Clinical trial NCT03124368
Conditions: C3 Glomerulonephritis Dense Deposit Disease C3 Glomerulopathy Immune Complex Mediated Membranoproliferative Glomerulonephritis Membranoproliferative Glomerulonephritis Types I, II, and III
Keywords: factor D FD alternative pathway complement mediated disease idiopathic MPGN MPGN Type I MPGN Type II MPGN Type III Primary MPGN MCGN Mesangiocapillary Glomerulonephritis C3 Glomerulopathy C3G Membranoproliferative Glomerulonephritis C3GN Dense Deposit Disease DDD
Sponsor: Alexion Pharmaceuticals, Inc.
Start date: 2017-08-09; Completion date: 2019-01-09
Enrollment: 6 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objective of this study was to determine whether ACH-0144471 (also known as danicopan and ALXN2040) increases blood C3 complement protein (C3) levels in participants with low C3 levels due to either C3G or IC-MPGN.

Detailed description:

Arms: arm 1: All participants received 100 milligrams (mg) of danicopan three times per day (TID) during the Treatment Period. arm 2: All participants received not more than 200 mg of danicopan TID depending on the available safety, pharmacokinetic, and pharmacodynamic data from Group 1 (Sentinel) during the Treatment Period.
Interventions: intervention 1: Danicopan
Intervention descriptions: intervention 1: Participants received study drug for 14 days (Treatment Period), followed by a taper over the next 7 days (Taper Period).

Protocol documents:
Prot_000.pdf: 
A Phase 2a Proof-of-Mechanism, Open-Label Study to 
Determine the Effect of ACH-0144471 on C3 Levels in 
Patients with Low C3 Levels Due to Either C3 
Glomerulopathy (C3G) or Immune-Complex 
Membranoproliferative Glomerulonephritis (IC-MPGN) 
 
Unique Protocol ID: 
ACH471-201 
NCT Number: 
NCT03124368 
EudraCT Number:  
2016-003525-42 
Date of Protocol:  
09 June 2017 
 


A C H- 0 1 4 4 4 7 1 
Ac hilli o n P har mace uticals, I nc. 
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Cli ni c al Tri al Pr ot o c ol  
A C H 4 7 1- 2 0 1 
 
St u d y Title: 
A P hase 2a Pr o of- of- Mec ha nis m, O pe n- La bel St u d y t o Det er mi ne t he Effect of 
A C H- 0 1 4 4 4 7 1 o n C 3 Le vels i n Patie nts wit h L o w C 3 Le v els D ue t o Eit her C 3 
Gl o m er ul o pat h y ( C 3 G) or I m m u n e- C o m ple x Me m bra n o pr oliferati ve 
Gl o m er ul o ne p hritis (I C- M P G N) 
St u d y N u m ber: 
A C H 4 7 1- 2 0 1 
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2a  
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A C H- 0 1 4 4 4 7 1 T a blets 
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A C H -0 1 4 4 4 7 1  
Ac hilli o n P har mace uticals, I nc.  
Cli nical Pr ot oc ol A C H 4 7 1 -2 0 1 A me n d me nt 2  
0 9  J u ne 2 0 1 7 ( Versi o n 3 . 0) 
 
C o nfi de ntial  
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S p o n s or Si g n at ur e( s)  
St u d y Title:  
A P hase  2a Pr o of -of -Mec ha nis m, O pe n -La bel St u d y t o Det er mi ne t he Effect 
of A C H - 0 1 4 4 4 7 1 o n C 3 Le v els i n Patie nts wit h L o w C 3 Le v els D ue t o 
Eit her C 3 Gl o mer ul o pat h y ( C 3 G) or I m m u ne- C o m ple x 
Me m bra n o pr oliferati ve Gl o mer ul o ne p hritis (I C- M P G N)  
St u d y N u m ber:  
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P P D
P P D
P P D


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-201 Amendment 2 
09 June 2017 (Version 3.0) 
 
Confidential 
Page 3 of 77 
 
 
Investigator’s Signature(s) 
Study Title: 
A Phase 2a Proof-of-Mechanism, Open-Label Study to Determine the Effect 
of ACH-0144471 on C3 Levels in Patients with Low C3 Levels Due to 
Either C3 Glomerulopathy (C3G) or Immune-Complex 
Membranoproliferative Glomerulonephritis (IC-MPGN) 
Study Number: 
ACH471-201 
Protocol Version and 
Date 
09 June 2017 (Version 3.0) 
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 
 
 
 
 
 


A C H -0 1 4 4 4 7 1  
Ac hilli o n P har mace uticals, I nc.  
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Pr o d u ct  
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N a m e of A cti v e 
I n gr e di e nt 
A C H -0 1 4 4 4 7 1  
N a m e of I n a cti v e 
I n gr e di e nt 
 
 
 
St u d y Titl e  
A P hase  2a Pr o of -of -Mec ha nis m, O pe n -La bel St u d y t o Deter mi ne t he Effect of A C H -0 1 4 4 4 7 1 o n 
C 3 Le vels i n P atie nts wit h L o w C 3 Le vels D ue t o Eit her C 3 Gl o mer ul o pat h y ( C 3 G) or  I m m u ne-
C o m ple x Me m bra n o pr oliferati ve Gl o mer ul o ne p hritis (I C -M P G N)  
St u d y N u m b er  
A C H 4 7 1 -2 0 1  
St u d y P h a s e  
P hase 2a  
Pri m ar y O bj e cti v e  
T o deter mi ne w het her t he a d mi nistrati o n of A C H -0 1 4 4 4 7 1 ca n i ncrease C 3 le vels i n patie nts wit h 
l o w C 3 le vels d ue t o eit her C 3 G or I C-M P G N  
S e c o n d ar y 
O bj e cti v e( s)  
•  
T o e val uate t he safet y a n d t olera bilit y of A C H -0 1 4 4 4 7 1 i n patie nts wit h C 3 G or I C -M P G N  
•  
T o e val uate t he p har mac o ki netic ( P K) pr ofile of A C H -0 1 4 4 4 7 1 i n patie nts wit h C 3 G or I C -
M P G N  
•  
T o e val uate t he effect of A C H -0 1 4 4 4 7 1 o n bi o mar kers of alt er nati ve pat h wa y ac ti vit y ( A P) i n 
patie nts wit h C 3 G or I C -M P G N  
•  
T o e x pl ore t he relati o ns hi p bet wee n st u d y dr u g e x p os ure a n d c ha n ges i n C 3 le vels a n d ot her 
bi o mar kers of alter nati ve pat h wa y acti vit y  
E x pl or at or y 
O bj e cti v e( s)  
•  
T o e x pl ore patie nts’ e x perie nc e of t heir disease ( C 3 G or I C -M G P N), its i m pact, a n d its 
ma na ge me nt o n e ver y da y li ves, fr o m first s y m pt o ms t o defi niti ve dia g n osis a n d be y o n d  
•  
T o e x pl ore patie nts’ e x pectati o ns of A C H -0 1 4 4 4 7 1 i n t he treat me nt of t heir disease  
P P D
C CI
C CI


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-201 Amendment 2 
09 June 2017 (Version 3.0) 
 
Confidential 
Page 5 of 77 
 
 
Study Design 
This open-label study will enroll up to 10 patients (between the ages of 16 and 65 years) with 
biopsy-confirmed C3G or idiopathic IC-MPGN and a low serum C3 level.  The trial will evaluate 
the ability of ACH-0144471 to increase C3 levels via inhibition of factor D (fD) by enrolling 
patients in two groups.  Group 1 will serve as a sentinel group consisting of two patients who will 
receive ACH-0144471 at a dose of 100 mg three times daily (TID) for 14 days followed by a taper 
over 7 days.  Group 2 will be initiated upon confirmation that dosing was well-tolerated in Group 1 
(based on Group 1 safety data through at least Day 28), and may include up to 8 patients.  As 
discussed in Section 3.2.2, the dose for Group 2 will be selected based on the available safety, PK, 
and PD data from Group 1, but will not exceed 200 mg TID.  The 100 mg TID dose level for 
Group 1 was selected based on safety, PK, and pharmacodynamics (PD) data from the Phase 1 
single-ascending dose (SAD) and multiple-ascending dose (MAD) studies (ACH471-001 and 
ACH471-002), which demonstrated that similar dosing regimens in healthy volunteers were well-
tolerated and able to inhibit the alternative pathway of complement.  In addition, the relative 
bioavailability study (ACH471-006) supports transition from the liquid filled capsule (LFC) dosage 
form used in the SAD and MAD studies to the tablet dosage form to be used in this study.  All 
patients will receive active drug.   
Patients will receive study drug for 14 days (Treatment Period), followed by a taper over the next 
7 days (Taper Period) to minimize the potential adverse effects of a rapid surge in complement 
activity following drug withdrawal.  Patients will have daily clinic visits for the first 3 days of the 
taper, and then will continue to be followed for 28 days after the last dose of study drug (Follow-
Up Period).  Long-term follow up visits to allow collection of longitudinal observational data are 
included, but are not required.  During the long-term follow up period, patients will be asked to 
return for an outpatient clinic visit approximately every 45 days for a maximum of 1 year. 
If a patient has a C3 level that, at 2 consecutive evaluations, is greater than 125% the upper limit of 
normal (ULN), or is greater than 3× their baseline and greater than or equal to the lower limit of 
normal (LLN), then the taper period will be initiated before completion of the 14 days of dosing, as 
proof-of-mechanism will already be established for that patient.  Furthermore, early tapering and 
possible prevention of supraphysiologic C3 levels may mitigate the theoretical risk for acute 
precipitation of C3 into the glomerulus upon drug discontinuation. 
Safety, PK, and PD data will be obtained at multiple time points during the Treatment, Taper and 
Follow-Up periods.  The primary endpoint for the study will be changes in C3 levels.  Additional 
endpoints include the incidence of adverse events (AEs), serious adverse events (SAEs), and 
discontinuations due to AEs.  Clinical measures of renal disease will be monitored (e.g., creatinine, 
proteinuria, and blood pressure), but are not expected to improve in this short-duration non-
therapeutic trial.  Additional secondary and exploratory endpoints will include functional assays of 
complement activity and measurement of selected complement components in blood and urine, as 
described in Section 6.15.  Finally, a PK/PD analysis will be conducted to explore the relationship 
between study drug exposure and changes in C3 levels and/or other secondary endpoints. 
Concomitant medications will be considered on a case-by-case basis, and decisions made jointly 
between the PI and Sponsor, based on knowledge of ACH-0144471 and risks for drug-drug 
interactions, as well as potential to interfere with interpretation of the study. 
Based on data from Groups 1 and 2, additional patients may be added to study additional dose 
levels or regimens (not to exceed 200 mg TID for two weeks, followed by a 7-day taper) or 
additional C3G or IC-MPGN patients. 
Study Population 
This study will be conducted in up to 10 patients with low C3 due to either C3G or IC-MPGN 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-201 Amendment 2 
09 June 2017 (Version 3.0) 
 
Confidential 
Page 6 of 77 
 
 
Dosing Regimen 
Group 1: 
Treatment Period: 100 mg TID for 14 days (Days 1 – 14)  
Taper Period: 
100 mg twice daily (BID) for 3 days (Days 15, 16, and 17) 
50 mg BID for 2 days (Days 18 and 19) 
50 mg once daily (QD) for 2 days (Days 20 and 21) 
Group 2: 
The dose and taper schedule will be determined based on data from Group 1, with a maximum 
possible dose of 200 mg TID followed by a 7 day taper. 
Inclusion Criteria 
Each patient must meet all of the following criteria to be enrolled in this study: 
1. Must be between the ages of 16 and 65 years, inclusive 
2. Must have a clinical diagnosis of C3G (C3 glomerulonephritis [C3GN] or dense deposit 
disease [DDD], the 2 types of C3G) or idiopathic immune-complex 
membranoproliferative glomerulonephritis (IC-MPGN) by renal biopsy for at least 
3 months prior to dosing, with the pathologic diagnosis verified by review of the renal 
biopsy by the study central pathologist 
3. C3 must be <50% of the lower limit of normal (LLN) 
4. C4 must be >90% of the LLN 
5. Female patients of childbearing potential must either agree to abstinence or to use two 
effective methods of contraception as defined in Section 5.5.5 from screening through 
3 months after the last dose of ACH-0144471.  Females who are of non-childbearing 
potential as defined in Section 5.5.5 need not employ a method of contraception. 
6. Male patients must either agree to abstinence or to use two effective methods of 
contraception as defined in Section 5.5.5 throughout the dosing period and for at least 3 
months after the last dose of ACH-0144471.  Males who are surgically sterile need not 
employ additional contraception.  Males must agree to not donate sperm throughout the 
dosing period and for at least 3 months following the last dose of ACH-0144471. 
7. Must be capable of providing written informed consent, must be willing and able to 
comply with the requirements and restrictions listed in the consent form and with the visit 
schedule, treatment plan, laboratory tests, pharmacokinetic sampling schedule, and other 
study procedures, and must be willing and able to return for all study visits 
8. Must be up-to-date on routine vaccinations, or be willing to be brought up-to-date, based 
on local guidelines 
9. Must be willing to comply with study-specific vaccination requirements for Haemophilus 
influenzae, Streptococcus pneumoniae, and Neisseria meningitidis strains A, C, W, and Y 
10. Must be willing, at all times for the duration of study participation, to have transportation 
and telephone access, and to be within one hour of an emergency medical center 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the study: 
1. History of a major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem 
cell/marrow transplant.  Individuals receiving renal replacement therapy are also excluded 
2. History or presence of any clinically relevant co-morbidities that would make the patient 
inappropriate for the study (for example, is likely to result in deterioration of the patient’s 
condition, affect the patient’s safety during the study, or confound the results of the study), in 
the opinion of the Principal Investigator 
3. Evidence of monoclonal gammopathy of unclear significance (MGUS), infections, 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-201 Amendment 2 
09 June 2017 (Version 3.0) 
 
Confidential 
Page 7 of 77 
 
 
malignancy, autoimmune diseases, or other conditions to which C3 glomerulopathy or IC-
MPGN may be secondary 
4. Patients with other renal diseases that would interfere with interpretation of the study 
5. Presence or evidence of hepatobiliary cholestasis 
6. Known Gilbert’s syndrome and/or patients with a history suggestive of Gilbert’s syndrome 
7. Females who are pregnant, nursing, or planning to become pregnant during the study or within 
90 days of study drug administration, or patients with a female partner who is pregnant, 
nursing, or planning to become pregnant during the study or within 90 days of study drug 
administration 
8. Estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2 at the time of screening or at 
any time over the preceding four-weeks 
9. History of febrile illness, a body temperature >38°C, or other evidence of a clinically 
significant active infection, within 14 days prior to study drug administration 
10. Patients with evidence of human immunodeficiency virus, hepatitis B or hepatitis C infection 
(positive serology for HIV-1 antibody, positive hepatitis B surface antigen, or positive anti-
HCV antibody at Screening or historically) 
11. History of meningococcal infection, or a first-degree relative or household contact with a 
history of meningococcal infection 
12. Contraindication to one or more of the required vaccinations 
13. 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 
14. Participation 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 study drug 
administration 
15. Receipt of eculizumab at any dose or interval within the past 75 days prior to dosing 
16. Use of tacrolimus or cyclosporine within 2 weeks of the first dose of ACH-0144471 
17. 12-lead electrocardiogram with a QTcF >500 msec or findings which, in the opinion of the PI, 
could put the patient at undue risk 
18. Any of the following laboratory abnormalities at screening: 
• 
Alanine transaminase > ULN  
• 
Aspartate aminotransferase > ULN  
• 
Alkaline phosphatase > ULN 
• 
Absolute neutrophil counts <1,000/μL 
• 
Total bilirubin >1.5× ULN 
• 
Indirect bilirubin > ULN 
• 
Any laboratory abnormality that, in the opinion of the PI, would make the patient 
inappropriate for the study, or put the patient at undue risk 
19. Donation of blood or blood products in excess of 500 mL within a 60 day period prior to the 
first dose of the current study 
20. Receipt of blood or blood products within 30 days of screening 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-201 Amendment 2 
09 June 2017 (Version 3.0) 
 
Confidential 
Page 8 of 77 
 
 
21. Clinically significant history of drug allergy as determined by the Investigator 
22. Unwilling or unable to comply with the study protocol for any reason 
Primary Endpoints 
• 
Increase in C3 levels relative to baseline 
Secondary 
Endpoints 
• 
The incidence of AEs, SAEs, and discontinuations due to AEs  
• 
Time (in days) to achieving peak C3 levels from the first day of dosing 
• 
The pharmacokinetic (PK) profiles of ACH-0144471 following the administration of multiple 
oral doses, and in the setting of dose taper 
• 
Changes in biomarkers of alternative pathway activity (AP) relative to baseline 
• 
The relationship between ACH-0144471 pharmacokinetics and changes in C3 levels, and 
inhibition of alternative pathway activity (PK/PD)  
Exploratory 
Endpoints 
• 
Patients’ experience of their disease (C3G or IC-MPGN), its impact, and its management on 
everyday lives, from first symptoms to definitive diagnosis and beyond 
• 
Patients’ expectations of ACH-0144471 in the treatment of their disease 
Group Stopping 
Rules 
Dosing will be terminated if one or more of the following occurs within a dose group: 
• 
Two or more patients experience the same or similar study drug-related serious adverse event 
• 
Two or more patients experience the same or similar study drug-related Grade 4 or higher 
adverse events 
If dosing is terminated in a group, all patients 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 Patients 
Any individual patient who meets any of the following criteria will be discontinued from further 
dosing: 
• 
The patient experiences any serious adverse event assessed as related to treatment with 
ACH-0144471 
• 
The PI believes that patient continuation in the study is not advisable 
• 
The patient becomes pregnant 
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 
Test Product, 
Dosage Form, and 
Strength 
ACH-0144471, administered orally as 50, 75, or 100 mg tablets 
Reference Therapy, 
Dose, and Mode of 
Administration 
No reference therapy (both groups receiving active ingredient) 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-201 Amendment 2 
09 June 2017 (Version 3.0) 
 
Confidential 
Page 9 of 77 
 
 
Duration of 
Treatment, 
Confinement, and 
Total Study 
Participation 
The maximum screening period is 45 days.  Each patient will receive multiple doses of 
ACH-0144471 for a total of up to 21 days and will be followed for 28 days after the final dose.  
The maximum duration for patient participation would be 94 days, including screening and follow-
up.  No overnight stays in the clinic are required; however, there are 2 extended clinic visits of 
8 hours each.  Patients will be asked to participate in a long-term follow up period in which clinic 
visits will occur approximately every 45 days for a maximum of 1 year; completion of these visits 
is not required. 
Safety 
Assessments: 
Safety assessments will include assessment of AEs, clinical laboratory tests, physical examination 
findings, 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). 
Pharmacokinetic 
Assessments: 
Serial blood samples will be collected on Days 1 and 7 to determine plasma and/or serum 
concentrations of ACH-0144471.  For each dose group, PK parameters (e.g., Cmax, tmax, AUC0-tau) 
will be calculated. 
Pharmacodynamic 
and Efficacy 
Assessments 
The primary PD assessment is C3 concentration in blood.  A PK/PD analysis will be conducted to 
explore the relationship between study drug exposure and changes in C3 levels and/or other 
secondary and/or exploratory endpoints.   
Additional complement biomarkers to be evaluated for efficacy are: C4, AH50, CH50, AP 
Wieslab, AP hemolysis, Bb, Ba, factor B (fB), fD, and terminal complement complex sC5b9 
(sC5b9).  
Blood and urine samples will be collected and stored for possible additional exploratory non-
genetic complement biomarker testing that includes: iC3b complement cleavage fraction of C3b 
(iC3b), C3a, C5, C5a, properdin, fH, factor I (fI), autoantibodies to C3 nephritic factor and fH, and 
C3 convertase activity.  These samples may also be used to assess patient response to vaccines. 
A blood sample will be collected and stored for possible exploratory evaluation of the genetic 
profile of selected complement components and regulators such as fH, fB, fI, fD, C3, membrane 
co-factor protein (MCP), complement fH related – 5 gene (CFHR-5), and thrombomodulin 
(THBD).  Note: if historic genetic work-up is not available in dosed patients, genetic profiling may 
be conducted during the study.   
Additional serum/plasma/WBCs samples may be collected and retained for possible research use.  
All biological samples will be stored for a maximum of 3 years after completion of the Clinical 
Study Report. 
Patient-Reported 
Outcomes 
Assessments 
Patients enrolled in the trial will be interviewed by an independent outcomes researcher chosen by 
the Sponsor during the Screening period.  Each patient will be interviewed once.  Interviews will 
be conducted by phone using a semi-structured study-specific guide, will last approximately 
30 minutes, and will be conducted by a trained psychologist/researcher, skilled in qualitative 
research.  Interviews will be audio-recorded, transcribed, and analyzed using validated qualitative 
software.  While completion of the interview is encouraged, it is not required, and eligible patients 
may participate in all other study activities whether or not they agree to the interview. 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-201 Amendment 2 
09 June 2017 (Version 3.0) 
 
Confidential 
Page 10 of 77 
 
 
Statistical 
Methods:  
Summary statistics will be provided for both original and change from baseline C3 levels at various 
time points at each dose level / group, during Treatment, Taper, and Follow-Up Periods.  Results 
may be presented by C3G and IC-MPGN if such presentations would be clinically meaningful. 
The following safety endpoints will be summarized for each dose level: 
• 
SAEs 
• 
Treatment emergent adverse events (TEAEs) leading to discontinuation of the study 
medication. 
• 
TEAEs (related and regardless of relationship to study medication) 
• 
Laboratory abnormalities by toxicity grade 
PK concentrations at each time points and relevant PK parameters will also be summarized by dose 
level. 
Summary statistics will be presented, by dose level / group, for the relevant measurements 
(markers) from analysis of complement testing results.  Time to achieving peak C3 level will be 
determined for each patient.  Descriptive time-to-event analysis techniques may be employed to 
estimate the time lapse for ACH-0144471 of restoring C3 levels.  The relationships between 
relevant AP component measurements and/or AP function with corresponding plasma 
concentrations and/or PK parameters will be explored to determine the nature of the correlations if 
they exist.  Graphic presentation techniques will also be employed. 
 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-201 Amendment 2 
09 June 2017 (Version 3.0) 
 
Confidential 
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Table of Contents 
Sponsor Signature(s) ....................................................................................................................................2 
Investigator’s Signature(s) ...........................................................................................................................3 
Synopsis .......................................................................................................................................................4 
Table of Contents .......................................................................................................................................11 
List of Tables .............................................................................................................................................15 
List of Figures ............................................................................................................................................15 
List of Appendices .....................................................................................................................................15 
List of Abbreviations and Definitions of Terms ........................................................................................17 
1 
Introduction ........................................................................................................................................19 
1.1 
Results of Nonclinical Studies ...................................................................................................19 
1.2 
Previous Human Experience with ACH-0144471 .....................................................................19 
1.2.1 Completed Studies ..................................................................................................................19 
1.2.2 Ongoing Studies .....................................................................................................................20 
1.3 
Background ................................................................................................................................21 
1.3.1 Complement Factor D ............................................................................................................21 
1.3.2 C3 Glomerulopathy ................................................................................................................21 
1.3.3 Potential Advantages of ACH-0144471 in the Treatment of C3G ........................................22 
1.3.4 Immune-Complex Membranoproliferative Glomerulonephritis (IC-MPGN) .......................22 
2 
Study Objectives .................................................................................................................................23 
2.1 
Primary Objective(s) ..................................................................................................................23 
2.2 
Secondary Objective(s) ..............................................................................................................23 
2.3 
Other Objective(s) ......................................................................................................................23 
3 
Investigational Plan ............................................................................................................................24 
3.1 
Overall Study Design and Plan ..................................................................................................24 
3.2 
Rationale for Study Design ........................................................................................................25 
3.2.1 Justification of Design ............................................................................................................25 
3.2.2 Justification of Dose ...............................................................................................................26 
3.2.3 Stopping Criteria ....................................................................................................................27 
3.2.3.1 
Group Stopping Rules ....................................................................................................28 
3.2.3.2 
Stopping Rules for Individual Patients ..........................................................................28 
3.2.4 Safety Considerations .............................................................................................................28 
3.2.4.1 
Risk of Infection ............................................................................................................28 


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3.2.4.2 
Hepatic Injury ................................................................................................................29 
3.3 
Study Duration and Dates ..........................................................................................................29 
4 
Study Population Selection ................................................................................................................30 
4.1 
Study Population ........................................................................................................................30 
4.2 
Inclusion Criteria .......................................................................................................................30 
4.3 
Exclusion Criteria ......................................................................................................................30 
5 
Study Treatment(s) .............................................................................................................................33 
5.1 
Description of Treatment(s) .......................................................................................................33 
5.1.1 Study Drug .............................................................................................................................33 
5.2 
Treatment(s) Administered ........................................................................................................33 
5.3 
Selection of Timing and Dose for Each Patient .........................................................................33 
5.3.1 Clinic Visit Dose Administration Instructions .......................................................................34 
5.3.2 Home Dose Administration Instructions ................................................................................34 
5.4 
Method of Assigning Patients to Treatment Groups .................................................................34 
5.5 
Restrictions ................................................................................................................................34 
5.5.1 Prior Therapy ..........................................................................................................................34 
5.5.2 Concomitant Therapy .............................................................................................................34 
5.5.3 Fluid and Food Intake .............................................................................................................35 
5.5.4 Patient Activity and Other Restrictions ..................................................................................35 
5.5.5 Contraception .........................................................................................................................35 
5.6 
Treatment Compliance ...............................................................................................................36 
5.7 
Packaging and Labeling .............................................................................................................36 
5.8 
Storage and Accountability ........................................................................................................37 
5.9 
Investigational Product Retention at Study Site ........................................................................37 
6 
Study Procedures ................................................................................................................................38 
6.1 
Informed Consent ......................................................................................................................38 
6.2 
Medical History .........................................................................................................................38 
6.3 
Review of Historical Renal Biopsy ...........................................................................................38 
6.4 
Vaccination ................................................................................................................................38 
6.5 
Physical Examination ................................................................................................................39 
6.6 
Vital Signs ..................................................................................................................................40 
6.7 
Body Temperature .....................................................................................................................40 
6.8 
Electrocardiography ...................................................................................................................40 


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6.9 
Clinical Laboratory Tests ...........................................................................................................41 
6.10 
Pregnancy Testing ......................................................................................................................42 
6.11 
Sample Collection, Storage, and Shipping ................................................................................42 
6.11.1 Blood Collection for Complement Assays (AH50, AP Wieslab, AP Hemolysis, Ba, Bb, C3, 
C4, CH50, fB, fD, and sC5b-9) ..............................................................................................42 
6.11.2 Blood collection for Genetic and Additional Non-genetic Complement-associated 
Biomarker Testing ..................................................................................................................42 
6.11.3 Urine Collection for Complement Components .....................................................................43 
6.11.4 PK Plasma Samples ................................................................................................................44 
6.11.5 Blood Volumes .......................................................................................................................44 
6.12 
Dispensing Study Drug ..............................................................................................................45 
6.13 
Safety Assessments ....................................................................................................................45 
6.14 
Pharmacokinetic Assessments ...................................................................................................45 
6.15 
Pharmacodynamic Assessments ................................................................................................45 
6.16 
Patient-Reported Outcomes Assessment Interview ...................................................................46 
6.17 
Adverse Events Assessments .....................................................................................................46 
6.17.1 Definitions ..............................................................................................................................46 
6.17.2 Criteria for Assessing Seriousness .........................................................................................48 
6.17.3 Documentation and Reporting of Adverse Events .................................................................49 
6.17.4 Treatment and Follow-Up of Adverse Events ........................................................................49 
6.17.5 Timeframe for Collection of Adverse Events ........................................................................49 
6.17.6 Severity and Grading of Adverse Events ...............................................................................50 
6.17.7 Assessment of Causality .........................................................................................................50 
6.17.8 Pregnancy ...............................................................................................................................51 
6.17.9 Reporting Serious Adverse Events .........................................................................................51 
6.17.10 
Investigator Reporting Requirements for SAEs ............................................................52 
6.18 
Concomitant Medication Assessments ......................................................................................52 
6.19 
Monitoring Patient Safety ..........................................................................................................53 
6.20 
Removal of Patients from the Trial or Study Drug ....................................................................53 
7 
Study Activities ..................................................................................................................................54 
7.1 
Screening Period ........................................................................................................................54 
7.1.1 Eligibility Visit (Days –45 to -1) ............................................................................................54 
7.1.2 Vaccination Visit (If Required; Day -14 or Earlier) ...............................................................55 
7.1.3 Patient Reported Outcomes Assessment Interview ................................................................55 


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7.2 
Treatment Period ........................................................................................................................55 
7.2.1 Pharmacokinetic/Pharmacodynamic Sampling Visits (Day 1 and Day 7) .............................56 
7.2.2 Outpatient Clinic Visits ..........................................................................................................56 
7.2.3 Telephone Visits .....................................................................................................................56 
7.3 
Taper Period ...............................................................................................................................56 
7.3.1 Outpatient Clinic Visits ..........................................................................................................57 
7.3.2 Telephone Visits .....................................................................................................................57 
7.4 
Follow-Up Period ......................................................................................................................57 
7.4.1 Outpatient Clinic Visits ..........................................................................................................57 
7.4.2 Telephone Visits .....................................................................................................................57 
7.4.3 Final Visit or Early Termination from the Study ...................................................................58 
7.5 
Long-Term Follow-Up Visits ....................................................................................................58 
7.6 
Unscheduled Visits ....................................................................................................................58 
8 
Quality Control and Assurance ..........................................................................................................59 
8.1 
Routine Monitoring ....................................................................................................................59 
8.2 
Site Audits ..................................................................................................................................59 
9 
Planned Statistical Methods ...............................................................................................................60 
9.1 
General Considerations ..............................................................................................................60 
9.2 
Determination of Sample Size ...................................................................................................60 
9.3 
Analysis Populations ..................................................................................................................60 
9.4 
Demographics and Baseline Characteristics ..............................................................................60 
9.5 
Efficacy Analysis – Complement C3 Measurements ................................................................60 
9.6 
Safety Analysis ..........................................................................................................................61 
9.7 
Pharmacokinetic (PK) Analysis .................................................................................................61 
9.8 
Pharmacodynamic (PD) Analysis ..............................................................................................61 
9.9 
PK/PD Assessments ...................................................................................................................62 
9.10 
Patient-Reported Outcome Measures Assessments ...................................................................62 
10 Administrative Considerations ...........................................................................................................63 
10.1 
Investigators and Study Administrative Structure .....................................................................63 
10.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) and Regulatory 
Approval ....................................................................................................................................63 
10.2.1 Ethical Approval .....................................................................................................................63 
10.2.2 Regulatory Approval ..............................................................................................................63 
10.2.3 Amendments ...........................................................................................................................63 


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10.3 
Ethical Conduct of the Study .....................................................................................................63 
10.4 
Patient Information and Consent ...............................................................................................64 
10.5 
Patient Confidentiality ...............................................................................................................64 
10.6 
Study Monitoring .......................................................................................................................64 
10.6.1 Access to Information for Monitoring ....................................................................................64 
10.6.2 Access to Information for Auditing or Inspections ................................................................64 
10.7 
Case Report Forms and Study Records .....................................................................................65 
10.7.1 Recording of Data ..................................................................................................................65 
10.7.2 Source Documentation and Medical/Study Records ..............................................................65 
10.8 
Data Monitoring Committee ......................................................................................................65 
10.9 
Protocol Deviations ....................................................................................................................65 
10.10 Access to Source Documentation ..............................................................................................65 
10.11 Data Generation and Analysis ...................................................................................................65 
10.12 Retention of Data .......................................................................................................................66 
10.13 Final Report, Publication and Disclosure Policy .......................................................................66 
11 References ..........................................................................................................................................68 
12 Appendices .........................................................................................................................................70 
 
List of Tables 
Table 1. 
Dose Levels for Group 1 ....................................................................................................33 
Table 2. 
Vaccination Schedule for Neisseria meningitidis, Serogroups A, C, Y, and W135 ..........39 
Table 3. 
Vaccination Schedule for Streptococcus pneumoniae .......................................................39 
Table 4. 
Vaccination Schedule for Haemophilus influenzae ...........................................................39 
Table 5. 
Clinical Laboratory Tests ...................................................................................................41 
Table 6. 
Approximate Total Blood Volumes ...................................................................................45 
Table 7. 
Schedule of Assessments ...................................................................................................70 
Table 8. 
PK and PD Sampling on Days 1 and 7 ..............................................................................74 
 
List of Figures 
Figure 1. 
Study Schematic.................................................................................................................25 
 
List of Appendices 
Appendix 1. 
Schedule of Assessments ...................................................................................................70 


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Appendix 2. 
Grading the Severity of Adult Adverse Events ..................................................................75 
Appendix 3. 
Fever Management Plan ....................................................................................................76 


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List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
ACE 
Angiotensin converting enzyme 
AE 
Adverse event 
AH50  
A method measuring the overall activity of complement alternative pathway 
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 
CH50 
A method measuring the overall activity of complement classical pathway 
Cmax 
Maximum plasma concentration 
CP 
Classical pathway (of complement) 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DDD 
Dense deposit disease 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ELISA 
Enzyme-linked immunosorbent assay 
EM 
Electron microscopy 
ESRD 
End stage renal disease 
fB 
(Complement) Factor B 
fD 
(Complement) Factor D 
FDA 
Food and Drug Administration 
fH 
(Complement) Factor H 
fI 
(Complement) Factor I 
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 
Insurance Portability and Accountability Act of 1996 
HIV 
Human immunodeficiency virus 


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Abbreviation 
Definition 
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 
kDa 
Kilodalton 
LFC 
Liquid filled capsule 
LLN 
Lower limit of normal 
MAD 
Multiple-ascending dose 
MCP 
Membrane Co-Factor Protein 
MDRD 
Modified Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGUS 
Monoclonal gammopathy of unclear significance 
MM 
Medical monitor 
MMF 
Mycophenolate mofetil 
MPA 
Mycophenolic acid 
msec 
Millisecond 
NOAEL 
No observed adverse effect level 
PAS 
Periodic acid-Schiff 
PD 
Pharmacodynamic(s) 
PI 
Principal investigator 
PK 
Pharmacokinetic(s) 
PR interval 
Period that extends from the beginning of the P wave until the beginning of the QRS complex 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QRS 
Group of electrocardiogram waves comprising the Q, R, and S waves 
QTcF 
QT interval Fridericia Correction Formula  
RBC  
Red blood cells 
Relative BA 
Relative bioavailability study 
RR 
Respiration rate 
SAD 
Single-ascending dose 
SAE  
Serious adverse event 
SAP  
Statistical Analysis Plan 
sC5b-9 
Soluble terminal complement complex  
SD 
Standard deviation 
TEAE 
Treatment-emergent adverse event 
THBD 
Thrombomodulin 
tmax 
Time after administration of a drug when the maximum plasma concentration is reached 
ULN 
Upper limit of normal 
WBC  
White blood cells 


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Clinical Protocol ACH471-201 Amendment 2 
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1 Introduction 
ACH-0144471, a small molecule, orally administered, factor D (fD) inhibitor, is in development by 
Achillion Pharmaceuticals, Inc. for the treatment of complement-related diseases.  Factor D is a serine 
protease that catalyzes the cleavage of factor B, a rate-limiting step in alternative pathway (AP) activity.  
By inhibiting fD, ACH-0144471 potently and specifically inhibits AP activity. 
Because C3 glomerulopathy (C3G) is a disease of AP over-activity, ACH-0144471 represents an ideal 
therapeutic approach to C3G, as it has the potential to reverse the underlying pathophysiology of the 
disease.  In addition, other renal diseases, such as IC-MPGN, in which complement likely plays a key 
role, may also be attractive therapeutic targets. 
This protocol is a multiple-center, open-label study in which patients with C3G or idiopathic IC-MPGN 
will receive ACH-0144471 for 2 weeks, followed by a one week taper.  In the preceding single-
ascending dose (SAD) and multiple-ascending dose (MAD) 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 patients with C3G or idiopathic IC-MPGN.  Doses for 
this study were selected based on available data from the ongoing SAD, MAD, and relative 
bioavailability (Relative BA) studies in healthy volunteers. 
1.1 Results of Nonclinical Studies 
Please refer to the Investigator’s Brochure [1] for an overview of the properties of ACH-0144471 and 
the results of the nonclinical investigations conducted. 
1.2 Previous Human Experience with ACH-0144471 
1.2.1 Completed Studies 
Three clinical studies with ACH-0144471 have been conducted: ACH471-001 (SAD), ACH471-002 
(MAD) and ACH471-006 (Rel BA).  One hundred and fifteen (115) healthy volunteers have participated 
in clinical trials with ACH-0144471, of which 87 have received ACH-0144471, and the remaining 
received placebo.  Results from all 3 studies are presented in the Investigator’s Brochure [1]. 
The SAD study was performed to evaluate the safety and tolerability of single ascending doses of 
ACH-0144471.  Healthy volunteers were dosed with ACH-0144471 in five separate groups.  Groups 1 
through 4 received escalating oral doses in the fasted state of 200, 600, 1200, and 2400 mg, respectively 
(2400 mg was administered as two divided doses of 1200 mg separated by 12 hours).  Group 5 received 
a 1200 mg oral dose in the fed state.  Overall, ACH-0144471 was well-tolerated at all dose levels.  There 
were no drug-related serious adverse events (SAEs), no treatment-emergent adverse events (TEAEs) 
leading to study discontinuation, and no study-drug related Grade 3 or 4 TEAEs.  There were no trends 
suggesting a drug-related effect on TEAEs, laboratory results, electrocardiogram (ECG) parameters, or 
vital signs.  There were no dose-related trends for infection, and no evidence for drug-induced liver 
injury. 
The MAD study was conducted to evaluate the safety and tolerability of multiple ascending doses of 
ACH-0144471 and to determine a recommended dose and schedule for treatment of patients in phase 2 
studies.  Healthy volunteers were dosed with ACH-0144471 in four separate groups.  Groups 1 through 


A C H -0 1 4 4 4 7 1  
Ac hilli o n P har mace uticals, I nc.  
Cl i nical Pr ot oc ol A C H 4 7 1-2 0 1 A me n d me nt 2  
0 9  J u ne 2 0 1 7 ( Versi o n 3. 0) 
 
C o nfi de ntial  
P a ge 2 0  of 7 7  
 
 
3 recei v e d m ulti ple dail y d oses of 2 0 0, 5 0 0, a n d 8 0 0 m g, res p ecti vel y, t wice dail y f or 1 4  da ys.  Gr o u p 4 
recei v e d d oses of 7 5 m g e ver y 8  h o urs f or 7 da ys.  All d oses were gi v e n i n t he faste d state.  Base d o n 
preli mi nar y i nf or mati o n, A C H - 0 1 4 4 4 7 1 a d mi nistere d as 2 0 0 m g e v er y 1 2  h o urs f or 1 4 da ys w as w ell-
t olerate d. 
 
  I n Gr o u p 4, a 
d osi n g re gi me n of 7 5 m g a d mi nistere d e ver y 8 h o urs f or 7  da ys w as well -t olerate d a n d res ulte d i n A C H-
0 1 4 4 4 7 1 tr o u g h c o nce ntr ati o ns t hat ha ve t he p ote ntial f or effi cac y i n C 3 G, I C- M P G N, a n d ot her 
c o m ple me nt -me diate d diseases.  
T he S A D a n d M A D st u dies were c o n d ucte d usi n g li q ui d- fille d ca ps ules ( L F C), w hile stu dies i n patie nts 
will be perf or me d usi n g a ta blet f or m ulati o n.  A Relati ve B A st u d y was p erf or me d t o c o m pare 
bi oa vaila bilit y of t he L F C a n d t he ta blet f or m ulati o ns.  T his was a ra n d o mize d, cr oss o ver, o pe n- la b el 
st u d y t o assess t he r elati v e bi oa vaila bilit y of A C H - 0 1 4 4 4 7 1 i n ta blet a n d s oft gel ca ps ule f or m ulati o ns 
relati ve t o t he e xte m p ora ne o usl y pr e pare d L F C us e d i n t he S A D a n d M A D st u dies.  Base d o n 
preli mi nar y i nf or mati o n, A U C 0- ∞ was bi oe q ui vale nt a n d Cma x  sli g htl y l o wer ( 1 9 %) f or A C H- 0 1 4 4 4 7 1 
ta blets a d ministere d wit h f o o d relati ve t o t he L F C f or m ulati o n gi ve n u n d er fasti n g c o n diti o ns as i n t he 
S A D a n d M A D st u dies.  A C H - 0 1 4 4 4 7 1 was w ell-t olerate d i n t his st u d y, a n d t here were n o S A Es, n o 
disc o nti n uati o ns d ue t o T E A Es, a n d n o dr u g- relate d Gra de 3 or 4 T E A Es.  As disc usse d i n Secti o n 3. 2. 2 , 
t he preli mi nar y data fr o m t his st u d y s u p p ort t he tra nsiti o n fr o m t he li q ui d fille d ca ps ule ( L F C) d osa ge 
f or m use d i n t he S A D a n d M A D st u dies t o t he ta blet d osa ge f or m t o be us e d i n t his st u d y. 
1. 2. 2  O n g oi n g St u di e s  
A C H 4 7 1 - 0 1 0 is a 3- part st u d y wit h eac h part b ei n g a n o p e n-la b el, fi x e d se q ue nce, 2-treat me nt st u d y i n 
healt h y s u bjects.  T his st u d y will i n vesti gate p ote ntial dr u g- dr u g i nteracti o ns bet wee n A C H - 0 1 4 4 4 7 1 
a n d mi daz ola m, bet wee n A C H- 0 1 4 4 4 7 1 a n d fe x ofe na di ne, a n d b et wee n A C H- 0 1 4 4 4 7 1 a n d 
m yc o p h e n olate m ofetil  ( M M F).  I n eac h p art of t he st u d y, s u bjects will recei ve a si n gle d os e of t he 
p ote ntiall y i nteracti n g dr u g ( mi daz ola m, fe x ofe na di ne, or M M F ) i n Peri o d 1, f oll o we d b y i nte nsi ve 
bl o o d sa m pli n g.  I n Peri o d 2, s u bjects will recei ve m ulti ple dail y d os es of A C H - 0 1 4 4 4 7 1.  O n Da y 4 of 
Peri o d  2 (after stea d y -state has bee n reac he d f or A C H- 0 1 4 4 4 7 1), s u bjects will recei ve a si n gl e d ose of 
t he p ote ntiall y i nter acti n g dr u g ( mi daz ola m, fe x ofe na di ne, or M M F ), f oll o we d b y i nte nsi ve bl o o d 
sa m pli n g.  I n b ot h Peri o d 1 a n d Peri o d 2, t he d urati o n of t he sa m pli n g will var y bet wee n parts, 
de pe n di n g o n t he c h aracteristics of t he p ote ntial l y i nteracti n g dr u g.  T his st u d y is o n g oi n g, a n d n o res ults 
are a v aila ble at t his ti me.  
A C H 4 7 1 -1 0 0 is a m ulti ple -ce nt er, o pe n -la bel, m ulti ple d ose st u d y t o e val u ate t he effi cac y of 
A C H - 0 1 4 4 4 7 1 i n c urr e ntl y u ntreate d par o x ys m al n oct ur nal he m o gl o bi n uri a ( P N H) patie nts.  E ac h 
patie nt will recei ve m ulti ple d oses of A C H - 0 1 4 4 4 7 1 f or a t otal of 2 8 da ys d uri n g Part 1, a n d ma y b e 
treate d f or a n a d diti o nal 8 wee ks if t he y p artici pat e i n Part  2.  C urre ntl y, t w o patie nts wit h P N H ha ve 
bee n treate d wit h A C H - 0 1 4 4 4 7 1 at d oses ra n gi n g fr o m 1 0 0 t o 1 5 0 m g TI D.   Preli mi nar y d ata s u g gest 
t hat t hese d oses ha ve a n acce pta ble safet y pr ofile, i ncl u di n g n o e vi de n ce of cli nicall y si g nifica nt A L T 
ele vati o ns.  B ot h patie nts starte d t he st u d y at a d os e of 1 0 0 m g TI D, a n d t he n i ncreas e d t o 1 5 0 m g TI D 
base d o n Da y 1 3 res ults w hic h de m o nstrate d i m pr o ve me nt i n, b ut n ot o pti mal c o ntr ol of, he m ol ysis.  
He m ol ysis was c o nsi der e d i m pr o ve d base d o n a cli nicall y si g nifica nt i m pr o ve me nt i n he m o gl o bi n a n d a 
s u bsta ntial d o w n war d tre n d i n lactate de h y dr o ge n ase ( L D H) i n b ot h patie nts.  At 1 5 0 m g TI D, 
he m o gl o bi n c o n ce ntrati o ns were mai ntai n e d wit hi n acce pta ble ra n ges, b ut t he L D H res p o nse was 
s u b o pti mal, as le vels re m ai ne d hi g h er t ha n n or mal.  T his data de m o nstrates t hat alt h o u g h d oses of 1 0 0 
a n d 1 5 0 m g T I D i n hi bit c o m ple me nt a n d decreas e he m ol ysis i n P N H patie nts, hi g her d os es ma y be 
C CI


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needed for optimal control.  Therefore, after consultation with the PI, PNH experts, and a hepatic safety 
advisory panel, Achillion has amended this PNH protocol to assess doses as high as 200 mg TID.  
1.3 Background 
1.3.1 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. 
1.3.2 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].  The clinical course is characterized by variable amounts of proteinuria, hematuria, 
hypertension, and decreased renal function, with approximately 30%-50% of patients reaching end-stage 
renal disease (ESRD) within 10 years of diagnosis [7, 9, 10, 11].  The diagnosis is based on predominant 
deposition of C3 in the glomerulus on renal biopsy along with clinical evidence of hyper AP activity.  
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 [11]. 
Unfortunately, no specific therapy has proven effective for the treatment of C3G.  Therefore, care is 
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.  Treatment is otherwise focused on management of hypertension, proteinuria and the 
manifestations of chronic kidney disease.  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 [11, 12]. 
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 evidence of 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 


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Clinical Protocol ACH471-201 Amendment 2 
09 June 2017 (Version 3.0) 
 
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the kidneys [13, 14].  These studies confirmed that removal of fD prevented the renal pathogenesis of 
C3G in the factor H-deficient mice. 
1.3.3 Potential Advantages of ACH-0144471 in the Treatment of C3G  
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.  Its use has 
been reported in more than 20 patients with C3G, of whom the majority were reported as individual 
cases, and only six were reported as part of an open-label proof-of-concept study [12, 15].  Of those 
presented as case reports, the majority had a successful response.  However, this may represent a 
publication bias, as the results of the open-label trial were less impressive.  Specifically, two of the six 
patients in the open-label trial seemed to have a good response, confirmed by worsening upon 
discontinuation of eculizumab.  Of the remaining four patients, three had an increase in serum creatinine 
while on treatment.  Based on the results of this open-label trial, 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, 11, 12, 15].  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 [15]. 
A fD inhibitor like ACH-0144471, which inhibits directly at the level of the AP C3 convertase 
formation, is expected to provide superior efficacy than eculizumab or complement inhibitors that target 
the other complement pathways.  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 [13, 14].  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 [11, 16]. 
1.3.4 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 idiopathic IC-MPGN.  Patients with idiopathic 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 there are 
current hypotheses suggesting that the majority of IC-MPGN is attributable to overactivity of the 
classical pathway, those patients with a low C3 and a normal C4 are likely to have significant 
overactivity of the alternative pathway [17].  Therefore, IC-MPGN patients with a low C3 and a normal 
C4 may benefit from alternative pathway inhibition. 


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2 Study Objectives 
2.1 Primary Objective(s) 
The primary objective(s) of this study is to determine whether ACH-0144471 can increase blood C3 
levels in patients with low C3 levels due to either C3G or IC-MPGN. 
2.2 Secondary Objective(s) 
The secondary objective(s) of this study is (are): 
• To evaluate the safety and tolerability of oral dosing with ACH-0144471 in patients with C3G or 
IC-MPGN by assessing SAEs, Grade 3 and higher adverse events (AEs), and AEs leading to 
discontinuation of study drug 
• To evaluate the PK profile of ACH-0144471 following oral dosing in patients with C3G or IC-
MPGN  
• To evaluate the effect of ACH-0144471 on biomarkers of alternative pathway activity in patients 
with C3G or IC-MPGN 
• To explore the relationship between study drug exposure and changes in C3 levels and other 
biomarkers of alternative pathway activity 
2.3 Other Objective(s) 
The exploratory objective(s) of this study is (are): 
• To explore patients’ experience of their disease (C3G or IC-MPGN), its impact, and its 
management on everyday lives, from first symptoms to definitive diagnosis and beyond 
• To explore patients’ expectations of ACH-0144471 in the treatment of their disease 
 


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3 Investigational Plan 
3.1 Overall Study Design and Plan 
This open-label study will enroll up to 10 patients (between the ages of 16 and 65 years) with biopsy-
confirmed C3G or idiopathic IC-MPGN and a low C3.  The trial will evaluate the ability of 
ACH-0144471 to increase C3 levels via inhibition of fD by enrolling patients in two groups.  Group 1 
will serve as a sentinel group consisting of two patients who will receive ACH-0144471 at a dose of 
100 mg three times daily (TID) for 14 days followed by a taper over 7 days.  Group 2 will be initiated 
upon confirmation that dosing was well-tolerated in Group 1 (based on Group 1 safety data through at 
least Day 28), and may include up to 8 patients.  As discussed in Section 3.2.2, the dose for Group 2 will 
be selected based on the available safety, PK, and PD data from Group 1, but will not exceed 200 mg 
TID.  The 100 mg TID dose level for Group 1 was selected based on safety, PK, and pharmacodynamics 
(PD) data from the Phase 1 SAD and MAD studies (ACH471-001 and ACH471-002, respectively), 
which demonstrated that similar dosing regimens in healthy volunteers were well-tolerated and able to 
inhibit the alternative pathway of complement.  In addition, the relative bioavailability study 
(ACH471-006) supports transition from the liquid filled capsule (LFC) dosage form used in the SAD 
and MAD studies to the tablet dosage form to be used in this study.  All patients will receive active drug. 
Patients will receive study drug for 14 days (Treatment Period), followed by a taper over the next 7 days 
(Taper Period) to minimize the potential adverse effects of a rapid surge in complement activity 
following drug withdrawal.  Patients will have daily clinic visits for the first 3 days of the taper, and then 
will continue to be followed until 28 days after the last dose of study drug (Follow-Up Period).  Long-
term follow up visits to allow collection of longitudinal observational data are included, but are not 
required.  During the long-term follow up period, patients will be asked to return for an outpatient clinic 
visit approximately every 45 days for a maximum of 1 year. 
If a patient has a C3 level that, at 2 consecutive evaluations, is greater than 125% the upper limit of 
normal (ULN), or is greater than 3× their baseline and greater than or equal to the lower limit of normal 
(LLN), then the taper period will be initiated before completion of the 14 days of dosing, as proof-of-
mechanism will already be established for that patient.  Furthermore, early tapering and possible 
prevention of supraphysiologic C3 levels may mitigate the theoretical risk for acute precipitation of C3 
into the glomerulus upon drug discontinuation. 
Safety, PK, and pharmacodynamic (PD) data will be obtained at multiple time points during the 
Treatment, Taper and Follow-Up periods.  The primary endpoint for the study will be changes in C3 
levels.  Additional endpoints include the incidence of AEs, SAEs, and discontinuations due to AEs.  
Clinical measures of renal disease will be monitored (e.g., creatinine, proteinuria, and blood pressure), 
but are not expected to improve in this short-duration non-therapeutic trial.  
The primary pharmacodynamic assessment is C3 concentration in serum/plasma.  In addition, inhibition 
of AP activity will be evaluated ex vivo using serum collected during the study with the AP Wieslab 
ELISA and AP hemolysis assay.  AH50 and CH50 functional assays will be used to qualitatively 
evaluate the effect of ACH-0144471 on AP and classical pathway (CP) activity.  Factor D concentration 
will be measured at baseline to determine whether it is elevated in the setting of underlying renal 
disease, as well as over the course of the study to evaluate any changes after dosing with ACH-0144471.  
Factor Bb concentration will be measured as it is the cleavage product generated by factor D.  The 


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Clinical Protocol ACH471-201 Amendment 2 
09 June 2017 (Version 3.0) 
 
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concentrations of additional complement-associated biomarkers will be determined, as described in 
Section 6.11.2. 
Finally, a PK/PD analysis will be conducted to explore the relationship between study drug exposure 
and changes in C3 levels and/or other secondary and/or exploratory endpoints. 
Most concomitant medications will be considered on a case-by-case basis, and decisions made jointly 
between the principal investigator (PI) and Sponsor, based on knowledge of ACH-0144471 and risks for 
drug-drug interactions, as well as potential to interfere with interpretation of the study.  Further 
information on concomitant medications is provided in Section 5.5.2.  
Based on data from Groups 1 and 2, additional patients may be added to study additional dose levels or 
regimens (not to exceed 200 mg TID for two weeks, followed by a 7-day taper) or additional C3G or IC-
MPGN patients. 
Figure 1. 
Study Schematic 
 
 
3.2 Rationale for Study Design 
3.2.1 Justification of Design 
This proof-of-mechanism study is an open-label study whose primary objective is to determine whether 
circulating C3 levels can be increased during two weeks of treatment with ACH-0144471.  Restoration 
of C3 levels to normal would indicate correction of uncontrolled AP activation, the central 
pathophysiological abnormality in C3G, and likely in some cases of IC-MPGN.  The overactive AP 
leads to excessive consumption of C3, resulting in low levels of C3.  As an inhibitor of the AP, 
ACH-0144471 should mitigate this excessive C3 consumption, and return C3 levels toward normal 
within a few days.  Since the increased C3 consumption results in accumulation of C3 breakdown 
products in the renal glomerulus and renal damage, prevention of excessive AP activity is predicted to 
prevent protect the glomerulus from further C3 deposition as well as ameliorate existing C3 deposits, 
preventing further disease progression and allowing recovery of reversible renal injury.  A rise in C3 in 
this study would demonstrate that ACH-0144471is able to reverse the underlying disease 
pathophysiologic driver in these diseases.  This data would provide a strong justification for proceeding 
with a trial of therapeutic duration to determine if inhibition of the AP and increases in C3 will translate 
into improvement in renal manifestations of disease, such as C3 deposition in glomeruli, glomerular 
inflammation, proteinuria, and estimated glomerular filtration rate (eGFR).  
The inclusion and exclusion criteria have been selected to ensure that enrolled patients have one of the 
relevant diseases (C3G or IC-MPGN), have a low enough C3 to allow an increase to be detected, and to 
Screening 
Period
Day
-45 to -1
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49
Clinic Visits
X
X* X
X
X
X* X
X
X
X
X
X
X
X
X
X
X
X
Dose with 
ACH-0144471
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Treatment Period
Taper Period**
Follow-up Period
Patients in Group 1 and Group 2 will follow the same schedule.
*    Intensive PK days.
**   If a patient has a serum C3 level >125% ULN after at least 7 days of treatment, then the taper will be initiated before completion of 14 days of dosing.


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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.  The key criteria that 
ensure that the patients have C3G, or the relevant subset of IC-MPGN, are the review of historical 
biopsy by a central study pathologist, demonstrated evidence of alternative pathway over-activation, and 
lack of evidence of another underlying disease to which the renal disease may be secondary (such as 
infections, malignancies and autoimmune disorders).  In addition, the patient must have had the 
diagnosis for at least 3 months to avoid inadvertent inclusion of patients with post-infectious 
glomerulonephritis.  The C3 cut-off selected was <50% of the lower limit of normal (LLN), which 
allows adequate opportunity for improvement in C3 before reaching the normal range.  Furthermore, 
low C3 with normal (or near-normal) C4 is strong evidence for a selective overactivity of the AP.  
Although available clinical and non-clinical data to date suggests that renal clearance does not play a 
major role in drug disposition, an eGFR cut-off of 45 mL/min/1.73 m2 was selected, as factor D levels 
may be elevated in patients with renal impairment.  This eGFR criteria takes into consideration that this 
is a short duration non-therapeutic trial in which there is no opportunity for dose adjustment and no 
likely clinical benefit for patients. 
In summary, the study is designed with regard to patient inclusion/exclusion, duration of treatment, 
monitoring, and PK/PD assessments to inform whether ACH-0144471 and fD inhibition can improve 
and/or normalize C3 levels in patients with C3G or IC-MPGN, while minimizing the risk to patients.  A 
two-week treatment duration was selected as changes in C3 may begin as early as the first 24 hours, but 
may take several days.  With two weeks of treatment, but intensive PK/PD assessments in the first 
24 hours, we believe we have maximized our opportunity to characterize the rate of change in C3, and 
may even have the opportunity to observe the new steady-state levels of C3 in the setting of fD 
inhibition.  The study includes a taper period and daily clinic visits during the first three days of the 
taper to mitigate any risk of rebound AP activity upon drug discontinuation.  In the event that C3 levels 
rise very quickly, and do not reach a new steady-state before exceeding 125% of the ULN, or 3× the 
baseline level (provided this is greater than or equal to the LLN), then the taper will begin early. 
3.2.2 Justification of Dose 
The level of AP inhibition required for efficacy in C3G patients is unknown.  Eculizumab, the only 
commercially available complement inhibitor, is effective in preventing hemolysis in PNH and may 
benefit some patients with C3G.  The pharmacodynamics and potential for clinical efficacy for 
ACH-0144471 is primarily associated with maintenance of exposure above a target trough level.  
Exploratory ex vivo AP hemolysis experiments using patient PNH cells showed that ACH-0144471 at 
concentrations of >20 ng/mL provided protection from hemolysis similar to eculizumab at a 
concentration of 35 μg/mL (an efficacious eculizumab trough concentration in PNH patients).  These 
data suggested that dosing regimens that provide plasma trough ACH-0144471 concentrations of 
>20 ng/mL may demonstrate efficacy in PNH patients. 
An ACH-0144471 regimen of 200 mg administered every 12 hours for 14 days to healthy volunteers 
was well tolerated and resulted in a mean plasma trough concentration above 20 ng/mL.  PK modeling 
based on data from the SAD and MAD studies predicts that a dose regimen of 100 mg TID will result in 
a higher plasma trough ACH-0144471 concentration while producing a lower Cmax and that 
ACH-0144471 trough concentrations of >30 and >60 ng/mL can be achieved with doses of 100 and 
150 mg 3 times daily (TID), respectively.  


A C H -0 1 4 4 4 7 1  
Ac hilli o n P har mace uticals, I nc.  
Cl i nical Pr ot oc ol A C H 4 7 1-2 0 1 A me n d me nt 2  
0 9  J u ne 2 0 1 7 ( Versi o n 3. 0) 
 
C o nfi de ntial  
P a ge 2 7  of 7 7  
 
 
Base d o n t h e a b o ve a nal ysis, t he starti n g d ose of A C H- 0 1 4 4 4 7 1 i n t he first P N H cli nical trial 
( A C H 4 7 1- 1 0 0) w as selecte d t o be 1 0 0 m g TI D.  T he first t w o patie nts i n t his st u d y b ot h starte d d osi n g 
at 1 0 0 m g TI D, a n d w ere escalate d t o a d ose of 1 5 0 m g TI D after Da y 1 3.  As descri be d i n 
Secti o n  1. 2. 2 , b ot h patie nts ha ve t olerate d t h e dr u g well, a n d n o cli nicall y si g nifica nt i ncreases i n A L T 
ha ve bee n n ote d at eit her d ose le vel.  At stea d y -st ate o n Da y 2 0, mea n Cma x , Ctr o u g h, a n d A U C were 
wit hi n t he e x pecte d e x p os ures base d o n h ealt h y v ol u nteer P K data.  I n b ot h patie nts, he m o gl o bi n 
c o nce ntr ati o ns were m ai ntai ne d wit hi n acce pta ble ra n ges b ut t he L D H  res p o nse was s u bo pti mal, as  
le vels, alt h o u g h dra maticall y decrease d u p o n i nitiati o n of t hera p y wit h A C H- 0 1 4 4 4 7 1, te n de d t o re mai n 
hi g her t h a n n or mal e v e n after 2 8 d a ys of dr u g treat me nt, s u g gesti n g t hat hi g her c o nce ntrati o ns are 
re q uire d t o mai ntai n t he cli nical res p o nse.  T h eref ore, aft er c o ns ultati o n wit h t he PI, P N H e x perts a n d a 
 Ac hilli o n has a me n de d t he P N H pr ot oc ol t o assess d oses as hi g h as 2 0 0 
m g TI D.  
Si nce it is n ot k n o w n w het her t he i deal d ose f or C 3 G will be t he sa me, hi g her, or l o wer t ha n t hat f or 
P N H, t he i nitial d ose f or t his st u d y will be t he s a me as t hat i nitiall y selecte d f or t he first P N H st u d y  
( A C H 4 7 1- 1 0 0), a n d t h e t w o patie nts i n Gr o u p 1 will recei ve a d os e of 1 0 0 m g TI D.  
T he d ose f or Gr o u p 2 will be selecte d wit h t he g o al of i de ntif yi n g a d os e w hic h ca n ret ur n A P f u ncti o n 
t o war d n or mal, as meas ure d b y i m pr o ve me nt i n ser u m a n d/ or plas ma C 3 c o nce ntrati o n.  T his d ose 
decisi o n will be i nf or me d b y t he s afet y, P K, a n d P D data fr o m Gr o u p 1, as well as b y e mer gi n g dat a 
fr o m ot her cli nical a n d n o n -cli nical st u dies wit h A C H - 0 1 4 4 4 7 1, i ncl u di n g t he P N H st u dies.  Gr o u p 2 
will n ot i nitiate d osi n g u ntil it has bee n c o nfir me d t hat d osi n g was w ell -t olerate d i n Gr o u p 1 ( bas e d o n 
safet y data t hr o u g h at least Da y 2 8).  T he d ose f or Gr o u p 2 c o ul d be l o w er, hi g her or t he sa me as Gr o u p 
1, b ut will n ot e x cee d 2 0 0 m g TI D.  Of n ote, a d ose of 2 0 0 m g TI D is li kel y t o be assesse d i n P N H 
patie nts pri or t o i nitiati o n of Gr o u p 2.  
 
 
  
3. 2. 3  St o p pi n g Crit eri a  
A n y d ecisi o n t o ter mi nat e dr u g a d mi nistrati o n i n o ne or m ore gr o u ps will be ma de b y t he S p o ns or 
Me dical M o nit or ( M M) base d o n o n g oi n g re vie w of safet y dat a fr o m all e nr olli n g sites.  If a PI b ec o mes 
a war e t hat a gr o u p st o p pi n g r ule h as bee n met, t he n he/s he s h o ul d i nf or m t he Ac hilli o n M M 
i m me diatel y.  If d osi n g is ter mi nate d i n a gr o u p, t he Ac hilli o n M M will deci de w het her or n ot t he ta per 
s h o ul d be i m ple me nte d. 
T he PI m a y st o p d osi n g i n a n y p atie nt w h o meets a n i n di vi d ual st o p pi n g r ule ( Secti o n 3. 2. 3. 2 ); h o w e ver, 
t he Ac hilli o n M M s h o ul d be n otifie d i m me diatel y, if p ossi ble bef ore d osi n g is ter mi nate d.  W he n d osi n g 
is st o p pe d i n a n i n di vi d ual patie nt, t he PI s h o ul d c o nsi der w het her it is i n t he best i nterest of t he p atie nt 
t o disc o nti n ue d osi n g i m me diatel y or t o ta per (as descri be d i n Secti o n  5. 2 ).  W he ne ver p ossi ble, t his 
decisi o n s h o ul d als o be disc usse d wit h t he Ac hilli o n M M pri or t o d osi n g ter mi nati o n.  
C CI
C CI
C CI


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When dosing is terminated, study participation is not necessarily immediately terminated.  Instead, 
whenever possible, the patient should advance to the Taper and/or Follow-Up Periods, as relevant, and 
complete all activities in these periods as described in Appendix 1. 
3.2.3.1 Group Stopping Rules 
Dosing will be terminated if one or more of the following occurs within a dose group: 
• Two or more patients experience the same or similar study drug-related SAE 
• Two or more patients experience the same or similar study drug-related Grade 4 or higher AEs 
If dosing is terminated in a group, all patients 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. 
3.2.3.2 Stopping Rules for Individual Patients 
Any individual patient who meets any of the following criteria will be discontinued from further dosing: 
• The patient experiences any SAE assessed as related to treatment with ACH-0144471 
• The PI believes that patient continuation in the study is not advisable, or the patient withdraws 
from the study or meets one of the conditions described in Section 6.20, including, but not 
limited to: 
o The patient becomes pregnant 
o Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree 
o Patient requests to discontinue for any reason 
Discontinuation of treatment should also be considered for:  
o ALT or AST >8× ULN  
o ALT or AST >5× ULN for more than 2 weeks  
o ALT or AST >3× ULN and concomitant total bilirubin >2× ULN and/or International 
Normalized Ratio [INR] >1.5 
 
3.2.4 Safety Considerations 
3.2.4.1 Risk of Infection 
One of the primary functions of the complement system is to fight infections as part of the innate 
immune system.  As suggested by individual case reports with complement system deficiencies 
including complement factor D, inhibition of the complement system may result in a lifetime increased 


A C H -0 1 4 4 4 7 1  
Ac hilli o n P har mace uticals, I nc.  
Cl i nical Pr ot oc ol A C H 4 7 1-2 0 1 A me n d me nt 2  
0 9  J u ne 2 0 1 7 ( Versi o n 3. 0) 
 
C o nfi de ntial  
P a ge 2 9  of 7 7  
 
 
ris k of i nfecti o n, n ota bl y wit h Nei sseri a me ni n giti dis ( N. me ni n giti dis) [ 1 8, 1 9, 2 0], a n d ot her 
e nca ps ulate d or ga nis ms.  
Beca use of t his p ote ntial ris k, s pecial safet y preca uti o ns will be ta ke n f or p atie nts partici pati n g i n 
A C H 4 7 1 - 2 0 1.  Patie nts will be re q uire d t o be pre vi o usl y vacci nate d, or t o recei v e vacci nati o ns f or N. 
me ni n giti dis  (ser o gr o u ps A, C, Y a n d W 1 3 5), Stre pt oc occ us p ne u m o ni ae  (S. p ne u m o ni a e), a n d 
H ae m o p hil us i nfl ue nz ae  (H. i nfl ue nz ae ) pri or t o recei vi n g A C H- 0 1 4 4 4 7 1 (see Secti o n 6. 4 ).   
T hr o u g h o ut t he st u d y, i n cl u di n g at cli nic visits, patie nts will be m o nit ore d f or t he de v el o p me nt of fe ver.  
A s pecific Fe v er Ma n a ge me nt Pla n ( A p pe n di x 3 ) has bee n de v el o pe d f or t his st u d y. 
Patie nts will als o be c o u nsele d a b o ut be ha vi ors t o a v oi d d uri n g t he st u d y, a n d t o rec o g nize earl y a n d 
react a p pr o priat el y t o si g ns a n d s y m pt o ms of i nfecti o n (A p pe n di x 3 ).   
 
 
 
 
 
3. 3   St u d y D ur ati o n a n d D at e s 
T he scree ni n g peri o d is u p t o 4 5 da ys.  E ac h patie nt will recei ve m ulti ple d oses of A C H - 0 1 4 4 4 7 1 f or a 
t otal of u p t o 2 1 da ys a n d will be f oll o we d f or 2 8 d a ys after t h e fi nal d ose.  T he d urati o n f or p atie nt 
partici pati o n w o ul d be a p pr o xi ma tel y 9 4 d a ys, i ncl u di n g scree ni n g a n d f oll o w- u p.  N o o ver ni g ht sta ys i n 
t he cli nic are re q uir e d; h o we ver, t here are 2 e xte n de d cli nic visits of 8 h o urs eac h ( Da ys 1 a n d 7; see 
Secti o n  7. 2. 1 ).  Patie nts will be as ke d t o partici pate i n a l o n g-t er m f oll o w u p peri o d i n w hic h cli nic visits 
will occ ur a p pr o xi matel y e ver y 4 5  da ys f or a m a xi m u m of 1 year; c o m pleti o n of t hese visits is n ot 
re q uire d. 
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4 Study Population Selection 
4.1 Study Population 
This study will be conducted in up to 10 patients with low C3 due to either C3G or IC-MPGN who meet 
eligibility criteria. 
4.2 Inclusion Criteria 
Each patient must meet all of the following criteria to be enrolled in this study. 
1. Must be between the ages of 16 and 65 years, inclusive 
2. Must have a clinical diagnosis of C3G (C3 glomerulonephritis [C3GN] or dense deposit disease 
[DDD], the 2 types of C3G) or idiopathic immune-complex membranoproliferative 
glomerulonephritis (IC-MPGN) by renal biopsy at least 3 months prior to dosing, with the 
pathologic diagnosis verified by review of the renal biopsy by the study central pathologist 
3. C3 must be <50% of the LLN 
4. C4 must be >90% of the LLN 
5. Female patients of childbearing potential must either agree to abstinence or to use two effective 
methods of contraception as defined in Section 5.5.5 from screening through 3 months after the 
last dose of ACH-0144471.  Females, who are of non-childbearing potential as defined in 
Section 5.5.5 need not employ a method of contraception. 
6. Male patients must either agree to abstinence or to use two effective methods of contraception, as 
defined in Section 5.5.5, throughout the dosing period and for at least 3 months after the last dose 
of ACH-0144471.  Males who are surgically sterile need not employ additional contraception.  
Males must agree to not donate sperm throughout the dosing period and for at least 3 months 
following the last dose of ACH-0144471. 
7. Must be capable of providing written informed consent, 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 
8. Must be up-to-date on routine vaccinations, or willing to be brought up-to-date, based on local 
guidelines 
9. Must be willing to comply with study-specific vaccination requirements for Haemophilus 
influenzae, Streptococcus pneumoniae, and Neisseria meningitidis strains A, C, W, and Y 
10. Must be willing, at all times for the duration of study participation, to have transportation and 
telephone access, and to be within one hour of an emergency medical center 
 
4.3 Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the study. 
1. History of a major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem 
cell/marrow transplant.  Individuals receiving renal replacement therapy are also excluded 


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2. History or presence of any clinically relevant co-morbidities that would make the patient 
inappropriate for the study (for example, is likely to result in deterioration of the patient’s 
condition, affect the patient’s safety during the study, or confound the results of the study), in the 
opinion of the PI 
3. Evidence of monoclonal gammopathy of unclear significance(MGUS), infections, malignancy, 
autoimmune diseases, or other conditions to which C3G or IC-MPGN may be secondary 
4. Patients with other renal diseases that would interfere with interpretation of the study 
5. Presence or evidence of hepatobiliary cholestasis  
6. Known Gilbert’s syndrome and/or patients with a history suggestive of Gilbert’s syndrome 
7. Females who are pregnant, nursing, or planning to become pregnant during the study or within 
90 days of study drug administration or patients with a female partner who is pregnant, nursing, 
or planning to become pregnant during the study or within 90 days of study drug administration 
8. Estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2 at the time of screening or at 
any time over the preceding four-weeks.  Calculation of eGFR will be based on the Modified 
Diet for Renal Disease (MDRD) equation for patients ≥18 years of age, and will be based on the 
Schwartz equation for patients <18 years of age 
9. History of febrile illness, a body temperature >38°C, or other evidence of a clinically significant 
active infection, within 14 days prior to study drug administration 
10. Patients with evidence of human immunodeficiency virus (HIV), hepatitis B or hepatitis C 
infection (positive serology for HIV- antibody (HIV Ab), positive hepatitis B surface antigen 
(HbsAg), or positive anti-HCV antibody (HCV Ab) at Screening or historically) 
11. History of meningococcal infection, or a first-degree relative or household contact with a history 
of meningococcal infection 
12. Contraindication to one or more of the required vaccinations 
13. 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. 
14. Participation 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 study drug 
administration  
15. Receipt of eculizumab at any dose or interval within the past 75 days prior to dosing 
16. Use of tacrolimus or cyclosporine within 2 weeks of the first dose of ACH-0144471 
17. 12-lead ECG with a QTcF >500 msec or findings which, in the opinion of the PI, could put the 
patient at undue risk 


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09 June 2017 (Version 3.0) 
 
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18. Any of the following laboratory abnormalities at screening:  
 Alanine transaminase (ALT) > ULN  
 Aspartate aminotransferase (AST) > ULN  
 Alkaline phosphatase (ALP) > 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 patient 
inappropriate for the study 
19. Donation of blood or blood products in excess of 500 mL within a 60 day period prior to the first 
dose of the current study 
20. Receipt of blood or blood products within 30 days of screening 
21. Clinically significant history of drug allergy as determined by the Investigator 
22. Unwilling or unable to comply with the study protocol for any reason 


A C H -0 1 4 4 4 7 1  
Ac hilli o n P har mace uticals, I nc.  
Cl i nical Pr ot oc ol A C H 4 7 1-2 0 1 A me n d me nt 2  
0 9  J u ne 2 0 1 7 ( Versi o n 3. 0) 
 
C o nfi de ntial  
P a ge 3 3  of 7 7  
 
 
5 
St u d y Tr e at m e nt( s)  
5. 1   D e s cri pti o n of Tr e at m e nt( s) 
5. 1. 1  St u d y Dr u g  
A C H - 0 1 4 4 4 7 1 will be d ose d as a ta blet f or m ulati o n c o ntai ni n g t he dr u g s u bsta nce,
 
 
5. 2  Tr e at m e nt( s) A d mi ni st er e d  
A C H - 0 1 4 4 4 7 1 ta blets will be a d mi nistere d at o ne of t w o d ose le vels as m ulti ple d oses o ver a peri o d of 
1 4 da ys ( Treat me nt Peri o d), f oll o we d b y a ta p er o ver t he ne xt 7 da ys ( Ta p er Peri o d) t o mi ni mize t he 
p ote ntial a d verse eff ects of a ra pi d s ur ge i n c o m pl e me nt a cti vit y f oll o wi n g dr u g wit h dra wal.  If a p atie nt 
has a ser u m C 3 le vel t hat, at 2 c o nsec uti ve e val uati o ns, is greater t ha n 1 2 5 % t he U L N, or is greater t ha n 
3 × t heir baseli ne ( pr o vi d e d t his is greater t ha n or e q ual t o t he L L N), t he n t he ta per p eri o d will be 
i nitiate d bef ore c o m pleti o n of 1 4 da ys of d osi n g.  I n or der t o e ns ure t hat a n earl y ta per is i m ple me nte d 
w he n a p pr o priate, it is i m p orta nt t hat i n vesti gat ors recei ve a n d re vie w C 3 le vels i n a ti mel y f as hi o n.  
T he d osi n g re gi me n f or Gr o u p 1 is descri be d i n T a ble  1. 
T a bl e  1. 
D o s e L e v el s f or Gr o u p 1  
St u d y D a y  
D ose  
Treat me nt P eri o d ( Da ys 1 -1 4)  
1 0 0  m g TI D  
Da ys 1 5, 1 6, 1 7 ( T a per Da ys 1, 2, 3) 1 
1 0 0  m g BI D  
Da ys 1 8, 1 9 ( T a per Da ys 4, 5)  
5 0  m g BI D  
Da ys 2 0, 2 1 ( T a per Da ys 6, 7)  
5 0  m g Q D  
1  
If t he ta per is i nitiate d bef ore 1 4 da ys of d osi n g, f oll o w t his sc he d ule starti n g wit h T a per Da y 1 o n t he first da y of t he 
ta per. 
 
T he d ose a n d ta p er sc h e d ule f or Gr o u p 2 will be deter mi ne d bas e d o n data fr o m Gr o u p 1, wit h a 
ma xi m u m p ossi ble d ose of 2 0 0 m g TI D f oll o we d b y a 7 d a y ta per. 
5. 3   S el e cti o n of Ti mi n g a n d D o s e f or E a c h P ati e nt 
Patie nts will ta ke A C H - 0 1 4 4 4 7 1 ta blets t hree ti mes dail y ( TI D): a d os e i n t he m or ni n g, a sec o n d d os e 
8 h o urs later, a n d a t hir d d ose 8 h o urs after t he sec o n d d ose.  D oses s h o ul d be ta ke n at a p pr o xi matel y t he 
same ti me eac h d a y a n d as cl ose as p ossi ble t o 8  h o urs a part.  Patie nts s h o ul d be i nstr ucte d t o fi nis h a 
m o derate f at meal or s n ac k wit hi n 1 5  mi n utes pri or t o d osi n g wit h A C H- 0 1 4 4 4 7 1.  Water i nta ke is n ot 
restricte d.  If a d ose is misse d, it s h o ul d be ta ke n wit hi n 4  h o urs of t he ori gi nall y sc he d ul e d ti me.  After 
4 h o urs, t he misse d d ose s h o ul d be s ki p pe d.  I n eit her cas e, t he ne xt d ose s h o ul d be ta ke n acc or di n g t o 
t he ori gi nal d osi n g sc h e d ule.  
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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 patients on how to take their study medication at home between 
visits.  Patients will be instructed to fast for at least 8 hours and to 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.  Patients should be instructed to finish a moderate fat meal or snack 
within 15 minutes prior to dosing with ACH-0144471.  Patients will be required to bring back their 
study drug at each visit so that study site personnel may perform drug accountability. 
5.3.2 Home Dose Administration Instructions 
Patients should be instructed to finish a moderate fat meal or snack within 15 minutes prior to dosing 
with ACH-0144471.  Patients should also take their medication such that doses are as close as possible 
to 8 hours apart. 
Patients should be instructed to keep their study medications at room temperature. 
5.4 Method of Assigning Patients to Treatment Groups 
All patients will receive ACH-0144471.  Each patient will be assigned a sequential subject identification 
number within the study site. 
The first two patients will form Group 1, and will receive ACH-0144471 at a dose of 100 mg TID.  
Group 2 will be initiated upon confirmation that dosing was well-tolerated in Group 1 (based on 
Group 1 safety data through at least Day 28), and may include up to 8 patients.  The dose for Group 2 
will be selected based on the data from Group 1, but will not exceed 200 mg TID.  
5.5 Restrictions 
5.5.1 Prior Therapy 
Patients may not have received another investigational agent within 30 days or 5 half-lives of the 
investigational agent prior to dosing with ACH-0144471, whichever is greater.  Patients may not have 
received eculizumab within 75 days prior to dosing with ACH-0144471.  Patients may not have received 
tacrolimus or cyclosporine within 2 weeks prior to dosing with ACH-0144471. 
5.5.2 Concomitant Therapy 
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].  
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 
patient’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 folic acid, and/or erythropoiesis-stimulating agents is permitted if on 
stable doses for at least 4 weeks prior to start of study drug. 
• 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 steroids is permitted if on stable doses for at least 3 months prior to 
start of study drug. 
• Concomitant administration of mycophenolate mofetil (MMF) may be considered based on 
emerging data for ACH-0144471, but may require reduction of MMF dose and/or measurement of 
mycophenolic acid (MPA) levels. 
• Oral, injectable, implantable, transdermal, or intravaginal hormonal therapies are allowed for either 
contraception or hormonal replacement therapy. 
• Concomitant administration of angiotensin converting enzyme (ACE) inhibitors, angiotensin 
receptor blockers (ARBs), loop diuretics, and thiazide diuretics should be allowable since these 
drugs are renally cleared, and it is unlikely that ACH-0144471 will interfere with their 
pharmacokinetic disposition. 
• If it is necessary to treat a fever (see Appendix 3), 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. 
 
5.5.3 Fluid and Food Intake 
Patients should be instructed to finish a moderate fat meal (~550 calories with approximately 25% - 35% 
of the calories from fat that should be entirely consumed within 30 minutes) or snack within 15 minutes 
prior to dosing with ACH-0144471.  Patients should also take their medication such that doses are as 
close as possible to 8 hours apart. 
5.5.4 Patient Activity and Other Restrictions 
Patients should refrain from heavy exercise 24 hours prior to and after having blood drawn for safety 
laboratory evaluations.  Walking and light exercise are acceptable. 
5.5.5 Contraception 
All male participants who have not had a vasectomy must use effective contraception from the first day 
of dosing (Day 1) through at least 3 months after their last dose of study drug.  Effective contraception 
for males is defined as abstinence, or use of a condom plus one of the following for a female partner: 
• 
Intrauterine device or barrier (e.g., occlusive cap) 
• 
Oral, injectable, implantable, transdermal, or intravaginal hormonal contraceptive 
Male patients must agree to refrain from sperm donation from the first day of dosing (Day 1) until at 
least 3 months after their last dose of study drug. 
Female patients of non-childbearing potential, as defined by one of the following, need not employ a 
method of contraception: 


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Clinical Protocol ACH471-201 Amendment 2 
09 June 2017 (Version 3.0) 
 
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• 
Surgical sterilization by hysterectomy, bilateral salpingo-oophorectomy or oophorectomy, at 
least 6 months prior to dosing 
• 
Postmenopausal with amenorrhea for at least 1 year prior to dosing and FSH serum levels 
consistent with postmenopausal status 
Female patients of child-bearing potential must have a negative serum pregnancy test at screening and a 
negative urine pregnancy test at baseline, and must agree to the use of effective contraception from the 
date of screening to 3 months after their last dose of study drug.  Effective contraception for females is 
defined as abstinence or use of a condom for the male partner plus one of the following: 
• Intrauterine device or barrier (e.g., occlusive cap) 
• Oral, injectable, implantable, transdermal, or intravaginal hormonal contraceptive  
• Bilateral tubal ligation or fallopian tube inserts  
 
5.6 Treatment Compliance 
Treatment compliance assessments shall be performed at each visit.  Patients will be required to bring 
their supply of ACH-0144471 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. 
Patients will record the time they take each daily dose of ACH-0144471 and will 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 patient directly.  
5.7 Packaging and Labeling 
Labels for ACH-0144471 tablets will include, at a minimum, the following information, in English: 
• 
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 Statement such as “For Clinical Trial Use Only” or “Caution: New Drug—Limited by 
Federal (or United States) law to investigation use” or similar statements. 
 


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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.  Patients should be instructed to keep their 
study medications at room temperature. 
Patients will be required to bring back their study drug at each 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 patient 
dispensing records and returned or destroyed drug.  Dispensing records will document quantities 
received from Achillion Pharmaceuticals, Inc. (or designee) and quantities dispensed to patients, 
including lot number, date dispensed, patient identifier number, patient 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, Inc. 
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, Inc. requirements for disposal, 
arrangements will be made between the site and Achillion Pharmaceuticals, Inc. or its representative, for 
destruction or return of unused study drug supplies. 


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Clinical Protocol ACH471-201 Amendment 2 
09 June 2017 (Version 3.0) 
 
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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 
The PI or designee is responsible for administering and obtaining freely given consent, in writing, before 
entering the patient into the study and performing any study-related procedures.  Each patient 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 patients being accepted into the study.  Because participation in the patient-reported 
outcomes interview (Section 6.16) is encouraged but not required, patients will be asked to provide a 
separate informed consent for this activity. 
6.2 Medical History 
At Screening, the PI or designee will interview each patient and obtain a complete medical and 
medication history to determine whether the patient meets the eligibility criteria.  The history should 
include the specific type of C3 glomerulopathy (for C3G patients), date of diagnosis of C3G or IC-
MPGN, 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 30 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.  The history 
should also include the results of any genetic testing related to the disease, and a full vaccination history.  
The medical/medication history will be reviewed at each visit and at the Day 49 follow-up visit, as 
applicable and as is outlined in the Schedule of Assessments (Appendix 1).  The medical history must be 
recorded in the patient’s source documents and in the patient’s CRF. 
6.3 Review of Historical Renal Biopsy 
For each patient, the diagnosis of C3GN, DDD, or IC-MPGN must be confirmed by the study’s central 
pathologist(s).  The site will need to obtain renal biopsy slides for each patient, and provide them to the 
designated central pathology laboratory.  Digitally scanned slides are also acceptable if the quality is 
adequate.  Representative diagnostic slides should be provided and should include hematoxylin and 
eosin (H&E), periodic acid-Schiff (PAS), methenamine silver, and trichrome stains.  If 
immunohistochemistry has been performed on paraffin sections those slides should also be submitted.  
In addition, electron microscopy (EM) images should be sent and also images of immunofluorescence 
where available.  A copy of the full biopsy report should also be provided.  All information should be 
provided in an anonymized fashion.  Detailed instructions will be provided in a separate manual. 
6.4 Vaccination 
As discussed in Section 6.2, a full vaccination history will be gathered.  The need for vaccinations 
against Neisseria meningitidis, serogroups A, C, Y, and W135, Streptococcus pneumoniae, and 
Haemophilus influenzae will be evaluated independently, as discussed in the following sections.  Any 
patients who do not have a sufficient history of these particular vaccines will receive their vaccines 
during the screening period.  For any vaccines given as part of this study, full identifying information, 


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Clinical Protocol ACH471-201 Amendment 2 
09 June 2017 (Version 3.0) 
 
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including the brand, should be recorded in the patient’s CRF.  The vaccination schedule for each is 
provided in Table 2, Table 3, and Table 4.  The brand of vaccine is not specified to allow flexibility 
based on the available of vaccines in different geographic regions.  Note, however, that it is important 
that the administered meningococcal vaccine is a quadrivalent ACWY conjugate vaccine and not a 
monovalent serogroup C vaccine, or serogroup B vaccine.  In addition, it should be noted that the 
administered Streptococcus pneumoniae vaccine should be the 13-valent vaccine, and not the 23-valent 
vaccine.  Samples will be collected during at the times indicated in the Schedule of Assessments 
(Appendix 1) to evaluate patient response to the vaccines. 
Table 2. 
Vaccination Schedule for Neisseria meningitidis, Serogroups A, C, Y, and 
W135 
 
Not vaccinated or 
vaccination status 
unknown 
Received 1 dose of 
vaccine previously 
Received 2 doses of 
vaccine >5 years ago 
Received 2 doses of 
vaccine <5 years ago 
At least two 
weeks prior to 
dosing with 
ACH-0144471  
Administer 1 dose of 
vaccine  
Administer 1 dose of 
vaccine  
Administer 1 dose of 
vaccine 
No action required 
prior to ACH-0144471 
dosing 
 
Table 3. 
Vaccination Schedule for Streptococcus pneumoniae 
 
Streptococcus pneumoniae 
 
Not vaccinated or 
vaccination 
status unknown 
Vaccinated 
>2 years ago with 
23-valent 
conjugate vaccine 
Vaccinated 
<2 years ago with 
23-valent 
conjugate vaccine 
Vaccinated 
>5 years ago with 
13-valent 
conjugate vaccine 
Vaccinated 
<5 years ago with 
13-valent 
conjugate vaccine 
At least two 
weeks prior to 
dosing with 
ACH-0144471 
Administer 1 dose 
of 13-valent 
conjugate S. 
pneumoniae 
vaccine 
Administer 1 dose 
of 13-valent 
conjugate S. 
pneumoniae 
vaccine 
No action required 
Administer 1 dose 
of 13-valent 
conjugate S. 
pneumoniae 
vaccine 
No action required 
 
Table 4. 
Vaccination Schedule for Haemophilus influenzae 
 
Not vaccinated or 
vaccination status 
unknown 
Vaccinated >5 years ago 
Vaccinated <5 years ago 
At least two weeks prior to 
dosing with ACH-0144471 
Administer 1 dose of H. 
influenzae vaccine 
Administer 1 dose of H. 
influenzae vaccine 
No action required 
 
6.5 Physical Examination 
A complete physical examination will be conducted by the PI (or designee) at Screening, Day 1, and the 
Day 49 visit.  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 (height and BMI at Eligibility visit only).  Measurements of height and 
weight should be taken with the patients in light clothing or underwear and without shoes. 


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Clinical Protocol ACH471-201 Amendment 2 
09 June 2017 (Version 3.0) 
 
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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).  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 patient’s source documents and in the patient’s CRF as an adverse event. 
6.6 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.  Vital signs may be measured using an automated vital signs monitor, 
although manual measurements of blood pressure are preferred.  All blood pressure measurements 
should be taken on the same arm throughout the study.  Vital sign values, including whether measured 
manually or via an automated monitor, will be recorded in the patient’s source documents and in the 
patient’s CRF. 
6.7 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 site will 
provide each patient with an oral thermometer, and train each patient on its proper use.  In addition, the 
Fever Management Plan (Appendix 3) outlines measures that the site must take to ensure that outside the 
clinic, the patient will be able to promptly identify a fever, and seek emergency medical attention if 
needed.  Any temperature measurement ≥38.0°C, measured either at the clinic or by the patient outside 
the clinic, requires action as outlined in the Fever Management Plan (Appendix 3). 
6.8 Electrocardiography 
The PI or designee will obtain ECG measurements at the times indicated in Appendix 1.  All ECG 
recordings should be 12-lead, and should be performed after the patient has rested quietly for at least 
5 minutes in a supine position 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 place 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 6.17.1 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 patient’s source documents and 
in the patient’s CRF.  Any clinically significant finding must be reported as an adverse event. 


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6.9 Clinical Laboratory Tests 
Blood and urine samples will be collected for safety and pharmacodynamic laboratory evaluation 
according to Table 5 below, at the times listed in Appendix 1.  Patients will be fasted and 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. 
Table 5. 
Clinical Laboratory Tests  
Hematology 
Chemistry 
Urinalysis 
Additional Tests 
at Screening Only 
Other Assessments1 
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) 
Bile Acids2 
Bilirubin (fractionated)3 
Blood urea nitrogen 
(BUN) 
Calcium 
Calculated eGFR4 
Chloride 
C-reactive protein (CRP) 
Creatine kinase5 
Creatinine 
Gamma-glutamyl 
transferase (GGT) 
Glucose6 
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 
Dipstick Analysis 
including: 
- Bilirubin 
- Color 
- Glucose 
- Ketones 
- Leukocytes 
- Nitrite 
- Occult blood 
- pH 
- Protein 
- Specific 
gravity 
- Urobilinogen 
Microscopic 
examination of 
sediment7 
Spot Urine sample, 
including: 
- Albumin 
- Creatinine 
- Albumin: 
creatinine ratio 
HCV Ab 
HbsAg 
HIV Ab 
FSH8 
Serum Pregnancy 
test9 
Urine drug screen10 
Sample for 
potential genetic 
biomarker testing 
(white blood 
cells)11 
 
Complement 
Biomarkers: 
- AH50 
- AP Wieslab 
- AP Hemolysis 
- Ba 
- Bb 
- C3 
- C4 
- CH50 
- fB 
- fD 
- sC5b-9 
PT/PTT/INR 
Plasma/Serum/Urine 
samples for 
additional potential 
non-genetic 
biomarker testing11 
Urine pregnancy test9 
Samples for 
assessment of patient 
response to vaccines 
1 
Check the Schedule of Assessments (Appendix 1) for specific times when these tests should be done. 
2 
Days 1, 14, and 49 only.  
3 
Fractionate and obtain measurements of direct and indirect bilirubin for all patients.  If indirect bilirubin levels are 
> ULN at Screening but ALT and AST are normal, test for Gilbert’s syndrome. 
4 
Provide eGFR based on MDRD equation for patients ≥18 years of age, and based on the Schwartz equation for patients 


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<18 years of age. 
5 
Perform at screening, and then subsequently only as a reflex if AST > ULN.  
6 
If glucose is > ULN, reflexively test HbA1c 
7 
Only if occult blood, protein, or leukocytes present on dipstick analysis. 
8 
FSH for postmenopausal women at screening only.   
9 
Serum pregnancy test at Screening 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. 
10 Urine drug screen will be measured at screening.  For all patients, the urine drug test should include, at a minimum, 
cotinine, amphetamines, barbiturates, cocaine metabolites, opiates, benzodiazepines, and cannabinoids.  
11 See Section 6.11.2 for a description of tests that may be conducted with these samples.  
 
6.10 Pregnancy Testing 
All females of childbearing potential (as determined at screening) will have a serum pregnancy test 
during screening, and urine pregnancy tests on Day 1 (prior to the start of drug administration) and again 
every 4 weeks for the duration of the study including follow-up.  A final urine pregnancy test will be 
done at the last study visit.  On Day 1, the urine pregnancy test must be done before dosing and be 
negative to begin dosing.   
For female patients of childbearing potential who require vaccinations (see Section 6.4), they must also 
have a negative urine pregnancy test on the days of vaccination, before any vaccine or booster is 
administered.  
Any positive urine pregnancy test will be confirmed by a serum pregnancy test. 
6.11 Sample Collection, Storage, and Shipping 
6.11.1 Blood Collection for Complement Assays (AH50, AP Wieslab, AP Hemolysis, Ba, 
Bb, C3, C4, CH50, fB, fD, and sC5b-9) 
AH50, AP Wieslab, AP hemolysis, Ba, Bb, C3, C4, CH50, fB, fD, and sC5b-9 assays will be run for all 
patients at the time points indicated in Appendix 1, Table 7 and Table 8.  Depending on the type of 
complement test, either serum or plasma will be used.  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.  Specific instructions for sample 
collection, processing, and shipping will be provided in a separate laboratory manual. 
6.11.2 Blood collection for Genetic and Additional Non-genetic Complement-associated 
Biomarker Testing  
Serum/plasma samples will be collected and stored according to the schedule in Appendix 1 for possible 
assessment of additional non-genetic complement-associated biomarkers.  Specific evaluations that may 
be conducted with the non-genetic samples include: 
• Concentrations of other complement components, their split and terminal products, and complement 
regulators in serum/plasma: C3a, C5, C5a, fH, factor I (fI), iC3b, and properdin 
• C3 convertase activity in serum 


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• The existence of autoantibodies to complement components and/or regulators: fH and C3 nephritic 
factor 
• Serum samples will be collected to assess patient response to vaccinations at various time points in 
the study 
• Concentrations of additional complement components, their split and terminal products, and 
complement regulators in blood samples may be measured if deemed necessary 
• Western blot or other methods that specifically detect full-length C3 
White blood cells will be collected according to the schedule in Appendix 1 and stored for possible 
assessment of the genetic profiles* of selected complement components and regulators: 
• C3 
• Complement Factor H Related – 5 gene (CFHR-5) 
• fB  
• fD 
• fH 
• fI 
• Membrane Co-Factor Protein (MCP) 
• Thrombomodulin gene (THBD) 
 
*Note: if historic genetic work-up is not available in dosed patients, genetic profiling may be conducted 
during the study.   
Lastly, serum/plasma/WBCs samples may be collected and retained for possible research use.  All 
genetic samples will be stored for a maximum of 3 years.  
Depending on the type of complement test, either serum or plasma will be used.  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.  Specific 
instructions for sample collection, processing, and shipping will be provided in a separate laboratory 
manual.  As an exploratory approach, the level of intact C3 in the blood will be measured through 
Western blot or other methods that specifically detect full-length C3 in a subject before and during 
treatment.  The data might have an effect on patient selection and efficacy determination. 
6.11.3 Urine Collection for Complement Components 
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, including:  
• Ba, Bb 
• C3a 


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• C5 
• C5a 
• sC5b-9 
• fB 
• fD 
• fH 
• Properdin 
Concentrations of additional complement components, their split and terminal products, and 
complement regulators in urine samples may be measured if deemed necessary.  Specific instructions for 
sample collection, processing, and shipping will be provided in a separate laboratory manual. 
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). 
6.11.4 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. 
6.11.5 Blood Volumes 
Approximate blood volumes to be drawn are detailed in Table 6 below.  The total planned blood volume 
to be collected per individual is 863.9 mL.  This does not include discarded blood from pre-collection 
used to flush catheters.  The discarded volume is not expected to exceed 30 mL.  Unanticipated 
additional blood may be collected throughout the study for such things as safety monitoring and 
additional PK or PD assessments, should it be necessary. 


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Table 6. 
Approximate Total Blood Volumes 
TESTS 
Screening 
(mL) 
Treatment/Taper 
(to Day 28) 
(mL) 
Follow-up 
(Post Day 28) 
(mL) 
Total 
Volume 
(mL) 
Chemistry 
8.5 
93.5 
85 
187 
Hematology 
2 
22 
20 
44 
Coagulation 
2.7 
13.5 
2.7 
18.9 
Serum C3 
2 
46 
20 
68 
Plasma C3, fB, fH, properdin, iC3b 
2 
46 
20 
68 
AP Weislab, AP hemolysis 
3.5 
66.5 
35 
105 
Bb 
2 
38 
20 
60 
Ba, sC5b-9 
3 
33 
27 
63 
C4, AH50, CH50, fD 
5 
20 
45 
70 
Pt Response to Vaccine 
3.5 
10.5 
3.5 
17.5 
PK 
 
54 
0 
54 
Ab to fH 
2 
0 
2 
4 
C3Nefs 
3 
0 
3 
6 
C5, C5a, C3a 
 
16 
4 
20 
C3 Convertase, fI 
3.5 
35 
31.5 
70 
Genetic Assessment 
8.5 
0 
0 
8.5 
TOTALS 
51.2 
494 
318.7 
863.9 
 
6.12 Dispensing Study Drug 
ACH-0144471 will be supplied as 50, 75, and 100 mg tablets.  At each visit, the site will dispense study 
drug as required to provide patients with sufficient study drug for dosing until their next clinic visit. 
6.13 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). 
6.14 Pharmacokinetic Assessments 
Serial blood samples will be collected on Days 1 and 7, at the times indicated in the Schedule of 
Assessments (Appendix 1) to determine plasma and/or serum concentrations of ACH-0144471.  Both 
free and total drug concentrations will be measured.  Concentrations of ACH-0144471 metabolites may 
also be measured.  Multiple-dose PK parameters of ACH-0144471, including tmax, Cmax, and AUC0-tau 
will be determined.  Single trough PK samples will be taken at other time points.  
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 patient and study day. 
6.15 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, WBCs, and urine collected 


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during the study with the assays outlined in Sections 6.11.1, 6.11.2, and 6.11.3.  Additional information 
on sample collection and shipping instructions will be provided in a separate laboratory manual. 
The primary pharmacodynamic (PD) assessment is C3 concentration in blood which will be extensively 
monitored throughout the study.  Blockage of C3 convertase formation by inhibition of fD presumably 
reduces the consumption of C3 in C3G and IC-MPGN patients, resulting in an elevated C3 level from 
the baseline.   
Pharmacodynamics will be evaluated ex vivo using serum collected during the study with the AP 
Wieslab ELISA and AP hemolysis assay.  Additional functional assays are AH50 and CH50 to 
qualitatively evaluate the effect of ACH-0144471 on AP and CP activity.   
Additional exploratory complement biomarkers that might be evaluated are listed in Section 6.11.1. 
Blood and urine samples will also be collected and stored for possible additional exploratory non-
genetic complement biomarker testing (see Section 6.11.2 and 6.11.3).  C3 convertase activity, the 
presence of autoantibodies to complement components or regulators, and the concentrations of multiple 
complement components and their split and terminal products in non-genetic serum/plasma 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 6.11.2) for possible exploration of the understanding of the 
underlining etiology of C3G and IC-MPGN and any correlation with patients’ response to 
ACH-0144471.   
6.16 Patient-Reported Outcomes Assessment Interview 
Patients enrolled in the trial will be interviewed by an independent outcomes researcher chosen by the 
Sponsor during the screening period.  Each patient will be interviewed once.  Interviews will be 
conducted by phone using a semi-structured study-specific guide.  Each interview will last 
approximately 30 minutes, and will be conducted by a trained psychologist/researcher, skilled in 
qualitative research.  Interviews will be audio-recorded, transcribed, and analyzed using validated 
qualitative software.  In order to collect as much information as possible about the impact of the disease 
on patients’ well-being, participation in the interview will be available to all screened patients, whether 
or not they qualify or choose to participate in the study.  While completion of the interview is 
encouraged, it is not required, and eligible patients may participate in all other study activities whether 
or not they agree to the interview.  
6.17 Adverse Events Assessments 
6.17.1 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 


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combination with another drug) and with any route of administration, formulation, or dose, including an 
overdose. 
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 the final follow-up visit will be considered 
treatment-emergent.  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 6.17.8). 
• 
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 the following criteria: 
• 
Associated with accompanying symptoms; and/or, 
• 
Require medical/surgical intervention; and/or, 
• 
Lead to a change in study drug dosing or discontinuation from the study; and/or 
• 
Lead to significant additional concomitant drug treatment, or other therapy; and/or, 
• 
Lead to any of the outcomes included in the definition of a serious adverse event; and/or, 


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• 
Are considered clinically significant by the investigator. 
 
Whenever possible, the etiology of the abnormal findings (rather than the abnormal finding(s) itself) 
should be documented as the adverse event.  Repeated additional tests and/or other evaluations 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 adverse event. 
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 adverse events, if the condition(s) was (were) 
known before the start of the study treatment and documented in the patient’s medical record.  In the 
latter case, the condition should be reported as medical history. 
All patients 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. 
6.17.2 Criteria for Assessing Seriousness 
All AEs must be evaluated as potential SAEs.  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 patient 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 adverse 
event 
 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 adverse event or with the worsening of the 
pre-existing condition 
− Observation/same day/ambulatory procedure 


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• 
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 patient who was exposed to the study drug) 
• 
Is an important medical event or reaction 
 
6.17.3 Documentation and Reporting of Adverse Events 
AEs, including TEAEs, may be spontaneously reported by a patient or his/her representative, or elicited 
during questioning and examination of a patient.  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, intensity, 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 patient’s medical record.  The relationship to study 
drug or study procedures should be assessed using the definitions in Section 6.17.7. 
6.17.4 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). 
6.17.5 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 
patient provides informed consent through the 28 days following the patient’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 


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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), the PI (or designee) should promptly 
document and report the event to Achillion Pharmaceuticals. 
6.17.6 Severity and Grading of Adverse Events 
The intensity of an adverse event will be graded according to the CTCAE Adverse Event Severity 
Grading Table (Appendix 2) [21].  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 patient. 
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. 
6.17.7 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 adverse event: 
• 
Unrelated: In the opinion of the investigator, there is no association between the study drug and the 
adverse event. 
• 
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’. 


A C H -0 1 4 4 4 7 1  
Ac hilli o n P har mace uticals, I nc.  
Cl i nical Pr ot oc ol A C H 4 7 1-2 0 1 A me n d me nt 2  
0 9  J u ne 2 0 1 7 ( Versi o n 3. 0) 
 
C o nfi de ntial  
P a ge 5 1  of 7 7  
 
 
6. 1 7. 8  Pr e g n a n c y  
A n y pre g na n c y, i n cl u di n g f e male part ner pre g na n cies of male p atie nts t hat occ urs or b ec o mes c o nfir me d 
d uri n g a cli nical st u d y (ti me fra mes o utli ne d i n Secti o n  6. 1 7. 5 ) m ust be re p orte d t o Ac hilli o n ( or 
desi g nee) wit hi n o ne b usi ness da y of first k n o wle d ge of t he pre g na nc y.  T he re p ort s h o ul d be pr o vi de d 
o n t he pre g na n c y f or m.  W hile pre g na n c y itself is n ot c o nsi dere d a n A E, f or t he p ur p oses of trac ki n g, it 
s h o ul d be ca pt ure d as a n A E as well as re p orte d o n t he pre g na n c y f or ms. 
All pre g n a ncies s h o ul d b e f oll o we d a n d disc uss e d wit h t he me dical m o nit or as f oll o ws: 
•  
T he i n vesti gat or will f oll o w u p wit h t he patie nt e v er y 3  m o nt hs t hr o u g h o ut t he pre g na n c y a n d 
re p ort t o Ac hilli o n ( or desi g nee) usi n g t he pre g n a nc y f or ms. 
•  
F oll o wi n g t he esti mate d date of deli ver y, t he i n vesti gat or  will f oll o w u p wit h t he patie nt a n d 
re p ort t o Ac hilli o n ( or desi g nee) usi n g t he pre g n a nc y f or ms. 
•  
T he fi nal o utc o me of t h e deli ver y will be re p orte d t o Ac hilli o n ( or desi g n ee) usi n g t he pre g na n c y 
f or ms. 
A n y S A Es r elate d t o t he pre g na nc y (see b el o w), or occ urri n g d uri n g t he patie nt’s pre g na n c y, or after 
deli ver y, m ust be d oc u m e nte d a n d r e p orte d t o A c hilli o n ( or desi g nee) o n b ot h t he S A E F or m a n d t h e 
pre g na nc y f or ms.  S A Es occ urri n g i n t he c hil d (e. g., c o n ge nital a n o malies or ot her c o n diti o ns prese nt at 
birt h, w het her ge n eticall y i n herite d or occ urri n g i n uter o) m ust als o be d oc u me nte d o n b ot h t he S A E 
f or m a n d t he pr e g na nc y f or ms. 
Re p orta ble S A Es ass oci ate d wit h pre g na nc y i n cl u de, b ut are n ot li mite d t o: 
•  
Pre g n a nc y l osses ( e. g., s p o nta ne o us a b orti o n, late fetal deat h, electi ve ter mi nati o n) 
•  
Lif e -t hreate ni n g de vel o p me nts (e. g., place ntal a br u pti o n, fetal distress) 
•  
C o n ge nital a n o malies  
•  
Ne o natal or mat er nal d eat h, or 
•  
A n y e ve nt res ulti n g i n mater nal or n e o natal h os pit alizati o n/ pr ol o n ge d h os pitalizati o n. 
 
6. 1 7. 9  R e p orti n g S eri o u s A d v er s e E v e nt s  
Ac hilli o n P har mace uticals, I n c. has r e q uire me nts f or t he e x pe dite d re p orti n g of s afet y e v e nts meeti n g 
s pecific r e q uire me nts t o w orl d wi de re g ul at or y a ut h orities; t heref ore, Ac hilli o n P har mace uticals m ust be 
n otifie d i m me diatel y r e gar di n g t h e occ urre n ce of a n y S A E a n d/ or pre g na n c y t h at occ urs d uri n g t h e 
st u d y (ti me fr a mes o utli ne d i n Secti o n 6. 1 7. 5 ).  
T he pr oce d ures f or re p orti n g all S A Es a n d/ or pre g na ncies, re gar dless of ca usal relati o ns hi p, are as 
f oll o ws: 
S A E  
•  
Rec or d t he S A E o n t he S A E re p orti n g f or m pr o vi de d b y Ac hilli o n ( o r desi g nee) 
•  
Se n d t he S A E f or m t o b ot h 
( via fa x) A N D t o Ac hilli o n P har mace uticals ( via e mail) wit hi n 
2 4 h o urs of bec o mi n g a w are of t h e S A E. 
C CI


A C H -0 1 4 4 4 7 1  
Ac hilli o n P har mace uticals, I nc.  
Cl i nical Pr ot oc ol A C H 4 7 1-2 0 1 A me n d me nt 2  
0 9  J u ne 2 0 1 7 ( Versi o n 3. 0) 
 
C o nfi de ntial  
P a ge 5 2  of 7 7  
 
 
Pre g n a nc y  
•  
Rec or d t he pr e g na nc y o n t he pre g na n c y f or m pr o vi de d b y A c hilli o n ( or desi g nee) 
•  
Se n d t he pre g na n c y f or m t o b ot h  
 ( via fa x) A N D t o Ac hilli o n P har mace uticals ( via e mail) 
wit hi n o ne b usi ness da y of bec o mi n g a w are of t he pre g na nc y. 
All c o ntact i nf or mati o n is pr o vi de d bel o w. 
S A E C O N T A C T  
 P h ar m ac o vi gil a nce 
 
F a x: 
 P h o ne: 
 
S A E H otli ne, f or q uesti o ns a b o ut c o m pleti n g t he f or ms: 
P h o ne: 
 
 
Ac hilli o n P h ar m ace utic als  
 
 
F or f atal or life -t hreate ni n g e v e nts, als o fa x c o pies of h os pital disc har ge re p orts, a ut o ps y re p orts a n d 
ot her d oc u me nts, as a p pli ca ble.  A c hilli o n P har mace uticals ma y re q uest a d diti o nal i nf or mati o n fr o m t he 
PI t o e ns ur e t he ti mel y c o m pleti o n of acc urate safet y re p orts.  
A n y f oll o w - u p i nf or mati o n c ollecte d o n a n y re p ort of a n S A E a n d/ or pre g n a nc y m ust be re p orte d b y t he 
i n vesti gat or wit hi n o ne b usi ness da y. 
A c o p y of t he s u b mitte d S A E f or m m ust be retai n e d o n file b y t he i n vesti gat or.  If re q uire d, t he 
i n vesti gat or m ust s u b mit c o pies of t he S A E f or ms t o t he I R B or E C a n d retai n d oc u me ntati o n of t hes e 
s u b missi o ns i n t he site st u d y file. 
I n t he cas e of a me di cal e mer ge nc y, please use t h e c o ntact pr o vi de d o n t he title pa ge of t he pr ot o c ol. 
6. 1 7. 1 0  I n v e sti g at or R e p orti n g R e q uir e m e nt s f or S A E s 
Ac hilli o n is res p o nsi ble f or e ns uri n g t hat I n vesti gat ors a n d ce ntral E Cs/I R Bs are n otifie d of all A Es t hat 
are seri o us, u ne x pecte d a n d c o nsi dere d relate d, pr o ba bl y relate d, or p ossi bl y relate d t o t he 
i n vesti gati o nal pr o d u ct.  A C R O ma y be d esi g nate d t o perf or m t his n otificati o n.  T his n otificati o n will 
be i n t he f or m of a M e d Watc h/ CI O M S re p ort.  T he PI will n otif y t he l ocal E Cs or I R Bs as per E C or 
I R B re q uire me nts.  U p o n recei vi n g s uc h n otices, t he PI m ust re vie w a n d retai n t he n otice.  T he S p o ns or, 
i n vesti gat or, a n d E C or I R B will deter mi ne if t he i nf or me d c o nse nt re q uires re visi o n.  T he PI s h o ul d als o 
c o m pl y wit h E C or I R B pr oce d ur es f or re p orti n g a n y ot h er safet y i nf or mati o n. 
6. 1 8   C o n c o mit a nt M e di c ati o n A s s e s s m e nt s 
Details of all p ri or ( wit hi n 3 0 da ys of t he scree ni n g e v al uati o n) a n d c o nc o mita nt me dicati o n use, 
i ncl u di n g all me dicati o ns a d mi nistere d f or t he treat me nt of A Es, will be rec or de d i n t he patie nt’s C R F at 
eac h st u d y visit.  
P P D
P P D
C CI
C CI
P P D
P P D


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6.19 Monitoring Patient Safety 
The safety of patients will be monitored by Investigators and by a medical monitor (or designee) at 
Achillion Pharmaceuticals, Inc. on an ongoing basis while patients are receiving ACH-0144471.  
Additionally, a Fever Management Plan (Appendix 3) has been developed for this study to enable rapid 
assessment, detection and treatment of any potential serious infection. 
6.20 Removal of Patients from the Trial or Study Drug 
A patient is free to withdraw from the study at any time without jeopardizing future medical care.  In 
addition, the PI (or designee) may decide, for reasons of medical prudence or patient noncompliance, to 
discontinue dosing in a patient.  The PI should also stop dosing in any patient 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 patient.  When dosing is terminated, study participation is not necessarily 
immediately terminated.  Instead, whenever possible, the patient 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 patient 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 patient’s best interest to 
continue the study  
• 
Patient request to discontinue for any reason 
• 
A female patient becomes pregnant or wishes to become pregnant 
• 
Patient noncompliance 
• 
Discontinuation of the study at the request of Achillion Pharmaceuticals, Inc., regulatory agency, 
or Ethics Committee or IRB 
• 
Any other condition or circumstance that would jeopardize the welfare of the patient if s/he were 
to continue in the trial 
The reason for any patient’s discontinuation and the date of withdrawal will be recorded in the patient’s 
CRF.  The patient’s CRF, which will be completed up to the point of withdrawal, will be retained for the 
Sponsor. 


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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 study period, physical examinations, assessment of vital signs, ECG measurements, all 
required safety laboratory testing, and collection of blood and urine samples for PK and PD evaluation 
will be performed at various time points through the study.  There will be multiple follow-up visits after 
the last dose of study drug. 
During the periods when multiple assessments occur at the same time, they should be conducted in the 
following order: 
• 
ECG and vital signs prior to blood sampling 
• 
PK samples should be taken at the specified times, within the windows described in Table 8 
• 
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 patient’s CRF. 
7.1 Screening Period 
7.1.1 Eligibility Visit (Days –45 to -1) 
Prospective patients should be screened within 45 days of first administration of study drug.  During the 
screening period, informed consent will be obtained and patient eligibility determined according to the 
criteria specified in this protocol.  The procedures listed in the Schedule of Assessments (Appendix 1) 
must be performed and documented.  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 patient’s medical history 
should be reviewed as described in Section 6.2, and a complete physical examination should be 
conducted as described in Section 6.5.  In addition, the patient’s historical renal biopsy will be reviewed 
by a central pathologist for confirmation of the diagnosis (see Section 6.3).  Patients who meet all 
eligibility criteria will be educated about the restrictions on concomitant medication usage and other 
substances. 
All evaluations required for eligibility determination must be completed before the patient is accepted 
into the study for dosing.  If the patient is unable to receive study drug within 45 days of screening the 
patient may be re-screened once. 
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, Inc. 
Medical Monitor (or designee). 
Exemptions to inclusion and exclusion criteria are discouraged, but can occasionally be considered at 
the discretion of Achillion Pharmaceuticals, Inc. Medical Monitor or designee. 
Once the patient is entered into the study, all protocol deviations should be reported to Achillion 
Pharmaceuticals, Inc. for review by the Medical Monitor or designee.  The Medical Monitor (or 


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designee) will assess all protocol deviations.  Any protocol deviation which is deemed to impact patient 
safety or data integrity will be considered a significant protocol deviation.  The rationale for considering 
a protocol deviation significant will be documented. 
7.1.2 Vaccination Visit (If Required; Day -14 or Earlier) 
As part of the screening process, patients will be evaluated to determine whether vaccination against N. 
meningitidis, S. pneumoniae, or H. influenzae is required.  The criteria for evaluation and the specific 
timing of any required vaccinations are described in Section 6.4.  For patients that require vaccinations, 
all other screening procedures must be completed, and patients must qualify for the study prior to 
vaccinations being administered.  Female patients of childbearing potential must have a negative urine 
pregnancy test on the day of vaccination, before any vaccine or booster is administered.  
7.1.3 Patient Reported Outcomes Assessment Interview 
Each patient will be interviewed once by telephone by an independent outcomes researcher selected by 
the Sponsor during the Screening period.  A Contact Order Form including patient contact details will be 
completed and sent to a dedicated independent unit in charge of scheduling and setting up the interview.  
The interview will be conducted by a trained, experienced interviewer in the local language and will last 
approximately 30 minutes.  The interviewer will follow a semi-structured interview guide, specifically 
developed for the study and the time-point (provided in a separate manual).  The guide summarizes the 
objectives of the study, and the methodology and process of the interview.  It contains the themes to be 
covered during the interview.  Amongst those, the main themes that will be explored will include 
patients’ experience of the disease and the disease trajectory, in order to document the symptoms and 
manifestations, and its impact on everyday lives. 
While completion of the interview is encouraged, it is not required, and eligible patients may participate 
in all other study activities whether or not they agree to the interview. 
7.2 Treatment Period 
During the Treatment Period, physical examinations, assessment of vital signs, ECG measurements, 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.   
Patients should be instructed to fast prior to coming to a clinic visit and to bring their study drug with 
them for administration at the site. 
At clinic visits, patients should be instructed how to take their medication at home and record the time 
they took it.  The first dose of the day should be taken at the same time each morning, the second dose 
taken approximately 8 hours later, and a third dose 8 hours after the second.  Patients should be 
instructed to finish a moderate fat meal or snack within 15 minutes prior to dosing with ACH-0144471.  
Dosing should be at the same time(s) each day.  Patients should record the time they take their doses at 
home.  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.  
Patients should be instructed to store their study drug at room temperature.   


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7.2.1 Pharmacokinetic/Pharmacodynamic Sampling Visits (Day 1 and Day 7) 
On Day 1 and Day 7, patients should arrive at the clinic in the fasted state at the time designated by site 
personnel, and will remain at the clinic for intensive PK and PD sampling over 8 hours.  The first and 
second doses of ACH-0144471 should be administered at the clinic.  The second dose should be 
administered approximately 8 hours after the first dose following the completion of the 8-hour blood 
draws.  Patients should take the third dose 8 hours after the second, after discharge from the clinic. 
The assessments listed in Table 7 of the Schedule of Assessments (Appendix 1) should be performed 
prior to the administration of the first daily dose.  Following dosing, PK and PD samples should be 
collected as listed in Table 8 of the Schedule of Assessments (Appendix 1).  
7.2.2 Outpatient Clinic Visits 
As listed in the Schedule of Assessments (Appendix 1), patients will be evaluated at the clinical site on 
Days 1, 2, 4, 5, 7, 8, 10, 12, and 14 during the Treatment Period.  Patients should arrive at the clinic in 
the fasted state at the time designated by site personnel.  The assessments listed in Table 7 of 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.  
7.2.3 Telephone Visits 
As listed in the Schedule of Assessments (Appendix 1), patients will be called by the site on the phone 
on Days 3, 6, 9, 11, and 13 during the Treatment Period.  During these phone calls, the investigator 
should review compliance with the protocol restrictions, remind the patient of their dosing schedule, 
confirm dose dates and times since the last contact with the patient, collect information about any 
adverse events, and collect any updates to their concomitant medications.  If preferable or more 
convenient, these activities may take place at the investigator’s clinic rather than by phone.  
7.3 Taper Period 
During the Taper Period, physical examinations, assessment of vital signs, ECG measurements, 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.  The taper period will begin after 
14 days of dosing unless a patient has a serum C3 level that, at 2 consecutive evaluations, is greater than 
125% the ULN, or is greater than 3× their baseline (provided this greater than or equal to the LLN), in 
which case the taper period will be initiated before completion of 14 days of dosing.  As described in 
Section 5.2, investigators must receive and review C3 levels in a timely manner to ensure that an early 
taper is implemented when appropriate.  
Patients should be instructed how to take their medication at home and record the time they took it.  The 
first dose of the day should be taken at the same time each morning, the second dose taken 
approximately 8 hours after the first dose, and a third dose 8 hours after the second.  Patients should be 
instructed to finish a moderate fat meal or snack within 15 minutes prior to dosing with ACH-0144471.  
Dosing should be at the same time(s) each day.  Patients should record the time they take their doses at 
home. 
Patients should be instructed to store their study drug at room temperature. 


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Patients should be instructed to fast prior to coming to a clinic visit and to bring their study drug with 
them for administration at the site.   
Details of the Taper Schedule can be found in Section 5.2.  
7.3.1 Outpatient Clinic Visits 
As listed in the Schedule of Assessments (Appendix 1), patients will be evaluated at the clinical site on 
Days 15, 16, 17, and 21 during the Taper Period.  Patients should arrive at the clinic at the time 
designated by site personnel.   
The assessments listed in Table 7 of 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.   
7.3.2 Telephone Visits 
As listed in the Schedule of Assessments (Appendix 1), patients will be called by the site on the phone 
on Days 18, 19, and 20 during the Taper Period.  During these phone calls, the investigator should 
review compliance with the protocol restrictions, remind the patient of their dosing schedule, confirm 
dose dates and times since the last contact with the patient, collect information about any adverse events, 
and collect any updates to their concomitant medications.  If preferable or more convenient, these 
activities may take place at the investigator’s clinic rather than by phone.  
7.4 Follow-Up Period 
During the Follow-Up Period, physical examinations, assessment of vital signs, ECG measurements, 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.   
Patients should be instructed to fast prior to coming to a clinic visit. 
7.4.1 Outpatient Clinic Visits 
As listed in the Schedule of Assessments (Appendix 1), patients will be evaluated at the clinical site on 
Days 24, 28, and 35 during the Follow-up Period.  Patients should arrive at the clinic at the time 
designated by site personnel.  The assessments listed in Table 7 of 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.  If necessary, clinic visits during the Follow-Up Period may occur up to 2 days earlier or 
later than scheduled.  
7.4.2 Telephone Visits 
As listed in the Schedule of Assessments (Appendix 1), patients will be called by the PI or designee on 
Days 22, 23, 25, 26, 27, 29, 30, 31, 32, 33, and 34 during the first 2 weeks of the Follow-up Period.  In 
addition, if one of the outpatient clinic visits described in Section 7.4.1 is rescheduled, the patient should 
be contacted by the PI or designee on the day when the clinic visit was originally scheduled.  During 
these phone calls, the investigator should review compliance with the protocol restrictions, collect 


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information about any adverse events, and collect any updates to their concomitant medications.  If 
preferable or more convenient, these activities may take place at the investigator’s clinic rather than by 
phone.  
7.4.3 Final Visit or Early Termination from the Study 
The final visit is scheduled to occur on Day 49.  Patients who terminate participation in this study should 
have the assessments listed for Day 49 in Table 7 of the Schedule of Assessments (Appendix 1).  
Patients who terminate participation within 7 days of their last dose of ACH-0144471 should also have a 
blood sample collected for PK evaluation.  Of note, a patient who discontinues dosing does not 
necessarily discontinue from the protocol, and whenever possible, such a patient should continue with 
follow-up visits as per the protocol. 
7.5 Long-Term Follow-Up Visits 
Long-term follow up visits to allow collection of longitudinal observational data are included, but are 
not required.  During the long-term follow up period, patients will be asked to return for an outpatient 
clinic visit approximately every 45 days for a maximum of 1 year.  Patients participating in this portion 
of the study should have the assessments listed for Long-Term Follow-up (LTF) in Table 7 of the 
Schedule of Assessments (Appendix 1).  
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: 
• 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 patient’s CRF. 
 


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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 subjects 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, subject 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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9 Planned Statistical Methods 
9.1 General Considerations 
Due to the small sample size, only descriptive and exploratory statistical methods will be utilized to 
present results from data analysis. 
Patient listings will be provided for all efficacy (including PK and PD) and safety parameters.  Summary 
statistics will be computed, by dose level and all dose levels combined, for selected efficacy and safety 
parameters so that meaningful clinical interpretations can be made.  Results may be presented by C3G 
and IC-MPGN if such presentations would be clinically meaningful.  Graphic presentations will also be 
produced for selected efficacy and safety parameters. 
No summary tables will be provided for long-term follow-up observational data since patients are not 
required complete the visits.  
A statistical analysis plan (SAP) will be developed to provide details of the data analysis procedures and 
presentations. 
9.2 Determination of Sample Size 
The sample size is determined based on very limited clinical cases of C3G and IC-MPGN and the 
exploratory nature of this study to evaluate effectiveness of ACH-0144471. 
9.3 Analysis Populations 
All patients receiving at least one dose of ACH-0144471 will be included in the efficacy, safety, 
pharmacokinetic, and pharmacodynamic analyses. 
9.4 Demographics and Baseline Characteristics 
Demographic parameters (age, gender, race, weight, BMI) and baseline C3G or IC-MPGN disease 
characteristics will be summarized, by dose level and all dose levels combined, to provide an overall 
description of study population. 
9.5 Efficacy Analysis – Complement C3 Measurements 
The primary efficacy endpoint will be an increase in blood C3 levels relative to baseline during the 
14-day Treatment Period.   
Summary statistics will be provided for both original and change from baseline C3 levels at various time 
points, including Treatment, Taper, and Follow-up periods, at each dose level and all dose levels 
combined.  Time (in days) to peak C3 level for each patient will be estimated and summarized.  
Descriptive time-to-event analysis techniques may be employed to estimate the time lapse for 
ACH-0144471 of restoring C3 levels.  
C3 levels, both original and changes from baseline, will be plotted against time.  


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Inferential statistical methods, e.g., confidence interval procedures, time-to-event techniques, etc., may 
also be utilized if available data deem such analyses being feasible and meaningful. 
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 patient.  Descriptive summary statistics may be 
provided for selected lab tests. 
Data on physical exam, vital signs, and ECG will be examined either through patient 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. 
9.7 Pharmacokinetic (PK) Analysis 
Pharmacokinetic analysis will be done using a validated computer program for the PK concentrations.  
For each patient, the PK characteristics of ACH-0144471, including, but not limited to, the standard PK 
parameters outlined in the table below, will be derived from the individual concentration time data 
following intensive PK sampling on study Days 1 and 7.  Descriptive statistics (number of patients, 
arithmetic mean / geometric mean, SD, median, minimum, and maximum) will be used to summarize 
the calculated PK parameters for Day 1 and Day 7. 
AUC 
Area under the curve 
Cmax 
Maximum plasma concentration 
tmax 
Time after administration of a drug when the maximum plasma concentration is reached 
 
Trough plasma concentrations will be listed and summarized to assess the amounts of ACH-0144471 in 
the body at steady state prior to daily dose.  Graphic presentations will also be provided to depict PK 
profiles of ACH-0144471 from C3G and IC-MPGN patients. 
9.8 Pharmacodynamic (PD) Analysis 
As described in Section 6.15, PD markers include selected laboratory tests to assess the effects of 
ACH-0144471 on complement alternative and classical pathways. 
Except for the alternative pathway functional assay result AH50 and results from AP Wieslab assay, 
change from baseline values at various time points will be computed for selected PD markers; summary 
statistics may be provided for these selected markers if they are deemed clinically meaningful. 


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The derivation from the raw data of AP Wieslab assay to the reported percentages will be presented in 
the SAP.  The two reported measures (in unit of %), along with complement Bb, are central for 
assessing the inhibitory effect of ACH-0144471 on the complement alternative pathway activity. 
Concentration versus time graphic presentations may be utilized for selected markers.   
9.9 PK/PD Assessments 
The relationships between C3 levels and selected AP component measurements, e.g., AP Wieslab 
reported percentages, etc. with corresponding plasma concentrations and/or PK parameters may be 
explored if available data deem such assessment being clinically meaningful. 
9.10 Patient-Reported Outcome Measures Assessments 
De-identified transcripts of the patients’ interviews will be qualitatively analyzed following a thematic 
analysis.  The analysis of patient interviews will be based on the grounded theory approach, allowing the 
voice of the patient to be heard rather than apply a priori concepts or hypotheses [22].  A validated 
software package will be used to facilitate the storage, coding, analysis, and retrieval of qualitative data. 
The interviews will be conducted prior to initiation of study treatment and will be analyzed cross-
sectionnally, on all the patients interviewed.  Concepts relevant in the disease and important to the 
patients will be elicited.  Based on findings collected a conceptual model will be developed to obtain 
comprehensive pictures of C3G and IC-MPGN, the signs and symptoms, their impact on patients’ lives, 
their diagnosis, and their management from the perspective of the patients.  
A separate report may be provided for the patient interview data if deemed feasible and clinically 
appropriate. 
 


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10 Administrative Considerations 
10.1 Investigators and Study Administrative Structure 
The PI must maintain a screening log of all patients seen and considered for the study.  For those 
patients 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, patient information and consent form, the Investigator Brochure, available safety 
information, patient recruitment procedures (e.g., advertisements), information about payments and 
compensation available to the patients 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 patient 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 patient’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 Patient Information and Consent 
In obtaining and documenting informed consent, the investigator should comply with the applicable 
regulatory requirements and should adhere to ICH GCP (E6).  Each patient 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 at any time without affecting their medical care.  If important new 
information is incorporated in the ICF and approved by the EC, all patients still actively participating in 
the study must be re-consented. 
Written informed consent should be documented by the patient’s personally dated signature and the 
personally dated signature of the investigator or designee who conducted the informed consent 
discussion.  The investigator or designee should supply all enrolled patients with a copy of their signed 
informed consent.  The monitor will inspect the original consent form for all patients. 
10.5 Patient Confidentiality 
The investigators and Sponsor and its designees will preserve the confidentiality of all patients 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 patient’s notes, confidentiality of all patient 
identities will be maintained.  Only patient initials, date of birth, and study number will be used on the 
CRF and in all study correspondence, as permitted.  No material bearing a patient’s name will be kept on 
file by the Sponsor. 
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 patient 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, Inc. 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, Inc. Medical Monitor immediately.  The 
investigator agrees to provide to representatives of a regulatory agency or Achillion Pharmaceuticals, 
Inc. access to records, facilities, and personnel for the effective conduct of any inspection or audit. 


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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, patient-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 patient 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 patient status throughout the 
course of the study.  CRFs will be completed within 5 days of the last patient visit. 
10.7.2 Source Documentation and Medical/Study Records 
The patient’s number and date of entry into the study, along with the study code, should be recorded in 
the patient’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 patient’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. 
10.8 Data Monitoring Committee 
There will be no formal data monitoring committee. 
10.9 Protocol Deviations 
Protocol deviations will be assessed on a case-by-case basis.  Significant protocol deviations will be 
reported to the Ethics Committee or IRB according to local regulations. 
10.10 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, 
patient 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. 
Patients will have access to safety laboratory results upon request at any time during the study.  PK 
levels will not be available until after all study analysis is completed. 
10.11 Data Generation and Analysis 
Data generation and analysis will be specified and detailed in the SAP. 


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10.12 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 
• 
Patient 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. 
Patient 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, patient 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 required to retain 
documents longer if required by applicable regulatory requirements, by local regulations, or by an 
agreement with Achillion Pharmaceuticals, Inc.  The investigator (or designee) must contact Achillion 
Pharmaceuticals prior to destroying any records associated with the study.  Achillion Pharmaceuticals, 
Inc. 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, Inc.  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, Inc. 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 patient, appropriate copies should be made for 
storage outside of the site. 
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, Inc. may use data derived from this trial for the purpose of research and 
development.  The data may be disclosed by Achillion Pharmaceuticals, Inc. 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, Inc. approval.  To gain 


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approval, a copy of the manuscript for review must, therefore, be sent to Achillion Pharmaceuticals, Inc. 
60 days before submission for publication. 
It is the intent of Achillion Pharmaceuticals, Inc. to present the results of this study at future scientific 
meetings.  Additionally, it is the intent of Achillion Pharmaceuticals, Inc. 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, Inc.  Achillion 
Pharmaceuticals, Inc. will determine additional authors.  Presentations and manuscripts will be provided 
and agreed to by the authors and Achillion Pharmaceuticals, Inc. 


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11 References 
 
1. 
Investigator’s Brochure Version 5.0. New Haven (CT): Achillion 
Pharmaceuticals, Inc.; 2017. 95 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. 
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. 
10. 
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.  
11. 
Barbour TD, Pickering MC, Cook HT. Dense deposit disease and C3 glomerulopathy. Semin 
Nephrol. 2013 Nov;33(6):493-507. 
12. 
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. 
13. 
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. 
 


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14. 
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. 
15. 
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. 
16. 
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. 
17. 
Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis--a new look at an old entity. N 
Engl J Med. 2012 Mar 22;366(12):1119-31. 
18. 
Hiemstra PS, Langeler E, Compier B, Keepers Y, Leijh PC, van den Barselaar MT, Overbosch D, 
Daha MR. Complete and partial deficiencies of complement factor D in a Dutch family. J Clin 
Invest. 1989 Dec;84(6):1957-61. 
19. 
Biesma DH, Hannema AJ, van Velzen-Blad H, Mulder L, van Zwieten R, Kluijt I, Roos D. A 
family with complement factor D deficiency. J Clin Invest. 2001 Jul;108(2):233-40. 
20. 
Sprong T, Roos D, Weemaes C, Neeleman C, Geesing CL, Mollnes TE, van Deuren M. Deficient 
alternative complement pathway activation due to factor D deficiency by 2 novel mutations in the 
complement factor D gene in a family with meningococcal infections. Blood. 2006 Jun 
15;107(12):4865-70. 
21. 
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. 
22. 
Bowen GA. Grounded theory and sensitizing concepts. Int J Qual Methods. 2006;5(3):12-23. 
 


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12 Appendices 
Appendix 1. 
Schedule of Assessments 
Table 7. 
Schedule of Assessments  
 
Screening 
Day -45 to 
Day -1 
Visit Day(s)1 
Treatment 
Taper 
Follow-Up2 
LTF4 
 
Elig Vacc3 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15-
17 
18-
20 
21 
22-
23 
24 
25-
27 
28 
29-
34 
35 49 
Drug 
Administration5 
 
 
X 
X 
X 
X 
X 
X 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
X5 
 
 
 
 
 
 
 
 
Outpatient Clinic 
Visit6 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Telephone Visit 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Dosing Reminder 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Screening 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol 
Restrictions 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central review of 
historical renal 
biopsy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test8 
X 
X9 
X10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Urine drug 
screen11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient-Reported 
Outcomes 
Assessment 
Interview 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccinations12 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Screening 
Day -45 to 
Day -1 
Visit Day(s)1 
Treatment 
Taper 
Follow-Up2 
LTF4 
 
Elig Vacc3 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15-
17 
18-
20 
21 
22-
23 
24 
25-
27 
28 
29-
34 
35 49 
Clinical 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam & 
Vital Signs13 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Body 
Temperature14 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
12-Lead ECGs 
(single) 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
AE/SAE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Con Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK samples15 
 
 
X10,16 
 
 
X 
 
 
X16 
 
 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
Hematology, 
Chemistry, and 
Urinalysis17 
X 
 
X10 
 
 
X10 
 
 
X10 
 
 
X10 
 
 
 
X10 X10 
 
X10 
 
X 
 
X 
 
X 
X 
X 
PT, PTT, and INR 
X 
 
X10 
 
 
 
 
 
X10 
 
 
 
 
 
 
X10 
 
 
X10 
 
 
 
X 
 
 
X 
 
Complement 
biomarkers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AP Wieslab, AP 
Hemolysis, Bb 
(serum/plasma) 
X 
 
X10,16 
 
 
X10 
 
 
X16 
 
 
X10 
 
 
 
X10 X10 
 
X10 
 
X 
 
X 
 
X 
X 
X 
C3 (serum and 
plasma) 
X 
 
X10,16 X10 
 
X10 X10 
 
X16 X10 
 
X10 
 
X10 
 
X10 X10 
 
X10 
 
X 
 
X 
 
X 
X 
X 
Ba, sC5b-9 
(plasma) 
X 
 
X10 
 
 
X10 
 
 
X10 
 
 
X10 
 
 
 
X10 X10 
 
X10 
 
X 
 
X 
 
 
X 
X 
C4, AH50, CH50, 
fD (serum) 
X 
 
X10 
 
 
 
 
 
X10 
 
 
 
 
 
 
X10 
 
 
X10 
 
 
 
 
 
 
X 
X 
fB (plasma) 
 
 
X10 
 
 
 
 
 
X10 
 
 
 
 
 
 
X10 
 
 
X10 
 
 
 
 
 
 
X 
X 
Sample for 
assessment of 
patient response 
to vaccines 
X 
 
X10 
 
 
 
 
 
X18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 


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Screening 
Day -45 to 
Day -1 
Visit Day(s)1 
Treatment 
Taper 
Follow-Up2 
LTF4 
 
Elig Vacc3 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15-
17 
18-
20 
21 
22-
23 
24 
25-
27 
28 
29-
34 
35 49 
Samples for 
potential 
assessment of 
additional non-
genetic 
biomarkers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Auto-antibodies to 
fH and C3 
nephritic factor 
(plasma/serum) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
C5, C5a, fH, fI, 
properdin, C3a 
(plasma/serum) 
 
 
X10 
 
 
 
 
 
X10 
 
 
 
 
 
 
X10 
 
 
X10 
 
 
 
 
 
X 
 
 
C3 convertase 
activity (serum) 
X 
 
X10 
X10 
 
X10 X10 
 
X10 X10 
 
X10 
 
X10 
 
X10 
 
 
X10 
 
 
 
 
 
X 
 
X 
iC3b (plasma) 
X 
 
X10 
 
 
X10 
 
 
X10 
 
 
X10 
 
 
 
X10 X10 
 
X10 
 
X 
 
X 
 
 
X 
X 
Urine complement 
components 
X 
 
X10 
 
 
X10 
 
 
X10 
 
 
X10 
 
 
 
X10 X10 
 
X10 
 
X 
 
X 
 
 
X 
X 
Sample for 
potential genetic 
assessment of 
complement 
genes 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE = Adverse event; AH50 = 50% hemolytic activity of complement alternative pathway; AP = Alternative pathway; BMI = Body mass index; ECG = Electrocardiogram; Elig = Eligibility 
evaluation; fD = Factor D; LTF = Long-Term Follow-Up visits; PK = Pharmacokinetic; SAE = Serious adverse event; Unsch = Unscheduled visit; Vacc = Vaccination visit 
1 
Where Visit Day is a range, the specified activities should take place on each day of the range. 
2 
If necessary, clinic visits during the Follow-Up Period may occur up to 2 days earlier or later than scheduled.  If a visit is rescheduled, a telephone visit should be conducted on the day 
when the clinic visit was originally scheduled. 
3 
If required, vaccinations must be at least 2 weeks prior to dosing with ACH-0144471.  With the exception of the historical biopsy review, patients should be confirmed to be eligible 
based on all other inclusion and exclusion criteria before being vaccinated. 
4 
Long-term follow-up visits should be every 45 days, ±15 days, for a maximum of one year.  Patients are not required to complete these visits.  
5 
If a patient has a serum C3 level that, at 2 consecutive evaluations, is greater than 125% the ULN, or is greater than 3× their baseline (provided this is greater than or equal to the LLN), 
then the taper period will be initiated before completion of the 14 days of dosing.  In this instance, skip to Day 15 of the study schedule on the first day of the taper. 
6 
Patients will be offered the opportunity to stay within the inpatient clinical research unit and/or offered local overnight accommodations for the two extended clinic visit days (Day 1 
and Day 7), and during the period of daily outpatient visits. 


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Screening 
Day -45 to 
Day -1 
Visit Day(s)1 
Treatment 
Taper 
Follow-Up2 
LTF4 
 
Elig Vacc3 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15-
17 
18-
20 
21 
22-
23 
24 
25-
27 
28 
29-
34 
35 49 
7 
FSH for postmenopausal women at screening only.  
8 
Serum pregnancy test at Screening and urine pregnancy tests at other time points for women of childbearing potential only.  On Day 1, urine pregnancy test must be done pre-dose and 
be negative to continue.  Any positive urine pregnancy test will be confirmed by a serum pregnancy test. 
9 
Female patients of childbearing potential who require vaccinations (see Section 6.4) must have a negative urine pregnancy test on the day of vaccination, before any vaccine or booster 
is administered.  
10 Blood draws and urine collection should be done pre-dose. 
11 Urine drug screen should include, at a minimum, cotinine, amphetamines, barbiturates, cotinine, cocaine metabolites, opiates, benzodiazepines, and cannabinoids.  All analytes can be 
evaluated in a single urine sample. 
12 If needed, per the guidance in Section 6.4. 
13 Full physical exam and vital signs, including height, weight, and BMI at screening.  Full physical exam and vital signs, including weight on Day 1 and Day 49 visit.  Brief physical 
exam and vital signs for all other visits, per Section 6.5 and Section 6.6.  Vital signs may be measured using an automated vital signs monitor, although manual measurements of blood 
pressure are preferred. 
14 Oral temperature, per Section 6.7. 
15 Except on Days 1 and 7, collect only one sample prior to dose administration (trough sample). 
16 For PK and PD sampling schedule on Days 1 and 7, refer to Table 8. 
17 Hematology, Chemistry, and Urinalysis tests as listed in Section 6.9, Table 5.  
18 Collect samples at Hour 0 (before dosing) and Hour°2 of Day 7, as indicated in Table 8. 
 


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Table 8. 
PK and PD Sampling on Days 1 and 7 
 
Time After Dosing (hr) 
Houra 
0b 
1 
1.5 
2 
2.5 
3 
4 
6 
8 
PK plasma samples 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C3 (serum and plasma) 
X 
 
 
X 
 
 
X 
X 
X 
AP Wieslab (serum) 
X 
 
 
X 
 
 
X 
X 
X 
Bb (plasma) 
X 
 
 
X 
 
 
X 
X 
X 
AP Hemolysis (serum) 
X 
 
 
X 
 
 
X 
X 
X 
Sample for assessment of 
patient response to vaccines 
Xc 
 
 
Xc 
 
 
 
 
 
a 
Samples at 0, 1, 1.5, 2, and 2.5 hours should be drawn at ± 5 min of the scheduled time.  Later samples should be drawn at ± 10 min of the scheduled time. 
b 
Prior to dosing 
c 
Day 7 only 
 
 


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Appendix 2. 
Grading the Severity of Adult Adverse Events 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0, Published: May 28, 2009 
(v4.03: June 14, 2010) 
To view or print the table, go to:  
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
 


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Appendix 3. 
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 subjects 
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 patient; instead, 
they are intended to facilitate rapid initiation of assessment and management of fever. 
A. General Management for outpatients 
 
All patients in this study 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 
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 patients 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. They will be advised not to wait for site staff to return their phone call before seeking emergency 
medical attention. They should go to the nearest emergency 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 and telephone, and be within one hour of an 
emergency medical center 
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 
 
B. General Management for Any Fever Detected in the Clinic  
For Any fever, the site needs to: 
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: 


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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 
Intravenous (IV) antibiotics should be given as soon as meningococcal disease is suspected.  The choice 
of antibiotics should be selected to provide adequate coverage for N. meningitidis - suggestions are 2 g 
of ceftriaxone IV after basic blood draws for CBC and blood culture are completed, or 2 g Meropenem 
IV every 8 hours.  Cefotaxime IV may be used as well.  If unavailable, penicillin G IV could be used 
(the recommended dose in persons with normal renal function is 2 million units every 2 h, or 4 million 
units every 4 hours (24 million units/day).  As far as possible, 2 sets of blood cultures should be 
collected prior to antibiotic administration.  Other investigations should not delay antimicrobial therapy. 
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. 
 

SAP_001.pdf: 
A Phase 2a Proof-of-Mechanism, Open-Label Study to 
Determine the Effect of ACH-0144471 on C3 Levels in 
Patients with Low C3 Levels Due to Either C3 
Glomerulopathy (C3G) or Immune-Complex 
Membranoproliferative Glomerulonephritis (IC-MPGN) 
 
Unique Protocol ID: 
ACH471-201 
NCT Number: 
NCT03124368 
EudraCT Number:  
2016-003525-42 
Date of SAP:  
02 January 2019 
 


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STATISTICAL ANALYSIS PLAN 
ACH471-201 
 
Study Title: 
A Phase 2a Proof-of-Mechanism, Open-Label Study to Determine the Effect of 
ACH-0144471 on C3 Levels in Patients with Low C3 Levels Due to Either C3 
Glomerulopathy (C3G) or Immune-Complex Membranoproliferative 
Glomerulonephritis (IC-MPGN) 
 
Study Number: 
ACH471-201 
Study Phase: 
2 a 
Product Name: 
ACH-0144471 Tablet 
 
 
 
Version Number: 
V1.0 
Effective Date: 
02 January 2019 
 
 
 
 
Protocol Version: 
Amendment 2, 09 June 2017 (Version 3.0) 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document, particularly unpublished data, is the property or under the 
control of Achillion 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.  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, Inc., except to the extent necessary to 
obtain informed consent from those persons to whom the drug may be administered. 


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Table of Contents 
List of Appendices .......................................................................................................................................3 
List of Abbreviations ...................................................................................................................................4 
1 
Overview ..............................................................................................................................................5 
2 
Objective ..............................................................................................................................................5 
2.1 
Primary Objectives ......................................................................................................................5 
2.2 
Secondary Objectives ..................................................................................................................5 
2.3 
Other Objectives ..........................................................................................................................5 
3 
Endpoints ..............................................................................................................................................6 
3.1 
Efficacy Outcome Measures ........................................................................................................6 
3.1.1 Primary Efficacy Outcome Measures .......................................................................................6 
3.1.2 Secondary Efficacy Outcome Measures ...................................................................................6 
3.1.3 Other Efficacy / PD Outcome Measures ..................................................................................6 
3.2 
Safety Outcome Measure .............................................................................................................7 
3.3 
Pharmacokinetic (PK) Parameters ...............................................................................................7 
4 
Study Description .................................................................................................................................7 
4.1 
Study Design ................................................................................................................................7 
4.2 
Treatment Assignment .................................................................................................................8 
4.3 
Blinding and Unblinding .............................................................................................................8 
4.4 
Protocol Amendments ..................................................................................................................8 
5 
Sample Size ..........................................................................................................................................9 
6 
Analysis Set ..........................................................................................................................................9 
7 
Statistical Analyses ...............................................................................................................................9 
7.1 
General Methods ..........................................................................................................................9 
7.2 
Study Population ........................................................................................................................10 
7.2.1 Subject Discontinuation and Disposition ...............................................................................10 
7.2.2 Demographic and Baseline Characteristics ............................................................................10 
7.2.3 Medical History ......................................................................................................................10 
7.3 
Extent of Exposure .....................................................................................................................11 
7.4 
Concomitant Medications ..........................................................................................................11 
7.5 
Efficacy and Selected PD Markers Assessment ........................................................................11 
7.5.1 Analysis of Primary Efficacy Outcome Measures .................................................................11 


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7.5.2 Analysis of Secondary Efficacy Outcome Measures .............................................................11 
7.5.3 Analysis of Other Outcome Measures ....................................................................................12 
7.6 
Safety Assessment .....................................................................................................................12 
7.6.1 Treatment-Emergent Adverse Events (TEAE) .......................................................................12 
7.6.2 Clinical Laboratory Parameters – Safety and Complement Biomarkers ...............................13 
7.6.3 12-lead ECG ...........................................................................................................................14 
7.6.4 Vital Signs and Body Weights ...............................................................................................15 
7.6.5 Physical Exam ........................................................................................................................15 
7.7 
Pharmacokinetic (PK) Assessments ..........................................................................................15 
7.7.1 PK Parameters ........................................................................................................................15 
7.7.2 PK Analysis ............................................................................................................................16 
7.8 
PK/PD Assessment ....................................................................................................................17 
8 
Changes from Protocol Specified Analysis ........................................................................................17 
9 
Document History ..............................................................................................................................17 
 
List of Appendices 
Appendix 1. 
Grading the Severity of Laboratory Values .......................................................................18 
 
 
 


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List of Abbreviations 
 
ACR 
(Urine) albumin:creatinine ratio 
AE 
Adverse event 
AP 
Alternative Pathway (Complement) 
AUCtau 
Area under the plasma concentration-time curve from time of administration to the 
end of dosing interval 
BLQ 
Below the lower limit of quantification 
C3G 
C3 glomerulopathy 
Cmax 
Maximum plasma concentration 
CL/F 
Apparent oral drug clearance  
CTCAE 
Common Terminology Criteria for Adverse Events 
CV% 
Coefficient of variation 
ECG 
Electrocardiogram 
IC-MPGN 
Immune-Complex Membranoproliferative Glomerulonephritis 
LLN 
Lower limit normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
QTcF 
QT interval corrected using Fridericia’s formula 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
TE 
Treatment emergent 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time after administration of a drug when the maximum plasma concentration is 
reached 
ULN 
Upper limit normal 
 
 
  


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1 Overview 
This statistical analysis plan (SAP) document describes in detail the statistical procedures and 
presentations to be implemented for the data from Study ACH471-201.  
All eligible patients are expected to complete the three sequential study periods: 14-day Treatment 
Period, 7-day Taper Period, and 28-day Follow-Up Period as briefly described in section 4.1 of this 
document.  Afterwards, patients can participate in the optional long-term no-treatment observational 
follow-up visits for up to a year.  Statistical procedures and presentations described in the SAP will 
focus on data collected during Treatment, Taper, and Follow-Up study periods.  Data available from 
long-term follow-up visits will be listed, but will not be analyzed. 
Note that the expressions ‘subject’ and ‘patient’ are used interchangeably throughout this document.   
2 Objective 
2.1 Primary Objectives 
The primary objective(s) of this study is to determine whether ACH-0144471 can increase blood C3 
levels in patients with low C3 levels due to either C3G or IC-MPGN.  
 
2.2 Secondary Objectives 
The secondary objective(s) of this study is (are): 
• To evaluate the safety and tolerability of oral dosing with ACH-0144471 in patients with C3G or 
IC-MPGN by assessing SAEs, Grade 3 and higher adverse events (AEs), and AEs leading to 
discontinuation of study drug 
• To evaluate the PK profile of ACH-0144471 following oral dosing in patients with C3G or IC-
MPGN  
• To evaluate the effect of ACH-0144471 on biomarkers of alternative pathway activity in patients 
with C3G or IC-MPGN 
• To explore the relationship between study drug exposure and changes in C3 levels and other 
biomarkers of alternative pathway activity. 
 
2.3 Other Objectives 
The exploratory objective(s) of this study is (are): 
• To explore patients’ experience of their disease (C3G or IC-MPGN), its impact, and its 
management on everyday lives, from first symptoms to definitive diagnosis and beyond 
• To explore patients’ expectations of ACH-0144471 in the treatment of their disease. 


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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 Primary Efficacy Outcome Measures 
There are two related outcome measures of evaluating the increases of blood C3 levels in patients with 
low C3 levels due to either C3G or IC-MPGN for this study: 
• Change from baseline in serum C3 level after 14 days of ACH-0144471 treatment, as measured 
by conventional Roche immunoturbidimetric assay method 
• Change from baseline in plasma intact C3 level after 14 days of ACH-0144471 treatment, as 
measured by a novel multiplex assay method  
3.1.2 Secondary Efficacy Outcome Measures 
• Changes from baseline after 14 days of ACH-0144471 treatment for the following (serum) 
biomarkers:  
- 
Total complement classical pathway activities, Total CP activities (IU/L) 
- 
AP Complement Functional Activity (AP Wieslab) 
• Time (in days) to achieving peak serum C3 levels from the first day of dosing to last day of 
Treatment Period 
3.1.3 Other Efficacy / PD Outcome Measures 
• Changes from baseline after 14 days of ACH-0144471 treatment for the following (serum / 
plasma) biomarkers:  
- 
fD (Factor D) 
- 
fB (Factor B) 
- 
Bb 
- 
Bb / fB ratio 
- 
C4 
- 
sC5b-9 
- 
C3 fragment (iC3b) 
- 
C3 fragment (C3b+iC3b) 
- 
C3 fragment (C3b+iC3b) / intact C3 ratio 
• Change from baseline after 14 days of ACH-0144471 treatment in urine albumin:creatinine ratio 
(ACR) 


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Note that the patient-reported outcome measures through patient interviews will be assessed and stored 
in a separate database (from study clinical database).  Therefore, they are excluded from this SAP. 
3.2 Safety Outcome Measure 
• Frequency of SAE 
• Frequency of TEAEs leading to discontinuation of the study medication 
• Frequency of TEAEs (related and regardless of relationship to study medication) 
• Frequency of treatment-emergent laboratory abnormalities by toxicity grade 
• Change from baseline on selected laboratory test results over treatment duration and Follow-Up 
Period 
• Change from baseline on parameters of vital signs and weight over treatment duration and 
Follow-Up Period 
• Treatment emergent abnormalities on selected ECG parameters 
• Change from baseline on ECG parameters over treatment duration and Follow-Up Period 
Note that ‘treatment duration’ includes data from both Treatment Period and Taper Period. 
 
3.3 Pharmacokinetic (PK) Parameters  
• Cmax, AUC0-tau, tmax, CL/F for Days 1 and 7 
• Ctrough concentrations for other days 
 
4 Study Description 
4.1 Study Design 
This is an open-label study.  The study has planned to enroll up to 10 patients with biopsy-confirmed 
C3G or idiopathic IC-MPGN and a low C3 level.  All patients receive ACH-0144471 and enroll into two 
sequential groups.  Group 1 serves as a sentinel group consisting of two patients receiving 
ACH-0144471 at a dose of 100 mg three times daily (TID).  Group 2 is initiated upon confirmation that 
dosing was well-tolerated - based on the available safety, PK, and PD data - in Group 1.  The dose 
regimen for Group 2 would not exceed 200 mg TID. 
Patients receive study drug for 14 days (Treatment Period), followed by a taper over the next 7 days 
(Taper Period) to minimize the potential adverse effects of a rapid surge in complement activity 
following drug withdrawal.  Patients have daily clinic visits for the first 3 days of the taper, and then 
continue to be followed for 28 days after the last dose of study drug (Follow-Up Period).  Long-term 
follow up visits to allow collection of longitudinal observational data are included but not required.  
During the long-term follow up period, patients are asked to return for an outpatient clinic visit 
approximately every 45 days for a maximum of 1 year. 


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If a patient has a C3 level that, at 2 consecutive evaluations, is greater than 125% the upper limit of 
normal (ULN), or is greater than 3× their baseline and greater than or equal to the lower limit of normal 
(LLN), then the taper period will be initiated before completion of the 14 days of dosing, as proof-of-
mechanism will already be established for that patient.  Furthermore, early tapering and possible 
prevention of supraphysiologic C3 levels may mitigate the theoretical risk for acute precipitation of C3 
into the glomerulus upon drug discontinuation. 
4.2 Treatment Assignment 
All patients receive ACH 0144471.  Each patient is assigned a sequential subject identification number 
within the study site. 
The first two patients from Group 1 and receive ACH-0144471 at a dose of 100 mg TID.  The remaining 
enrolled patients are included in Group 2.  The dose for Group 2 is selected based on the data from 
Group 1 but does not exceed 200 mg TID. 
4.3 Blinding and Unblinding 
This is an open-label study.  
4.4 Protocol Amendments 
There are two amendments to the original protocol. 
Amendment 
No. 
Amendment 
Date 
Main Purposes of Amendment 
1 
07-APR-2017 
1. Change Study Phase from 1b to 2a. 
2. Update the dose levels based on the current PK modeling and 
clinical safety in healthy volunteers.   
3. The circumstances under which an early dosing taper would be 
initiated are modified.  
4. Potential long-term follow-up visits are added. 
5. Adverse Event definitions are clarified. 
6. The grading of Adverse Events is changed from the DAIDS criteria 
to CTCAE. 
2 
09-JUN-2017 
1. Update the maximum dose based on the current PK modeling and 
clinical safety in healthy volunteers.  
2. The eGFR calculation method is revised.  
3. The approximate blood volume to be collected is updated to 
include blood drawn in the optional long-term follow-up visits.  
4. Adverse Event definitions are (further) clarified. 
5. The previous human experience is updated. 
 


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5 Sample Size 
The sample size is determined based on very limited clinical cases of C3G and IC-MPGN and the 
exploratory nature of this study to evaluate effectiveness of ACH-0144471. 
6 Analysis Set 
All patients receiving at least one dose of ACH-0144471, with baseline and at least one measurement 
during Treatment Period, will be included in the efficacy, safety, pharmacokinetic (PK), and 
pharmacodynamic (PD) analyses. 
7 Statistical Analyses 
Statistical analyses and data presentations are performed using the version of SAS 9.12. 
7.1 General Methods 
Data listings by subject identification will be provided for all data, including efficacy, safety, PD, and 
PK parameters.  Note that data listings also include data from the optional long-term follow-up visits 
whenever available.  
To summarize continuous data, descriptive statistics will include: number of subjects, 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. 
Summary results for all patients will be presented alongside Group 1 and Group 2 for all summary 
tables.  In addition, if there are more than two dose levels administered to the patients and it is deemed 
clinically meaningful, summary tables may be presented by dose levels, instead of, or in addition to, 
Group 1 and Group 2.   
Both inferential and descriptive statistical procedures will be performed on most of the efficacy outcome 
measures.  For safety measures, only descriptive statistical procedures will be utilized, unless otherwise 
specified. 
 
As stated in section 1 Overview, summary tables and statistical procedures will be presented for data 
collected during Treatment, Taper, and Follow-Up study periods.  Data from the optional long-term 
follow-up visits will be listed; no planned summary tables will be provided. 
Unscheduled assessments taken after dosing will not be used in the summarization.  
Longitudinal summaries of efficacy and safety parameters use pre-defined visit Day as described in 
Appendix 1, schedule of assessment, of the protocol.     
For laboratory test results, when both local and central laboratory values are collected on the same date, 
the central laboratory value will be used.  


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Baseline values for efficacy / PD and safety parameters are defined as the last measurement, including 
unscheduled visits, prior to first dose of ACH-0144471.  
Separate analysis and presentation by diagnosis, C3G or IC-MPGN, may be provided if it is deemed 
clinically feasible and meaningful. 
7.2 Study Population 
7.2.1 Subject Discontinuation and Disposition 
The summary table(s) will include the following:  
• Number of patients (enrolled / treated) 
• Number of patients who completed 14 days of Treatment Period 
• Reasons for not completing 14 days of Treatment Period 
• Number of patients entering Taper Period: 
o Number of patients who completed dose tapering 
o Reasons for not completing dose tapering 
• Number of patients entering Follow-Up Period: 
o Number of patients who completed Follow-Up Period 
o Reasons for not completing Follow-Up Period 
 
7.2.2 Demographic and Baseline Characteristics  
The following demographic and baseline characteristics will be summarized by treatment group and 
both group combined: 
• demographics: age, gender, race, country / geographic region 
• physical measurement at baseline: height, weight, BMI 
• disease characteristics at baseline: duration of the disease, biopsy results 
• selected PD markers and laboratory tests at baseline 
• prior medications. 
 
Demographic and physical measurements will be listed together. 
 
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. 


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7.3 Extent of Exposure  
Treatment durations will be computed for each patient as (last date of dose – first date of dose + 1).  The 
last date of dose will be the end date of Treatment Period.  Number of doses taken during Treatment 
Period will also be provided for each patient. 
Duration of tapering dosing period may also be provided, as a separate computation, if patients enter the 
7-day Taper Period schedule.  The duration will be calculated similarly as (last date of taper dose – first 
date of taper dose +1).  Number of doses taken during Taper Period will also be provided for each 
patient. 
Compliance with study drug will be estimated for each patient as: (number of tablets actually taken / 
number of tablets should be taken) *100.   
Treatment duration, duration of tapering dosing, number of doses for both Treatment and Taper Period, 
and compliance will be summarized and by-patient listing will be provided. 
7.4 Concomitant Medications 
Concomitant medications will be listed and summarized. These are medications taken any time on or 
after the first dose of ACH-0144471 and on or before the last dose of ACH-0144471. Medications are 
presented alphabetically by anatomic class, therapeutic class and generic name using the most recent 
version of WHO dictionary. 
7.5 Efficacy and Selected PD Markers Assessment 
7.5.1 Analysis of Primary Efficacy Outcome Measures 
Change from baseline for serum C3 levels on study Day 15, after 14 days of treatment ACH-0144471, 
will be computed for each patient.   
Ninety-five (95%) confidence interval, based on t-distribution, will be provided for the mean changes 
from baseline from all patients on Day 15, Group 1 and Group 2 combined.  Ninety-five (95%) 
confidence interval will also be provided for the mean changes from baseline from patients in Group 2, 
and dose levels or diagnosis (C3G or IC-MPGN) when the individual group / dose level / diagnosis has 
4 or more patients. 
Summary statistics will be provided for both original and change from baseline serum C3 levels at 
scheduled time points for the three study periods, Treatment, Taper, and Follow-Up.  The serum C3 
levels, both original and changes from baseline, will be plotted against time. 
Same analysis and graphic procedures will also be employed for intact C3 level data. 
7.5.2 Analysis of Secondary Efficacy Outcome Measures 
For the biomarkers listed in section 3.1.2, similar analysis and graphic procedures as described in the 
above section 7.5.1 will be utilized to assess the effect of ACH-0144471 on complement pathway 
activities. 


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Mean change from baseline and corresponding 95% confidence interval on Day 15 for AP Wieslab will 
be provided.  However, mean change from baseline and corresponding 95% confidence interval on Day 
14 for total CP activities will be provided.  Note that total CP activities have not been measured on Day 
15 as it is not expected any change in values, if any, from Day 14 to Day 15.  Graphic presentations will 
be provided to these secondary efficacy outcome measures. 
 
For data on time (in days) to achieving peak serum C3 level, Kaplan-Meier plot and descriptive analysis 
procedure will be applied for visual examination and interpretation.  The time (in days) to achieving 
peak serum C3 level for each patient will be summarized and listed. 
7.5.3 Analysis of Other Outcome Measures 
For biomarkers and laboratory tests listed in Section 3.1.3, changes from baseline at the protocol-defined 
time points will be computed.  Note that the biomarkers of AH50, factor B and factor D are measured 
with less frequency than the other biomarkers and laboratory tests.  In addition, spot urine laboratory 
measurements of albumin and creatinine may also be summarized similarly. 
Ninety-five confidence intervals may be constructed on mean changes from baseline on Day 15 for 
selected other outcome measures as clinically deemed beneficial in interpreting the biological effects of 
ACH-0144471. 
7.6 Safety Assessment  
Evaluation of safety includes assessment of the following clinical parameters and will be described in 
detail in the subsequent subsections.  Summary tables will be provided for selected clinical parameters.  
All summary tables will include data points during Treatment Period and Taper Period, unless otherwise 
specified.  The summary table will be presented by treatment group and both groups combined.  By-
subject listings will provide all data points throughout the entire study period, including data from 
optional long-term follow-up visits. 
1. Treatment emergent adverse events, including discontinuations due to adverse event 
2. Clinical laboratory parameters 
3. 12-lead ECG 
4. Vital signs 
5. Body weights 
6. Physical findings. 
 
7.6.1 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 
ACH-0144471 (Treatment Period and Taper Period) and Follow-Up Period, having been absent pre-
treatment, or worsens relative to the pre-treatment state.   


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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 subject 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 ACH-0144471.  
TEAEs will be summarized by preferred term and SOC for the number of subjects reporting the TEAE, 
the number of TEAEs reported, and the number of events by severity and relationship to study drugs as 
described in Section 3.2.  Summaries of AEs include both non-serious and SAEs as defined in the 
protocol.  AEs with missing severity are included only in summaries of all severity grades (related or 
regardless of relationship to study drug).  If a subject had an AE with different severities during 
treatment, then only the greatest severity is reported, unless otherwise specified.  In addition, a TEAE 
summary table with decreasing frequencies in terms of MedDRA® preferred terms, based on overall 
patient population, will also be provided. 
Note that there could be two separate summary tables for the number of subjects reporting the TEAE 
and the number of TEAEs reported. 
It is not anticipated to encounter AE with missing start date in this study.  Any AE with missing start 
time will be treated as TEAE.  AEs that are missing resolution dates are considered to be lost-to-follow-
up.  
All events captured in the database will be listed in by-subject data listings.  However, only TEAEs will 
be summarized.  Separate subject listings will be provided for pre-treatment AEs, TEAEs, and AEs 
occurred during the optional long-term follow-up visits. 
Should any serious adverse events (SAEs) or discontinuation of ACH-0144471 due to adverse events 
(TEAE or SAE) occur, subject 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’. 
7.6.2 Clinical Laboratory Parameters – Safety and Complement Biomarkers 
Descriptive statistics will be provided, at a minimum, for the following laboratory test results of 
hematology, serum chemistry, urinalysis, coagulation tests, and complement biomarkers as listed in 
Table 5 of the protocol. Descriptive statistics may be provided for additional laboratory parameters, if 
clinically warranted.  
• hematocrit (Hct), hemoglobin (Hgb), mean corpuscular volume (MCV), platelet count, and WBC 
count   
• all chemistry laboratory test results 
• pH, specific gravity 
• urine albumin, urine creatinine, albumin:creatinine ratio 


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• PT/PTT/INR 
• all complement biomarker results 
 
Levels and changes from baseline in the laboratory measurements will be summarized at baseline and at 
pre-defined visits.  Baseline is the last assessment before the first dose of ACH-0144471, including 
unscheduled assessments.  
Laboratory parameters are summarized using US standard values and units.  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. 
Laboratory abnormalities during treatment period will be further summarized by baseline toxicity grade 
and treatment therapy (shift tables). Shift tables will be provided for liver function test (LFT) results and 
other selected laboratory test results based on CTCAE grades.  The other selected laboratory tests may 
include: albumin, serum calcium, serum creatinine, eGFR or CrCL, urine protein, urine WBC, urine 
RBC and complement biomarkers.   
Values from unscheduled visits after first dose of study drugs will be excluded from descriptive 
statistics.  Unscheduled values will be labeled as unscheduled in the listings. 
Exploratory graphic presentations may be provided when data indicate that such analyses are 
appropriate and clinically meaningful. 
7.6.3 12-lead ECG 
Subject listing 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. 
Values and changes from baseline in ECG measurements are summarized at baseline and at each 
scheduled time points.  Baseline ECG is the last assessment before first dose of ACH-0144471. 
ECG results will also be classified as normal, abnormal (not clinically significant), and abnormal 
(clinically significant).  Summary table will be provided for clinically significant abnormalities by 
treatment group.  If no clinically significant abnormalities are found, the table should state ‘No clinically 
significant ECG abnormality reported’. 
The frequency of subjects with a maximum increase from baseline in QTcF interval will be summarized 
according to the following categories: >30, >60, and ≤30 ms.  All incidences of >30 and >60 ms will be 
flagged on the listing. 


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Clinical Trial Protocol 
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The treatment-emergent (TE) ECG events indicate that the abnormality / prolongations were not present 
at baseline.  TE abnormalities will be summarized for the following parameters.  Note that TE QTcF 
interval abnormalities are based on CTCAE criteria.  
• Treatment-emergent (TE) PR interval  > 200 msec; 
• TE QTcF interval: 
o Grade 1: 450 – 480 msec  
o Grade 2: 481 – 500 msec 
o Grade 3: ≥ 501 msec on at least 2 separate ECG readings 
o Grade 4: ≥ 501 msec or > 60 msec change from baseline and Torsade de pointes, 
polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia 
The maximum interval (or increase from baseline) during Treatment Period is reported for each ECG 
parameter 
ECG readings from unscheduled visits after first dose of study medication will be excluded from 
descriptive statistics.  Unscheduled readings will be labeled as unscheduled in the listings. 
7.6.4 Vital Signs and Body Weights 
Subject listing will be provided for vital signs parameters: body temperature, systolic and diastolic blood 
pressures in triplicate, heart rate, and respiration rate.   
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.  Additional analysis and presentations may be required based on the emerging 
data.   
7.6.5 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. 
7.7 Pharmacokinetic (PK) Assessments 
PK assessments will be performed on plasma concentrations from patients whose PK profiles can be 
determined.  PK parameters may be presented by dose levels when clinically appropriate. 
7.7.1 PK Parameters 
PK parameters from plasma concentrations for ACH-0144471 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.   
Subjects for whom there is insufficient data to calculate the PK parameters will have available data 
included in the concentration tables with descriptive statistics only. 


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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 Days 1 and 7, 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.  
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. 
In addition, the trough concentrations at protocol specified visits will be provided. 
7.7.2 PK Analysis 
Individual PK parameters 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 the calculated PK parameters of ACH-0144471. 
Individual concentration profiles with actual post-dose time will be listed. Descriptive summary 
statistics (N, arithmetic mean, SD, median, CV%, minimum, maximum, geometric mean and geometric 
CV%) will be used to summarize the concentration profiles. 


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Individual time-concentration graphs will be provided for each subject in both linear and semi-log 
scales. Mean time-concentration graphs will also be provided. 
7.8 PK/PD Assessment 
To assess the relationships between C3 levels and the PD markers listed in section 3.1.2 with 
corresponding plasma concentrations and/or PK parameters, graphic presentations on time-matched PK 
concentration and C3 levels / selected PD markers will be provided for visual examinations and clinical 
interpretations. 
8 Changes from Protocol Specified Analysis 
There are no changes from protocol specified analysis for efficacy / PD and safety variables.   
Note that the efficacy endpoints described in the protocol have been expanded to include specific 
biomarkers / laboratory tests of clinical interest. 
The protocol Section 9.8 states “derivation from the raw data of AP Wieslab assay to the reported 
percentages will be presented in the SAP”.  Since the derivation is now detailed in the appropriate 
laboratory manual, it is not included in this document. 
9 Document History 
Version No. 
Author(s) 
Descriptions 
1.0 
Original dated 02Jan2019 
 
 
 
 
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 


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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 
- 
 
 
 
 
 
 
 
 


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