs measurements, and 12-lead ECG recordings at 
screening, baseline, and at various time points during the study as listed in the schedule of 
assessments (Appendix 1).  


ACH 0144471 
Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
Clinical Protocol ACH471 205 Amendment 6 
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Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.) 
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Pharmacokinetic 
Assessments: 
Single trough PK samples will be taken at the time points as listed in the schedule of 
assessments (Appendix 1). 
Pharmacodynamic 
and Efficacy 
Assessments 
Pharmacodynamics will be evaluated using serum, plasma, and/or urine collected at the 
time points as listed in the schedule of assessments (Appendix 1). 
Samples will be collected and retained for non-genetic complement-associated biomarker 
testing. 
Patient-Reported 
Outcomes 
Assessments 
Patient-reported outcome (PRO) questionnaires will be administered at screening, Week 
28, 52 and 104, and at follow-up as specified in the Schedule of Assessments in 
Appendix 1, to assess participants’ health-related quality of life, fatigue, and kidney-
related symptoms, and to determine health states value over the course of treatment with 
ACH-0144471.  The questionnaires are: 
 
Adult participants: 
• 
KDQOL-SF v1.3 questionnaire 
• 
FACIT-Fatigue scale version 4.0 
• 
EQ-5D-3L questionnaire 
Adolescent participants: 
• 
Peds-FACIT-F questionnaire 
• 
EQ-5D-Y questionnaire 
Statistical 
Methods:  
Primary efficacy endpoints: 
• 
Change from baseline in biopsy, based on a score incorporating changes in both 
the activity index and C3 staining at the end of 12 months of treatment. 
• 
Number and percent of participants with reduction in proteinuria relative to 
baseline at the end of 12 months of treatment 
Secondary efficacy endpoints: 
Number and proportion of participants with significant (≥25%) increase in eGFR 
relative to baseline at the end of 12 months of treatment  
• 
Change and percent change from baseline in proteinuria and eGFR over 12 
months of treatment period for all participants  
• 
Change and percent change from baseline in eGFR over 12 months of 
treatment for participants meeting eGFR inclusion criterion at study entry  
• 
Descriptive analysis of slope of GFR over the treatment period of 
ACH-0144471 therapy 
Safety endpoints: 
• 
Number and incidence of 
− 
SAEs 


ACH 0144471 
Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
Clinical Protocol ACH471 205 Amendment 6 
15 May 2020 (Version 7.0) 
Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.) 
Page 11 of 91 
− 
AEs leading to discontinuation of the study medication 
− 
Grade 3 or 4 AEs (related and regardless of relationship to study 
medication) 
− 
Grade 3 or 4 Laboratory abnormalities 
− 
Treatment-emergent vital signs, physical exam results, and ECG 
abnormalities 
Descriptive statistical and confidence interval procedures will be utilized for both primary 
and secondary efficacy endpoints.  Summary statistics will be provided for safety 
endpoints.  No inferential statistical procedures will be used for safety endpoints, unless 
clinically deemed necessary and appropriate.  
Details of statistical analysis strategies and methodologies will be described in the 
statistical analysis plan (SAP). 
 


ACH 0144471 
Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
Clinical Protocol ACH471 205 Amendment 6 
15 May 2020 (Version 7.0) 
Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.) 
Page 12 of 91 
TABLE OF CONTENTS 
SPONSOR SIGNATURE(S) ...........................................................................................................2 
INVESTIGATOR’S SIGNATURE(S) ............................................................................................3 
SYNOPSIS ......................................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................12 
LIST OF TABLES .........................................................................................................................16 
LIST OF FIGURES .......................................................................................................................16 
LIST OF APPENDICES ................................................................................................................17 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................18 
1. 
INTRODUCTION ......................................................................................................21 
1.1. 
Previous Experience with ACH-0144471 ..................................................................21 
1.2. 
Background .................................................................................................................21 
1.2.1. 
Complement Factor D .................................................................................................21 
1.2.2. 
C3 Glomerulopathy ....................................................................................................22 
1.2.3. 
Immune-Complex Membranoproliferative Glomerulonephritis (IC-MPGN) ............23 
2. 
STUDY OBJECTIVES ..............................................................................................24 
2.1. 
Primary Objective .......................................................................................................24 
2.2. 
Secondary Objectives .................................................................................................24 
2.3. 
Other Objectives .........................................................................................................24 
3. 
INVESTIGATIONAL PLAN .....................................................................................25 
3.1. 
Overall Study Design and Plan ...................................................................................25 
3.2. 
Rationale for Study Design .........................................................................................26 
3.2.1. 
Justification of Design ................................................................................................26 
3.2.1.1. 
Participant Population .................................................................................................27 
3.2.1.2. 
Endpoints ....................................................................................................................27 
3.2.1.3. 
Duration of Treatment ................................................................................................30 
3.2.1.4. 
Safety Monitoring Plan ...............................................................................................30 
3.2.2. 
Justification of Dose ...................................................................................................31 
3.2.3. 
Stopping Criteria and End-of-Study Definition ..........................................................32 
3.2.3.1. 
Study Stopping Rules .................................................................................................33 
3.2.3.2. 
Stopping Rules for Individual Participants .................................................................33 
4. 
STUDY POPULATION SELECTION ......................................................................35 


ACH 0144471 
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4.1. 
Study Population .........................................................................................................35 
4.2. 
Inclusion Criteria ........................................................................................................35 
4.3. 
Exclusion Criteria .......................................................................................................36 
5. 
STUDY TREATMENT(S) .........................................................................................38 
5.1. 
Description of Treatment(s) ........................................................................................38 
5.1.1. 
Study Drug ..................................................................................................................38 
5.2. 
Treatment(s) Administered .........................................................................................38 
5.2.1. 
ACH-0144471 .............................................................................................................38 
5.2.2. 
Vaccines ......................................................................................................................38 
5.2.3. 
Prophylactic Antibiotics .............................................................................................38 
5.3. 
Selection of Timing and Dose for Each Participant ...................................................39 
5.3.1. 
Clinic Visit Dose Administration Instructions ...........................................................39 
5.3.2. 
Home Dose Administration Instructions ....................................................................39 
5.3.3. 
Dose Adjustment ........................................................................................................39 
5.4. 
Method of Assigning Participants to Treatment Groups ............................................40 
5.5. 
Restrictions .................................................................................................................40 
5.5.1. 
Prior and Concomitant Therapy ..................................................................................40 
5.5.2. 
Fluid and Food Intake .................................................................................................41 
5.5.3. 
Participant Activity and Other Restrictions ................................................................42 
5.5.4. 
Contraception ..............................................................................................................42 
5.5.4.1. 
Contraception for Male Participants ...........................................................................42 
5.5.4.2. 
Contraception for Female Participants .......................................................................43 
5.6. 
Treatment Compliance ................................................................................................44 
5.7. 
Packaging and Labeling ..............................................................................................44 
5.8. 
Storage and Accountability .........................................................................................44 
5.9. 
Investigational Product Retention at Study Site .........................................................45 
6. 
STUDY PROCEDURES ............................................................................................46 
6.1. 
Informed Consent or Assent .......................................................................................46 
6.2. 
Medical History ..........................................................................................................46 
6.3. 
Percutaneous Renal Biopsy ........................................................................................46 
6.3.1. 
Renal Biopsy Assessment ...........................................................................................47 
6.4. 
Vaccination .................................................................................................................47 


ACH 0144471 
Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
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6.5. 
Prophylactic Antibiotics .............................................................................................48 
6.6. 
Urine Collection ..........................................................................................................48 
6.6.1. 
24-Hour Urine Collection ...........................................................................................48 
6.6.2. 
First Morning Urine Collection ..................................................................................48 
6.7. 
Physical Examination .................................................................................................49 
6.8. 
Vital Signs ..................................................................................................................49 
6.9. 
Body Temperature ......................................................................................................49 
6.10. 
Electrocardiography ....................................................................................................50 
6.11. 
Clinical Laboratory Tests ...........................................................................................51 
6.12. 
Pregnancy Testing ......................................................................................................53 
6.13. 
Sample Collection, Storage, and Shipping .................................................................53 
6.13.1. 
Blood and Urine Collection for Complement Assays ................................................53 
6.13.2. 
Blood Collection for Genetic Complement-Associated Biomarker Testing ..............54 
6.13.3. 
PK Plasma Samples ....................................................................................................54 
6.13.4. 
Blood Volumes ...........................................................................................................55 
6.14. 
Dispensing Study Drug ...............................................................................................55 
6.15. 
Safety Assessments .....................................................................................................55 
6.16. 
Pharmacokinetic Assessments ....................................................................................55 
6.17. 
Pharmacodynamic Assessments .................................................................................55 
6.18. 
Patient-Reported Outcomes Assessments ...................................................................56 
6.18.1. 
Quality of Life Questionnaires ...................................................................................56 
6.19. 
Adverse Events Assessments ......................................................................................56 
6.19.1. 
Definitions ..................................................................................................................56 
6.19.2. 
Criteria for Assessing Seriousness ..............................................................................58 
6.19.3. 
Documentation and Reporting of Adverse Events .....................................................59 
6.19.4. 
Treatment and Follow-Up of Adverse Events ............................................................59 
6.19.5. 
Timeframe for Collection of Adverse Events .............................................................59 
6.19.6. 
Severity and Grading of Adverse Events ....................................................................60 
6.19.7. 
Assessment of Causality .............................................................................................60 
6.19.8. 
Pregnancy ...................................................................................................................61 
6.19.9. 
Reporting Serious Adverse Events .............................................................................61 
6.19.10. 
Investigator Reporting Requirements for SAEs .........................................................62 


ACH 0144471 
Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
Clinical Protocol ACH471 205 Amendment 6 
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6.20. 
Concomitant Medication Assessments .......................................................................62 
6.21. 
Monitoring Participant Safety .....................................................................................62 
6.22. 
Removal of Participants from the Trial or Study Drug ..............................................63 
6.23. 
Study Assessments When Clinic Visits are Not Possible due to the COVID-19 
Pandemic .....................................................................................................................63 
6.24. 
Study Drug Compliance and Supply When Clinic Visits are Not Possible ...............64 
6.25. 
Renal Biopsies When Clinic Visits are Not Possible .................................................64 
7. 
STUDY ACTIVITIES ................................................................................................65 
7.1. 
Screening Period (Days –75 to -1) ..............................................................................65 
7.1.1. 
Screening or Pre-Treatment Renal Biopsy .................................................................66 
7.1.2. 
Vaccination .................................................................................................................66 
7.2. 
Treatment Period ........................................................................................................66 
7.3. 
Taper Period ................................................................................................................66 
7.4. 
Follow-Up Period .......................................................................................................67 
7.5. 
Early Termination from the Study ..............................................................................67 
7.6. 
Unscheduled Visits .....................................................................................................67 
8. 
QUALITY CONTROL AND ASSURANCE ............................................................69 
8.1. 
Routine Monitoring ....................................................................................................69 
8.2. 
Site Audits ..................................................................................................................69 
9. 
PLANNED STATISTICAL METHODS ...................................................................70 
9.1. 
General Considerations ...............................................................................................70 
9.2. 
Determination of Sample Size ....................................................................................70 
9.3. 
Analysis Populations ..................................................................................................70 
9.4. 
Demographics and Baseline Characteristics ...............................................................70 
9.5. 
Efficacy, including Pharmacodynamics Analysis ......................................................71 
9.6. 
Safety Analysis ...........................................................................................................72 
10. 
ADMINISTRATIVE CONSIDERATIONS ..............................................................73 
10.1. 
Investigators and Study Administrative Structure ......................................................73 
10.2. 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) and 
Regulatory Approval ..................................................................................................73 
10.2.1. 
Ethical Approval .........................................................................................................73 
10.2.2. 
Regulatory Approval ..................................................................................................73 
10.2.3. 
Amendments ...............................................................................................................73 


ACH 0144471 
Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
Clinical Protocol ACH471 205 Amendment 6 
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(a subsidiary of Alexion Pharmaceuticals, Inc.) 
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10.3. 
Ethical Conduct of the Study ......................................................................................73 
10.4. 
Participant Information and Consent ..........................................................................74 
10.5. 
Participant Confidentiality ..........................................................................................74 
10.6. 
Study Monitoring ........................................................................................................75 
10.6.1. 
Access to Information for Monitoring ........................................................................75 
10.6.2. 
Access to Information for Auditing or Inspections ....................................................75 
10.7. 
Case Report Forms and Study Records ......................................................................75 
10.7.1. 
Recording of Data .......................................................................................................75 
10.7.2. 
Source Documentation and Medical/Study Records ..................................................75 
10.8. 
Protocol Deviations ....................................................................................................76 
10.9. 
Access to Source Documentation ...............................................................................76 
10.10. 
Data Generation and Analysis ....................................................................................76 
10.11. 
Retention of Data ........................................................................................................76 
10.12. 
Study and Site Closure ................................................................................................77 
10.13. 
Final Report, Publication and Disclosure Policy ........................................................77 
11. 
REFERENCES ...........................................................................................................79 
12. 
APPENDICES ............................................................................................................83 
 
LIST OF TABLES 
Table 1. 
ACH-0144471 Taper Schedule ...................................................................................38 
Table 2. 
Clinical Laboratory Tests ...........................................................................................52 
Table 3. 
Approximate Total Blood Volumes ............................................................................55 
Table 4. 
Schedule of Assessments – Screening through Week 12 ...........................................83 
Table 5. 
Schedule of Assessments – Week 16 through Week 52 .............................................86 
Table 6. 
Schedule of Assessments – 27 Month Long Term Follow-up, with Taper and 
Follow-up ....................................................................................................................89 
 
LIST OF FIGURES 
Figure 1. 
Study Schematic .........................................................................................................26 
Figure 2. 
Simulated Adult PK Profile of ACH-0144471 after 200 mg TID for 14 days ...........32 
Figure 3. 
Simulated Adolescent PK Profile of ACH-0144471 after 165 mg TID for 
14 days ........................................................................................................................32 
 


ACH 0144471 
Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
Clinical Protocol ACH471 205 Amendment 6 
15 May 2020 (Version 7.0) 
Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.) 
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LIST OF APPENDICES 
Appendix 1. Schedule of Assessments ........................................................................................83 
Appendix 2. Fever Management Plan .........................................................................................91 
 


ACH 0144471 
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Clinical Protocol ACH471 205 Amendment 6 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
Ab 
Antibody 
ACE 
Angiotensin converting enzyme 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
AP 
Alternative Pathway (of complement)  
ARBs 
Angiotensin receptor blockers 
AST 
Aspartate aminotransferase 
AUC  
Area under the curve 
BA 
Bioavailability 
Ba 
Ba fragment of complement factor B 
Bb 
Bb fragment of complement factor B 
BID 
“bis in die” or twice daily 
BMI 
Body mass index 
BP 
Blood pressure 
°C 
Degrees Celsius 
C3 
C3 complement protein 
C3a 
Complement cleavage fraction of C3 
C4 
C4 complement protein 
C5 
C5 complement protein 
C5a 
Complement cleavage fraction of C5 
C6 
C6 complement protein 
CFHR-5 
Complement Factor H Related – 5 gene 
C3G 
C3 glomerulopathy 
C3GN 
C3 glomerulonephritis 
CFU 
Colony-forming unit 
CKD 
Chronic kidney disease 
CKD-EPI 
Chronic kidney disease - Epidemiology collaboration 
Cmax 
Maximum plasma concentration 
CP 
Classical pathway (of complement) 
CRF 
Case report form 
CT 
Computed tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DDD 
Dense deposit disease 
DDI 
Drug-drug interaction 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ELISA 
Enzyme-linked immunosorbent assay 
EM 
Electron microscopy 
EQ-5D-3L 
Three-level version of EuroQol 5 Dimensions questionnaire 
ESRD 
End stage renal disease 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy-Fatigue scale version 4.0 
fB 
(Complement) Factor B 
fD 
(Complement) Factor D 
FDA 
Food and Drug Administration 
fH 
(Complement) Factor H 
fI 
(Complement) Factor I 


ACH 0144471 
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Alexion Pharmaceuticals, Inc.). 
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Abbreviation 
Definition 
FSH  
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
HbsAg 
Hepatitis B surface antigen 
Hct 
Hematocrit 
HCV 
Hepatitis C virus 
Hgb 
Hemoglobin  
H&E 
Hematoxylin & eosin stain 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
Human immunodeficiency virus 
HRQOL 
Health-related quality of life 
HR 
Heart rate 
iC3b 
Complement cleavage fragment of C3b 
IC-MPGN 
Immune-Complex Membranoproliferative Glomerulonephritis  
ICH 
International Conference on Harmonisation 
IEC  
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional review board 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
kDa 
Kilodalton 
KDQOL-SF 
v1.3 
Kidney Disease Quality of Life short form questionnaire version 1.3 
LFC 
Liquid filled capsule 
LLN 
Lower limit of normal 
LP 
Lectin pathway (of complement) 
MAD 
Multiple-ascending dose 
MCP 
Membrane Co-Factor Protein 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MenB 
Meningococcal B 
MGUS 
Monoclonal gammopathy of unclear significance 
MM 
Medical monitor 
MMF 
Mycophenolate mofetil 
MPA 
Mycophenolic acid 
msec 
Millisecond 
NIH 
National Institute of Health (US) 
NOAEL 
No observed adverse effect level 
PAS 
Periodic acid-Schiff 
PD 
Pharmacodynamic(s) 
PI 
Principal investigator 
PK 
Pharmacokinetic(s) 
POC 
Proof of Concept 
PR interval 
Period that extends from the beginning of the P wave until the beginning of the QRS complex 
PRO 
Patient-reported outcome 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QRS 
Group of electrocardiogram waves comprising the Q, R, and S waves 
QT 
Period (in milliseconds) from the beginning of the QRS complex until the end of the T wave 
QTcF 
QT interval Fridericia Correction Formula  
RBC  
Red blood cells 
Relative BA 
Relative bioavailability study 
RR 
Respiration rate 
SAD 
Single-ascending dose 


ACH 0144471 
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Abbreviation 
Definition 
SAE  
Serious adverse event 
SAP  
Statistical Analysis Plan 
sC5b-9 
Soluble terminal complement complex  
SD 
Standard deviation 
SLE 
Systemic lupus erythematosus 
SUSAR 
Serious, unexpected suspected adverse reaction 
TEAE 
Treatment-emergent adverse event 
THBD 
Thrombomodulin 
tmax 
Time after administration of a drug when the maximum plasma concentration is reached 
UGT 
UDP-gluronosyltransferase 
ULN 
Upper limit of normal 
WBC  
White blood cells 
Wk 
Week 


ACH 0144471 
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1. 
INTRODUCTION 
ACH-0144471, a small molecule, orally administered, factor D (fD) inhibitor, is in development 
by Achillion Pharmaceuticals, Inc. (“Achillion”, or the sponsor), a subsidiary of Alexion 
Pharmaceuticals, Inc., for the treatment of complement-related diseases, such as paroxysmal 
nocturnal hemoglobinuria (PNH) and C3 glomerulopathy (C3G).  Factor D is a serine protease 
that catalyzes the cleavage of factor B, a rate-limiting step in the alternative pathway (AP) of 
complement.  By inhibiting fD, ACH-0144471 potently and specifically inhibits AP activity. 
Because C3G is a disease of AP hyperactivity, ACH-0144471 represents an ideal therapeutic 
approach to C3G, as it has the potential to reverse the underlying pathophysiology of the disease.  
Primary immune-complex membranoproliferative glomerulonephritis (IC-MPGN), which shares 
many clinical, pathologic, genetic, and laboratory features with C3G and in which complement 
also likely plays a key role, may also be an attractive therapeutic target. 
This protocol is a multiple-center, open-label study in which participants with C3G or primary 
IC-MPGN will receive ACH-0144471 for approximately 40 months (including the taper period).  
In preceding studies, it has been demonstrated that ACH-0144471 inhibits AP activity.  This 
study will assess the ability of ACH-0144471 to inhibit AP activity, in the setting of AP over-
activation in participants with C3G or primary IC-MPGN.  Doses for this study were selected 
based on available data from the completed and ongoing studies in healthy volunteers, and from 
PNH patients and C3G patients treated in other clinical studies. 
1.1. 
Previous Experience with ACH-0144471 
A detailed description of the chemistry, pharmacology, efficacy, and safety of ACH-0144471 is 
provided in the Investigator’s Brochure [1]. 
1.2. 
Background 
1.2.1. 
Complement Factor D 
Factor D is one of nine serine proteases in the complement system.  It is a highly specific 
enzyme with only one known substrate, fB.  Of all the complement proteins, it has the lowest 
abundance in serum with a concentration of approximately 2 µg/mL and is the rate-limiting step 
of AP activation [2, 3].  It is a low molecular weight protein (24 kDa) that is primarily produced 
by adipocytes, but can also be produced and secreted by monocytes/macrophages and astrocytes 
in humans [2, 3].  Due to its small size, it is freely filtered at the glomerulus, and then taken up 
by the proximal tubule cell where it is catabolized with an estimated fractional catabolic rate of 
60% per hour.  It is this rapid catabolism that is responsible for maintaining low circulating fD 
levels.  As a result, renal dysfunction is associated with elevated fD levels, which may lead to 
increased alternative pathway activity and inflammation [4, 5].  The biochemical, physiological, 
and functional features of fD make it an attractive target for pharmacological inhibition as this 
may prove useful in the treatment of a wide spectrum of complement-mediated diseases, 
including C3G and IC-MPGN. 


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1.2.2. 
C3 Glomerulopathy  
C3 glomerulopathy (C3G) is an ultra-rare disease with an incidence rate of approximately 2 per 
million people worldwide [6, 7].  It is widely accepted that C3G is attributable to excessive 
alternative pathway (AP) activity [8].  Although the disease is typically diagnosed during early 
adulthood in a majority of patients, the manifestations of glomerular C3 deposition can be 
detected in childhood and thus, it may be clinically meaningful to treat patients as young as 
12 years of age [7, 9, 10].  The clinical course of C3G is characterized by variable amounts of 
proteinuria, hematuria, hypertension, and decreased renal function, with approximately 30% to 
50% of patients reaching end-stage renal disease (ESRD) within 10 years of diagnosis [7, 11, 12, 
13].  The diagnosis is based on predominant deposition of C3 in the glomerulus on renal biopsy 
along with clinical evidence of AP hyperactivity.  C3G can be further subdivided into two 
separate entities, dense deposit disease (DDD) and C3 glomerulonephritis (C3GN), based on 
electron microscopic features of the renal pathology [8].  Although the two disorders have 
similar clinical features, DDD tends to present earlier in life than C3GN.  However, both 
diseases can present in either childhood or adulthood [13]. 
Unfortunately, no specific therapy has proven effective for the treatment of C3G.  Care is 
therefore largely non-specific and supportive.  Given the lack of available therapeutic options, 
immunosuppressive and plasma infusion/exchange therapy are often attempted, as a subset of 
patients may benefit [13, 14].  Treatment is otherwise focused on management of hypertension, 
proteinuria and the manifestations of chronic kidney disease.   
The overall prognosis of C3G is poor, with approximately 30% to 50% of patients progressing to 
ESRD within 10 years of diagnosis.  Dialysis and renal transplantation are options available for 
patients who reach ESRD; however, disease recurrence is frequent after transplantation, 
occurring in more than 50% of patients.  Only about 50% of patients have a functioning graft 
5 years after transplantation, which is significantly lower than renal graft survival in other 
settings [13, 14, 15]. 
Studies in animal models have indicated that the pathophysiology of C3G strongly relates to an 
excessive AP activity at the level of the C3 convertase.  Specifically, mouse factor H-deficient 
animals have evidence of uncontrolled alternative pathway activation, with low plasma levels of 
intact C3, high levels of C3 breakdown product and renal pathology consistent with C3G; yet, in 
mice deficient in both factor H (fH) and fD (knock-out mice), serum C3 levels were similar to 
wild-type and dense deposits were not present in the kidneys [16, 17].  These studies confirmed 
that removal of fD prevented the renal pathogenesis of C3G in the factor H-deficient mice. 
Given that the pathophysiology of C3G derives from excessive C3 activation through the AP, 
treatment of the disease with an AP complement inhibitor is logical.  Eculizumab, the only 
commercially available complement inhibitor, has been tested in patients with C3G, even though 
its mechanism of action (targeting the terminal complement pathway) would not be expected to 
affect C3 activation.  Based on the published results of an open-label trial in 20 patients, the 
general consensus is that only a subset of patients appears to benefit from eculizumab therapy; 
however, identification of these patients prior to treatment remains a challenge [8, 13, 14, 18].  It 
has been suggested that response to eculizumab may be more likely in those patients with 
elevated soluble C5b-9 levels, indicative of excessive terminal pathway activity, although this 
hypothesis remains to be established [18]. 


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A fD inhibitor like ACH-0144471, which inhibits directly at the level of the AP C3 convertase 
formation, provides a more targeted rationale for efficacy than existing complement inhibitors 
that target the terminal complement pathway.  This hypothesis is supported by animal data in 
which the renal disease observed with factor H deficiency, which is similar to human C3G, was 
completely prevented in the setting of simultaneous fD or fB deficiency [16, 17].  In contrast C5 
deficiency only ameliorated, but did not prevent, renal disease.  Furthermore, C6 deficiency had 
no effect on the renal disease in fH deficient mice.  Taken together, the data from the C5 and C6 
deficient mice provide evidence that the membrane attack complex itself plays little role in renal 
pathogenesis of C3G in the setting of fH deficiency, but that C5a production may be a factor 
contributing to disease [13, 19]. 
1.2.3. 
Immune-Complex Membranoproliferative Glomerulonephritis (IC-MPGN) 
Immune-complex membranoproliferative glomerulonephritis (IC-MPGN) is a renal disease 
which shares many clinical, pathologic, genetic, and laboratory features with C3G, and therefore 
can be considered a sister disease of C3G.  In the majority of patients with IC-MPGN, an 
underlying disease or disorder (most commonly infections, autoimmune diseases or monoclonal 
gammopathies) are identified to which the renal disease is secondary.  Of note, the most common 
infections associated with IC-MPGN are hepatitis B and C.  Up to 40% of patients with IC-
MPGN have no identifiable underlying etiology and are considered to have primary IC-MPGN.  
Patients with primary IC-MPGN can have low C3 and normal C4 levels, similar to those 
observed in C3G, as well as many of the same genetic or acquired factors that are associated with 
abnormal alternative pathway activity.  Although IC-MPGN pathology is at least in part 
attributable to overactivity of the classical pathway, evidence of C3 and/or C3 fragment staining 
on renal biopsy suggests alternative pathway-related pathophysiology [20].  IC-MPGN patients 
should therefore benefit from fD inhibition. 


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of 12 months of oral treatment 
with ACH-0144471 in participants with C3G or IC-MPGN. 
Evaluation of efficacy will be based on significant improvement in histologic scoring and 
proteinuria relative to baseline. 
2.2. 
Secondary Objectives 
The secondary objectives of this study are: 
• To evaluate the clinical effect of 12 months of oral ACH-0144471 in participants with 
C3G or IC-MPGN based on significant improvement in slope of estimated glomerular 
filtration rate (eGFR) relative to baseline over time 
• To evaluate for improvement in eGFR following treatment with ACH-0144471  
• Where available evaluate the change in measured (m) eGFR relative to baseline at the 
end of 12 months of treatment with ACH-0144471 
• To evaluate the safety and tolerability of ACH-0144471 in participants with C3G or 
IC-MPGN by assessing serious adverse events (SAEs) 
2.3. 
Other Objectives 
The exploratory objectives of this study include: 
• To evaluate whether changes in histopathology scoring correlate with observed 
clinical changes in those participants with biopsy results before and after treatment 
with ACH-0144471 
• To explore the effect of ACH-0144471 on complement biomarkers including 
alternative pathway (AP) activity in participants with C3G or IC-MPGN over a 12-
month treatment period 
• To evaluate plasma concentrations of ACH-0144471 in participants with C3G or IC-
MPGN 
• To evaluate kidney disease and health-related quality of life instruments in 
participants with C3G or IC-MPGN, over the course of ACH-0144471 treatment 
• To explore participants’ experience of their disease (C3G or IC-MPGN), its impact, 
and its management on their everyday lives, from first symptoms to definitive 
diagnosis and beyond 
• To explore participants’ expectations and perceptions of ACH-0144471 treatment 
 


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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This is an open-label study in which all participants will receive active treatment with 
ACH-0144471 for approximately 40 months.  The study will enroll approximately 
20 participants with biopsy-confirmed C3G or IC-MPGN, 12 years of age or older, who have not 
undergone renal transplant.  Participants who completed ACH471-201 are eligible to participate, 
as long as they do not meet any exclusion criteria. 
Participants who did not participate in ACH471-201 must meet all inclusion and exclusion 
criteria to be eligible.  In particular, they must have a biopsy-confirmed diagnosis of C3G or IC-
MPGN.  The initial diagnosis should have been made at least 3 months prior to dosing, unless 
otherwise approved by the sponsor.  Participants must also have clinical evidence of ongoing 
disease (defined as proteinuria of ≥500 mg/day of protein in a 24-hour urine) that is attributable 
to C3G or IC-MPGN in the opinion of the Principal Investigator (PI).  Participants who 
completed ACH471-201 may enroll in this study following a washout period of at least 30 days 
between the last dose of ACH-0144471 in study ACH471-201 and the renal biopsy (if collected 
during screening; Section 6.3) or the 24-hour urine collection during screening.  These 
participants will not be required to re-establish their diagnosis of C3G or IC-MPGN, but must 
meet the other eligibility requirements described in Section 4.  
For all participants, eligibility will be confirmed based on the results from the screening 
eligibility assessments.  Once eligibility is confirmed, arrangements can be made for a renal 
biopsy (if necessary to confirm the diagnosis of C3G or IC-MPGN as described in Section 6.3.1, 
or to establish a baseline for adult participants who choose to participate in the renal biopsy sub-
study) and/or vaccinations.  Biopsies will not be obtained from participants less than 18 years of 
age (unless a biopsy is determined to be clinically indicated by the treating provider), or from 
participants for whom a biopsy is contraindicated.  The initial screening visit must occur no more 
than 75 days before the first dose date.  
All participants should be vaccinated against Haemophilus influenzae (H. influenzae), 
Streptococcus pneumoniae (S. pneumoniae), and Neisseria meningitidis (N. meningitidis) as 
recommended by the Advisory Committee on Immunization Practices (ACIP) guidelines at least 
2 weeks before the start of dosing with ACH‑0144471, as described in Section 6.4, to minimize 
the risk of serious infection with an encapsulated organism, unless otherwise recommended by 
local vaccination guidelines, or precluded by licenses or availability.  The PI may institute 
additional prophylactic measures, including the use of prophylactic antibiotics, if deemed 
appropriate by local clinical practice and/or guidelines for treatment with a complement 
inhibitor.  
The starting dosage will be 100 mg of ACH-0144471 TID, for a total daily dose of 300 mg.  
After 2 weeks of treatment, dosing will be escalated to 200 mg TID (or 150 mg TID for 
participants less than 60 kg).  Additional dosage regimens may be investigated if supported by 
emerging data from this and other clinical studies. For each participant, the medical monitor will 
consult with the investigator before making the decision to dose escalate.  Upon treatment 
discontinuation, regardless of the timing or reasons for discontinuation, a 6-day taper period is 
required unless the PI determines this taper period poses a risk to the participant.  The taper 


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period is in place to prevent the theoretical risk of marked increase or rebound in complement 
activity, as described in Section 5.1.1. 
A sub-study is being conducted to evaluate the effects of ACH‑0144471 on renal pathology; 
participation in this study is not required.  For participants in the renal biopsy sub-study, biopsies 
will be obtained prior to dosing and after approximately 28 and 104 weeks of dosing.  If for any 
reason, any additional renal biopsies are performed (e.g., for a clinical indication), then every 
effort will be made to make these biopsy samples and results available to the central pathology 
laboratory for evaluation.  
Patient-reported outcome (PRO) questionnaires will be administered to participants at various 
time points as specified in the Schedule of Assessments (Appendix 1), to assess participants’ 
health-related quality of life (HRQOL), fatigue, and kidney-related fears and worries (e.g. kidney 
failure, dialysis, kidney transplant), and to determine health states value, over the course of 
treatment with ACH-0144471.  
Figure 1 provides the study schematic. 
Figure 1. 
Study Schematic 
 
 
3.2. 
Rationale for Study Design 
3.2.1. 
Justification of Design 
This trial is one of two proof-of-concept studies planned to obtain data demonstrating that fD 
inhibition can reduce AP hyperactivity, and thereby halt, and possibly even reverse, progression 
of C3G and IC-MPGN.  Disease progression and activity will be assessed using evaluation of 
clinical manifestations of the disease, namely proteinuria and abnormal eGFR, and the sponsor 
will attempt to correlate any such improvements in clinical manifestations with changes in 
histopathology, to the extent biopsy data is available.  This proof-of-concept trial enables 
participants with C3G or IC-MPGN (including those who have completed the non-therapeutic 
ACH471-201 trial) to receive ACH-0144471 for what we expect to be a therapeutic duration.  
The open-label design, in which all participants receive active treatment, ensures that all 
participants have the opportunity to receive active drug.  Further rationale is provided below for 
the participant population selected, the endpoints to be evaluated, the duration of treatment, and 
the safety monitoring plan.  Rationale for dose selection and dose adjustment parameters are 
detailed in Section 3.2.2. 


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3.2.1.1. 
Participant Population 
The participant population enrolled in this study will be patients with biopsy-confirmed C3G or 
IC-MPGN.  For those who participated and completed study ACH471-201, additional 
inclusion/exclusion criteria are designed to ensure that there are no new circumstances that 
would make the participant inappropriate for an ACH-0144471 clinical trial.   
Achillion hypothesizes that a fD inhibitor will reduce AP hyperactivity, halting deposition of 
complement by-products in the kidney.  These complement by-products induce an inflammatory 
response that affects glomerular function, and over time this chronic inflammation can lead to 
irreversible scarring of the renal parenchyma.  As discussed in Section 3.2.1.2.1, the primary 
clinical manifestations of these processes are proteinuria and/or abnormal eGFR, and 
intervention during the period of active inflammation is expected to reverse damage and yield 
improvements in the clinical manifestations of the disease.  In contrast, intervention once the 
kidney is irreversibly damaged may only provide minimal benefit, and even in non-ESRD 
participants, there is likely to be some component of irreversible renal damage that could limit 
the maximal response to a fD inhibitor.  Therefore, we aim to enrich the population for those 
participants with the greatest likelihood for significant improvements by targeting participants 
with enough reversible renal disease to enable a detectable response to a fD inhibitor (proteinuria 
of at least 500 mg/day) but who do not have ESRD. 
Because C3G and IC-MPGN are diseases that can present in childhood, and because early 
intervention is ideal for the greatest potential benefit, this study will enroll both adult and 
adolescent (12 years of age and older) participants.  
The remaining criteria further ensure that the appropriate population is enrolled based on the 
available supporting data from the clinical and nonclinical programs for ACH-0144471 at the 
time of study conduct.   
3.2.1.2. 
Endpoints 
Demonstrating definitive efficacy with well-established endpoints for renal diseases, such as 
time to end-stage renal disease, or doubling of serum creatinine, is impractical in clinical trials 
for ultra-rare diseases such as C3G and IC-MPGN where these endpoints typically occur over 
many years, and unfortunately, there are no existing validated surrogate endpoints for 
progression of these diseases.  
  In the absence of validated surrogate endpoints, proteinuria and reduced eGFR 
are mechanistically important markers for glomerular loss and inflammation, as discussed in 
Section 3.2.1.2.1, and as such will be endpoints measured in this study.  
In patients with reversible renal disease due to C3G or IC-MPGN, successful treatment should be 
marked by improvement in the clinical, pathologic, and laboratory evidence of the disease, 
namely improvements in proteinuria and/or eGFR (clinical), improvements in complement 
deposits and glomerular inflammation (pathologic), and correction of AP hyperactivity reflected 
by improvements in systemic C3 levels, as well as changes in factor B breakdown products (Bb 
and Ba), and other complement components (laboratory).  Improvements in clinical findings are 
selected as primary endpoints for this Phase 2 clinical trial, as these are believed to most closely 
correlate with improvement in long-term outcomes such as time to end-stage renal disease.  
CCI


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Pathology-based endpoints will be examined as an exploratory endpoint for correlation, noting 
that improvements in histology may lag behind clinical improvements. 
3.2.1.2.1. Clinically-Based Endpoints  
Since there are no validated surrogate endpoints for C3G or IC-MPGN for use in clinical trial 
design, Achillion has considered meaningful clinical endpoints that would be indicative of 
improvements in disease, based on currently available information for C3G, IC-MPGN, and 
other primary glomerular diseases.  Based on two large case series, clinical features of C3G at 
the time of biopsy diagnosis included proteinuria >3.5 g/day and/or nephrotic syndrome in 
26.8% to 44.0%, microscopic hematuria in 64.3% to 76%, and high blood pressure in 20.7% to 
44% of patients.  It should be noted that at the time of diagnosis, many patients were on steroids 
and/or other immunosuppressive agents as well as treatment with angiotensin converting enzyme 
(ACE) inhibitors or angiotensin receptor blockers (ARBs), which confounds interpretation of the 
frequency and extent of both proteinuria and high blood pressure.  With regard to blood pressure, 
there is little additional data in the literature on the extent of high blood pressure, or its 
responsiveness to anti-hypertensive therapy and management, either at presentation or during the 
disease course.  Up to 50% of patients may also have an abnormal creatinine/eGFR at time of the 
biopsy diagnosis.  Of note, the disease can present with acute kidney injury and/or as a rapidly 
progressive glomerulonephritis, although these represent a minority of cases [6, 9, 21, 22, 23, 
24, 25]. 
Considering that the primary clinical manifestations of both C3G and IC-MPGN are proteinuria 
and/or abnormal eGFR, and that current treatment strategies heavily focus on management of 
these clinical features, Achillion has focused its attention on these two parameters.  It is well-
accepted within the nephrology community that for glomerular diseases, especially 
glomerulonephritis, the following earlier changes will translate to long-term clinical benefit, 
including renal survival: conversion of nephrotic to non-nephrotic proteinuria, decreasing 
proteinuria (assuming baseline proteinuria is significant [≥500 mg/day]), eliminating proteinuria 
or reducing it to less than 300 mg/day, normalizing serum creatinine if abnormal at baseline, 
and/or improving or stabilizing eGFR  relative to baseline if abnormal at baseline [26, 27, 28, 
29].  Further data in the literature supports a relationship between reduction in proteinuria and 
improved renal survival across chronic kidney disease (CKD), and especially across multiple 
different primary glomerular diseases with multiple different types of interventions [30, 31, 32, 
33].  Therefore, it is reasonable to expect that improvement in these clinical markers of C3G 
(proteinuria and/or eGFR) would be indicative of reduced glomerular injury and inflammation, 
and would translate to improved renal survival. 
As the clinical presentation and course of both C3G and IC-MPGN are quite heterogeneous, 
patients are likely to have only a subset of the possible clinical manifestations.  Given the small 
number of participants, it is not practical to create multiple stratified response criteria (e.g., as 
often done in trials for SLE nephritis) [28, 29].  Instead, the study will focus on two clinical 
endpoints, which are among those expected to translate to clinical benefit: decrease in proteinuria 
relative to baseline, and/or improvement in eGFR relative to baseline.  


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3.2.1.2.2. Pathology-Based Endpoints  
Renal biopsy scoring is a proximal and direct measure of renal disease.  An improvement in 
disease activity scoring by renal histopathology is expected to translate into observed 
improvements in clinical manifestations, and hopefully into improvements in long-term renal 
outcomes.  There has been no formal assessment correlating histologic features and outcomes in 
C3G or IC-MPGN, however, there are some data showing that the presence of crescents and 
more tubular atrophy in the initial biopsy are associated with worse outcomes [10, 34, 35].  In 
addition, the extent of C3c staining will be a key feature for biopsy analysis for this disease and 
considering the mechanism of action for ACH-0144471.  Achillion is therefore conducting an 
optional sub-study to evaluate the effects of ACH-0144471 on renal pathology, as described in 
Section 6.3.1.  Since this study is not powered to show improvements in histologic scoring and it 
is not known if improvements in histology are synchronized with clinical changes, the pathology 
endpoint will be exploratory, however, histopathologic findings will be important in confirming 
a mechanistic reason for improvements in other markers if all are present in this study. 
Biopsies will not be obtained from participants less than 18 years of age (unless they are 
determined to be clinically indicated by the treating provider), or from adult participants for 
whom a biopsy is contraindicated. 
The pathology assessments will be described in more detail in a Pathology Manual, and the 
specific analysis of pathology endpoints for this study will be described in the Statistical 
Analysis Plan. 
3.2.1.2.3. PRO-Based endpoints 
Findings from the analysis of qualitative interviews conducted with C3G and IC-MPGN adult 
patients (n = 10) and with key opinion leaders (n = 7; clinicians and patient advocacy group 
leaders) have shown that C3Gand IC-MPGN have a detrimental impact on patients’ everyday 
lives.  The C3G and IC-MPGN populations appear highly heterogeneous in terms of disease 
symptomatology, occurrence and evolution of symptoms, and level of impact on patients’ lives.  
However, fatigue and lack of energy are the symptoms the most frequently reported.  In addition, 
patients expressed their fear and worries, mainly due to the likelihood of kidney failure, dialysis 
and/or transplant.  In turn, this significantly affects their everyday lives and quality of life.  These 
symptoms and impacts were salient in C3G patient testimonials during the 04 August 2017 FDA 
Patient-Focused Drug Development Meeting that was organized by the National Kidney 
Foundation.  Therefore, the PRO strategy for this study will include questionnaires selected to 
focus on these facets of patients’ lives.  In particular, participants will complete PRO 
questionnaires (adult participants will complete the KDQOL-SF v1.3, FACIT-Fatigue, and EQ-
5D-3L questionnaires; adolescent participants will complete the Peds-FACIT-F and EQ-5D-Y 
questionnaires) during the screening period and at Week 28, Week 52 and Week 104, and 
follow-up (or, in case of a participant’s early termination, at the termination visit) as specified in 
Appendix 1, to assess their HRQOL, fatigue, and kidney-related fears and worries (e.g. kidney 
failure, dialysis, kidney transplant), and to determine health states value, over the course of 
treatment with ACH-0144471.. 


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3.2.1.2.4. Safety Endpoints 
Safety endpoints: 
• Number and incidence of 
− SAEs 
− AEs leading to discontinuation of the study medication 
− Grade 3 or 4 AEs (related and regardless of relationship to study medication) 
− Grade 3 or 4 Laboratory abnormalities 
− Treatment-emergent vital signs, physical exam results, and ECG abnormalities 
Descriptive statistical and confidence interval procedures will be utilized for both primary and 
secondary efficacy endpoints.  Summary statistics will be provided for safety endpoints.  No 
inferential statistical procedures will be used for safety endpoints, unless clinically deemed 
necessary and appropriate.  
Details of statistical analysis strategies and methodologies will be described in the statistical 
analysis plan (SAP). 
3.2.1.3. 
Duration of Treatment 
Unfortunately, there is no precedent available for this disease to guide our decision about the 
length of therapy required to see improvements in clinical manifestations of renal disease (e.g., 
proteinuria and/or eGFR).  A 12-month treatment period with an additional up to 27-month long 
term extension was selected 
 as 
a feasible timeframe for changes in proteinuria and/or eGFR.  
3.2.1.4. 
Safety Monitoring Plan 
The primary focus of the safety monitoring plan will be to regularly monitor safety, including 
any adverse events, safety laboratory measurements including liver function test and serum 
creatinine, and the urine albumin: creatinine ratio.  In addition, there are specific safety 
monitoring plans for the potential risk of infection (Appendix 2) and elevation in liver function 
tests (Section 3.2.3.2). 
3.2.1.4.1. Infection 
Since one of the primary functions of the complement system is to fight infections, 
pharmacologic inhibition of the complement system could theoretically result in an increased 
rate or severity of infections.  However, high doses of C1 esterase inhibitor in transplant patients 
with rejection did not show a signal for infection [36].  Thus, it remains unclear as to whether fD 
inhibition would increase risk for infection. 
In vitro work was done to understand potential infection risk, especially meningococcal infection 
risk that is associated with AP inhibition.  As summarized in Sections 4.1.2 and 6.5.1 of the 
Investigator's Brochure [1], ACH-0144471 showed minimal inhibition of protective bactericidal 
and opsonophagocytic activities in studies that included several strains of the clinically important 
pathogen N. meningitidis and blood samples from immunized individuals, suggesting that 
CCI


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vaccination should provide protection from meningococcal infections in participants receiving 
ACH-0144471. 
Nonetheless, this study takes steps to minimize the risk of serious infection.  Participants should 
be vaccinated according to applicable national and/or local guidelines or local clinical practice 
for N. meningitidis, H. influenza, and S. pneumonia (see Section 6.4), and antibiotic prophylaxis 
is permitted if deemed appropriate by local clinical practice and/or guidelines, as described in 
Section 6.5.  Achillion will also create and distribute a wallet card for outpatient studies with 
warning signs and symptoms of serious infection, and appropriate steps of action for all 
participants.  Finally, a fever management plan has been incorporated into the study protocol (see 
Appendix 2). 
3.2.1.4.2. Hepatic Injury 
Hepatobiliary cholestasis has been observed in dog toxicology studies at exposures higher than 
those intended for clinical use, and higher than those planned for this study.  Based on clinical 
observations, the cholestasis is reversible and can be monitored with hepatic safety biomarkers.  
Elevations of transaminases have occurred clinically with ACH-0144471.  Grade 3 or Grade 4 
liver enzyme elevations occurred in 2 active phase 1 study participants receiving higher doses of 
ACH-0144471 (500 mg twice daily [BID] and 800 mg BID), although these elevations occurred 
after dosing was completed (3 days and 7 days after last dose).  One PNH participant had 
elevated transaminases associated with breakthrough hemolysis and discontinued ACH-0144471.  
All abnormal transaminase findings were transient, were not associated with evidence of hepatic 
decompensation, and resolved within a short time period.  Transaminases will be monitored in 
this study.  
Stopping criteria have been included ensuring prompt discontinuation of any participant with 
evidence of unexplained liver injury.  Finally, participants with evidence of active hepatic or 
hepatobiliary disease will be excluded.  
3.2.2. 
Justification of Dose 
The starting dosage will be 100 mg TID.  This dose has been demonstrated to inhibit the 
alternative pathway in PNH patients and in C3G patients, and dosing regimens with similar 
exposures (e.g., 200 mg BID) have demonstrated AP inhibition in healthy volunteers.  Early data 
shows some clinically relevant reduction in proteinuria associated with AP inhibition, and ACH-
0144471 has been well tolerated to date in participants with C3G or IC-MPGN.  In order to 
maximize inhibition of the AP, the dosage will be escalated after 2 weeks, unless the participant 
has not tolerated treatment, or the investigator feels escalation would not be in the participant’s 
interest.  Participants of 60 kg or more will be escalated to a dosage of 200 mg TID, and 
participants of less than 60 kg will be escalated to a dosage of 150 mg TID. 
Based on adult pharmacokinetic data, a PBPK (physiologically-based pharmacokinetics) model 
was developed and validated to determine a dose of ACH-0144471 in adolescents equivalent to 
the starting dose of 100 mg TID in adults.  A range of doses were simulated in virtual pediatric 
(adolescent) participants (n=500/1000) to find a dose level that resulted in exposures comparable 
to those of adults (Figure 2 and Figure 3).  


ACH 0144471 
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Figure 2. 
Simulated Adult PK Profile of ACH-0144471 after 200 mg TID for 14 days 
 
 
Figure 3. 
Simulated Adolescent PK Profile of ACH-0144471 after 165 mg TID for 
14 days 
 
 
The result of these simulations was that a mean dosage regimen of 165 mg TID in adolescents 
(age ≥12 to <18 years) resulted in comparable exposure to adults receiving 200 mg TID.  Since 
ACH-0144471 exhibits linear pharmacokinetic behavior, for a 100-mg TID dosage in adults, the 
equivalent dosage in adolescents would be 82.5 mg TID.  Based on these modeling data, 
adolescents will receive the same 100 mg TID starting dosage as adults.  Adolescents of 60 kg or 
more may be escalated to the same 200 mg TID dosage as adult participants of 60 kg or more; 
adolescents of less than 60 kg may be escalated to a dosage of 150 mg TID.  
3.2.3. 
Stopping Criteria and End-of-Study Definition 
The Sponsor reserves the right to close a study site or terminate the study at any time for any 
reason at the sole discretion of the Sponsor. 


ACH 0144471 
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Study and Individual Stopping Rules are provided below in Sections 3.2.3.1 and 3.2.3.2, 
respectively.  The Achillion Medical Monitor (MM) will review safety data from all enrolling 
sites on an ongoing basis.  If at any time, a Group Stopping Rule is met, then dosing continuation 
will be assessed.  If a PI becomes aware that a Group Stopping Rule has been met, then he/she 
should inform the Achillion MM immediately.  If dosing is terminated in any participant in the 
study, the Achillion MM in consultation with the PI will decide whether or not the taper should 
be implemented. 
The PI may stop dosing in any participant who meets an Individual Stopping Rule 
(Section 3.2.3.2); however, the Achillion MM should be notified immediately, and if possible, 
before dosing is terminated.  When dosing is stopped in an individual participant, the PI should 
consider whether it is in the best interest of the participant to discontinue dosing immediately or 
to taper (as described in Section 5.2).  Whenever possible, the taper decision should also be 
discussed with the Achillion MM prior to dosing termination.  
When dosing is terminated, study participation is not necessarily immediately terminated.  
Instead, whenever possible, the participant should advance to the Taper and/or Follow-Up 
Periods, as relevant, and complete all activities as described in Appendix 1. 
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last scheduled procedure shown in the Schedule of Assessments. 
3.2.3.1. 
Study Stopping Rules 
The safety of dose continuation will be assessed within 24 hours if one or more of the following 
occurs: 
• Two or more participants experience the same or similar study drug-related SAE 
• Two or more participants experience the same or similar study drug-related Grade 4 
or higher AE 
• Two or more participants discontinue study therapy due to study drug-related liver 
function test abnormalities detailed in the Stopping Rules for Individual Participants  
If dosing is terminated in one or more study participants, all these participants will be expected 
to complete the early termination activities described in Section 7.5, and comply with the 
schedule for the Taper Period (if relevant) and Follow-Up Period.  Of note, additional visits 
beyond those specified in the protocol may be required if needed to ensure adequate safety 
monitoring. 
3.2.3.2. 
Stopping Rules for Individual Participants 
Any individual participant who meets any of the following criteria may be discontinued from 
further dosing: 
• The participant experiences a SUSAR 
• The PI believes that participant continuation in the study is not advisable, or the 
participant withdraws from the study or meets one of the conditions described in 
Section 6.22, including, but not limited to: 


ACH 0144471 
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 The participant becomes pregnant 
 Intercurrent illness that would, in the judgment of the investigator, affect assessments 
of clinical status to a significant degree 
 Participant requests to discontinue for any reason 
Discontinuation of treatment should also be considered for:  
• ALT or AST >8× ULN  
• ALT or AST >5× ULN for more than 2 weeks  
• ALT or AST >3× ULN and concomitant total bilirubin >2× ULN and/or International 
Normalized Ratio [INR]* >1.5 
• ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
* Participants, particularly those with nephrotic syndrome, may be receiving ongoing warfarin, 
resulting in increased INR values.  The PI should evaluate INR in the context of any concomitant 
medications to determine if any observed increases are due to an effect on liver function or are 
secondary to anticoagulation.   
Upon dosing termination, a participant will be expected to complete the study, if possible, by 
complying with the schedule for the Taper Period (if relevant) and Follow Up Period.  Of note, 
additional visits beyond those specified in the protocol may be required if needed to ensure 
adequate safety monitoring. 


ACH 0144471 
Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
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Clinical Protocol ACH471 205 Amendment 6 
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4. 
STUDY POPULATION SELECTION 
4.1. 
Study Population 
This study will be conducted in approximately 20 participants with biopsy-confirmed C3G or IC-
MPGN.  Participants may not have undergone renal transplant and must have an eGFR 
>30 mL/min/1.73 m2. 
4.2. 
Inclusion Criteria 
Each participant must meet all the following criteria to be enrolled in this study. 
1. Must have completed the ACH471-201 Proof of Mechanism (POM) study (participation 
in the long-term follow-up portion of ACH471-201 is not required), followed by a 
washout period of at least 30 days,  
OR 
 
Must meet all the following criteria: 
a. Must have biopsy-confirmed primary C3G or IC-MPGN  
b. Must have clinical evidence of ongoing disease based on significant proteinuria 
(defined as ≥500 mg/day of protein in a 24-hour urine) attributable to C3G disease or 
IC-MPGN in the opinion of the PI, and present prior to study entry and confirmed 
during Screening.   
c. If a pre-treatment biopsy is obtained, or if a historical biopsy is available for review, 
it must have no more than 50% global fibrosis and no more than 50% of glomeruli 
with cellular crescents  
d. Must be 12 years of age or older and capable of swallowing tablets 
2. If on corticosteroids, anti-hypertensive medications, anti-proteinuric medications (e.g., 
ACE inhibitors or angiotensin receptor blockers [ARBs]), or mycophenolate mofetil 
(MMF), must be on a stable dose for at least 2 weeks prior to screening  
3. Female participants of childbearing potential must agree to use an acceptable method of 
contraception (as defined in Section 5.5.4) from the date of signing the informed consent 
to the first day of dosing (Day 1), and must agree to use a highly effective form of 
contraception (as defined in Section 5.5.4) from the first day of dosing to 30 days after 
their last dose of study drug.  Female participants of childbearing potential must also 
have a negative serum pregnancy test during Screening and negative urine pregnancy test 
on Day 1.  Female participants of non-childbearing potential need not employ a method 
of contraception.  
4. Non-sterile male participants must agree to use a highly effective form of contraception 
(as defined in Section 5.5.4) with their partner(s) of childbearing potential from the first 
day of dosing to 90 days after their last dose of study drug.  Male participants who are 
surgically sterile need not employ additional contraception.  Male participants must agree 
not to donate sperm while enrolled in this study and for up to 90 days after their last dose 
of study drug. 


ACH 0144471 
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Alexion Pharmaceuticals, Inc.). 
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5. Adult participants must be capable of providing written informed consent, and adolescent 
participants must be capable of providing written assent.  All participants must be willing 
and able to comply with the requirements and restrictions listed in the consent form and 
with all procedures in the protocol, including, the visit schedule, the treatment plan, the 
schedule for laboratory testing, and other study procedures 
6. Must be up-to-date on routine vaccinations, or willing to be brought up-to-date, based on 
local guidelines 
7. Must have access to emergency medical care 
4.3. 
Exclusion Criteria 
Participants who meet any of the following criteria will be excluded from the study. 
1. Have a history of a major organ transplant (e.g., heart, lung, kidney, liver) or 
hematopoietic stem cell/marrow transplant  
2. Have a history or presence of any clinically relevant co-morbidities that would make the 
participant inappropriate for the study (for example, a comorbidity which is likely to 
result in deterioration of the participant’s condition, affect the participant’s safety during 
the study, or confound the results of the study), in the opinion of the PI 
3. Have an estimated GFR <30 mL/min/1.73 m2 at the time of screening or at any time over 
the preceding four weeks 
4. Is a renal transplant recipient or receiving renal replacement therapy 
5. Have other renal diseases that would interfere with interpretation of the study  
6. Have evidence of monoclonal gammopathy of unclear significance (MGUS), infections, 
malignancy, autoimmune diseases, or other conditions to which C3G or IC-MPGN is 
secondary 
7. Have been diagnosed with or show evidence of hepatobiliary cholestasis  
8. Females who are pregnant, nursing, or planning to become pregnant during the study or 
within 90 days of ACH-0144471 administration or participants with a female partner who 
is pregnant, nursing, or planning to become pregnant during the study or within 90 days 
of ACH-0144471 administration 
9. Have a history of febrile illness, a body temperature >38°C, or other evidence of a 
clinically significant active infection, within 14 days prior to ACH-0144471 
administration 
10. Have evidence of human immunodeficiency virus (HIV), hepatitis B infection, or active 
hepatitis C infection at Screening  
11. Have a history of meningococcal infection within the prior year  
12. Have a history of hypersensitivity reactions to commonly used antibacterial agents, 
including beta-lactams, penicillin, aminopenicillins, fluoroquinolones, cephalosporins, 
and carbapenems, which, in the opinion of the investigator and/or an appropriately 


ACH 0144471 
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15 May 2020 (Version 7.0) 
Confidential Property of Achillion Pharmaceuticals, Inc. 
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qualified immunology or infectious disease expert, would make it difficult to properly 
provide either empiric antibiotic therapy or treat an active infection. 
13. Have participated in a clinical study in which an investigational drug was given within 
30 days, or within 5 half-lives of the investigational drug, whichever is longer, prior to 
the first dose of ACH-0144471  
14. Have received eculizumab at any dose or interval within the past 50 days prior to the first 
dose of ACH-0144471  
15. Have received tacrolimus or cyclosporine within 2 weeks of the first dose of 
ACH-0144471  
16. Have a 12-lead ECG with a QTcF >450 msec for males or >470 msec for females, or 
have ECG findings which, in the opinion of the PI, could put the participant at undue risk 
17. Have received any drug known to prolong the QTc interval within 2 weeks of the first 
dose of ACH-0144471 and which, in the opinion of the PI, could put the participant at 
undue risk 
18. Have any of the following laboratory abnormalities at screening:  
 Alanine transaminase (ALT) > upper limit of normal (ULN)  
 Aspartate aminotransferase (AST) > ULN  
 Absolute neutrophil counts (ANC) <1,000/μL 
 Total bilirubin >1.5× ULN 
 Indirect bilirubin > ULN 
 Any laboratory abnormality that, in the opinion of the PI, would make the participant 
inappropriate for the study 
19. Are unwilling or unable to comply with the study protocol for any reason 


ACH 0144471 
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5. 
STUDY TREATMENT(S) 
5.1. 
Description of Treatment(s) 
5.1.1. 
Study Drug 
ACH-0144471 will be dosed orally as a tablet formulation containing the drug substance, 
 
 
 Tablets will be 
provided in 50 and 100-mg strengths.  
5.2. 
Treatment(s) Administered 
5.2.1. 
ACH-0144471 
ACH-0144471 tablets will be administered at a starting dosage of 100 mg TID.  Study drug 
administration will then continue for the remainder of the 40-month Treatment Period.  When 
dosing is to be discontinued, the dose will be tapered over approximately 6 days (Taper Period) 
to minimize the potential adverse effects of a rapid surge in complement activity following drug 
withdrawal.   
The dosing taper regimen is described in Table 1.  If a dosing regimen not specified in the 
Table 1 is used, then the taper schedule will be defined by the Achillion MM prior to dosing 
termination.  In addition, the taper schedule may be adjusted to allow for slower taper in a 
participant who is not tolerating discontinuation of drug. 
Table 1. 
ACH-0144471 Taper Schedule 
Dose at Termination 
Taper Period 1 
(Taper Days 1-3) 
Taper Period 2 
(Taper Days 4-6) 
100 mg TID  
100 mg BID 
0mg 
150 mg TID 
100 mg TID 
50 mg TID 
200 mg TID 
100 mg TID 
100 mg BID 
5.2.2. 
Vaccines 
Depending on the participant’s vaccination history, the vaccines described in Section 6.4 may 
need to be administered according to the ACIP guidelines unless otherwise recommended by 
local vaccination guidelines or precluded by licenses or availability.  Because these are 
commercially available products, information about the specific vaccines can be found on the 
package inserts/product labels for those products.  Full identifying information for any 
administered vaccines, including the brand, should be recorded in the participant’s CRF. 
5.2.3. 
Prophylactic Antibiotics 
As described in Section 6.5, antibiotic prophylaxis is not mandated but allowed if deemed 
necessary by local clinical practice and/or guidelines for treatment with a complement inhibitor.  
Because commercially available products will be used, information about any specific antibiotics 
administered can be found on the package inserts/product labels for those products.  Full 
CCI


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identifying information for any antibiotics given as part of this study, including the brand, should 
be recorded in the participant’s CRF.   
5.3. 
Selection of Timing and Dose for Each Participant 
For the starting dose, participants will take one 100-mg ACH-0144471 tablet three times daily 
(TID): a dose in the morning, a second dose 8 hours later, and a third dose 8 hours after the 
second dose.  Doses should be taken at approximately the same time each day and as close as 
possible to 8 hours apart.  All doses should be taken approximately 15 to 30 minutes after 
completion of a meal.  Water intake is not restricted.  If a dose is missed, it should be taken 
within 4 hours of the originally scheduled time.  After 4 hours, the missed dose should be 
skipped.  In either case, the next dose should be taken according to the original dosing schedule.   
If a dosing interval other than TID is used during the study, then interval between doses should 
be equally distributed over a 24-hour period, and dosing should otherwise comply with the 
guidelines provided for a TID interval.  
5.3.1. 
Clinic Visit Dose Administration Instructions 
The morning doses on the days of each visit to the study center will be administered in the clinic 
by study site personnel, who will instruct participants on how to take their study medication at 
home between visits.  Participants will be instructed to fast for at least 8 hours before their clinic 
visit and to drink enough water to ensure they are adequately hydrated.  Participants must abstain 
from taking their study medication on the mornings of their study visits so that they can be dosed 
in the clinic following safety and pharmacokinetic assessments.  All doses should be taken 
approximately 15 to 30 minutes after completion of a meal.  Participants will be required to bring 
back their study drug at each visit so that study site personnel may perform drug accountability.  
If morning clinic visits are not possible, participant visits may be scheduled so that safety and 
pharmacokinetic assessments can be made before the second daily dose.  The 8-hour interval 
between doses should be maintained, as should the relative timing of dosing and all study-related 
activities. 
5.3.2. 
Home Dose Administration Instructions 
Participants should be instructed to finish a meal or snack approximately 15 to 30 minutes prior 
to dosing.  Participants should also take their medication such that doses are as close as possible 
to 8 hours apart (or the relevant interval in the event of a non-TID schedule). 
Participants should be instructed to keep their study medications at room temperature. 
5.3.3. 
Dose Adjustment 
After 2 weeks of treatment, dosing will be escalated to 200 mg TID (or 150 mg TID for 
participants less than 60 kg) unless the participant has not tolerated treatment.  While the intent is 
to maintain a steady dose for the duration of the study, dose adjustments are permitted for 
participant safety or in order to create the best opportunity for each participant to have a 
therapeutic benefit.  Dosing may be adjusted by the MM (or designee) in consultation with the 
PI, within the parameters provided below and based on review of available safety, PK, and PD 
results.  


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Dose increases should be such that the new total daily dose is no more than 2× the prior total 
daily dose.  
5.4. 
Method of Assigning Participants to Treatment Groups 
All participants will receive ACH 0144471 and will be assigned to the same treatment group.  
Participants entering following completion of ACH471-201 will retain the same participant 
identification as in study ACH471-201.  Newly enrolled participants will be assigned a 
sequential participant identification number within each study site. 
5.5. 
Restrictions 
5.5.1. 
Prior and Concomitant Therapy 
Participants who complete ACH471-201 are eligible to enter this study, following a washout 
period of at least 30 days between the last dose of ACH-0144471 in study ACH471-201 and the 
pre-treatment renal biopsy (if collected; Section 6.3).  This is to allow the renal histopathology to 
return toward baseline after completion of study drug administration in ACH471-201.  In 
addition, this 30-day window will also meet the study's exclusion criteria that requires no 
administration of an investigational agent within 30 days or 5 half-lives.  Of note, based on 
healthy volunteer data, the half-life of ACH-0144471 is 7 to 10 hours. 
Participants may not have received another investigational agent within 30 days or 5 half-lives of 
the investigational agent prior to the first dose of study drug, whichever is greater.  Participants 
may not have received eculizumab within 50 days prior to the first dose of study drug.  
Participants may not have received tacrolimus or cyclosporine within 2 weeks prior to the first 
dose of study drug. 
Based on in vitro data, ACH-0144471 has the potential to interact with several CYP enzymes as 
well as some transporters as a perpetrator but not as a victim drug.  In vitro results for various 
CYP enzymes and transporters are described in the Investigator’s Brochure [1].  
A drug-drug interaction study with ACH-0144471 has been conducted to determine the potential 
for ACH-0144471 to affect the PK of midazolam (substrate for CYP3A), fexofenadine (substrate 
for P-gp), and mycophenolic acid (substrate of UGT).  Preliminary results indicate that ACH-
0144471 is a weak inhibitor of CYP3A, a moderate inhibitor of P-gp, and had no effect on UGT.  
Although QT prolongation has not been observed in the studies with ACH-0144471 conducted to 
date a conservative approach is being taken for drugs that are known to prolong the QT interval 
since a thorough QT/QTc study has not yet been completed.  The use of drugs that are known to 
prolong the QT interval will be considered in the context of available information. 
Use of specific concomitant medications will be considered on a case-by-case basis, with 
decisions made jointly between the PI and Sponsor, based on available and emerging knowledge 
of ACH-0144471 as well as the characteristics of the potential concomitant medication.  Details 
of all concomitant medication use, including all medications administered for the treatment of 
AEs, must be recorded in the participant’s case report form (CRF).   
The following are some general guidelines for concomitant medication use based on currently 
available data:  


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• Concomitant administration of cyclosporine and tacrolimus are not allowed and must 
be stopped at least two weeks prior to study drug administration. 
• Concomitant administration of corticosteroids is permitted if on stable doses for at 
least 4 weeks prior to the first screening visit.  Doses should be maintained at the 
same dose throughout the study, whenever possible, unless the PI deems it necessary 
to do otherwise. 
• Concomitant administration of mycophenolate mofetil (MMF) is allowed if on stable 
doses for at least 2 weeks prior to the first screening visit.  Doses should be 
maintained at the same dose throughout the study, whenever possible, and unless the 
PI deems it necessary to do otherwise. 
• Concomitant administration of warfarin or low molecular weight heparin is permitted 
with prior approval. 
• Oral, injectable, implantable, transdermal, or intravaginal hormonal therapies are 
allowed for either contraception or hormonal replacement therapy. 
• Concomitant administration of anti-proteinuric medications (e.g., ACE inhibitors or 
ARBs) or anti-hypertensive medications is permitted if on stable doses for at least 
4 weeks prior to the first screening visit.  Doses should be maintained at the same 
dose throughout the study, whenever possible, unless the PI deems it necessary to do 
otherwise. 
• If it is necessary to treat a fever (see Appendix 2), or any minor ailment occurring 
while on study, ibuprofen (maximum 400 mg/day and up to 1200 mg/week) and/or 
acetaminophen (maximum 1000 mg/day) are permitted without prior approval. 
• Concomitant administration of drugs with the potential to cause QTc prolongation 
will be evaluated on a case-by-case basis by the medical monitor. 
• Antibiotic prophylaxis is allowed if deemed appropriate by local clinical practice 
and/or guidelines for treatment with a complement inhibitor.   
No new therapy for C3G/IC-MPGN should be added during the study unless the participant’s 
condition deteriorates to the extent that the PI deems it in the best interest of the participant to do 
so.  In addition, doses of medications for C3G (e.g., immunosuppressive agents, ACE inhibitors, 
etc.) should be maintained at the same dose throughout the study whenever possible, and unless 
the PI deems it necessary to do otherwise. 
5.5.2. 
Fluid and Food Intake 
Participants should be instructed to take each dose of ACH-0144471 with food.  As described in 
Section 5.2.3, ACH-0144471 should be taken three times daily, approximately 8 hours apart.  An 
appropriate schedule would be to take the three daily doses within 15 to 30 minutes of finishing 
breakfast, dinner, and a bedtime snack. 
Water or other non-alcoholic fluid intake is not restricted. 


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5.5.3. 
Participant Activity and Other Restrictions 
Participants should refrain from heavy exercise 24 hours prior to and after having blood drawn 
for safety laboratory evaluations.  Walking and light exercise are acceptable. 
5.5.4. 
Contraception 
5.5.4.1. 
Contraception for Male Participants 
All non-sterile male participants must use highly effective or acceptable contraception with their 
partner(s) of childbearing potential from the first day of dosing (Day 1) through 90 days after 
their last dose of study drug.   
Sterile is defined as having bilateral orchiectomy. 
Highly effective contraception for males is defined as any of the following:  
• 
Vasectomy with confirmed medical assessment of surgical success 
• 
Condom plus use of one of the following by partner(s) of child-bearing potential: 
 Oral, intravaginal, or transdermal combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of ovulation 
 Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation 
 Intrauterine device (IUD) or Intrauterine hormone-releasing system (IUS) 
 Bilateral tubal occlusion (including bilateral tubal ligation) 
• 
Sexual abstinence, defined as refraining from heterosexual intercourse during the entire 
period from the first day of dosing (Day 1) through 90 days after their last dose of study 
drug.  Periodic abstinence (e.g., calendar, symptothermal, post-ovulation methods) is not 
an acceptable method of contraception.  The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the participant.  If a participant is usually not sexually active but becomes 
active, they, with their partner(s), must comply with the contraceptive requirements 
described in this section. 
Acceptable contraception for males or female partner of childbearing potential is defined as any 
of the following:  
• 
Progestin-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action 
• 
Male or female condom with or without spermicide 
• 
Cap, diaphragm, or sponge with spermicide 
• 
Combinations of male condom with either cap, diaphragm, or sponge with spermicide 
(double-barrier methods) 
Male participants must agree to refrain from sperm donation from the date of screening until 
90 days after their last dose of study drug. 


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5.5.4.2. 
Contraception for Female Participants 
Female participants of child-bearing potential and/or their male partners must use a highly 
effective or acceptable method of contraception from the date of signing the informed consent to 
the first day of dosing (Day 1) through 30 days after their last dose of study drug.  Highly 
effective contraception for females is defined as any of the following: 
• Oral, intravaginal, or transdermal combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of ovulation 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation 
• Intrauterine device (IUD) or Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion (including bilateral tubal ligation) 
• Vasectomised partner(s) with confirmed medical assessment of surgical success 
• Sterile partner(s) (bi-lateral orchiectomy) 
• Sexual abstinence, defined as refraining from heterosexual intercourse during the 
entire period from the first day of dosing (Day 1) through 30 days after their last dose 
of study drug.  Periodic abstinence (e.g., calendar, symptothermal, post-ovulation 
methods) is not an acceptable method of contraception.  The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the participant.  If a participant is usually not sexually 
active but becomes active, they, with their partner(s), must comply with the 
contraceptive requirements described in this section. 
Acceptable contraception for females is defined as any of the following: 
• Progestin-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action 
• Male or female condom with or without spermicide 
• Cap, diaphragm or sponge with spermicide 
• Combinations of male condom with either cap, diaphragm, or sponge with spermicide 
(double-barrier methods) 
Female participants of childbearing potential must have a negative serum pregnancy test at 
screening and a negative urine pregnancy test at baseline in order to enter the study, and must 
have urine pregnancy tests throughout the study at the intervals defined in the Schedule of 
Assessments (Appendix 1). 
Female participants of non-childbearing potential, as defined by one of the following, need not 
employ a method of contraception: 
• Surgical sterilization by hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy 


ACH 0144471 
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• Postmenopausal with amenorrhea for at least 1 year prior to dosing and FSH serum 
levels consistent with postmenopausal status 
5.6. 
Treatment Compliance 
Treatment compliance assessments shall be performed at each visit.  Participants will be required 
to bring their supply of study drug to each visit so that study site personnel may perform drug 
accountability.  Site personnel will keep a record of all drug dispensed and returned at each visit.  
Drug dispensing records will be updated at each visit. 
Participants will be asked to confirm they take each daily dose of study drug and may receive 
automated reminders (e.g., via SMS text or phone call) in an effort to ensure compliance.  The 
site will receive notification of any non-response or non-compliance to follow up and address 
with the participant directly.  
5.7. 
Packaging and Labeling 
Labels for ACH-0144471 tablets will include, at a minimum, the following information: 
• 
Clinical Study Number 
• 
Sponsor Name and Address 
• 
Product Name and Strength 
• 
Dosage Form and Route of Administration 
• 
Direction for Use 
• 
Contents (Number of Tablets) 
• 
Lot Number (or Code) 
• 
Storage Instructions 
• 
Caution statement to keep out of the reach of children 
• 
Caution Statements such as “For Clinical Trial Use Only” or “Caution: New Drug—
Limited by Federal (or United States) law to investigation use” or similar statements 
5.8. 
Storage and Accountability 
At the pharmacy, the ACH-0144471 tablets must be stored as provided at controlled room 
temperature (20°C to 25°C), with allowed excursion of 15°C to 30°C.  Participants should be 
instructed to keep their study medications in the original container at room temperature. 
Participants will be required to bring back their study drug at each clinic visit so that study site 
personnel may perform drug accountability. 
The PI or designee (e.g., pharmacist) is responsible for ensuring storage as per the label on the 
drug product at the site and adequate accountability of all used and unused study drug.  This 
includes acknowledgment of receipt of each shipment of study drug (quantity and condition) and 
participant dispensing records and returned or destroyed drug.  Dispensing records will 
document quantities received from Achillion Pharmaceuticals (or designee) and quantities 


ACH 0144471 
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Page 45 of 91 
dispensed to participants, including lot number, date dispensed, participant identifier number, 
participant initials, and the initials of the person dispensing the medication.  All drug supplies 
and associated documentation will be periodically reviewed and verified by the Study Monitor 
over the course of the study. 
5.9. 
Investigational Product Retention at Study Site 
At study initiation, the Study Monitor will evaluate the site’s Standard Operating Procedure for 
study drug disposal/destruction in order to ensure that it complies with Achillion 
Pharmaceuticals requirements.  Drug may be returned to the Sponsor (or designee) or destroyed 
on an ongoing basis during the study, if appropriate, after drug accountability has been verified 
by the Study Monitor.  At the end of the study, following final drug inventory reconciliation by 
the Study Monitor, the study site will dispose of and/or destroy all unused study drug supplies, 
including empty containers, according to these procedures.  If the site cannot meet Achillion 
Pharmaceuticals requirements for disposal, arrangements will be made between the site and 
Achillion Pharmaceuticals or its representative, for destruction or return of unused study drug 
supplies. 


ACH 0144471 
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(a subsidiary of Alexion Pharmaceuticals, Inc.) 
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6. 
STUDY PROCEDURES 
The required study procedures are detailed in this section.  The timeline for these procedures 
may be found in Appendix 1. 
6.1. 
Informed Consent or Assent 
The PI or designee is responsible for administering and obtaining freely given consent, in 
writing, before the participant enters into the study and any study-related procedures are 
performed.  Each adult participant will sign an Ethics Committee (EC) or Institutional Review 
Board (IRB)-approved written informed consent form (ICF).  This may include additional 
consent forms for HIV testing or other procedures which may be performed prior to participants 
being accepted into the study.  Each participant 17 years of age or less will sign an EC or IRB-
approved written assent form, and their parent(s) or guardian(s) will sign an EC or IRB-approved 
written informed consent form (ICF).  
6.2. 
Medical History 
At Screening, the PI or designee will interview each participant and obtain a complete medical 
and medication history to determine whether the participant meets the eligibility criteria.  The 
history should include the specific type of C3 glomerulopathy (for participants with C3G), date 
of initial C3G or IC-MPGN diagnosis, family history of renal disease, all surgeries and past 
medical procedures, all past significant illnesses or current chronic conditions, all medication use 
currently and within the past 90 days (including over the counter medications, and use of herbal 
and nutrient supplements), any prior use of alcohol, illicit drugs and/or controlled substances, 
and any other relevant information.  Other relevant information should include any extrarenal 
manifestations of C3G or IC-MPGN, including ophthalmic manifestations such as drusen.  If any 
ophthalmic exams are performed (including any exams performed for reasons unrelated to the 
conduct of this study), then every effort will be made to include an anonymized copy of the exam 
results in the participants’ source documents.  The history should also include the results of any 
genetic testing related to the disease, and a full vaccination history.  The medical history must be 
recorded in the participant’s source documents and in the participant’s CRF. 
6.3. 
Percutaneous Renal Biopsy 
Percutaneous renal biopsies should be performed according to local practices for this procedure, 
including appropriate pre-biopsy evaluation, biopsy technique, choice of imaging technique (e.g., 
ultrasound-guided, CT-guided, or other), anesthesia, and post-biopsy care.  Biopsies will not be 
obtained from participants less than 18 years of age (unless they are determined to be clinically 
indicated by the treating provider), or from participants for whom a biopsy is contraindicated.  
All biopsies will be reviewed by the designated central pathology laboratory, and will be 
evaluated by light microscopy, electron microscopy, and immunofluorescence.   
Details on the processing of the biopsy sample and discussion of the final renal pathology 
assessment and scoring for this study will be provided in the Pathology Manual, and the method 
for analyzing the pathology data will be provided in the Statistical Analysis Plan.  However, the 
approach will be similar to that described for lupus in that it will assess features that indicate 
active glomerular inflammation, and those that indicate chronic fibrotic irreversible injury.  Each 


ACH 0144471 
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Alexion Pharmaceuticals, Inc.). 
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15 May 2020 (Version 7.0) 
Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.) 
Page 47 of 91 
of these will be quantitated and may be combined into a composite scoring system.  If a 
composite scoring system is not used, the score of each feature at baseline and post-treatment can 
be compared. 
If, for any reason, any additional renal biopsies are performed (e.g., for a clinical indication), 
then every effort will be made to make these biopsy samples and results available to the central 
pathology laboratory for evaluation.  
6.3.1. 
Renal Biopsy Assessment 
Participants must have biopsy-confirmed primary C3G or IC-MPGN.  This can be a historical 
biopsy.  If no historical biopsy is available, a renal biopsy should be performed during the 
screening period, and the results must be available and reviewed before the first dose of 
ACH-0144471.   
Participants who choose to participate in the sub-study should have a renal biopsy before the first 
dose of ACH-0144471 to establish a baseline histology score.  Only one biopsy will be obtained 
prior to dosing; if a biopsy is required to confirm the diagnosis of C3G or IC-MPGN. It will be 
considered the pre-treatment biopsy for the sub-study.  If a pre-treatment biopsy is required for a 
participant who completed study ACH471-201, the biopsy should be at least 30 days after the 
last dose of ACH-0144471 in that study.  If a participant has had a recent renal biopsy it may not 
be clinically reasonable to repeat the procedure, and in this situation, a biopsy collected within 
approximately 6 months of the first dose of ACH-0144471 may be accepted in lieu of a biopsy 
during screening if it meets the requirements for analysis, and with written sponsor approval 
prior to study enrolment.   
For all  subjects,  biopsy should be obtained approximately 12 months of treatment, as described 
in the Schedule of Assessments (Appendix 1), to allow evaluation of changes in renal pathology.   
A sub-study is being conducted to evaluate the effects of ACH-0144471 on renal pathology; 
participation in this sub-study is not required.  A separate informed consent will be required for 
participation.  
Participants who choose to participate in the sub-study should have a renal biopsy at Week 28 
and 104 as detailed on the Schedule of Assessments. The biopsy at the end of the treatment 
period should be performed during the last 2 weeks of study drug treatment. 
6.4. 
Vaccination 
Information regarding the risk of infection can be found in Section 6.5.1 of the Investigator's 
Brochure [1]. 
As discussed in Section 6.2, a full vaccination history will be gathered.  Based on the vaccination 
history, the need for vaccinations against N. meningitidis, S. pneumoniae, and H. influenzae in 
this study will be evaluated.  Participants who do not have a sufficient history for some or all of 
these vaccines should receive vaccinations as recommended in the ACIP guidelines at least 
2 weeks before the start of dosing with ACH-0144471, unless otherwise recommended by 
national and/or local guidelines or local clinical practice.  If local and/or national guidelines do 
not exist or do not fully address vaccination against these organisms, investigators should 


ACH 0144471 
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Confidential Property of Achillion Pharmaceuticals, Inc. 
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consider consulting the ACIP guidelines (available 
at https://www.cdc.gov/vaccines/acip/index.html).  
Full identifying information for any vaccines given as part of this study, including the brand, 
should be recorded in the participant’s CRF.  Laboratory samples will be collected at the times 
indicated in the Schedule of Assessments (Appendix 1) for possible evaluation of participant 
response to the vaccines. 
6.5. 
Prophylactic Antibiotics 
As described in Section 6.4, Achillion expects that participants will be vaccinated according to 
ACIP guidelines at least 2 weeks prior to dosing with ACH-0144471, and believes that this will 
provide sufficient protection against these organisms.  However, this is a global study and 
Achillion recognizes that some vaccines may not be available in all countries, and that guidelines 
and clinical practices differ by region and may include the use of prophylactic antibiotics in 
some instances.  Antibiotic prophylaxis is therefore allowed if deemed appropriate by the PI or 
local clinical practice and/or guidelines for treatment with a complement inhibitor.  
Full identifying information for any antibiotics given as part of this study, including the brand, 
dosage, and times of administration should be recorded in the participant’s CRF.  
6.6. 
Urine Collection 
6.6.1. 
24-Hour Urine Collection 
Collection of urine over 24 hours will occur according to the schedule of assessments 
(Appendix 1).  Urine collected will be assayed as described in Table 2 for total protein 
concentration, albumin, creatinine, albumin:creatinine ratio, total protein: creatinine ratio, and 
total volume.  Complement components may also be assessed using urine, as described in 
Section 6.13.1.   
The 24-hour urine during the screening period must be collected at least 30 days after the last 
dose of ACH-0144471 in study ACH471-201.  If the 24-hour urine collection period is to occur 
after a renal biopsy, it must be at least 7 days after the biopsy procedure.  If clinic visits are not 
possible during the COVID-19 global pandemic, urine samples may be collected during home 
healthcare visits or delivered to a local laboratory. 
Specific instructions for urine collection, processing, and shipping will be provided in a separate 
laboratory manual. 
6.6.2. 
First Morning Urine Collection 
Collection of urine will occur according to the schedule of assessments (Appendix 1).  Urine 
collected will be assayed as described in Table 2; in addition to standard urinalysis, urine 
collected will be assayed for total protein concentration, albumin, creatinine, and the protein: 
creatinine and albumin:creatinine ratios.  Complement components may also be assessed, as 
described in Section 6.13.1.  
Participants will be given a collection container to collect their first morning void.  Specific 
instructions for urine collection, processing, and shipping will be provided in a separate 


ACH 0144471 
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(a subsidiary of Alexion Pharmaceuticals, Inc.) 
Page 49 of 91 
laboratory manual.  If the first morning urine collection coincides with a renal biopsy, collection 
must be completed before or at least 7 days after the biopsy procedure. If clinic visits are not 
possible during the COVID-19 global pandemic, urine samples may be collected during home 
healthcare visits or delivered to a local laboratory. 
6.7. 
Physical Examination 
A complete physical examination will be conducted by the PI (or designee) at the times specified 
in the Schedule of Assessments (Appendix 1).  This will include an examination of all major 
body/organ systems (including skin, head, eyes, ears, nose, throat, neck, thyroid, lungs, heart, 
abdomen, lymph nodes, and extremities), height, weight and calculation for BMI.  Measurements 
of height and weight should be taken with the participants in light clothing or underwear and 
without shoes.  Assessment of edema is part of the complete physical exam.  If edema is present, 
then assessment of edema should be performed at each subsequent visit, even when a physical 
exam is not required.  
Brief physical examinations, to include general appearance and examination of cardiovascular 
and respiratory systems, abdomen, extremities, and skin will be performed by the PI (or 
designee) at the times specified in the Schedule of Assessments (Appendix 1).  Assessment of 
edema is part of the brief physical exam.  If edema is present, then assessment of edema should 
be performed at each subsequent visit, even when a physical exam is not required.  Additional 
complete, brief or targeted physical exams (e.g., targeted to any new signs or symptoms) may be 
performed at any time at the discretion of the Investigator or designee, for example to evaluate 
an AE.  All clinically significant physical examination findings that are new or worsened since 
the last physical examination must be recorded in the participant’s source documents and in the 
participant’s CRF as an adverse event. 
6.8. 
Vital Signs 
The PI or designee will obtain blood pressure (BP), heart rate (HR), and respiration rate (RR) at 
the visits indicated in the Schedule of Assessments (Appendix 1).  Vital signs will be measured 
in the supine position following a 5-minute rest.  All blood pressure measurements should be 
taken on the same arm throughout the study.  Vital signs may be measured using an automated 
vital signs monitor, although manual measurements of blood pressure are preferred.  All vital 
sign measurements must be done using a calibrated instrument.  For each participant, the same 
method of measurement should be used at all visits.  All vital sign values, including whether 
measured manually or via an automated monitor, will be recorded in the participant’s source 
documents and in the participant’s CRF. 
6.9. 
Body Temperature 
The PI or designee will obtain body temperature using an oral thermometer at the visits indicated 
in the Schedule of Assessments (Appendix 1).  Prior to discharge from the clinic on Day 1, the 
participant will: 
1. Be educated and counseled by site staff regarding the potential for serious, rapidly 
progressive bacterial infections which may be life threatening and therefore understand 
the need to identify fever rapidly and seek emergency medical evaluation without delay 


ACH 0144471 
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2. Be educated and counseled by site staff regarding high risk behaviors, which include 
drinking from the same beverage containers, sharing eating utensils with others, avoiding 
large crowds, and smoking (including second-hand exposure) 
3. Be provided a thermometer and taught how to use it.  All participants need to take these 
thermometers with them at all times.  They need to be able to take their temperature if 
feeling warm or unwell 
4. Be instructed to contact the investigator immediately and/or seek emergency medical 
attention for any temperature >38.0°C /100.4°F 
5. Be advised not to wait for site staff to return their phone call before seeking emergency 
medical attention, but should go to the nearest emergency or urgent care medical facility 
for evaluation. 
6. Be taught to be alert to the signs of possible serious infections, which are often flu-like 
symptoms 
7. At all times, have immediate access to transportation, telephone, and emergency medical 
care 
8. Be provided with a study contact card and instructed to carry this with them at all times.  
The study contact card should be provided to the emergency medical personnel who 
should be asked to contact the study site 
All abnormal body temperature measurements must be recorded or stored in the participant’s 
source documents and CRF.  Any clinically significant finding must be reported as an adverse 
event.  Any temperature measurement ≥38.0°C, measured either at the clinic or by the participant 
outside the clinic, requires action as outlined in the Fever Management Plan (Appendix 2). 
6.10. 
Electrocardiography 
The PI or designee will obtain ECG measurements at the screening visit only. The ECG 
recordings should be 12-lead, and should be performed after the participant has rested quietly for 
at least 5 minutes in a supine position prior to dosing and before blood is drawn (whenever 
possible).  The following parameters and intervals will be assessed: HR, RR, PR, QRS, QT, and 
QTcF.  The occurrence of depolarization or repolarization disorders, arrhythmic disorders or 
other abnormalities will be noted.  A designation of clinical significance shall also be noted. 
In some cases, it may be appropriate to repeat an abnormal ECG to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that the leads are placed in 
approximately the same positions each time in order to achieve precise ECG recordings. 
All ECGs must be read by the PI or designee.  The PI/designee needs to evaluate the finding of 
ECG abnormalities promptly (refer to Section 6.19.1 for a discussion of the circumstances under 
which ECG findings are to be reported as AEs). 
All ECG parameters and assessments must be recorded or stored in the participant’s source 
documents and in the participant’s CRF.  Any clinically significant finding must be reported as 
an adverse event. 


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6.11. 
Clinical Laboratory Tests 
Blood and urine samples will be collected for safety and PD laboratory evaluation as listed in 
Table 2, at the times in Appendix 1.  Participants will be in a seated or supine position during the 
blood collection.  Specific instructions for sample collection, processing, and shipping will be 
provided in a separate laboratory manual. 
In addition to the calculation of eGFR, some investigators may choose to measure GFR based on 
iohexol clearance.  Measurement of GFR is at the discretion of the investigator, but if performed, 
these measurements should be taken, at a minimum, at baseline and at Weeks 28 and 52, to align 
with the collection of 24-hour urine samples (or at the end of treatment, if a participant 
terminates early).  Additional measurements may also be done at the discretion of the 
investigator. 


ACH 0144471 
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Table 2. 
Clinical Laboratory Tests  
Hematology 
Chemistry 
Urinalysis 
Additional Tests 
at Screening 
Only 
Other Assessments 
Complete blood count 
(CBC), including: 
- Red blood cell 
(RBC) count 
- White blood cell 
(WBC) count 
- WBC differential 
(absolute and 
percent): 
- neutrophils 
- lymphocytes 
- monocytes 
- eosinophils 
- basophils 
- Hematocrit (Hct) 
- Hemoglobin 
(Hgb) 
- Mean corpuscular 
volume (MCV)  
- Mean corpuscular 
hemoglobin 
(MCH) 
- Mean corpuscular 
hemoglobin 
concentration 
(MCHC)  
- Mean platelet 
volume (MPV) 
- Platelet count 
- Red cell 
distribution width 
(RDW) 
- Reticulocyte 
count 
Alanine 
aminotransferase 
(ALT) 
Albumin 
Alkaline phosphatase 
Aspartate 
aminotransferase 
(AST) 
Bicarbonate (HCO3) 
Bilirubin 
(fractionated)1 
Blood urea nitrogen 
(BUN) 
Calcium 
Calculated eGFR2 
Chloride 
C-reactive protein 
(CRP) 
Creatine kinase3 
Creatinine 
Cystatin C 
Gamma-glutamyl 
transferase (GGT) 
Glucose4 
GFR (iohexol 
clearance)5 
Lipid Profile including: 
- Cholesterol/HDL 
ratio 
- High-density 
lipoprotein 
cholesterol (HDL-
C) 
- Low-density 
lipoprotein 
cholesterol (LDL-
C) 
- Non-HDL-C 
- Total cholesterol 
- Triglycerides 
- Very low-density 
lipoprotein 
cholesterol 
(VLDL-C) 
Phosphate 
Potassium 
Sodium 
Total protein 
Uric acid 
Dipstick 
Analysis 
including: 
- Bilirubin 
- Color 
- Glucose 
- Ketones 
- Leukocytes 
- Nitrite 
- Occult blood 
- pH 
- Protein 
- Specific 
gravity 
- Urobilinoge
n 
Microscopic 
examination of 
sediment6 
Spot Urine 
sample, 
including7: 
- Total protein  
- Albumin 
- Creatinine 
- Albumin: 
creatinine 
ratio 
- Total 
protein: 
creatinine 
ratio 
- Complement 
components 
24-Hour Urine 
collection 
sample, 
including: 
- Total protein  
- Albumin 
- Creatinine 
- Albumin: 
creatinine 
ratio 
- Total 
protein: 
HCV Ab8 
HbsAg 
HIV Ab 
FSH9 
Serum Pregnancy 
test10 
Urine drug 
screen11 
Sample for 
potential 
genetic 
biomarker 
testing (white 
blood cells) 
Complement 
Biomarkers: 
- AP Wieslab 
- AP Hemolysis 
- Ba 
- Bb 
- C3 
- C4 
- CP activity 
- fB 
- fD 
- sC5b-9 
PT/PTT/INR 
Urine pregnancy test 
Samples for 
assessment of 
participant 
response to 
vaccines 


ACH 0144471 
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Alexion Pharmaceuticals, Inc.). 
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Confidential Property of Achillion Pharmaceuticals, Inc. 
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creatinine 
ratio 
- Total 
volume 
- Complement 
components 
Check the Schedule of Assessments (Appendix 1) for specific times when these tests should be done. 
1. 
Fractionate and obtain measurements of direct and indirect bilirubin for all participants.   
2. 
Provide eGFR based on CKD-EPI creatinine equation (2009) for participants ≥19 years of age, and based on 
the “Bedside Schwartz” equation (2009) for participants <19 years of age. 
3. 
Perform at screening and Day 1, and then subsequently only as a reflex if AST > ULN.  
4. 
If glucose is > ULN, reflexively test HbA1c 
5. 
Optional, at the discretion of the investigator.  
6. 
Only if occult blood, protein, or leukocytes present on dipstick analysis. 
7. 
The spot urine sample should be a first-morning void.  
8. 
If positive, HCV RNA levels should be measured.  Participants with detectable HCV RNA will be excluded.  
9. 
FSH for postmenopausal women at screening only.  May be omitted if postmenopausal status confirmed in 
ACH471-201.  
10. Serum pregnancy test at Screening Visit 1 and urine pregnancy tests at other times as per the schedule in 
Appendix 1 for women of childbearing potential only.  Any positive urine pregnancy test will be confirmed 
by a serum pregnancy test. 
11. Urine drug screen will be measured at Screening Visit 1.  For all participants, the urine drug test should 
include, at a minimum, cotinine, amphetamines, barbiturates, cocaine metabolites, opiates, benzodiazepines, 
and cannabinoids.  
6.12. 
Pregnancy Testing 
All females of childbearing potential (as determined at screening) will have a serum pregnancy 
test during screening, and urine pregnancy tests for the duration of the study including follow-up, 
as indicated in Appendix 1.  On Day 1, the urine pregnancy test must be done before dosing and 
be negative to begin dosing.   
Female participants of childbearing potential who require vaccinations (see Section 6.4) must 
also have a negative urine pregnancy test before any vaccine or booster is administered.  
Any positive urine pregnancy test will be confirmed by a serum pregnancy test. 
6.13. 
Sample Collection, Storage, and Shipping 
6.13.1. 
Blood and Urine Collection for Complement Assays 
Serum/plasma samples will be collected at the time points indicated in Appendix 1.  It is 
important that samples for PD testing be collected, prepared, and shipped in a way that ensures 
minimum freeze-thaw cycles and avoids potential in vitro complement activation before testing.  
Whole blood will be collected and processed to obtain cell-free serum or plasma which will be 
aliquotted into cryovials, frozen on dry ice, stored in a -80°C freezer and shipped frozen to the 
designated laboratories for testing.  
Urine samples will be collected according to the schedule in Appendix 1 and stored for potential 
assessment of the concentrations of selected complement proteins in urine.  
Specific instructions for sample collection, processing, and shipping will be provided in a 
separate laboratory manual. 


ACH 0144471 
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Biological samples, such as serum, plasma and urine, may be kept for up to 3 years after 
completion of the Clinical Study Report and then will be destroyed by internationally accepted 
means (e.g., incineration). 
6.13.2. 
Blood Collection for Genetic Complement-Associated Biomarker Testing  
Subject to participant consent, a sample will also be collected at screening for potential genetic 
analysis.  Genetic analyses may be conducted if a participant does not respond to the 
investigative drug, to better understand a potential drug-related toxicity, or to further characterize 
the underlying disease.  Genes which may be sequenced include (but are not limited to): 
• Complement component C3 
• Complement factor H-related proteins (CFHR1, CFHR3, CFHR4, CFHR5) 
• Complement factor B  
• Complement factor D 
• Complement factor H 
• Complement factor I 
• Membrane Co-Factor Protein (MCP/CD46) 
• Thrombomodulin (THBD) 
All genetic samples will be stored for a maximum of 3 years after completion of the Clinical 
Study Report.  During that time, samples may be retested if other mutations are discovered that 
may be associated with C3G.  Participants may withdraw their consent for genetic testing and 
withdraw their samples from further genetic testing at any time by notifying the study 
investigator verbally and in writing.  After the 3-year storage period defined above, or once the 
sponsor is informed of withdrawal of consent for further analysis, the sample will be destroyed 
consistent with accepted laboratory standards and no further testing or analysis will be 
completed.  Any data already generated from the sample may continue to be used for the 
purposes of this study and future research. 
6.13.3. 
PK Plasma Samples 
For samples collected for pharmacokinetic analysis, whole blood (2 mL) will be collected into 
3 mL vacutainers containing K2EDTA.  The vacutainers should be gently inverted 5 to 8 times to 
thoroughly mix the preservative with the blood and kept chilled in an ice bath.  The tubes should 
be centrifuged at 4°C for 15 minutes at 1300 g within 30 minutes of blood collection.  
Approximately 400 µL of plasma shall be pipetted into each of 2 pre-labeled cryovials (a 
primary and back-up sample) and stored at -80°C within one hour of having collected the blood.  
The primary PK samples will be shipped to the bioanalytical laboratory at pre-determined 
intervals, while the backup sample will remain at the clinic.  Information on when and where to 
ship samples will be provided separately. 


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6.13.4. 
Blood Volumes 
Approximate blood volumes to be drawn are detailed in Table 3 below.  The total planned blood 
volume to be collected per individual is approximately 559 mL.  This does not include discarded 
blood from pre-collection used to flush catheters.  The discarded volume is not expected to 
exceed 40 mL.  Unanticipated additional blood may be collected throughout the study for such 
things as safety monitoring and additional PK or PD assessments, if necessary, and if there are 
blood samples collected during any unscheduled visits. 
Table 3. 
Approximate Total Blood Volumes 
 
Volume (mL) 
Period 
Screening 
Treatment 
(Weeks 1 to 54) 
Long Term 
Follow-up 
(Weeks 55 
to 169) 
Taper & 
Follow-up 
Total 
Volume 
Totals 
34 
269 
176 
80 
559 
The maximum volume drawn in an 8-week window is 115 mL, from Day 1 to Week 8 (Day 56), inclusive.  The 
maximum volume drawn in a 24-hour period is 35 mL, on Week 12.  
6.14. 
Dispensing Study Drug 
ACH-0144471 will be supplied as 50 and 100 mg tablets.  At each visit, the site will dispense 
study drug as required to provide participants with sufficient study drug for dosing until their 
next clinic visit. If a clinic visit is not possible during the COVID-19 pandemic, study drug will 
be sent directly to participant’s home (Section 6.24). 
6.15. 
Safety Assessments 
Safety will be evaluated by monitoring and assessment of AEs, clinical laboratory tests, physical 
examination findings, and vital signs measurements at Screening, Baseline, and at various time 
points during the study as described in Section 7 and the Schedule of Assessments (Appendix 1). 
6.16. 
Pharmacokinetic Assessments 
Single trough PK samples will be taken at the times indicated in the Schedule of Assessments 
(Appendix 1).  
Concentrations of ACH-0144471 in plasma or serum will be measured using a validated 
bioanalytical method.  Actual sampling times will be checked for major aberrations.  Actual 
sampling times will be used in the PK analysis for that participant and study day. 
6.17. 
Pharmacodynamic Assessments 
PD markers monitor biological effects and are used in early drug development to assist in future 
decision making.  Pharmacodynamics will be evaluated using serum, plasma, and urine collected 
during the study.  Additional information on sample collection and shipping instructions will be 
provided in a separate laboratory manual. 
Pharmacodynamics will be evaluated by assessment of Bb levels in plasma samples collected 
during the study, which should provide a direct readout of AP inhibition in vivo.  In addition, the 


ACH 0144471 
Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
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Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.) 
Page 56 of 91 
CP activity assay is a functional assay to qualitatively evaluate the effect of ACH-0144471 on 
total CP activity.   
Inhibition of AP activity will also be evaluated with the AP Wieslab ELISA assay, AP 
hemolysis, and C3 convertase activity, the presence of autoantibodies to complement 
components or regulators, and the concentrations of selected complement components and their 
split and terminal products in serum, plasma, and/or urine may be explored to understand their 
association with the underlying disease and any changes in response to ACH-0144471 treatment.   
White blood cells will be collected and stored for possible genetic profiling of selected 
complement components and regulators (see Section 6.13.2) for possible exploration of the 
understanding of the underlining etiology of C3G and any correlation with participants’ response 
to ACH-0144471.   
6.18. 
Patient-Reported Outcomes Assessments 
6.18.1. 
Quality of Life Questionnaires 
All adult participants enrolled in the trial will self-administer questionnaires for the FACIT-
Fatigue (version 4), KDQOL version 1.3, and EQ-5D-3L scales, and all adolescent participants 
enrolled in the trial will self-administer questionnaires for the Peds-FACIT-F and EQ-5D-Y 
scales at the times specified in Appendix 1 to assess their HRQOL, fatigue, and kidney-related 
fears and worries (e.g. kidney failure, dialysis, kidney transplant), and to determine health states 
value, over the course of treatment with ACH-0144471.  Local language versions of each of the 
tools will be provided separately.  
6.19. 
Adverse Events Assessments 
6.19.1. 
Definitions 
Adverse events (AEs) must be assessed for the investigational product(s) in this study.  An 
investigational product is defined as a pharmaceutical form of an active ingredient or placebo 
being tested or used as a reference in the study, whether blinded or unblinded.  The term 
“adverse event” is defined as any untoward medical occurrence associated with the use of a drug 
in humans, whether or not considered drug related.  An AE can arise with any use of the drug 
(e.g., off-label use, use in combination with another drug) and with any route of administration, 
formulation, or dose, including an overdose. 
Medical occurrences, including pregnancies, that begin before the start of study intervention but 
after obtaining informed consent will be recorded on the Medical History/Current Medical 
Conditions section of the CRF, not the AE section.  This does not include pre- or post-treatment 
complications that occur as a result of protocol-mandated procedures (e.g., invasive procedures, 
such as venipuncture or biopsy), which should be reported as AEs.  While pregnancy itself is not 
considered an AE, for the purposes of tracking, a pregnancy occurring after the start of study 
intervention should be captured as an AE as well as reported on the pregnancy forms. 
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during treatment, 
having been absent prior to treatment, or worsens relative to the pretreatment state.  In this study, 
any AE first assessed after receipt of the first dose of ACH-0144471 until 28 days after the last 


ACH 0144471 
Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
Clinical Protocol ACH471 205 Amendment 6 
15 May 2020 (Version 7.0) 
Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.) 
Page 57 of 91 
dose of study drug will be considered treatment-emergent, as defined in Section 6.19.5.  All 
TEAEs will be recorded and reported. 
An AE (including a TEAE) can be one or more of the following: 
• 
Any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a drug and does not imply any judgment 
about causality. 
• 
Any new disease or exacerbation of an existing disease. 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at baseline. 
• 
Any case of abuse of alcohol, illicit drugs, or prescription drugs; abuse of study drug(s) 
or protocol-specified drug(s); addiction. 
• 
A pregnancy that occurs or becomes confirmed during a clinical study (see 
Section 6.19.8). 
• 
Laboratory test or other clinical test (e.g., ECG or X-ray) with a clinically significant 
abnormality (as defined below). 
• 
An effect of the study medication, including comparator. 
• 
Any dose of medication (study drug or other concomitant medication) that is taken at a 
dose higher than the prescribed dose (i.e., an overdose).  Overdose should be reported as 
an AE whether or not it is associated with any symptoms or signs. 
The following are not considered to be AEs: 
• 
Medical or surgical procedures (e.g., surgery, endoscopies, tooth extraction, transfusion, 
etc.) - the condition which leads to the procedure is the AE; 
• 
Preexisting diseases or conditions or laboratory abnormalities present or detected prior to 
the screening evaluation that do not worsen; 
• 
Situations where an untoward medical occurrence has not occurred (e.g., hospitalization 
for elective surgery, social and/or convenience admissions, etc.) 
Clinically significant changes in objective findings (e.g., laboratory, ECG, physical examination) 
should be considered AEs only if they meet one or more of the following criteria: 
• 
Associated with accompanying symptoms;  
• 
Require medical/surgical intervention;  
• 
Lead to a change in study drug dosing or discontinuation from the study;  
• 
Lead to significant additional concomitant drug treatment, or other therapy;  
• 
Lead to any of the outcomes included in the definition of a serious adverse event;  
• 
Are considered clinically significant by the investigator. 
Whenever possible, the etiology of the abnormal finding (rather than the abnormal finding itself) 
should be documented as the adverse event.  Repeated additional tests and/or other evaluations 


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Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
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Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.) 
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required to establish the significance and etiology of an abnormal result should be obtained when 
clinically indicated. 
Any abnormal test result that is determined to be an error does not require reporting as an AE. 
Surgical procedures themselves are not AEs but are therapeutic measures for conditions that 
require surgery.  The condition for which the surgery is required may be an adverse event, if it 
occurs or is detected during the study period.  Planned surgical measures permitted by the 
clinical study protocol (if any) and the condition(s) leading to these measures are not AEs, if the 
condition(s) was (were) known before the start of the study treatment and documented in the 
participant’s medical record.  In the latter case, the condition should be reported as medical 
history. 
All participants who have AEs, whether considered to be associated with the use of the 
investigational product or not, must be monitored to determine the outcome of the event(s).  The 
clinical course of the AE will be followed according to accepted standards of medical practice, 
even after the end of the period of observation, until a satisfactory explanation is found, or the 
investigator considers it medically justifiable to terminate follow-up. 
6.19.2. 
Criteria for Assessing Seriousness 
All AEs must be evaluated as potential SAEs.  If an event is not an AE per definition above, then 
it cannot be an SAE even if serious conditions are met.  An SAE is any untoward medical 
occurrence that occurs at any dose and meets at least one of the following criteria: 
• 
Results in death 
• 
Is life-threatening i.e., the participant was at immediate risk of death from the AE as it 
occurred.  (This does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death.) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization for the AE 
 The following types of hospitalizations are not considered SAEs for regulatory 
reporting purposes: 
− Hospitalization(s) for planned (pre-scheduled) medical procedures known at the 
time of screening 
− Protocol-specific hospital admission 
− Respite care 
− Admission for the treatment of pre-existing condition (known at the time of 
screening) not associated with the development of a new AE or with the 
worsening of the pre-existing condition 
− Observation/same day/ambulatory procedure 
• 
Is a persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions 
• 
Is a congenital anomaly/birth defect (in the child of a participant who was exposed to the 
study drug) 


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(a subsidiary of Alexion Pharmaceuticals, Inc.) 
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• 
Is an important medical event or reaction 
6.19.3. 
Documentation and Reporting of Adverse Events 
AEs, including TEAEs, may be spontaneously reported by a participant or his/her representative, 
or elicited during questioning and examination of a participant.  All AEs will be assessed by the 
Investigator and documented regardless of apparent causality from use of the study treatment(s).  
For each AE, the investigator will evaluate and report the date of onset and resolution, outcome, 
severity, relationship to study treatment(s), action taken, additional treatments required to 
manage the event, and determination of seriousness.  All identified AEs occurring during the trial 
and follow-up period must be fully recorded and described on the appropriate CRF page.  The 
AE should be reported in standard medical terminology.  Whenever possible, the AE should be 
evaluated and reported as a diagnosis, rather than as individual signs or symptoms.  A cluster of 
signs and symptoms that results from a single cause should be reported as a single AE (e.g., 
fever, elevated WBC, cough, abnormal chest X-ray, etc. can all be reported as “pneumonia”). 
If a definitive diagnosis is not possible, the individual symptoms and signs should be recorded.  
Documentation must be supported by an entry in the participant’s medical record.  The 
relationship to study drug or study procedures should be assessed using the definitions in 
Section 6.19.7. 
6.19.4. 
Treatment and Follow-Up of Adverse Events 
All AEs should be followed up (including obtaining relevant laboratory tests) until they have 
returned to baseline status or stabilized.  If a clear explanation is established, it should be 
recorded.  Follow-up of AEs will continue through the last day on study (including the follow-up 
period) or until the events have resolved or stabilized to the satisfaction of the PI and the 
Achillion Pharmaceuticals Medical Monitor (or designee).  Achillion Pharmaceuticals may 
request that certain AEs be followed until resolution or stabilization. 
6.19.5. 
Timeframe for Collection of Adverse Events 
AEs include events that have appeared or worsened during the course of the clinical trial.  AEs 
may also include pre- or post-treatment complications that occur as a result of protocol-mandated 
procedures (e.g., invasive procedures, such as venipuncture, biopsy, etc.). 
Any AE (i.e., a new event or an exacerbation of a preexisting condition) with an onset date after 
the participant provides informed consent through the 28 days following the participant’s last 
study drug dose will be recorded as an AE on the appropriate CRF page(s). 
All SAEs, regardless of cause or relationship, occurring within 28 days of last study drug dose 
must be documented and reported. 
Follow-up of SAEs will continue through the last day on study or until the event has resolved or 
stabilized to the satisfaction of the PI and the Achillion Pharmaceuticals Medical Monitor (or 
designee).  Investigators are not obligated to actively seek out SAEs beyond the follow-up 
period.  However, if the PI (or designee) learns of an SAE occurring after completion of the final 
follow-up visit, and the SAE is deemed by the PI (or designee) to be related to the study drug (s), 


ACH 0144471 
Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
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15 May 2020 (Version 7.0) 
Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.) 
Page 60 of 91 
the PI (or designee) should promptly document and report the event to Achillion 
Pharmaceuticals. 
6.19.6. 
Severity and Grading of Adverse Events 
The severity of an adverse event will be graded according to the Common Terminology Criteria 
for Adverse Events (CTCAE) v4.03 [37].  The PI (or designee) should determine the severity of 
the AE based on the overall clinical importance or significance of the finding for that individual 
participant.  If a lab abnormality is deemed to be clinically significant, according to the criteria 
described in Section 6.19.1, it should be reported as an AE and the AE grade reported should 
correspond to the grade of the lab abnormality on the CTCAE grading scale. 
If an AE that was reported during the study increases or decreases in severity, then that AE is 
given a resolution date and time and a new record initiated with the new severity.  If the severity 
of an AE remains the same, the AE will be kept open through to resolution. 
6.19.7. 
Assessment of Causality 
The investigator must assess the likelihood that the study drug caused or contributed to each AE, 
and document this assessment assigning one of the following relatedness criteria to each AE: 
• 
Unrelated: In the opinion of the investigator, there is no association between the study drug 
and the AE. 
• 
Unlikely: In the opinion of the investigator, it is unlikely that there is an association between 
the study drug and the reported event. 
• 
Possible: In the opinion of the investigator, treatment with the study drug may have caused 
or contributed to the AE, but could also have been produced by other factors (i.e., the event 
follows a reasonable temporal sequence from the time of drug administration and/or follows 
a known response pattern to the study drug, but is also known to be caused by other factors). 
• 
Probable: In the opinion of the investigator, it is likely that the study drug caused or 
contributed to the AE based on a reasonable temporal sequence of the event with drug 
administration and, the known pharmacologic action and/or adverse reactions of the drug (or 
class of drugs) or the investigator’s clinical judgment. 
• 
Definite: In the opinion of the investigator, it is definite that the study drug caused or 
contributed to an AE, and other conditions (e.g., concurrent illness, progression/expression of 
disease state, or concurrent medication reaction) do not explain the event. 
For the purposes of determining expedited reporting status to Health Authorities, Achillion 
considers the assessments of ‘unrelated’ and ‘unlikely’ as unrelated to study drug and ‘possible’, 
‘probable’, and ‘definite’ as related to study drug. 
In addition, for any analyses of AE data in which only two categories of ‘related’ and ‘unrelated’ 
are used, the assessments of ‘unrelated’ and ‘unlikely’ will be combined into the category of 
‘unrelated’, and the assessments of ‘possible’ and ‘probable’ and ‘definite’ will be combined into 
the category of ‘related’. 


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Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
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Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.) 
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6.19.8. 
Pregnancy 
Any pregnancy, including in a female partner of a male participant, that occurs or becomes 
confirmed during a clinical study (time frames outlined in Section 6.19.5) must be reported to 
Achillion (or designee) within one business day of first knowledge of the pregnancy.  The report 
should be provided on the pregnancy form.  While pregnancy itself is not considered an AE, for 
the purposes of tracking, it should be captured as an AE as well as reported on the pregnancy 
forms. 
All pregnancies temporally related to study drug should be followed and discussed with the 
medical monitor as follows: 
• 
The investigator will follow up with the participant or the participant’s female partner 
approximately every 3 months throughout the pregnancy and report to Achillion (or 
designee) using the pregnancy forms.  Generally, follow-up will not be required for 
longer than 6-8 weeks beyond the estimated delivery date.  
• 
The investigator will report any information on the status of the pregnancy to Achillion 
(or designee) using the pregnancy forms. 
• 
The outcome of the pregnancy will be reported to Achillion (or designee) using the 
pregnancy forms.  Any termination of pregnancy will be reported, regardless of fetal 
status (i.e., presence or absence of anomalies) or indication for the procedure.  
Any SAEs related to the pregnancy (see below), or occurring during the participant’s pregnancy, 
or after delivery, must be documented and reported to Achillion (or designee) on both the SAE 
Form and the pregnancy forms.  SAEs occurring in the child (e.g., congenital anomalies or other 
conditions present at birth, whether genetically inherited or occurring in utero) must also be 
documented on both the SAE form and the pregnancy forms. 
Reportable SAEs associated with pregnancy include, but are not limited to: 
• 
Pregnancy losses (e.g., spontaneous abortion, late fetal death, elective termination) 
• 
Life-threatening developments (e.g., placental abruption, fetal distress) 
• 
Congenital anomalies 
• 
Neonatal or maternal death, or 
• 
Any event resulting in maternal or neonatal hospitalization/prolonged hospitalization. 
6.19.9. 
Reporting Serious Adverse Events 
Achillion Pharmaceuticals has requirements for the expedited reporting of safety events meeting 
specific requirements to worldwide regulatory authorities; therefore, Achillion Pharmaceuticals 
must be notified immediately regarding the occurrence of any SAE and/or pregnancy that occurs 
during the study (time frames outlined in Section 6.19.5).  
The procedures for reporting all SAEs and/or pregnancies, regardless of causal relationship, are 
as follows: 
SAE 


ACH 0144471 
Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
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• 
Record the SAE within 24 hours of becoming aware of the event by  
• 
Logging into the EDC system 
 and completing an initial SAE report. 
This will trigger an email notification to the 
 Achillion Pharmaceuticals distribution  
Pregnancy 
• 
Record the pregnancy into the EDC system 
 form 
• 
This will trigger an email notification to the 
 Achillion Pharmaceuticals 
distribution lists. 
Contact information is provided below. 
SAE CONTACT 
SAE Telephone Number: 
In the event of System failure, or for questions about completing the forms in 
EDC: 
 
  
 
For fatal or life-threatening events, provide copies of hospital discharge reports, autopsy reports, 
and other documents, as applicable.  Achillion Pharmaceuticals may request additional 
information from the PI to ensure the timely completion of accurate safety reports. 
In the case of a medical emergency, please use the contact provided on the title page of the 
protocol. 
6.19.10. 
Investigator Reporting Requirements for SAEs 
Achillion is responsible for ensuring that Investigators and central ECs/IRBs are notified of all 
AEs that are serious, unexpected and considered related, probably related, or possibly related to 
the investigational product.  A CRO may be designated to perform this notification.  This 
notification will be in the form of a MedWatch/CIOMS report.  The PI will notify the local ECs 
or IRBs as per EC or IRB requirements.  Upon receiving such notices, the PI must review and 
retain the notice.  The Sponsor, investigator, and EC or IRB will determine if the informed 
consent requires revision.  The PI should also comply with EC or IRB procedures for reporting 
any other safety information. 
6.20. 
Concomitant Medication Assessments 
Details of all prior (within 90 days of the screening evaluation) and concomitant medication use, 
including all medications administered for the treatment of AEs as well as prior administration of 
ACH-0144471 in study ACH471-201, will be recorded in the participant’s CRF at each study 
visit. 
6.21. 
Monitoring Participant Safety 
The safety of participants will be monitored by Investigators and by a medical monitor (or 
designee) at Achillion Pharmaceuticals on an ongoing basis while participants are receiving 
PPD
PPD
CCI
CCI
CCI
CCI
CCI
PPD
PPD


ACH 0144471 
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ACH-0144471.  Additionally, a Fever Management Plan (Appendix 2) has been developed for 
this study to enable rapid assessment, detection and treatment of any potential serious infection. 
6.22. 
Removal of Participants from the Trial or Study Drug 
A participant is free to withdraw from the study at any time without jeopardizing future medical 
care.  The PI (or designee) may decide, for reasons of medical prudence or participant 
noncompliance, to discontinue dosing in a participant.  The PI should also stop dosing in any 
participant who meets an individual stopping rule (Section 3.2.3.2).  In either case, whenever 
possible, the Achillion MM should be notified immediately, and if possible, before dosing is 
terminated.  
If dosing is to be terminated, it may be done so immediately, or a taper can be implemented as 
described in Section 5.2, whichever is considered to be in the best interest of the participant.  
When dosing is terminated, study participation is not necessarily immediately terminated.  
Instead, whenever possible, the participant should complete all activities in the Taper and 
Follow-Up periods (if tapered) or in the Follow-Up period (if discontinued immediately), as 
described in Appendix 1. 
Reasons for participant withdrawal include (but are not limited to): 
• 
One or more of the stopping criteria described in Section 3.2.3 is met 
• 
Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree 
• 
Unacceptable toxicity (including a clinically significant laboratory abnormality) 
necessitating discontinuation of study or that, in the judgment of the investigator, 
compromises the ability to continue study-specific procedures, or it is considered not to 
be in the participant’s best interest to continue the study  
• 
Participant request to discontinue for any reason 
• 
A female participant becomes pregnant or wishes to become pregnant 
• 
Participant noncompliance 
• 
Discontinuation of the study at the request of Achillion Pharmaceuticals, regulatory 
agency, or Ethics Committee or IRB 
• 
Any other condition or circumstance that would jeopardize the welfare of the participant 
if s/he were to continue in the trial 
The reason for any participant’s discontinuation and the date of withdrawal will be recorded in 
the participant’s CRF.  The participant’s CRF, which will be completed up to the point of 
withdrawal, will be retained for the Sponsor. 
6.23. 
Study Assessments When Clinic Visits are Not Possible due to the 
COVID-19 Pandemic 
If a study participant is unable to get to a clinic visit, study data collection may still occur: 
Option 1 (preferred option) 


ACH 0144471 
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(a subsidiary of Alexion Pharmaceuticals, Inc.) 
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•
Home Healthcare Visits: At these home visits, nurses may collect 24-hour urine, first
morning urine, and safety labs, including pregnancy testing, for shipment to the central
laboratory. Serum/plasma biomarker laboratory assessments, and serum C3 and C4
assessments cannot be collected at home visits, due to the stringent storage and handling
requirements of these specimens. Other assessments will include adverse events, vital
signs, concomitant medications, and study drug accountability. Physical examinations,
weights, and patient-reported outcomes will not be collected at home health visits.
Option 2 (if Option 1 is not possible) 
•
Telephone visits: If home visits are not possible, participants may have telephone visits
with the PI or designee. Data collection should include adverse events and concomitant
medications. Physical examinations cannot be performed during a telephone visit. Patients
will be asked about study drug compliance.
o
Local Laboratories: If home visits are not possible, the participant should go to a
local laboratory to drop off 24-hour urine collections, and for safety laboratory
testing, including pregnancy testing (if applicable), to be performed.
6.24. 
Study Drug Compliance and Supply When Clinic Visits are Not 
Possible 
If a study participant is unable to get to a clinic visit during the COVID-19 global pandemic, 
study drug may be shipped to the participant’s home.  
Treatment compliance assessments shall be made at each home visit or telephone visit.  
Participants will be asked about their supply of study drug so that drug accountability may be 
assessed. Study staff will address any non-compliance issues with the participant.  
6.25. 
Renal Biopsies When Clinic Visits are Not Possible 
If a study participant is unable to get to a clinic visit during the COVID-19 global pandemic, 
optional renal biopsies at Week 52 and Week 104 should be performed when possible, even if 
the biopsy is done outside the visit window of ± 7 days. In addition, an unscheduled 24-hour 
urine collection should be obtained at the same time as the optional renal biopsies at Week 52 
and Week 104. If the collection of 24-hour urine is to occur after a renal biopsy, it must be done 
at least 7 days after the biopsy procedure.  


ACH 0144471 
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Alexion Pharmaceuticals, Inc.). 
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Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.) 
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7. 
STUDY ACTIVITIES 
Activities for each visit are provided in the Schedule of Assessments (Appendix 1).  Additional 
details for the various activities are provided in Section 6. 
During the periods when multiple assessments occur at the same time, they should be conducted 
in the following order: 
• 
Vital signs prior to blood sampling 
• 
PK samples should be taken before the first daily dose  
• 
Blood for laboratory safety test may be collected prior to PK sampling, provided that PK 
sampling times are not affected 
The actual times of procedures and sample collections will be recorded in the participant’s CRF. 
7.1. 
Screening Period (Days –75 to -1) 
For each participant, informed consent or assent will be obtained as described in Section 6.1 
before the participant enters into the study and any study-related procedures are performed, and 
participant eligibility will be determined according to the criteria specified in this protocol.  All 
screening eligibility assessments listed in the Schedule of Assessments (Appendix 1) should be 
performed and documented prior to dosing.  This should include a review of the inclusion and 
exclusion criteria, and a review of the study restrictions, as defined in Section 5.5.  The 
participant’s medical history should be reviewed as described in Section 6.2, and a complete 
physical examination should be conducted as described in Section 6.7.  A 24-hour urine sample 
should be collected as described in Section 6.6.1 and a first morning urine sample should be 
collected as described in Section 6.6.2; participants may be provided with collection containers 
and bring their samples to the clinic prior to dosing.   
If the participant remains eligible, then arrangements can be made for any required vaccinations 
(see Section 6.4).  If required, vaccinations should be at least 2 weeks before the start of dosing 
with ACH-0144471, unless otherwise recommended by national and/or local guidelines or local 
clinical practice.  Participants who meet all eligibility criteria will be educated about the 
restrictions on concomitant medication usage and other substances. 
Each adult participant will complete the KDQOL-SF v1.3, FACIT-Fatigue, and EQ-5D-3L 
questionnaires and each adolescent participant will complete the Peds-FACIT-F and EQ-5D-Y 
questionnaires during the screening period, prior to study treatment administration. 
All evaluations required for determination of eligibility must be completed before the participant 
is accepted into the study for dosing.   
If the participant is unable to receive study drug within 75 days of screening the participant may 
be re-screened once (for all assessments except the renal biopsy).   
The repeating of individual screening laboratory results that fall outside the protocol-required 
range may be permitted on a case-by-case basis with the written pre-approval of the Achillion 
Pharmaceuticals Medical Monitor (or designee). 


ACH 0144471 
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Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.) 
Page 66 of 91 
7.1.1. 
Screening or Pre-Treatment Renal Biopsy 
If necessary to confirm eligibility (as discussed in Section 6.3.1) or as a pre-treatment biopsy for 
the renal biopsy sub-study, a renal biopsy should be performed during screening according to the 
procedures described in Section 6.3.  When obtained to confirm eligibility, the results must be 
available and reviewed prior to dosing.  Given that the renal biopsy is an invasive procedure, a 
participant should be confirmed as eligible by all other criteria before the renal biopsy is 
performed.   
Biopsies will not be obtained from participants less than 18 years of age (unless they are 
determined to be clinically indicated by the treating provider), or from participants for whom a 
biopsy is contraindicated.  
7.1.2. 
Vaccination  
As part of the screening process, participants will be evaluated to determine whether vaccination 
against N. meningitidis, S. pneumoniae, or H. influenzae is to be performed, as described in 
Section 6.4.  Female participants of childbearing potential must have a negative urine pregnancy 
test on the day of vaccination, before any vaccine or booster is administered.  
7.2. 
Treatment Period 
During the Treatment Period, physical examinations, assessment of vital signs, all required 
safety laboratory testing, and collection of blood and urine samples for PK and PD evaluation 
will be performed at various time points as specified in Appendix 1.   
Participants should be instructed to fast prior to coming to a clinic visit; however, they may drink 
water or other non-alcoholic beverages.  Participants should be instructed to bring their study 
drug with them for administration at the site. 
At clinic visits, participants should be instructed how to take their medication at home, as 
described in Section 5.3, and record the time they took it.  
Participants should be instructed to store their study drug at room temperature, as described in 
Section 5.8.   
Patient visits will be scheduled as listed in the Schedule of Assessments (Appendix 1).  The final 
treatment period visit will be at Week 169.  Participants should arrive at the clinic at the time 
designated by site personnel.  The assessments listed in the Schedule of Assessments 
(Appendix 1), including collection of blood for determination of trough levels of study drug and 
measurement of the listed complement markers should be performed prior to the administration 
of the first daily dose of ACH-0144471.  
Each adult participant will be asked to complete the KDQOL-SF v1.3 questionnaire, EQ-5D-3L 
and the FACIT-Fatigue scale and adolescent participants will be asked to complete the Peds-
FACIT-F and EQ-5D-Y at the visits specified in the Schedule of Assessments (Appendix 1). 
7.3. 
Taper Period 
It is recommended that participants who discontinue ACH-0144471 have study drug tapered over 
6 days, as described in Section 5.2.  If a participant meets an Individual Stopping Rule 


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(Section 3.2.3.2) and dosing is stopped, the PI should consider whether it is in the best interest of 
the participant to discontinue dosing immediately or to taper (as described in Section 5.2).  
Whenever possible, the taper decision should also be discussed with the Achillion MM prior to 
dosing termination.  If a Group Stopping Rule is met and dosing is terminated in the study, the 
Achillion MM in consultation with the PI will decide whether or not the taper should be 
implemented.  When dosing is terminated, study participation is not necessarily immediately 
terminated.  Instead, whenever possible, the participant should advance to the Taper and/or 
Follow-Up Periods, as relevant, and complete all activities in those periods as described in 
Appendix 1.  Participants who are completing the taper will have assessments indicated in 
Appendix 1 performed on Days 3 (T3) and 6 (T6) of the taper period.   
Participants will be instructed to bring their study drug with them for administration at the site.  
Participants will continue taking their medication at home in the same way as previously 
described (see Section 5.2).   
Participants will be instructed to store their study drug at room temperature, as described in 
Section 5.8.  
Participants should be instructed how to take their medication at home, as described in 
Section 5.3.2, and record the time they took it.  
7.4. 
Follow-Up Period 
During the Follow-Up Period, physical examinations, assessment of vital signs, all required 
safety laboratory testing, and collection of blood and urine samples for PD evaluation will be 
performed at various time points as specified in Appendix 1.   
As listed in the Schedule of Assessments (Appendix 1), participants will be evaluated at the 
clinical site 2 weeks after the last dose of study drug, and again 4 weeks after the last dose of 
study drug during the Follow-up Period.  Participants should arrive at the clinic at the time 
designated by site personnel.  If necessary, clinic visits during the Follow-Up Period may occur 
up to 2 days earlier or later than scheduled.   
7.5. 
Early Termination from the Study 
A participant who discontinues dosing does not necessarily discontinue from the protocol, and 
whenever possible, should have the assessments listed for Follow-up Visit 2 in the Schedule of 
Assessments (Appendix 1) and should continue with the Taper and/or Follow-Up Periods, as 
relevant, and complete all activities in those periods as described in Appendix 1.  If this is not 
possible, a participant who withdraws from this study should at a minimum have the assessments 
listed for the second follow up visit in the Schedule of Assessments (Appendix 1).  If withdrawal 
from the study occurs within 7 days of the last dose of ACH-0144471, a blood sample should 
also be collected for PK evaluation.   
7.6. 
Unscheduled Visits 
Additional clinic visits may be added if deemed necessary by the Investigator.  Activities at these 
visits will be directed by the circumstances, but should include at a minimum: 


ACH 0144471 
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• Assess for compliance with protocol restrictions 
• Assess for AEs and SAEs 
• Record concomitant medications 
• Measure body temperature 
• Additional tests or procedures as appropriate 
The reason for the visit and the results of any tests or procedures must be recorded in the 
participant’s CRF. 
 


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Alexion Pharmaceuticals, Inc.). 
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8. 
QUALITY CONTROL AND ASSURANCE 
8.1. 
Routine Monitoring 
The PI is responsible for the validity of all data collected at the clinical site and must accept the 
various monitoring procedures employed by the Sponsor.  The purpose of monitoring is to verify 
that the rights and well-being of human participants are protected; that trial data are accurate, 
complete, and verifiable with source data; that the trial is conducted in compliance with the 
protocol, GCP, and the applicable regulatory requirements. 
A monitor assigned by the Sponsor will conduct regular site visits for the purpose of monitoring 
various aspects of the study.  Visits will take place usually within a predetermined interval, but 
this may vary during the course of the study.  The PI must agree to allow the study monitor and 
authorized representatives of the Sponsor to inspect all CRFs and corresponding source 
documents, e.g., original medical records, participant records and laboratory raw data, access to 
the clinical supplies, dispensing, and storage areas and agree to assist with their activities if 
requested.  The PI should provide adequate time and space for monitoring visits. 
The monitor will query any missing or spurious data with the PI (or designee), which should be 
resolved in a timely manner.  A monitoring log will be maintained recording each visit, the 
reason for the visit, the monitor’s signature, and PI or designee’s confirmation signature. 
8.2. 
Site Audits 
For the purpose of compliance with GCP and regulatory agency guidelines, it may be necessary 
for Sponsor authorized Quality Assurance personnel and/or authorized personnel from an 
external regulatory agency to conduct an audit/inspection of an investigational site.  The purpose 
of an audit is to assess the quality of data with regard to accuracy, adequacy, and consistency, 
and to assure that studies are in accordance with GCP, and Regulatory Agency guidelines.  
Having the highest quality data from studies is an essential aspect of drug development. 
The PI will be given sufficient notice to prepare for such visits, which are planned to take usually 
between one and two days and may be conducted at any stage during the study.  The audit will 
involve the review of all study related documentation, which is required by GCP to be 
maintained by each site, review of drug storage, dispensing, and return, review of all study 
related supplies and review of source documents against the CRFs to assure the adequacy and 
accuracy of the information that has been recorded, including the verification of any AEs that 
have occurred. 
In the event of the site being notified of a regulatory inspection, the Sponsor will help with the 
preparation and it is essential that they be notified of the inspection as soon as possible. 


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Alexion Pharmaceuticals, Inc.). 
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9. 
PLANNED STATISTICAL METHODS 
9.1. 
General Considerations 
Summary statistics will be provided for efficacy and safety parameters. 
To summarize continuous data, descriptive statistics will include: number of participants, mean, 
standard deviation, median, minimum, and maximum.  To summarize categorical data, frequency 
counts and percentages will be presented.  
Longitudinal summaries of efficacy and safety parameters use pre-defined visit week as 
described in Appendix 1, Schedule of Assessments.  Laboratory measures will be summarized 
using US standard values and units. 
Participant listings will be provided for all efficacy (including PK and PD) and safety 
parameters.  
Subgroup analysis may be performed if data deem such analysis feasible.  The grouping criteria 
could be disease type (C3G or IC-MPGN) or prior study status (ACH471-201 or none) or other 
clinically relevant demographic and baseline characteristics. 
A statistical analysis plan (SAP) will be developed to provide details of the data analysis 
procedures and presentations, including relevant subgroup analysis. 
Note that analysis procedures for addressing exploratory objectives, except for patient-reported 
outcomes (PRO) interviews, will also be included in the SAP which will be finalized prior to 
database lock.   
9.2. 
Determination of Sample Size 
The sample size is determined based on limited clinical cases of C3G and IC-MPGN.  Note that 
the sample of 20 participants include those who completed study ACH471-201. 
9.3. 
Analysis Populations 
All participants receiving at least one dose of ACH-0144471 will be included in the efficacy, 
safety, pharmacokinetic (PK), and pharmacodynamics (PD) analyses.   
9.4. 
Demographics and Baseline Characteristics 
The following will be summarized for treated participants: 
• demographics: age, gender, race, country / geographic region 
• disease characteristics at baseline: disease diagnosis, duration of the disease, biopsy 
results 
• physical measurement at baseline: height, weight, BMI 
• laboratory tests at baseline 
• prior medications. 
Additional baseline characteristics may also be summarized as clinically indicated. 


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9.5. 
Efficacy, including Pharmacodynamics Analysis 
The primary efficacy endpoint is: 
• 
Change from baseline in biopsy, based on a score incorporating changes in both the 
activity index and C3 staining at the end of 12 months of treatment. 
• 
Number and percent of participants with reduction in proteinuria relative to baseline at 
the end of 12 months of treatment 
The secondary efficacy endpoints include: 
Number and proportion of participants with significant (≥25%) increase in eGFR relative to 
baseline at the end of 12 months of treatment  
• 
Change and percent change from baseline in proteinuria and eGFR over 12 months of 
treatment period for all participants  
• 
Change and percent change from baseline in eGFR over 12 months of treatment for 
participants meeting eGFR inclusion criterion at study entry  
• 
Descriptive analysis of slope of GFR over the treatment period of ACH-0144471 therapy 
Calculation of eGFR will be based on the following formulas: 
• 
For participants 19 years old and older the CKD-EPI creatinine equation (2009) will be 
used for inclusion/exclusion and primary endpoint analysis.  However, cystatin C will 
also be measured and as exploratory analysis, eGFR will be calculated by the CKD-EPI 
creatinine-cystatin equation (2012), the CKD-EPI cystatin C equation (2012), and the 
MDRD equation.  Cystatin C will be measured to allow use of formulas requiring this 
parameter. 
• 
For participants <19 years old the creatinine-based “Bedside Schwartz” equation (2009) 
will be used for inclusion/exclusion and primary endpoint analysis.  However, cystatin C 
will also be measured and as exploratory analyses, eGFR will be calculated by the 
cystatin C-based equation (2012) and the creatinine-cystatin C-based CKiD equation 
(2012).  Cystatin C will be measured to allow use of formulas requiring this parameter.  
The calculation of eGFR will be described in detail in the laboratory manual. 
When possible, proteinuria will be evaluated in 24-hour urine collections, but if a 24-hour urine 
is not available, a calculated equivalent will be derived from albumin:creatinine and/or total 
protein: creatinine ratios, obtained from spot urine samples.  The process for deriving this 
calculated equivalent will be described in detail in the laboratory manual. 
Ninety-five percent (95%) confidence intervals will be constructed for mean change and mean 
percent change at the end of 12 months of treatment.    
In addition to the calculation of eGFR, some investigators may choose to measure GFR based on 
iohexol clearance.  Change and percent change from baseline in measured GFR over the 
12 months of treatment will be calculated for participants for whom this data is available.  


ACH 0144471 
Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
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9.6. 
Safety Analysis 
Treatment-emergent AEs (TEAEs) will be summarized and listed by system-organ-class and 
preferred term using the most current version of the Medical Dictionary for Regulatory Activities 
(MedDRA®).  All SAEs and discontinuation due to AEs will be listed in tabulated format. 
All clinical laboratory data (hematology, serum chemistry, and urinalysis) with normal ranges, 
out-of-range flags, and toxicity grades will be listed by participant.  Descriptive summary 
statistics may be provided for selected lab tests. 
Data on physical exam and vital signs will be examined either through participant listings or by 
summary statistics of selected parameters. 
Other exploratory techniques, e.g., graphic presentations, may also be employed to facilitate 
clinical interpretations of the safety results. 


ACH 0144471 
Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
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10. 
ADMINISTRATIVE CONSIDERATIONS 
10.1. 
Investigators and Study Administrative Structure 
The PI must maintain a screening log of all participants seen and considered for the study.  For 
those participants who are not eligible to participate in the study, the reason for their exclusion 
should be recorded. 
10.2. 
Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) and Regulatory Approval 
10.2.1. 
Ethical Approval 
The study protocol, participant information, and consent and assent forms, the Investigator 
Brochure, available safety information, participant recruitment procedures (e.g., advertisements), 
information about payments and compensation available to the participants and documentation 
evidencing the investigator’s qualifications should be submitted by the investigator to the EC or 
IRB for ethical review and approval according to local regulations, prior to the start of the study.  
The written approval should identify all documents reviewed by name, version, and the date on 
which the committee met and granted the approval. 
Any modifications to EC or IRB approved documents must also be submitted to the EC or IRB 
for approval before implementation. 
10.2.2. 
Regulatory Approval 
As required by local regulations, the Sponsor’s (or designee’s) Regulatory Affairs group will 
ensure all legal aspects are covered, and approval of the appropriate regulatory bodies obtained, 
prior to study initiation. 
10.2.3. 
Amendments 
Any change to the protocol will be effected by means of a protocol amendment.  Any changes, 
which affect participant safety or welfare, will be submitted to the EC or IRB and regulatory 
authority (where applicable) for approval prior to implementation.  The investigator, EC, and 
Sponsor must agree on all amendments.  No amendment will be implemented until it is approved 
and signed by the investigator and Sponsor.  Exceptions to this are when the investigator 
considers that the participant’s safety is compromised.  Protocol amendments detailing minor 
administrative changes should be submitted by the investigator (or designee) to the EC or IRB 
for notification. 
10.3. 
Ethical Conduct of the Study 
This study will be performed in accordance with: 1) the principles of ICH Guideline E6 for Good 
Clinical Practice (CPMP/ICH/135/95 January 1997); 2) European Directive 2001/20/EC, 3) 
standard operating procedures and/or guidelines, 4) the U.S. Food and Drug Administration 
(FDA) regulations, 5) the Declaration of Helsinki, and 6) all applicable federal, state, and local 
laws, rules and regulations relating to the conduct of the clinical study. 


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10.4. 
Participant Information and Consent 
In obtaining and documenting informed consent or assent, the investigator should comply with 
the applicable regulatory requirements and should adhere to ICH GCP (E6).  Each participant 
must be adequately informed in a language that they can understand and read of the aims, 
methods, anticipated benefits, potential hazards and the discomfort the study may entail, as well 
as their right to abstain from participating in the study and to withdraw their consent/assent at 
any time without affecting their medical care.  If important new information is incorporated in 
the ICF and approved by the EC, all participants still actively participating in the study must be 
re-consented. 
Written informed consent for adult participants should be documented by the participant’s 
personally dated signature and the personally dated signature of the investigator or designee who 
conducted the informed consent discussion.  Written assent for adolescent participants should be 
documented by the participant’s personally dated signature and the personally dated signature of 
the investigator or designee who conducted the assent discussion, and by the personally dated 
signature of the participant’s parent or guardian.  The investigator or designee should supply all 
enrolled participants with a copy of their signed informed consent or assent.  The monitor will 
inspect the original forms for all participants. 
10.5. 
Participant Confidentiality 
The investigators and Sponsor and its designees will preserve the confidentiality of all 
participants taking part in the study, in accordance with GCP, local regulations and, to the extent 
applicable, the Health Insurance Portability and Accountability Act of 1996 (“HIPAA”).  Subject 
to the requirement for source data verification by the study personnel by reference to the 
participant’s notes, confidentiality of all participant identities will be maintained.  Only 
participant initials, date of birth, and study number will be used on the CRF and in all study 
correspondence, as permitted.  No material bearing a participant’s name will be kept on file by 
the Sponsor.  
Audio files of the interviews will be transcribed and de-identified (any identifying information 
such as dates, names, locations will be removed).  The de-identified transcripts will be delivered 
for analysis and a single audio file will be kept as a source document in the Trial Master File.  
Any copies of the audio file will be destroyed immediately upon confirmation of receipt of the 
transcript.  
Data protection and privacy regulations will be observed in capturing, forwarding, processing, 
and storing participant contact details and data.  Participants will be informed accordingly and 
will be requested to give their consent on contact details data handling procedures in accordance 
with national regulations.  In order to secure data privacy protection, participant contact details 
will be sent to a dedicated unit in charge of scheduling and setting up the interviews 
independently from study sponsor, monitor, data management and data analysis structures and 
other study stakeholders.  The specific information about participant contact details management 
will be provided on a Contact Order Form to be completed by Investigator and participant, 
signed by the participant and sent to the unit in charge of scheduling and setting up the 
interviews.  This form will not include health data. 


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10.6. 
Study Monitoring 
10.6.1. 
Access to Information for Monitoring 
In accordance with ICH-GCP guidelines, the Study Monitor must have direct access to the 
investigator’s source documentation in order to verify the consistency of the data recorded in the 
CRFs. 
The Study Monitor is responsible for routine review of the CRFs at regular intervals throughout 
the study, to verify adherence to the protocol, and the completeness, consistency, and accuracy of 
the data being entered.  The Study monitor should have access to any participant records needed 
to verify the entries on the CRFs.  The investigator agrees to cooperate with the Study Monitor to 
ensure that any problems detected in the course of these monitoring visits are resolved. 
10.6.2. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or Achillion Pharmaceuticals may conduct inspections 
or audits of the clinical study.  If the investigator is notified of an inspection by a regulatory 
authority, the investigator agrees to notify the Achillion Pharmaceuticals Medical Monitor 
immediately.  The investigator agrees to provide to representatives of a regulatory agency or 
Achillion Pharmaceuticals access to records, facilities, and personnel for the effective conduct of 
any inspection or audit. 
10.7. 
Case Report Forms and Study Records 
10.7.1. 
Recording of Data 
All data collected during the study will be recorded in individual, participant-specific electronic 
case report forms (eCRFs).  All eCRFs should be completed by the investigator (or designee), 
who should be identified and agreed upon with the Sponsor before the start of the study.  A 
signature log identifying personnel who can enter data and/or sign off an eCRF will be 
maintained.  Instructions for data entry will be provided. 
A CRF must be completed for each participant who signs a consent form and is admitted to the 
study.  Corrections to the data on the CRF will only be made by the investigator (or designee). 
CRFs should be kept current to enable the study monitor to review the participant status 
throughout the course of the study.  CRFs will be completed within 5 days of the last participant 
visit. 
10.7.2. 
Source Documentation and Medical/Study Records 
The participant’s number and date of entry into the study, along with the study code, should be 
recorded in the participant’s medical/study records by the investigator (or designee).  The 
investigator (or designee) should also record, in the medical/study records, confirmation of 
written and oral consent, the participant’s clinical status/disease being treated, date of every 
study visit, date study drug started and stopped, concomitant medications, copies of all relevant 
reports and laboratory tests, comments on results and reference to any AEs. 


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10.8. 
Protocol Deviations 
Protocol deviations will be assessed on a case-by-case basis.  Withdrawal of consent for one or 
more activities within the protocol will not necessarily be considered to be a protocol deviation, 
and will not necessarily result in the removal of the participant from further study activities.  The 
available data from any such participants will be included in analyses as appropriate.  Significant 
protocol deviations will be reported to the Ethics Committee or IRB according to local 
regulations. 
10.9. 
Access to Source Documentation 
The investigator and staff must agree to allow the study monitor and authorized representatives 
of the Sponsor to inspect all eCRFs and corresponding source documents, e.g., original medical 
records, participant records, and laboratory raw data; to have access to the clinical supplies, and 
dispensing and storage areas; and to agree to assist with their activities if requested.  The 
investigator and staff should provide adequate time and space for monitoring visits. 
Participants will have access to safety laboratory results upon request but should be aware that 
these typically are not immediately available.  The results of the baseline biopsy evaluation can 
be provided to the investigator, who may share them with the participant.  PK levels will not be 
available until after all study analysis is completed. 
10.10. 
Data Generation and Analysis 
Data generation and analysis will be specified and detailed in the SAP. 
10.11. 
Retention of Data 
The investigator (or designee) must maintain adequate and accurate records to enable the 
conduct of the study to be fully documented and the study data to be subsequently verified.  
These documents should be classified into at least two separate categories as follows: 
• 
Investigator study file, and 
• 
Participant clinical source documents 
The investigator study file will contain the protocol/amendments, CRF and query forms, EC or 
IRB and governmental approval with correspondence, informed consent, drug records, staff 
curricula vitae and authorization forms, and other appropriate documents and correspondence. 
Participant clinical source documents (usually defined by the protocol-specified procedures and 
data collection requirements in advance to record key efficacy/safety parameters independent of 
the CRFs) include, but are not limited to, participant hospital/clinic records, physician and nurse 
notes, appointment book, original laboratory reports, ECG and/or EEG tracings, pathology and 
special assessment reports, consultant letters, screening and enrollment logs. 
All clinical study documents must be retained by the investigator for at least 2 years after the last 
approval of a marketing application in an ICH region (i.e., United States, Europe, or Japan) and 
until there are no pending or contemplated marketing applications in an ICH region; or, if no 
application is filed or if the application is not approved for such indication, until 2 years after the 
investigation is discontinued and regulatory authorities have been notified.  Investigators may be 


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required to retain documents longer if required by applicable regulatory requirements, by local 
regulations, or by an agreement with Achillion Pharmaceuticals.  The investigator (or designee) 
must contact Achillion Pharmaceuticals prior to destroying any records associated with the 
study.  Achillion Pharmaceuticals will notify the PI when the trial records are no longer needed. 
If the investigator withdraws from the study (e.g., relocates, retires, or dies), the records shall be 
transferred to a mutually agreed upon designee (e.g., another investigator, EC).  Notice of such 
transfer will be given in writing to Achillion Pharmaceuticals.  If the investigator cannot 
guarantee this archiving requirement at the study site for any or all of the documents, special 
arrangement must be made between the PI and Achillion Pharmaceuticals to store these in sealed 
containers outside of the site, so that they can be returned sealed to the PI in case of a regulatory 
audit.  Where source documents are required for the continued care of the participant, 
appropriate copies should be made for storage outside of the site.  
The interviews will be audio recorded in a de-identified way.  The audio files will serve as 
source documents and will be archived in Trial Master File.  Any additional copy of audio 
recordings temporarily retained by interviewers and / or transcription unit will be destroyed after 
transcription process completion.  The audio recordings will be transcribed word by word for the 
analysis. 
10.12. 
Study and Site Closure 
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor.  Study sites will be closed upon study completion.  A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the investigator 
• Discontinuation of further study intervention development 
10.13. 
Final Report, Publication and Disclosure Policy 
All information contained in this protocol and the trial results are considered to be confidential.  
The investigator agrees to use this information for purposes of conducting this trial.  It is 
understood that Achillion Pharmaceuticals may use data derived from this trial for the purpose of 
research and development.  The data may be disclosed by Achillion Pharmaceuticals. to other 
investigators, the FDA, other government agencies, or foreign drug regulatory authorities, or to 
the public.  No publication of trial design or results is permitted without specific Achillion 
Pharmaceuticals approval.  To gain approval, a copy of the manuscript for review must, 
therefore, be sent to Achillion Pharmaceuticals 60 days before submission for publication. 


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Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
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Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.) 
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It is the intent of Achillion Pharmaceuticals to present the results of this study at future scientific 
meetings.  Additionally, it is the intent of Achillion Pharmaceuticals to publish the results of this 
study in leading scientific journals.  The investigator of each investigative site will be invited to 
be an author in conjunction with the investigator(s) from Achillion Pharmaceuticals.  Achillion 
Pharmaceutical will determine additional authors.  Presentations and manuscripts will be 
provided and agreed to by the authors and Achillion Pharmaceuticals. 


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11. 
REFERENCES 
1. 
ACH-0144471 Investigator’s Brochure Version 7.0. New Haven (CT): 
Achillion Pharmaceuticals, Inc.; Aug 2018. 92 p. 
2. 
Volanakis JE, Narayana SV. Complement factor D, a novel serine protease. Protein 
Science. 1996;5(4):553-64. 
3. 
Figueroa JE, Densen P. Infectious diseases associated with complement deficiencies. 
Clinical microbiology reviews. 1991;4(3):359-95. 
4. 
Miyata T, Inagi R, Oda O, et al. Deterioration of immune complex solubilization activity 
of serum by increased concentration of factor D. Nephron. 1991;59(3):409-15. 
5. 
Kobayakawa H, Miyata T, Inagi R, et al. Effects of excess factor D on early- and late-
phase activation of the complement cascade. Nihon Jinzo Gakkai Shi. 1992;34(1):103-6. 
6. 
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. 
7. 
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. 
8. 
Pickering MC, D'Agati VD, Nester CM, et al. C3 glomerulopathy: consensus report. 
Kidney Int. 2013 Dec;84(6):1079-89. 
9. 
Nasr SH, Valeri AM, Appel GB, et al. Dense deposit disease: clinicopathologic study of 32 
pediatric and adult patients. Clin J Am Soc Nephrol. 2009 Jan;4(1):22-32. doi: 
10.2215/CJN.03480708. Epub 2008 Oct 29.  
10. 
Medjeral-Thomas N, Malik TH, Patel MP, et al. A novel CFHR5 fusion protein causes C3 
glomerulopathy in a family without Cypriot ancestry. Kidney Int. 2014 Apr;85(4):933-7. 
11. 
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. 
12. 
Smith RJ, Alexander J, Barlow PN, et al. New approaches to the treatment of dense deposit 
disease. J Am Soc Nephrol. 2007 Sep;18(9):2447-56.  
13. 
Barbour TD, Pickering MC, Cook HT. Dense deposit disease and C3 glomerulopathy. 
Semin Nephrol. 2013 Nov;33(6):493-507. 
 
 
PPD
PPD


ACH 0144471 
Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
Clinical Protocol ACH471 205 Amendment 6 
15 May 2020 (Version 7.0) 
Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.) 
Page 80 of 91 
 
14. 
De Vriese AS, Sethi S, Van Praet J, et al. Kidney disease caused by dysregulation of the 
complement alternative pathway: an etiologic approach. J Am Soc Nephrol. 2015 
Dec;26(12):2917-29. 
15. 
Achillion White Paper. The Natural History of C3G. May 5, 2017 
16. 
Pickering MC, Cook HT, Warren J, et al. Uncontrolled C3 activation causes 
membranoproliferative glomerulonephritis in mice deficient in complement factor H. Nat 
Genet. 2002 Aug;31(4):424-8. 
17. 
Abrera Abeleda, Maria Asuncion. The role of the alternative pathway of the complement 
system in the development of dense deposit disease. University of Iowa, Iowa Research 
Online, Thesis and Dissertations, 2010. 
18. 
Bomback AS, Smith RJ, Barile GR, et al. Eculizumab for dense deposit disease and C3 
glomerulonephritis. Clin J Am Soc Nephrol. 2012 May;7(5):748-56. 
19. 
Pickering MC, Warren J, Rose KL, et al. Prevention of C5 activation ameliorates 
spontaneous and experimental glomerulonephritis in factor H-deficient mice. Proc Natl 
Acad Sci U S A. 2006 Jun 20;103(25):9649-54. 
20. 
Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis--a new look at an old 
entity. N Engl J Med. 2012 Mar 22;366(12):1119-31. 
21. 
National Organization for Rare Disorders (NORD). 2015. Available at: 
https://rarediseases.org/rare-diseases/c3-glomerulopathy-dense-deposit-disease-and-c3-
glomerulonephritis/.  
22. 
Sandhu G, Bansal A, Ranade A, et al. C3 glomerulopathy masquerading as acute 
postinfectious glomerulonephritis. Am J Kidney Dis. 2012 Dec;60(6):1039-43. doi: 
10.1053/j.ajkd.2012.04.032. Epub 2012 Jul 6.  
23. 
Vernon KA, Goicoechea de Jorge E, Hall AE, et al. Acute presentation and persistent 
glomerulonephritis following streptococcal infection in a patient with heterozygous 
complement factor H-related protein 5 deficiency. Am J Kidney Dis. 2012 Jul;60(1):121-5. 
doi: 10.1053/j.ajkd.2012.02.329. Epub 2012 Apr 13.  
24. 
Fervenza FC, Smith RJ, Sethi S. Association of a novel complement factor H mutation 
with severe crescentic and necrotizing glomerulonephritis. Am J Kidney Dis. 2012 
Jul;60(1):126-32. doi: 10.1053/j.ajkd.2012.03.007. Epub 2012 Apr 26. 
25. 
Krmar RT, Holtbäck U, Linné T, et al. Acute renal failure in dense deposit disease: 
complete recovery after combination therapy with immunosuppressant and plasma 
exchange. Clin Nephrol. 2011 Feb;75 Suppl 1:4-10.  
 


ACH 0144471 
Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
Clinical Protocol ACH471 205 Amendment 6 
15 May 2020 (Version 7.0) 
Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.) 
Page 81 of 91 
 
26. 
Hladunewich MA, Cattran D, Beck LH, et al. A pilot study to determine the dose and 
effectiveness of adrenocorticotrophic hormone (H.P. Acthar® Gel) in nephrotic syndrome 
due to idiopathic membranous nephropathy. Nephrol Dial Transplant. 2014 
Aug;29(8):1570-7. 
27. 
Stevens LA, Greene T, Levey AS. Surrogate End Points for Clinical Trials of Kidney 
Disease Progression. Clin J Am Soc Nephrol. 2006 Jul;1(4):874-84. 
28. 
Corapi KM, Dooley MA, Pendergraft WF. Comparison and evaluation of lupus nephritis 
response criteria in lupus activity indices and clinical trials. Arthritis Res Ther. 
2015;17(1):110. 
29. 
Renal Disease Subcommittee of the American College of Rheumatology Ad Hoc 
Committee on Systemic Lupus Erythematosus Response Criteria. The American College 
of Rheumatology response criteria for proliferative and membranous renal disease in 
systemic lupus erythematosus clinical trials. Arthritis Rheum 2006 Feb;54(2):421–32. 
30. 
Inker LA, Levey AS, Pandya K, et al, Early Change in Proteinuria as a Surrogate Endpoint 
for Kidney Disease Progression: An Individual Patient Meta-analysis. Am J Kidney Dis. 
2014 Jul;64(1):74-85. 
31. 
Lambers Heerspink HJ, Gansevoort RT. Albuminuria Is an Appropriate Therapeutic Target 
in Patients with CKD: The Pro View. Clin J Am Soc Nephrol. 2015 Jun 5;10(6):1079-88. 
32. 
Inker LA, Mondal H, Greene T, et al. Early Change in Urine Protein as a Surrogate End 
Point in Studies of IgA Nephropathy: An Individual-Patient Meta-analysis. Am J Kidney 
Dis. 2016 Sep;68(3):392-401. 
33. 
Thompson A, Cattran DC, Blank M, Nachman PH. Complete and Partial Remission as 
Surrogate End Points in Membranous Nephropathy. J Am Soc Nephrol. 2015 
Dec;26(12):2930-7. 
34. 
Little MA, Dupont P, Campbell E, et al. Severity of primary MPGN, rather than MPGN 
type, determines renal survival and post-transplantation recurrence risk. Kidney Int. 2006 
Feb;69(3):504-11. 
35. 
Cameron JS, Turner DR, Heaton J, et al. Idiopathic mesangiocapillary glomerulonephritis. 
Comparison of types I and II in children and adults and long-term prognosis. Am J Med. 
1983 Feb;74(2):175-92. 
36. 
Montgomery RA, Orandi BJ, Racusen L, et al. Plasma-Derived C1 Esterase Inhibitor for 
Acute Antibody-Mediated Rejection Following Kidney Transplantation: Results of a 
Randomized Double-Blind Placebo-Controlled Pilot Study. Am J Transplant. 2016 
Dec;16(12):3468-78.  
 


ACH 0144471 
Achillion Pharmaceuticals, Inc. (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
Clinical Protocol ACH471 205 Amendment 6 
15 May 2020 (Version 7.0) 
Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.) 
Page 82 of 91 
 
37. 
U.S. Department of Health and Human Services, National Institutes of Health, National 
Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 
4.0. [CTCAE 4.03 June 2010]. Downloaded from 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf 01 April 2017.  


ACH 0144471 
 
Achillion Pharmaceuticals (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
Clinical Protocol ACH471 205 Amendment 6 
 
15 May 2020 (Version 7.0) 
Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.)  
Page 83 of 91 
12. 
APPENDICES 
Appendix 1. Schedule of Assessments 
Table 4. 
Schedule of Assessments – Screening through Week 12 
Study Period 
Screening1 
Treatment2 
Study Week 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
7 
Wk 
8 
Wk 
10 
Wk 
12 
Study Day 
Day -75 to Day -1 
1 
3 
7 
14 
21 
28 
35 
49 
56 
70 
84 
Required Clinic Visit 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
Phone Visit 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
Screening Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion Criteria3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
FSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccinations 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
Sample for potential genetic 
assessment of complement 
genes 
X 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG (single) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Dispensing 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
AE/SAE/Protocol 
Restrictions/Con Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient-Reported Outcomes 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
FACIT-Fatigue OR 
Peds-FACIT-F 
X 
 
 
 
 
 
 
 
 
 
 
 
 
KDQOL (Adults only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
EQ-5D-3L OR 
EQ-5D-Y 
X 
 
 
 
 
 
 
 
 
 
 
 
 


ACH 0144471 
 
Achillion Pharmaceuticals (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
Clinical Protocol ACH471 205 Amendment 6 
 
15 May 2020 (Version 7.0) 
Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.)  
Page 84 of 91 
Table 4 
Schedule of Assessments – Screening through Week 12(Continued) 
Study Period 
Screening1 
Treatment2 
Study Week 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
7 
Wk 
8 
Wk 
10 
Wk 
12 
Study Day 
Day -75 to Day -1 
1 
3 
7 
14 
21 
28 
35 
49 
56 
70 
84 
Required Clinic Visit 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
Phone Visit 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Exam  
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Brief Physical Exam4 
 
 
 
X 
X 
X 
 
X 
 
 
X 
 
X 
Weight 
X 
X 
X4 
X4 
X4 
X4 
 
X4 
 
 
X4 
 
X4 
Vital Signs4 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
Other Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
Renal Biopsy 
 
X5 
 
 
 
 
 
 
 
 
 
 
 
Standard Laboratory 
Assessments6 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK samples7 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
Safety Labs  
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry 
X 
 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
Hematology 
X 
 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
Coagulation (PT/PTT/INR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum C3 and C4 
X 
 
X 
 
 
X 
 
 
 
 
 
 
X 
First Morning urine sample8 
X 
 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
24-Hour Urine Collection9 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy Test10 
X 
X 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Complement Biomarkers6 
X 
 
X 
 
X 
X 
 
X 
 
 
X 
 
X 


ACH 0144471 
 
Achillion Pharmaceuticals (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
Clinical Protocol ACH471 205 Amendment 6 
 
15 May 2020 (Version 7.0) 
Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.)  
Page 85 of 91 
AE = Adverse event; Con Meds = concomitant medications; ECG = Electrocardiogram; PK = Pharmacokinetic; SAE = Serious adverse event 
1. 
Screening assessments do not need to occur on the same day. 
2. 
Visits may be ± 2 days after Week 4.  Unless the PI feels a clinic visit is required, the visits on Weeks 3, 5, 6, 7 and 10 should be conducted by 
phone. 
3. 
Patients should be confirmed to be eligible based on all other inclusion and exclusion criteria, except the renal biopsy, before being vaccinated.  
4. 
Prior to dosing 
5. 
If obtained during screening to confirm eligibility, the results must be available and reviewed prior to dosing.   
6. 
During the treatment period, blood draws and urine collection should be done prior to dosing 
7. 
Collect only one sample prior to dose administration (trough sample).  
8. 
If the first morning urine collection coincides with a renal biopsy, collection must be completed before or at least 7 days after the biopsy 
procedure. 
9. 
The 24-hour urine collection period may be at any time during screening, but if it is to occur at least 7 days after the biopsy procedure. 
10. 
Serum pregnancy test at the initial screening visit and urine pregnancy tests at other time points for women of childbearing potential only.   
 


ACH 0144471 
 
Achillion Pharmaceuticals (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
Clinical Protocol ACH471 205 Amendment 6 
 
15 May 2020 (Version 7.0) 
Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.)  
Page 86 of 91 
Table 5. 
Schedule of Assessments – Week 16 through Week 52 
Study Period 
Treatment1 
Study Week Wk 16 Wk 18 Wk 20 
Wk 22 
Wk 24 
Wk 26 
Wk 28 
Wk 32 Wk 36 Wk 40 Wk 44 
Wk 48 
Wk 52 
Study Day 
112 
126 
140 
154 
168 
182 
196 
224 
252 
280 
308 
336 
364 
Clinic Visit1 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Phone Visit 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
Study Drug Dispensing 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
AE/SAE/Protocol 
Restrictions/Con Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient-Reported 
Outcomes Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
FACIT-Fatigue OR 
Peds-FACIT-F 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
KDQOL (Adults only) 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
EQ-5D-3L OR 
EQ-5D-Y 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief Physical Exam2 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Weight 
X3 
 
X3 
 
 
 
X3 
 
X3 
 
X3 
 
X3 
Vital Signs4 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Biopsy Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
Renal Biopsy  
 
 
 
 
 
 
X5 
 
 
 
 
 
X 
Standard Laboratory 
Assessments6 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK samples7 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Safety labs 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry6 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Hematology6 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 


ACH 0144471 
 
Achillion Pharmaceuticals (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
Clinical Protocol ACH471 205 Amendment 6 
 
15 May 2020 (Version 7.0) 
Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.)  
Page 87 of 91 
Table 5. 
Schedule of Assessments – Week 16 through Week 52 (Continued) 
Study Period 
Treatment1 
Study Week Wk 16 Wk 18 Wk 20 
Wk 22 
Wk 24 
Wk 26 
Wk 28 
Wk 32 Wk 36 Wk 40 Wk 44 
Wk 48 
Wk 52 
Study Day 
112 
126 
140 
154 
168 
182 
196 
224 
252 
280 
308 
336 
364 
Clinic Visit1 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Phone Visit 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
Serum C3 and C4 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
First Morning urine 
sample8 
X 
 
X 
  
 
  
X 
 
X 
 
X 
 
X 
24-Hour urine collection9 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Pregnancy Test10 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Complement 
Biomarkers6 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
AE = Adverse event; Con Med = concomitant medications; PK = Pharmacokinetic; SAE = Serious adverse event 
1 
Clinic visits may be ± 2 days.  Starting with the Week 28 visit, visits may be ± 1 week.  Unless the PI feels a clinic visit is required, the visits on Weeks 18, 
22, 24, 26, 32, 40, 48, should be conducted by phone. If a patient is unable to get to a clinic visit during the COVID-19 global pandemic (Section 6.23), 
study data collection should still occur. The preferred option is home healthcare visits; nurses may collect 24-hour urine, first morning urine, and safety 
labs, including pregnancy testing. Additional assessments should include AEs, vital signs, and concomitant medications. Nurses will perform study drug 
accountability. If a home healthcare visit is not possible, patients may have telephone visits with the PI or designee. Data collection will include AEs and 
concomitant medications, and patients will be asked about study drug compliance.   
2 
Conduct as described in Section 6.7; during the treatment period exam should be prior to dosing.  Assessment of edema is part of the brief physical exam.   
3 
Prior to dosing  
4 
Vital signs include body temperature, blood pressure in triplicate, heart rate and respiratory rate.  During the treatment period, assessments should be done 
prior to dosing. 
5 
For all subjects, a biopsy should be obtained at Week 52. If clinic visits are not possible during the COVID-19 global pandemic, the Week 52 biopsy should 
be done when safely possible, even if the biopsy is unable to be done within 7 days of the target date. In addition, an unscheduled 24-hour urine collection 
should be obtained at the same time as the Week 52 renal biopsy. If the collection of 24-hour urine is to occur after a renal biopsy, it must be done at least 7 
days after the biopsy procedure. Subjects in the renal biopsy sub-study, will have biopsies obtained after approximately 6 months and/or at the end of dosing.  
The end of treatment renal biopsy can occur anytime between the Week 91 visit and the Week 104 visit but should be prior to the last dose. 
6 
During the treatment period, blood draws and urine collection should be done prior to dosing. Collected as described in the laboratory manual. Blood 
collection for biomarkers will not be done at home health visits or at local laboratories. If a home visit occurs but laboratory samples cannot be shipped to 
the central laboratory by the nurse conducting home visits, the nurse should go to a local laboratory to drop off all laboratory samples, including 24-hour 
urine collections and safety labs. If home visits are not possible, the participant should go to a local laboratory to drop off 24-hour urine collections and for 
safety laboratory testing, including pregnancy testing (if applicable), to be performed. 


ACH 0144471 
 
Achillion Pharmaceuticals (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
Clinical Protocol ACH471 205 Amendment 6 
 
15 May 2020 (Version 7.0) 
Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.)  
Page 88 of 91 
7 
Collect one sample prior to dose administration (trough sample) 
8 
If the first morning urine collection coincides with a renal biopsy, collection should be completed before or at least 7 days after the biopsy procedure. 
9 
The 24-hour urine collection period is to occur after a renal biopsy, it must be at least 7 days after the biopsy procedure.  
10 Urine pregnancy tests for women of childbearing potential only.  Any positive urine pregnancy test will be confirmed by a serum pregnancy test.  Pregnancy 
tests should be done monthly. 


ACH 0144471 
 
Achillion Pharmaceuticals (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
Clinical Protocol ACH471 205 Amendment 6 
 
15 May 2020 (Version 7.0) 
Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.)  
Page 89 of 91 
Table 6. 
Schedule of Assessments – 27 Month Long Term Follow-up, with Taper and Follow-up 
Study Period 
Long Term Follow-up1 
Taper2 
Follow-up3 
Study Week 
Wk 65 
Wk 117 
Wk 156 
Wk 78 
Wk 130 
Wk 169 
Wk 91 
Wk 143 
Wk 104 
 
T3 
T6 
F/U 1 
F/U 2 
Clinic Visits1 
X 
X 
X 
X 
X 
X 
X 
X 
Phone Call 
 
 
 
 
 
 
 
 
Study Drug Dispensing 
X 
X 
X 
X 
X 
 
 
 
AE/SAE/Protocol Restrictions/Con Meds 
X 
X 
X 
X 
X 
X 
X 
X 
Patient-Reported Outcomes Assessments 
FACIT-Fatigue OR Peds-FACIT-F  
 
 
 
X 
 
 
X 
 
KDQOL (Adults only) 
 
 
 
X 
 
 
X 
 
EQ-5D-3L OR EQ-5D-Y 
 
 
 
X 
 
 
X 
 
Clinical Assessments 
Complete Physical Exam4 
 
 
 
X 
 
 
 
 
Brief Physical Exam4 
 
X 
 
 
X 
X 
X 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs4 
X 
X 
X 
X 
X 
X 
X 
 
Histology 
Renal Biopsy5  
 
 
 
X 
 
 
 
 
Standard Laboratory Assessments6 
Safety labs: Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
Safety labs: Hematology 
 
 
X 
X 
 
X 
 
X 
Coagulation (PT/PTT/INR) 
 
 
 
 
 
 
 
 
Serum C3 and C4 
 
X 
 
X 
X 
 
X 
 
First Morning Urine7 
X 
X 
X 
X 
X 
X 
X 
X 
24-Hour Urine8 
 
 
 
 
 
 
 
 
Pregnancy Test9 
 
X 
 
X 
X 
 
X 
X 
Complement Biomarkers10 
X 
X 
X 
X 
X 
X 
X 
X 
AE = Adverse Event; F/U = Follow-up Visit; SAE = Serious Adverse Event; T3 = Day 3 of the taper; T6 = Day 6 of the taper; Wk = Weeks 
1. 
Clinic visits may take place within a window of ±7 days relative to the specified day for week 65 to week 104, except as noted for the Taper, Follow-Up, 
and Dose Escalation visits.  If clinic visits are not possible during the COVID-19 global pandemic, home visits or telephone visits may be done. If a 
patient is unable to get to a clinic visit (Section 6.23), study data collection may still occur. The preferred option is home healthcare visits; nurses may 
collect 24-hour urine, first morning urine, and safety labs, including pregnancy testing. Additional assessments should include AEs, vital signs, and 
concomitant medications. Nurses will perform study drug accountability. If a home healthcare visit is not possible, patients may have telephone visits 
with the PI or designee. Data collection will include AEs and concomitant medications, and patients will be asked about study drug compliance.  


ACH 0144471 
 
Achillion Pharmaceuticals (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
Clinical Protocol ACH471 205 Amendment 6 
 
15 May 2020 (Version 7.0) 
Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.)  
Page 90 of 91 
 
If a home healthcare visit is not possible or specimens cannot be shipped to the central laboratory, a patient may go to a local laboratory to drop off 24-
hour urine collections, and for safety lab and pregnancy testing. 
2. 
Participants should gradually decrease the daily total dose of ACH 0144471 during the taper.  Visits should be on the 3rd (T3) and 6th (T6) day of the 
taper. 
3. 
Follow-up visits should be conducted 2 and 4 weeks after the last dose of ACH 0144471 (including the taper, if applicable), within a window of ±2 days.  
4. 
During the treatment periods, exam should be prior to dosing.   
5. 
The end of treatment renal biopsy can occur anytime between the Week 91 and the Week 104 visit, but should be prior to the last dose 
6. 
If a home visit occurs but laboratory samples cannot be shipped to the central laboratory by the nurse conducting home visits, the nurse should go to a 
local laboratory to drop off all laboratory samples, including 24-hour urine collections and safety labs. If home visits are not possible, the participant 
should go to a local laboratory to drop off 24-hour urine collections and for safety laboratory testing, including pregnancy testing (if applicable), to be 
performed. 
7. 
If the first morning urine collection coincides with a renal biopsy, collection should be completed before or at least 7 days after the biopsy procedure. 
8. 
The 24-hour urine collection should be within a window of ± 1 week.  The 24-hour urine collection period must be at least 7 days after the biopsy 
procedure. If a clinic visit is not possible during the COVID-19 global pandemic and a home healthcare visit is done, the home healthcare nurse will 
collect the 24-hour urine sample. If a telephone visit is done instead, the patient should take the 24-hour urine to the local laboratory, if possible.  
9. 
Urine pregnancy tests for women of childbearing potential only.  Any positive urine pregnancy test will be confirmed by a serum pregnancy test.  
10. 
Blood collection for biomarkers will not be done at home health visits or at local laboratories. 


ACH 0144471 
 
Achillion Pharmaceuticals (a subsidiary of 
 
Alexion Pharmaceuticals, Inc.). 
Clinical Protocol ACH471 205 Amendment 6 
 
15 May 2020 (Version 7.0) 
Confidential Property of Achillion Pharmaceuticals, Inc. 
(a subsidiary of Alexion Pharmaceuticals, Inc.)  
Page 91 of 91 
 
Appendix 2. 
Fever Management Plan 
Treatment with complement inhibitors may lead to an increased lifetime risk of acute 
meningococcal disease, or other encapsulated bacterial infection.  Because of this risk, it is 
essential to monitor participants for signs and symptoms of infection.   
Minimum Requirements 
The points mentioned below are to be considered as a minimum diagnostic and management 
procedure.  These are not meant to replace or bypass a systematic and thorough assessment of 
the participant; instead, they are intended to facilitate rapid initiation of assessment and 
management of fever. 
A 
General Management for Any Fever Detected in the Clinic  
For any fever, the site must: 
1. Assess for symptoms - consider meningococcal disease as a diagnosis.  When 
meningococcal disease is suspected, early treatment is critical 
2. Repeat and confirm all temperature measurements >38.0°C 
3. Notify the PI and Sponsor for all confirmed temperature measurements >38.0°C 
4. Consider if referring to an emergency medical facility is appropriate.  If so, refer.  
Otherwise: 
a. PI or designee to perform a complete physical examination (including assessing if fever 
is accompanied by a severe headache, stiff neck, or other signs of meningeal irritation, 
shortness of breath, skin rashes, or other unusual signs or symptoms), document a plan 
based on her/his clinical judgment, and possibly an ID consult depending on assessment 
b. CBC (if not done in the last 12 hours) and blood culture  
c. Treat any suspicion of meningococcal infection aggressively; consider initiation of 
empirical antimicrobial therapy (assuming there are no other obvious sources of fever) at 
least until culture results become available and/or an alternative etiology is found 
d. Infectious disease consult is required once the PI or designee initiates empiric antibiotic 
treatment 
e. Measure temperature hourly until <38.0°C 
f. All cases of fever will be assessed by the Investigator, regardless of apparent causality 
from use of the study treatment(s) 
g. All activities performed as part of the Fever Management Plan should be documented 
Acute Meningococcal Disease 
If acute meningococcal disease is diagnosed, immediate medical and antibiotic management by 
local physician must be initiated documented and reported to the sponsor’s medical monitor 
immediately, but not more than 24 hours from diagnosis. 
Normal body temperature varies over the course of the day.  The normal daily temperature 
variation is typically 0.5°C (0.9°F).  During a febrile illness, daily low and high temperature 
readings are maintained but at higher levels.  However, this daily variation can be as high as 
1.0°C in some individuals recovering from a febrile illness.