A Phase 2 Open-Label Proof of Concept Study to Assess the Efficacy, Safety, and Pharmacokinetics of ACH-0144471 in Untreated Patients With Paroxysmal Nocturnal Hemoglobinuria
Phase: PHASE2
Conditions: Paroxysmal Nocturnal Hemoglobinuria (PNH)
Sponsor: Alexion Pharmaceuticals, Inc.

A Phase 2 Open-Label Proof of Concept Study to Assess the 
Efficacy, Safety, and Pharmacokinetics of ACH-0144471 in 
Untreated Patients with Paroxysmal Nocturnal 
Hemoglobinuria (PNH) 
 
Unique Protocol ID: 
ACH471-100 
NCT Number: 
NCT03053102 
EudraCT Number:  
2016-002652-25 
Date of Protocol:  
13 March 2018 
 

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Clinical Trial Protocol 
ACH471-100 
Study Title: 
A Phase 2 Open-Label Proof of Concept Study to Assess the Efficacy, Safety, 
and Pharmacokinetics of ACH-0144471 in Untreated Patients With 
Paroxysmal Nocturnal Hemoglobinuria (PNH) 
Study Number: 
ACH471-100 
Study Phase: 
2 
Product Name: 
ACH-0144471 Tablets 
EudraCT Number: 
2016-002652-25 
Universal Trial 
Number (UTN): 
U1111-1190-3490 
Indication: 
Paroxysmal Nocturnal Hemoglobinuria (PNH) 
Investigators: 
Multi-center 
Sponsor: 
Achillion Pharmaceuticals, Inc. 
Sponsor Contact: 
 
 
 
Medical Monitor: 
 
 
Approval Date 
Original Protocol: 
22 November 2016 (Version 1.0) 
Amendment 1 
07 March 2017(Version 2.0) 
Amendment 2 
19 April 2017 (Version 3.0) 
Amendment 3 
18 May 2017 (Version 4.0) 
Amendment 3.1 
18 May 2017 (Version 4.1) 
Amendment 4.0 
09 Oct 2017 (Version 5.0; Italy only) 
Amendment 5 
05 December 2017 (Version 6.0) 
Amendment 6 
21 December 2017 (Version 7.0) 
Amendment 7 
13 March 2018 (Version 8.0) 
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The information contained in this document, particularly unpublished data, is the property or under the control of Achillion 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 or Independent Ethics Committee.  The 
information is only to be used by you and in connection with authorized clinical studies of the investigational drug 
described in the protocol.  You will not disclose any of the information to others without written authorization from 
Achillion Pharmaceuticals, Inc., except to the extent necessary to obtain informed consent from those persons to whom the 
drug may be administered. 
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Sponsor Signature(s) 
Study Title: 
A Phase 2 Open-Label Proof of Concept Study to Assess the Efficacy, 
Safety, and Pharmacokinetics of ACH-0144471 in Untreated Patients With 
Paroxysmal Nocturnal Hemoglobinuria (PNH) 
Study Number: 
ACH471-100 
Protocol Version and 
Date 
Protocol ACH471-100, Amendment 7 
13 March 2018 (Version 8.0) 
This clinical study protocol has been approved by the sponsor. 
Achillion Pharmaceuticals, Inc. 
300 George Street 
New Haven, CT 06511 
Date 
3/13/2018 | 6:04 PM EDT
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Investigator’s Signature(s) 
Study Title: 
A Phase 2 Open-Label Proof of Concept Study to Assess the Efficacy, 
Safety, and Pharmacokinetics of ACH-0144471 in Untreated Patients With 
Paroxysmal Nocturnal Hemoglobinuria (PNH) 
Study Number: 
ACH471-100 
Protocol Version and 
Date 
Protocol ACH471-100, Amendment 7 
13 March 2018 (Version 8.0) 
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 
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Clinical Protocol ACH471-100, Amendment 7 
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Synopsis 
Sponsor: 
Achillion Pharmaceuticals, Inc. 
300 George Street 
New Haven, CT 06511 
Phone: 
 
Name of Finished 
Product: 
ACH-0144471 Tablet, 50, 75, and 100 mg 
Name of Active 
Ingredient: 
ACH-0144471 
Name of Inactive 
Ingredient: 
ACH-0144471 Tablet: Lactose, Microcrystalline Cellulose, Croscarmellose Sodium, Sodium 
Lauryl Sulphate, Magnesium Stearate, Colloidal Silicon Dioxide and Hypromellose Acetate 
Succinate.  The coating components are: polyvinyl alcohol, titanium dioxide, 
macrogol/polyethylene glycol and talc 
Study Title: 
A Phase 2 Open-Label Proof of Concept Study to Assess the Efficacy, Safety, and 
Pharmacokinetics of ACH-0144471 in Untreated Patients With Paroxysmal Nocturnal 
Hemoglobinuria (PNH) 
Study Number: 
ACH471-100 
Study Phase: 
Phase 2 
Primary Objective: 
To evaluate the efficacy of 28 days of oral dosing with ACH-0144471 in currently untreated 
PNH patients, based on decreases in lactate dehydrogenase (LDH) 
Secondary 
Objectives: 
•
To evaluate the efficacy of 28 and 84 days of oral dosing with ACH-0144471 in currently
untreated PNH patients, based on increases in hemoglobin (Hgb) levels
•
To evaluate the safety and tolerability of ACH-0144471 in currently untreated PNH
patients receiving daily oral dosing by assessing SAEs, AEs ≥ Grade 3, and laboratory
abnormalities ≥ Grade 3, and events leading to discontinuation of study drug
•
To evaluate the pharmacokinetic (PK) and pharmacodynamics (PD) profile of
ACH-0144471 in currently untreated PNH patients receiving daily oral dosing for 28 days
Exploratory 
Objectives: 
•
To evaluate the relationship between ACH-0144471 multiple-dose pharmacokinetics and
pharmacodynamics biomarkers through inhibition of complement alternative pathway
(AP) activity (PK/PD)
•
To evaluate health-related quality of life measures in patients with PNH based on patient-
reported outcome instruments and their evolution over the course of ACH-0144471
treatment
•
To explore the benefits of ACH-0144471 treatment as perceived by patients with PNH, by:
o
Exploring patients’ experiences of PNH, its impact on everyday lives and the disease
trajectory, from first symptoms to definitive diagnosis and beyond
o
Documenting the evolution of PNH over the course of ACH-0144471 treatment from
a patient’s perspective
•
To explore patients’ expectations towards ACH-0144471 treatment
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Study Design: 
This is a multiple-center, open-label, multiple dose study.  Patients may be enrolled in a 
pretreatment screening protocol to establish baseline values for the PD, efficacy and safety 
parameters evaluated in this study, or may be directly enrolled into this study. 
During the screening period, patients will be evaluated for eligibility criteria and have 
screening assessments performed.  Screening procedures may be spread over more than one 
visit.  Once patients have been confirmed as eligible, they will be evaluated for history of 
vaccination against Neisseria meningitidis (N. meningitidis), Haemophilus influenzae (H. 
influenzae), and Streptococcus pneumoniae (S. pneumoniae).  Those who have not been 
vaccinated will receive vaccinations during this study, as described in Section 6.3.  Those who 
have been previously vaccinated will receive recommended boosters as described in 
Section 6.3. 
After screening (including vaccinations, when applicable), patients will enter the treatment 
portion of the study which will be conducted in 2 parts.  In Part 1, each participant will receive 
daily oral doses of ACH-0144471 for 28 days.  Based on data from the Phase 1 single-
ascending dose (SAD), multiple-ascending dose (MAD), and Relative Bioavailability (Rel BA) 
studies, and emerging data from the first two patients in this study, the starting dose will be 
150 mg TID and the maximum dose will be 250 mg TID. 
Patients will begin dosing on Day 1.  Patients will return to the clinic on Days 6, 13, and 20 for 
additional intensive PK sampling and other assessments, and will be evaluated for potential 
dose escalations after review of Days 6 and 13 safety and LDH values.  Patients will continue 
dosing until Day 28 for continued collection of safety information.  Dosing for patients not 
continuing to Part 2 will then be tapered over 6 days, as described in Section 5.2.1.  The 
primary efficacy endpoint will be the relative decrease in LDH from baseline after 28 days of 
dosing. 
Based on a review of safety and efficacy data through Day 20 for each individual, patients with 
reductions in LDH meeting specified criteria will be offered continued dosing beyond Day 28 
for up to 8 additional weeks (Part 2).  Patients who do not meet the criteria may be offered 
participation in Part 2 if there has been clinically significant improvement during Part 1 (see 
Section 3.2.3).  Participation in Part 2 will be based on Day 20 data to allow adequate time for 
review and decision making prior to the scheduled end of dosing in Part 1 on Day 28.  Patients 
participating in Part 2 of the study will continue to receive daily oral doses of ACH-0144471, 
and will return for additional visits on Days 42, 56, 70, and 84.  After Day 84, dosing will then 
be tapered over 6 days, as described in Section 5.2.1.  For all patients, a final follow-up visit 
will be conducted approximately 14 days after the last dose. 
Considering PNH is a serious life threatening disease, a long-term extension study, beyond the 
3 months of dosing included in this study, may be offered to patients, if supported by clinical 
and nonclinical data.  Pending regulatory and ethics committee approval of such a study, 
patients who, in the opinion of the Principal Investigator (PI), are receiving benefit from 
ACH-0144471 may be enrolled directly into that study without interruption from this study, 
and will continue to receive daily treatment with ACH-0144471 and safety and efficacy 
monitoring.  Any patients so enrolled will not require a dosing taper or the follow-up visits 
described in this protocol. 
Treatment Groups: 
A single treatment group is planned.  ACH-0144471 will be administered as multiple doses 
over a period of at least 28 days, followed by a taper over 6 days.   
Study Population:  
Currently untreated PNH patients meeting eligibility criteria. 
Number of Patients 
A total of approximately 4 to 12 patients are planned. 
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Inclusion Criteria: 
1.
Currently untreated PNH patients with PNH Type III erythrocyte and/or granulocyte clone
size ≥10% and anemia (Hgb <12 g/dL) with adequate reticulocytosis (as determined by the
investigator)
2.
LDH ≥1.5× upper limit of normal (ULN)
3.
Platelet count ≥50,000/µL without the need for platelet transfusions
4.
Documentation of vaccination for N. meningitidis, H. influenzae, and S. pneumoniae, or
willingness to receive vaccinations as described in Section 6.3
5.
Age ≥18 years (or ≥ minimum adult age in accordance with local legal requirements)
6.
Female participants of childbearing potential must agree to use an acceptable method of
contraception (as defined in Section 5.5.5) from the date of signing the informed consent
to the first day of dosing (Day 1), and must agree to use a highly effective method of
contraception (as defined in Section 5.5.5) from the first day of dosing to 30 days after
their last dose of study drug.  Female participants of childbearing potential must also have
a negative serum pregnancy test during Screening and negative urine pregnancy test on
Day 1.
Female participants of non-childbearing potential need not employ a method of
contraception.
7.
Non-sterile male participants must agree to use a highly effective method of contraception
(as defined in Section 5.5.5) with their partner(s) of childbearing potential from the first
day of dosing to 90 days after their last dose of study drug.
Males who are surgically sterile need not employ additional contraception.
Males must agree not to donate sperm while enrolled in this study and for 90 days after
their last dose of study drug.
8.
Must agree to provide written informed consent
9.
Must be willing, at all times, to have transportation and telephone access, and to be within
one hour of an emergency medical center
Exclusion Criteria 
1.
History of a major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem
cell/marrow transplant
2.
History of dosing with another investigational agent within 30 days or 5 half-lives of the
investigational agent prior to study drug administration, whichever is greater
3.
History of dosing with eculizumab at any dose or interval within the past 75 days before
study drug administration
4.
Known or suspected complement deficiency
5.
Contraindication to one or more of the required vaccinations
6.
Active bacterial infection or clinically significant active viral infection, a body
temperature >38°C, or other evidence of infection on Day 1, or history of febrile illness
within 14 days prior to first study drug administration
7.
History of meningococcal infection, or a first-degree relative or household contact with a
history of meningococcal infection
8.
History of hypersensitivity reactions to commonly used antibacterial agents, including
beta-lactams, penicillin, aminopenicillins, fluoroquinolones (specifically including
ciprofloxacin), cephalosporins, and carbapenems, which in the opinion of the investigator
would make it difficult to properly provide either empiric antibiotic therapy or treat an
active infection
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9. 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) 
10. Laboratory abnormalities at screening, including: 
• 
Alkaline phosphatase (ALP) >1.5× upper limit of normal (ULN) 
• 
Absolute neutrophil count (ANC) <1,000/μL 
• 
Alanine aminotransferase (ALT) > ULN 
• 
Any other clinically significant laboratory abnormality that, in the opinion of the 
Primary Investigator (PI), would make the patient inappropriate for the study or put 
the patient at undue risk 
11. 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 
12. Prior history or current evidence of biliary cholestasis 
13.  Gilbert’s syndrome 
Patients with history or family history suggestive of Gilbert’s syndrome should be tested 
and excluded from study if positive for UGT1A1 genotyping polymorphism or missense 
change 
14. Evidence of human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection 
(positive serology for HIV-1 antibody (HIV Ab), positive hepatitis B surface antigen 
(HbsAg), or positive anti-HCV antibody (HCV Ab) at Screening or historically) 
Criteria to Escalate 
to a Higher Dose  
Decisions to dose escalate or change the dosing regimen will be made by the site PI.  The 
Sponsor will be notified of dose escalation/regimen changes and any study termination 
decisions. 
1st Dose Escalation Point (Day 7) 
On a patient-by-patient basis, if the starting dose of 150 mg TID is well tolerated and 
the available safety data are satisfactory, a patient may be escalated to 175 mg TID if 
his/her Day 6 LDH level, as measured locally, is still greater than 50% of his/her 
baseline value, unless the patient has achieved <1× ULN for LDH.  Depending on 
when these data are received and reviewed, if the patient is going to dose escalate, the 
site should contact the patient as soon as possible (Days 6-8) to provide new dosing 
instructions.  If necessary, the patient may be asked to return to the clinic for new 
drug supplies. 
2nd Dose Escalation Point (Day 14) 
On a patient-by-patient basis, if the patient was not dose escalated at Day 7, the 
150 mg TID dose is well tolerated, and the available safety data are satisfactory, a 
patient may be escalated to 175 mg TID if his/her Day 13 LDH level, as measured 
locally, is still greater than 20% of his/her baseline value, unless the patient has 
achieved <1× ULN for LDH.  Depending on when these data are received and 
reviewed, if the patient is going to dose escalate, the site should contact the patient as 
soon as possible (Days 13-15) to provide new dosing instructions.  If necessary, the 
patient may be asked to return to the clinic for new drug supplies. 
In addition to the dose escalation evaluations defined above, the PI, in consultation with the 
Sponsor, may escalate dosing in increments of 25 mg to a maximum of 250 mg TID after 
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evaluating the clinical benefit and the available safety, PK, and PD data (including laboratory 
test results) in order to improve control of hemolysis.  
The dose will not be escalated for a patient if one or more of the following occurs: 
• 
Patient experiences a study drug-related Grade 4 adverse event (AE) 
• 
It is determined that the limit of safety and/or tolerability has been reached.  This 
decision will be made following discussions between the sponsor’s Medical Monitor 
and the site PI 
• 
The maximum allowed dose of 250 mg TID has already been reached 
• 
LDH level, as measured locally, is reduced to ≤50% relative to baseline by Day 6, or 
to ≤20% relative to baseline by Day 13 
If a patient has been dose escalated, patients may be dose reduced to a lower dose for safety or 
tolerability reasons following consultation between the investigator and the Achillion medical 
monitor. 
Based on Day 20 LDH results, if a patient’s LDH level is still less than or equal to 20% of 
his/her baseline value and remains <1.5× ULN for LDH, then the patient will be permitted to 
continue dosing after Day 28 by entering Part 2 of the study without further approval from the 
sponsor.  
For patients who do not meet the preceding definition, the investigator will discuss with the 
sponsor about progressing the patient to Part 2 of the study if they believe that there has been 
clinically significant improvement in Part 1.  This discussion and the resulting decision and 
rationale will be documented in the site file. 
Individual Stopping 
Criteria: 
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 
(exceptions may be considered at the request of the investigator if the event can be 
managed by dose reduction or interruption); 
• 
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 
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 clinically significant elevation in Total Bilirubin* relative to 
baseline  
* Because patients may have ongoing hemolysis which may result in increased bilirubin and 
AST, increases in bilirubin and/or AST during the study must be evaluated in the context of 
any continuing hemolysis.  The PI should evaluate LDH and Hgb levels as well as baseline 
bilirubin and AST levels to determine if the increases observed are due to an effect on liver 
function or are secondary to hemolysis.   
Test Product; 
Dosage Form; and 
Strength: 
ACH-0144471, administered orally as 50, 75, or 100 mg tablets 
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Mode of 
Administration: 
Oral 
Duration of 
Treatment, 
Confinement, and 
Total Study 
Participation 
Each patient will receive multiple doses of ACH-0144471 tablets for a total of 28 days during 
Part 1, and may be treated for an additional 8 weeks if they participate in Part 2.  Additionally, 
there will be a 6-day taper at the end of treatment, for a total treatment duration of up to 90 
days.  Including the taper, the total study duration for patients who complete Part 1 but do not 
participate in Part 2 will be 48 days, not including screening.  For patients who participate in 
both Part 1 and Part 2, the total study duration will be up to 104 days, not including screening.  
There are no overnight stays in the clinic.  The maximum screening period is up to 60 days. 
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 the Schedule of Assessments.  Due to the 
increased risk of infection from treatment with complement inhibitors, patients in this study 
will receive vaccinations and will be carefully monitored for the development of fever.  
Pharmacokinetic 
Assessments: 
Blood samples will be collected as described in Section 6.14, at the times indicated in the 
schedule of assessments in Appendix 1, to determine plasma concentrations of ACH-0144471.  
Multiple-dose PK parameters of ACH-0144471, including tmax, Cmax and AUC0-tau will be 
determined at each dose level using validated bioanalytical methods.  Single trough PK 
samples will be taken at other time points. 
Pharmacodynamic 
and Efficacy 
Assessments 
Pharmacodynamics will be evaluated as described in Section 6.15, using serum, plasma, or 
whole blood collected during the study. 
Samples will be collected and retained for non-genetic complement-associated biomarker 
testing and potentially may also be retained for genetic complement-associated biomarker 
testing, as discussed in Section 6.11.2. 
Efficacy will be assessed using LDH and hemoglobin levels and other measures of hemolysis, 
as well as RBC transfusion requirements. 
Patient-reported 
Outcomes 
Assessments 
Quality of Life (QoL) assessments will be conducted at various time points as specified in 
schedule of assessment in Appendix 1 using the tools in Appendix 2.  The FACIT Fatigue scale 
(Version 4) questionnaire and the EORTC-QLQ-C30 scale will be administered to patients to 
collect patients’ health-related QoL at baseline and after treatment with ACH-0144471, 
respectively. 
In addition, interviews by independent outcomes researchers chosen by the Sponsor will be 
conducted with patients prior to initiation of study treatment (during the screening period) to 
collect patients’ experience of PNH, its impact on everyday lives and the disease trajectory.  
For patients enrolled in the Screening Study (ACH471-102), the interview conducted as part of 
that study will replace the screening interview in the current study.  At the end of Part 1 (Day 
28 ± 1 week), phone interviews will be conducted with all patients to collect patients’ 
experience of ACH-0144471 treatment and their perception of the evolution of their condition.  
Patients continuing in Part 2 will also be interviewed at the end of Part 2 (Day 84 ± 1 week).  
The interviews will be conducted over the phone by a trained, experienced interviewer and will 
last approximately 30 minutes.  For patients who terminate early, a follow-up interview will be 
obtained at the time of termination.  
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Statistical Methods:  
Summary statistics will be provided for the following efficacy, safety, PK, and PD parameters: 
• 
Efficacy parameters: 
o 
Primary: Change in LDH level relative to baseline at Day 28  
o 
Secondary:  
 
Change in Hgb level at Day 28 relative to baseline 
 
Change in Hgb level relative to baseline at Day 84 
 
Change in LDH level relative to baseline at Day 84 
• 
Safety parameters: 
o 
SAEs 
o 
AEs leading to discontinuation of the study medication 
o 
AEs (related and regardless of relationship to study medication) 
o 
Laboratory abnormalities by toxicity grade 
• 
PK, PD, and biomarker parameters: 
o 
Selected chemistry and hematology measures 
o 
PK parameters at various time points  
o 
PD markers/assays to assess the biological effect of ACH-0144471 on the classical 
and alternative pathways of complement 
• 
Patient-reported outcomes 
o 
FACIT Fatigue scale (Version 4) 
o 
EORTC QLQ-C30 
All continuous variables will be summarized using descriptive statistics including number of 
observations, number of missing data, mean, standard deviation (SD), minimum (min), median 
(med), and maximum (max).  All categorical variables will be summarized using frequency 
counts and percentages. 
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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 ........................................................................................16 
1 
Introduction ........................................................................................................................................18 
1.1 
Results of Nonclinical Studies ...................................................................................................18 
1.2 
Previous Human Experience with ACH-0144471 .....................................................................18 
1.3 
Rationale ....................................................................................................................................19 
1.3.1 Complement Factor D ............................................................................................................19 
1.3.2 Paroxysmal Nocturnal Hemoglobinuria (PNH) .....................................................................20 
1.3.3 Potential Advantages of ACH-0144471 in the Treatment of PNH ........................................20 
1.3.4 Safety Considerations .............................................................................................................21 
1.3.4.1 
Risk of Infection ............................................................................................................21 
1.3.4.2 
Hepatic Injury ................................................................................................................21 
2 
Study Objectives .................................................................................................................................22 
2.1 
Primary Objective ......................................................................................................................22 
2.2 
Secondary Objectives ................................................................................................................22 
2.3 
Exploratory Objectives ..............................................................................................................22 
3 
Investigational Plan ............................................................................................................................23 
3.1 
Overall Study Design and Plan ..................................................................................................23 
3.2 
Rationale for Study Design ........................................................................................................26 
3.2.1 Justification of Design ............................................................................................................26 
3.2.2 Justification of Dose ...............................................................................................................26 
3.2.3 Criteria to Escalate to a Higher Dose or Change the Dosing Regimen ..................................26 
3.2.4 Individual Stopping Criteria ...................................................................................................28 
3.3 
Study Duration and Dates ..........................................................................................................28 
4 
Study Population Selection ................................................................................................................29 
4.1 
Study Population ........................................................................................................................29 
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4.2 
Inclusion Criteria .......................................................................................................................29 
4.3 
Exclusion Criteria ......................................................................................................................29 
5 
Study Treatment(s) .............................................................................................................................31 
5.1 
Study Drug .................................................................................................................................31 
5.2 
Treatment(s) Administered ........................................................................................................31 
5.2.1 ACH-0144471 ........................................................................................................................31 
5.2.2 Vaccines .................................................................................................................................31 
5.3 
Selection of Timing and Dose for Each Patient .........................................................................31 
5.3.1 Clinic Visit Dose Administration Instructions .......................................................................32 
5.3.2 Home Dose Administration Instructions ................................................................................32 
5.4 
Method of Assigning Patients to Treatment Groups .................................................................32 
5.5 
Restrictions ................................................................................................................................32 
5.5.1 Prior Therapy ..........................................................................................................................32 
5.5.2 Concomitant Therapy .............................................................................................................32 
5.5.3 Fluid and Food Intake .............................................................................................................33 
5.5.4 Patient Activity and Other Restrictions ..................................................................................33 
5.5.5 Contraception .........................................................................................................................33 
5.5.5.1 
Contraception for Male Participants ..............................................................................33 
5.5.5.2 
Contraception for Female Participants ..........................................................................34 
5.6 
Treatment Compliance ...............................................................................................................35 
5.7 
Packaging and Labeling .............................................................................................................35 
5.8 
Storage and Accountability ........................................................................................................36 
5.9 
Investigational Product Retention at Study Site ........................................................................36 
6 
Study Procedures ................................................................................................................................37 
6.1 
Informed Consent ......................................................................................................................37 
6.2 
Medical History .........................................................................................................................37 
6.3 
Vaccination ................................................................................................................................37 
6.4 
Prophylactic Antibiotics ............................................................................................................38 
6.5 
Physical Examination ................................................................................................................38 
6.6 
Vital Signs ..................................................................................................................................38 
6.7 
Body Temperature .....................................................................................................................38 
6.8 
Electrocardiography ...................................................................................................................39 
6.9 
Clinical Laboratory Measurements ............................................................................................39 
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6.10 
Pregnancy Testing ......................................................................................................................41 
6.11 
Sample Collection, Storage, and Shipping ................................................................................41 
6.11.1 Blood Collection for Complement Assays (AP Wieslab, CH50, C3, Bb, and fD) ................41 
6.11.2 PD Samples for Genetic and Additional Non-genetic Complement-associated Biomarker 
Testing, and for Determination of Vaccine Response ............................................................41 
6.11.3 PK Plasma Samples ................................................................................................................41 
6.11.4 Blood Volumes .......................................................................................................................42 
6.12 
Dispensing Study Drug ..............................................................................................................43 
6.13 
Safety Assessments ....................................................................................................................44 
6.14 
Pharmacokinetic Assessments ...................................................................................................44 
6.15 
Pharmacodynamic and Efficacy Assessments ...........................................................................44 
6.16 
Patient-Reported Outcomes Assessments ..................................................................................45 
6.17 
Adverse Events Assessments .....................................................................................................45 
6.17.1 Definitions ..............................................................................................................................45 
6.17.2 Criteria for Assessing Seriousness .........................................................................................47 
6.17.3 Documentation and Reporting of Adverse Events .................................................................47 
6.17.4 Treatment and Follow-up of Adverse Events .........................................................................48 
6.17.5 Timeframe for Collection of Adverse Events ........................................................................48 
6.17.6 Severity and Grading of Adverse Events ...............................................................................48 
6.17.7 Assessment of Causality .........................................................................................................49 
6.17.8 Pregnancy ...............................................................................................................................49 
6.17.9 Reporting Serious Adverse Events .........................................................................................50 
6.17.10 
Investigator Reporting Requirements for SAEs ............................................................51 
6.18 
Concomitant Medication Assessments ......................................................................................51 
6.19 
Monitoring Patient Safety ..........................................................................................................52 
6.20 
Removal of Patients from the Trial ............................................................................................52 
7 
Study Activities ..................................................................................................................................53 
7.1 
Screening Activities ...................................................................................................................53 
7.1.1 Screening Visit (Days –60 to -1) ............................................................................................53 
7.1.2 Vaccination Visit(s) (Days -42 to Day -14, if required) .........................................................54 
7.1.3 Patient Reported Outcomes Interview - Screening ................................................................54 
7.2 
On-Study Activities ...................................................................................................................54 
7.2.1 Clinic Visits ............................................................................................................................54 
7.2.2 Safety Follow up at Local Laboratory ....................................................................................55 
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7.2.3 Safety Follow up After Escalation .........................................................................................55 
7.2.4 Patient Reported Outcomes Interview – Day 28 (± 1 week) and Day 84 (± 1 week) ............55 
7.2.5 Dosing Taper ..........................................................................................................................55 
7.2.6 Follow-Up Visit ......................................................................................................................55 
7.2.7 Unscheduled Visits .................................................................................................................56 
8 
Quality Control and Assurance ..........................................................................................................57 
8.1 
Routine Monitoring ....................................................................................................................57 
8.2 
Site Audits ..................................................................................................................................57 
9 
Planned Statistical Methods ...............................................................................................................58 
9.1 
General Considerations ..............................................................................................................58 
9.2 
Determination of Sample Size ...................................................................................................58 
9.3 
Analysis Populations ..................................................................................................................58 
9.4 
Demographics and Baseline Characteristics ..............................................................................58 
9.5 
Efficacy Analysis .......................................................................................................................58 
9.6 
Safety Analysis ..........................................................................................................................59 
9.7 
Pharmacokinetic (PK) Analysis .................................................................................................59 
9.8 
Pharmacodynamic (PD) Analysis ..............................................................................................59 
9.9 
PK/PD Assessments ...................................................................................................................60 
9.10 
Patient-Reported Outcomes Assessments ..................................................................................60 
9.10.1 Quality of Life Scales .............................................................................................................60 
9.10.2 Patient Interviews ...................................................................................................................60 
10 Administrative Considerations ...........................................................................................................61 
10.1 
Investigators and Study Administrative Structure .....................................................................61 
10.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) and Regulatory 
Approval ....................................................................................................................................61 
10.2.1 Ethical Approval .....................................................................................................................61 
10.2.2 Regulatory Approval ..............................................................................................................61 
10.2.3 Amendments ...........................................................................................................................61 
10.3 
Ethical Conduct of the Study .....................................................................................................61 
10.4 
Patient Information and Consent ...............................................................................................61 
10.5 
Patient Confidentiality ...............................................................................................................62 
10.6 
Study Monitoring .......................................................................................................................62 
10.6.1 Access to Information for Monitoring ....................................................................................62 
10.6.2 Access to Information for Auditing or Inspections ................................................................63 
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10.7 
Case Report Forms and Study Records .....................................................................................63 
10.7.1 Recording of Data ..................................................................................................................63 
10.7.2 Source Documentation and Medical/Study Records ..............................................................63 
10.8 
Data Monitoring Committee ......................................................................................................63 
10.9 
Protocol Violations/Deviations ..................................................................................................63 
10.10 Access to Source Documentation ..............................................................................................63 
10.11 Data Generation and Analysis ...................................................................................................64 
10.12 Retention of Data .......................................................................................................................64 
10.13 Final Report, Publication and Disclosure Policy .......................................................................65 
11 References ..........................................................................................................................................66 
12 Appendices .........................................................................................................................................68 
 
List of Tables 
Table 1. 
Dosing Taper Schedule ......................................................................................................31 
Table 2. 
Clinical Laboratory Tests ...................................................................................................40 
Table 3. 
Approximate Total Blood Volumes ...................................................................................43 
Table 4. 
Pharmacodynamic Markers ...............................................................................................44 
Table 5. 
Schedule of Assessments ...................................................................................................69 
Table 6. 
PK and PD Sampling on Days 6, 13, and 20 .....................................................................73 
 
List of Figures 
Figure 1. 
Study Schematic.................................................................................................................25 
 
List of Appendices 
Appendix 1. 
Schedule of Assessments ...................................................................................................69 
Appendix 2. 
Quality of Life Assessments ..............................................................................................74 
Appendix 3. 
Grading the Severity of Adult Adverse Events ..................................................................79 
Appendix 4. 
Fever Management Plan ....................................................................................................80 
 
 
 
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List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
1A1 
Cytochrome P450 family 1 subfamily A member 1 
ACIP 
Advisory Committee on Immunization Practices 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AP 
Alternative Pathway (of complement)  
AST 
Aspartate aminotransferase 
AUC  
Area under the curve 
BA 
Bioavailability 
Bb 
Bb fragment of complement factor B 
BID 
"bis in die" or twice daily 
BP 
Blood pressure 
BMI 
Body mass index 
°C 
Degrees Celsius 
C3 
C3 complement protein 
C5 
C5 complement protein 
CH50 
a measurement of general function of complement classical pathway 
CK  
Creatine kinase 
Cmax 
Maximum plasma concentration 
CRF 
Case report form 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ELISA 
Enzyme-linked immunosorbent assay 
FDA 
Food and Drug Administration 
fB 
Complement Factor B 
fD 
Complement Factor D 
FSH  
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GPI 
glycosylphosphatidylinositol 
HbsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
Hct 
Hematocrit 
Hgb 
Hemoglobin  
HCV 
Hepatitis C virus 
HIPAA 
Insurance Portability and Accountability Act of 1996 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
HSCT 
Hematopoietic stem cell transplantation 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC  
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional review board 
IV 
Intravenous 
kDa 
Kilodalton 
LDH 
Lactate dehydrogenase 
LFC 
Liquid-filled capsule 
LLN 
Lower limit of normal 
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Abbreviation 
Definition 
MAC 
Membrane attack complex 
MAD 
Multiple-ascending dose 
max 
Maximum 
MDRD 
Modification of Diet in Renal Disease equation 
med 
Median  
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
Minimum  
NOAEL 
No observed adverse effect level 
NOEL 
No observable effect level 
PD 
Pharmacodynamic(s) 
PI 
Principal investigator 
PIGA 
Phosphatidylinositol N-acetylglucosaminyltransferase subunit A 
PK 
Pharmacokinetic(s) 
PNH 
Paroxysmal Nocturnal Hemoglobinuria 
PR 
PR interval 
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 
QoL 
Quality of Life 
QRS 
Group of electrocardiogram waves comprising the Q, R, and S waves 
QT 
QT interval 
QTc 
Corrected QT 
QTcF 
QT interval Fridericia Correction Formula  
RBC  
Red blood cells 
Rel BA 
Relative bioavailability study 
RR 
Respiration rate 
SAD 
Single ascending dose 
SAE  
Serious adverse event 
SAP  
Statistical Analysis Plan 
SD 
Standard deviation 
TE 
Treatment-emergent 
TEAE 
Treatment-emergent adverse event 
TID 
"ter in die" or three times daily 
tmax 
Time after administration of a drug when the maximum plasma concentration is reached 
UGT1A1 
Uridine diphosphate glucuronosyltransferase family 1 member A1 
ULN 
Upper limit of normal 
µM 
Micromolar 
WBC  
White blood cells 
 
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1 Introduction 
This is a multiple-center, open-label, multiple dose study, and will be the first study in which 
ACH-0144471 is administered to patients with paroxysmal nocturnal hemoglobinuria (PNH).  Dosing has 
been determined based on data from the first-in-human single-ascending dose (SAD), multiple ascending 
dose (MAD), and Relative Bioavailability (Rel BA) studies in healthy volunteers. 
Many inflammatory, autoimmune, neurodegenerative and age-related diseases, including PNH, are 
associated with either normal complement system activity acting on cells which are missing complement 
regulatory proteins, or alterations of complement regulation itself [1].  ACH-0144471 is a small 
molecule, orally administered complement factor D (fD) inhibitor being developed by Achillion 
Pharmaceuticals, Inc. for the treatment of patients with PNH to reduce hemolysis and other complement-
mediated diseases.  ACH-0144471 could potentially represent an important advance for the treatment of 
several complement-mediated diseases as it targets complement fD, the control point for the 
complement amplification loop [2] as well as providing the convenience of oral dosing. 
1.1 Results of Nonclinical Studies 
Please refer to the Investigator’s Brochure (IB) [3] 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 
Three clinical studies with ACH-0144471 have been conducted: ACH471-001 Single Ascending Dose 
Study (SAD), ACH471-002 Multiple Ascending Dose Study (MAD) and ACH471-006 Relative 
Bioavailability Study (Rel BA).  One hundred and fifteen (115) healthy volunteers have participated in 
clinical studies with ACH-0144471, of which 87 have received ACH-0144471, and the remaining 
received placebo.  Preliminary results from all 3 studies are presented in the IB [3]. 
The SAD study was performed to evaluate the safety and tolerability of single ascending doses of 
ACH-0144471.  Healthy volunteers were dosed with ACH-1044471 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 with PNH 
in phase 2 studies.  Healthy volunteers were dosed with ACH-1044471 in four separate groups.  
Groups 1 through 3 received multiple daily doses of 200, 500, and 800 mg, respectively, twice daily for 
14 days.  Group 4 received doses of 75 mg every 8 hours for 7 days.  All doses were given in the fasted 
state.  Based on preliminary information, ACH-0144471 administered as 200 mg every 12 hours for 
14 days was well-tolerated.  The higher doses studied (500 and 800 mg administered every 12 hours for 
14 days) were associated with elevations in alanine aminotransferase (ALT) levels in some patients.  In 
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Group 4, a dosing regimen of 75 mg administered every 8 hours for 7 days was well-tolerated and 
resulted in ACH-0144471 trough concentrations that have the potential for efficacy in PNH and other 
complement-mediated diseases. 
The pharmacodynamics (PD) and potential for clinical efficacy for ACH-0144471 is primarily 
associated with maintenance of exposure above a target trough level.  Exploratory ex vivo alternative 
pathway (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) [4].  
Pharmacokinetic modeling, based on data from the SAD and MAD studies, predicts that plasma trough 
ACH-0144471 concentrations can be increased substantially with minimal increase Cmax or AUC, 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.  Based on these analyses and additional emerging data from 
the first 2 patients enrolled in this study (see Section 3.2.2), 150 mg TID is expected to provide clinical 
efficacy, and is selected as the starting dose for this study.  All patients enrolled in ACH471-100 to date 
have dose escalated to 200 mg TID with no clinically significant alterations in liver enzymes.  
The SAD and MAD studies were conducted using liquid-filled capsules (LFC).  Studies in PNH patients 
will be performed using a tablet formulation.  A Relative BA study was performed to compare 
bioavailability of the LFC and the tablet formulations.  This was a randomized, crossover, open-label 
study to assess the relative bioavailability of ACH-0144471 in tablet and softgel capsule formulations 
relative to the extemporaneously prepared LFC used in the SAD and MAD studies.  Based on 
preliminary information, AUC0-∞ was bioequivalent and Cmax slightly lower (19%) for ACH-0144471 
tablets administered with food relative to the LFC formulation given under fasting conditions as in the 
SAD and MAD studies.  ACH-1044471 was well-tolerated in this study, and there were no SAEs, no 
discontinuations due to TEAEs, and no drug-related Grade 3 or 4 TEAEs.  
Another study in patients with C3 Glomerulopathy (C3G) or Immune-Complex Membranoproliferative 
Glomerulonephritis (IC-MPGN), ACH471-201, is ongoing.  The trial will evaluate the ability of 
ACH-0144471, given for 14 days, to increase C3 levels via inhibition of fD. 
1.3 Rationale 
1.3.1 Complement Factor D 
Factor D (fD) is one of nine serine proteases in the complement system.  It is a highly specific enzyme 
with only one known substrate, factor B (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, 5].  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, 5].  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 [6, 7].  The biochemical, physiological, and functional features of fD make it an attractive 
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target for pharmacological inhibition as this may prove useful in the treatment of a wide spectrum of 
complement-mediated diseases such as PNH. 
1.3.2 Paroxysmal Nocturnal Hemoglobinuria (PNH) 
PNH is a rare disease of unknown frequency both in the United States and worldwide.  One small study 
conducted in Great Britain and France, reported in 1995, provided an incidence rate of approximately 
1.3 cases/1 million inhabitants.  Attempts to get a more accurate incidence and to learn more about its 
natural course are currently under way under the auspices of the PNH Registry [8]. 
PNH may occur at any age; it has been reported in children as young as 2 years to adults as old as 
83 years, but it is most frequently diagnosed in adults, with a median age at diagnosis of approximately 
40 years.  Men and women are affected equally, and no familial tendencies exist.  It has been suggested 
that PNH, like aplastic anemia, with which it is associated, may be more frequent in Southeast Asia and 
in the Far East. 
PNH is caused by a somatic mutation in the PIGA gene in hematopoietic stem cells, resulting in the loss 
of glycosylphosphatidylinositol (GPI) anchored proteins, including the complement regulatory proteins 
CD55 and CD59, from the surface of mutant red blood cells (RBCs).  This leaves these mutant RBCs 
vulnerable to intravascular hemolysis mediated by the membrane attack complex (MAC) of complement 
and to extravascular hemolysis presumably mediated by C3 fragment opsonization primarily due to 
constitutive activation of the complement alternative pathway via tickover mechanism [9].  In addition 
to anemia that requires frequent RBC transfusions, there are other serious sequelae related to the 
liberation of intracellular hemoglobin and its consequent derangement of nitric oxide levels in the 
vasculature.  These effects include an increased risk of thrombotic events as well as painful vascular 
crises. 
The only curative treatment for PNH is hematopoietic stem cell transplantation (HSCT) using allogeneic 
donors.  Given the high transplant-related mortality, especially when using unrelated or mismatched 
donors, HSCT is generally not offered as initial therapy for most patients with classic PNH.  The only 
drug approved to treat PNH is eculizumab, a monoclonal antibody directed against complement C5, 
which prevents intravascular hemolysis by inhibiting formation of the terminal complement complex.  
Other supportive therapies include: recombinant erythropoietin, corticosteroids, and androgens to 
stimulate erythropoiesis; anticoagulants to treat thrombotic complications; and immunosuppressive 
agents to stimulate hematopoiesis in the aplastic phase. 
1.3.3 Potential Advantages of ACH-0144471 in the Treatment of PNH 
PNH is a serious life threatening disease and there are unmet needs in this population that are not 
addressed by eculizumab that could potentially be addressed by an effective oral fD inhibitor.  Three 
groups of patients who are not adequately served by eculizumab and could receive benefit from 
ACH-0144471 can be identified: 
• Patients who have a suboptimal response to eculizumab (approximately 25% - 30%), presumably 
largely due to extravascular hemolysis that is mediated by C3 opsonization.  Eculizumab treatment 
spares the hemolytic destruction of PNH erythrocytes by the MAC (terminal stage of the 
complement pathway); however, it does not prevent deposition of C3 fragments on PNH erythrocyte 
membranes which can direct their extravascular hemolysis [10].  ACH-0144471 has a potential 
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mechanistic advantage since it acts upstream of C3 cleavage and has been shown to block C3 
fragment deposition. 
• Patients who respond partially to eculizumab due to a genetic polymorphism in CR1 (e.g., HindIII 
H/L and L/L genotypes [11]), which has been postulated to result in an increased proportion of C3-
opsonized RBCs, may have an improved treatment response with ACH-0144471. 
• Rare patients (~1%) with no response to eculizumab due to mutations in C5 (e.g., Arg885His) [12] 
could also benefit from ACH-0144471 because ACH-0144471 acts at a different target in the 
complement cascade and should be unaffected by a mutation in C5. 
Additionally, oral administration of ACH-0144471 would be an advantage compared to systemic 
intravenous administration of eculizumab which is given weekly in the initial phase of treatment and 
then every two weeks as maintenance therapy. 
1.3.4 Safety Considerations 
1.3.4.1 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 fD, inhibition of the complement system may result in a lifetime increased risk of 
infection, notably with Neisseria meningitidis (N. meningitidis) [13, 14, 15], and other encapsulated 
organisms. 
Because of this potential risk, special safety precautions will be taken for patients participating in 
ACH471-100.  Patients will be required to be previously vaccinated, or to receive vaccinations for 
N. meningitidis, Streptococcus pneumoniae (S. pneumoniae), and Haemophilus influenzae (H. 
influenzae) (see Section 6.3). 
During clinic visits, patients will be monitored for the development of fever.  A specific Fever 
Management Plan (Appendix 4) has been developed for this study.  Patients will also be counseled about 
behaviors to avoid and also be asked to monitor themselves between clinic visits (Appendix 4). 
1.3.4.2 Hepatic Injury 
In humans, elevations in ALT levels have been observed in some healthy volunteers with doses of 
500 mg twice daily and 800 mg twice daily for 14 days, doses higher than the currently anticipated 
clinical dose.  The ALT elevations were not associated with signs or symptoms of hepatic failure, 
occurred after completion of dosing, and were self-limited. 
Additionally, DILIsym simulations indicate maximal loss of hepatocytes that occurred at the high doses 
in the MAD study would not have a significant effect on liver function [16].  Simulated dosing at 250, 
300, and 325 mg TID for up to 1 year predicted minor, clinically insignificant (<1× ULN) ALT 
increases 17].  
In nonclinical studies, hepatobiliary cholestasis has been observed in the dog toxicology studies at 
exposures higher than those intended for clinical use.  Therefore, alkaline phosphatase, gamma-glutamyl 
transferase (GGT), total/direct/indirect bilirubin, aspartate aminotransferase (AST), and ALT will be 
closely monitored in all clinical studies with ACH-0144471. 
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2 Study Objectives 
2.1 Primary Objective 
The primary objective of this study is to evaluate the efficacy of 28 days of oral dosing with 
ACH-0144471 in currently untreated PNH patients, based on decreases in lactate dehydrogenase (LDH). 
2.2 Secondary Objectives 
The secondary objectives of this study are: 
• To evaluate the efficacy of 28 and 84 days of oral dosing with ACH-0144471 in currently 
untreated PNH patients, based on increases in Hgb levels 
• To evaluate the safety and tolerability of ACH-0144471 in currently untreated PNH patients 
receiving daily oral dosing by assessing SAEs, adverse events (AEs) ≥ Grade 3, laboratory 
abnormalities ≥ Grade 3, and AEs leading to discontinuation of study drug 
• To evaluate the PK and PD profile of ACH-0144471 in currently untreated PNH patients 
receiving daily oral dosing for 28 days 
2.3 Exploratory Objectives 
The exploratory objectives of this study are: 
• To evaluate the relationship between ACH-0144471 multiple-dose pharmacokinetics and 
pharmacodynamic biomarkers through inhibition of AP activity (PK/PD) 
• To evaluate health-related QoL based on patient-reported outcome (PRO) instruments and its 
evolution over the course of ACH-0144471 treatment 
• To explore the benefits of ACH-0144471 treatment as perceived by patients with PNH, by: 
o Exploring patients’ experiences of PNH, its impact on everyday lives and the disease trajectory, 
from first symptoms to definitive diagnosis and beyond 
o Documenting the evolution of PNH over the course of ACH-0144471 treatment from a patient’s 
perspective 
• To explore patients’ expectations towards ACH-0144471 treatment 
 
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3 Investigational Plan 
3.1 Overall Study Design and Plan 
This is a multiple-center, open-label, multiple dose study.  Screening data may be collected during the 
Screening Phase of this study or if the patient has been previously enrolled in Study ACH471-102, 
during that study.  Baseline values for the PD and safety parameters will be evaluated during screening. 
During screening, patients will be evaluated for eligibility criteria and have screening assessments 
performed.  Screening procedures may be spread over more than one visit.  A window of up to 60 days 
is permitted to allow screening followed by any required vaccinations; if a patient is participating in the 
preliminary screening study (ACH471-102), vaccinations may already have been administered, and tests 
performed as part of that study within 30 days of first administration of study drug and may fulfill 
screening requirements for this study.  Once patients have been confirmed as eligible, they will be 
evaluated for history of vaccination against N. meningitidis, H. influenzae, and S. pneumoniae.  Those 
who have not been vaccinated will receive vaccinations during this study according to the schedule 
described in Section 6.3.  Those who have been previously vaccinated will receive recommended 
boosters as described in Section 6.3.  After screening and any vaccination procedures occurring before 
dosing, patients will enter the treatment portion of the study which will be conducted in 2 parts 
(Figure 1).  In Part 1, each participant will receive daily oral doses of ACH-0144471 for 28 days.  In 
Part 2, patients may continue dosing for an additional 8 weeks (56 days).  
Patients will begin dosing on Day 1.  Patients will return to the clinic on Days 6, 13, and 20 for 
additional intensive PK sampling and other assessments, and will be evaluated for dose escalation as 
described in Section 3.2.2.  Patients will continue dosing until Day 28 for continued collection of safety 
information.  Dosing for patients not continuing to Part 2 will then be tapered over 6 days, as described 
in Section 5.2.1.   
Based on a review of safety and efficacy data through Day 20 for each individual, patients with 
reductions in LDH meeting the criteria specified in Section 3.2.3 will be offered continued dosing 
beyond Day 28 for an additional 8 weeks (Part 2).  Patients who do not meet the criteria may be offered 
participation in Part 2 if there has been clinically significant improvement during Part 1, as described in 
Section 3.2.3.  Participation in Part 2 will be based on Day 20 data to allow adequate time for review 
and decision making prior to the scheduled end of dosing in Part 1 on Day 28.  Patients participating in 
Part 2 of the study will continue to receive daily oral doses of ACH-0144471, and will return for follow-
up visits on Days 42, 56, 70, and 84.  On Days 35, 49, 63, and 77 patients will have local safety labs 
drawn.  After Day 84, dosing will then be tapered over 6 days, as described in Section 5.2.1.  For all 
patients, a final follow-up visit will be conducted approximately 14 days after the last dose. 
The FACIT Fatigue Scale (Version 4) questionnaire and the EORTC-QLQ-C30 (Version 3) will be 
administered to patients at the schedule indicated in Appendix 1 using the tools provided in Appendix 2, 
to collect patients’ health-related quality of life at baseline and after treatment with ACH-0144471. 
In addition, patients will be interviewed by an independent outcomes researcher chosen by the Sponsor 
to collect their experience of PNH, its impact on everyday lives and the disease trajectory, and, 
following treatment, to collect patients’ experience of ACH-0144471 treatment and their perception of 
the evolution of their condition.  The interviews will be conducted over the phone by a trained, 
experienced interviewer and will last approximately 30 minutes. 
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Patients who have not been included in the Screening Study (protocol ACH471-102) will be interviewed 
during the screening period (prior to study initiation).  Interviews for all patients will be conducted at the 
end of Part 1 (Day 28 ± 1 week).  Patients continuing in Part 2 will also be interviewed at the end of 
Part 2 (Day 84 ± 1 week).  For patients who terminate early, a follow-up interview will be obtained at 
the time of termination. 
Considering PNH is a serious life threatening disease, a long-term extension study beyond the 3 months 
of dosing included in this study may be offered to patients, if supported by clinical and nonclinical data.  
Pending regulatory and ethics committee approval of such a study, patients who, in the opinion of the PI, 
are receiving benefit from ACH-0144471 may be enrolled directly into that study without interruption 
from this study, and will continue to receive daily treatment with ACH-0144471 and safety and efficacy 
monitoring.  Any patients so enrolled will not require a dosing taper or the follow-up visits described in 
this protocol. 
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Figure 1. 
Study Schematic 
 
 
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3.2 Rationale for Study Design 
3.2.1 Justification of Design 
This will be the first study of ACH-0144471 in patients diagnosed with PNH.  The study design 
therefore includes careful patient safety monitoring, and extensive laboratory, PK, and PD marker 
monitoring during Part 1 of the study.  At each of two protocol-defined dose escalation time points, the 
individual patient’s safety data and LDH values will be reviewed to determine if dose escalation is 
warranted.  In addition, the PI, in consultation with the Sponsor, may escalate dosing in increments of 
25 mg to a maximum of 250 mg TID after evaluating the clinical benefit and the available safety, PK, 
and PD data (including laboratory test results) in order to improve control of hemolysis, as discussed in 
Section 3.2.3. 
LDH has long been accepted as a marker for RBC hemolysis, as reported in prior studies of hemolytic 
anemia and in studies of patients with PNH.  Therefore, a reduction in LDH relative to baseline, 
reflecting a reduction in intravascular hemolysis, will be the primary endpoint.  
3.2.2 Justification of Dose 
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 suggest 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 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 plasma trough ACH-0144471 concentrations can be 
increased substantially with minimal increase Cmax or AUC, 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.  The starting dose in this study will therefore be 150 mg TID, which is expected to 
provide clinical efficacy.  
All patients enrolled in this study to date have dose escalated to 200 mg TID with no clinically 
significant alterations in liver enzymes, but the available data suggests that some patients may receive 
additional clinical benefit from further dose escalation.  If necessary to achieve an improved reduction in 
hemolysis, as measured by correction of serum LDH, dose escalation will be permitted in increments of 
25 mg to a maximum of 250 mg TID after evaluating the clinical benefit and the available safety, PK, 
and PD data (including laboratory test results).  
3.2.3 Criteria to Escalate to a Higher Dose or Change the Dosing Regimen 
Decisions to dose escalate or change the dosing regimen will be made by the site PI.  The Sponsor will 
be notified of dose escalation/regimen changes and any study termination decisions. 
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1st Dose Escalation Point (Day 7) 
On a patient-by-patient basis, if the starting dose of 150 mg TID is well tolerated and the 
available safety data are satisfactory, a patient may be escalated to 175 mg TID if his/her Day 6 
LDH level, as measured locally, is still greater than 50% of his/her baseline value, unless the 
patient has achieved <1× ULN for LDH.  Depending on when these data are received and 
reviewed, if the PI plans to dose escalate the patient, the site should contact the patient as soon as 
possible (Days 6-8) to provide new dosing instructions.  If necessary, the patient may be asked to 
return to the clinic for new drug supplies. 
2nd Dose Escalation Point (Day 14) 
On a patient-by-patient basis, if the patient was not dose escalated at Day 7, the 150 mg TID 
dose is well tolerated, and the available safety data are satisfactory, a patient may be escalated to 
175 mg TID if his/her Day 13 LDH level, as measured locally, is still greater than 20% of his/her 
baseline value, unless the patient has achieved <1× ULN for LDH.  Depending on when these 
data are received and reviewed, if the PI plans to dose escalate the patient, the site should contact 
the patient as soon as possible (Days 13-15) to provide new dosing instructions.  If necessary, the 
patient may be asked to return to the clinic for new drug supplies. 
Following the dose escalation evaluations defined above, the PI, in consultation with the Sponsor, may 
escalate dosing in increments of 25 mg to a maximum of 250 mg TID after evaluating the clinical 
benefit and the available safety, PK, and PD data (including laboratory test results).  Patients should 
have blood drawn (locally or at the clinic) 72 to 84 hours after starting the new dose for measurement of 
LDH and liver function tests (ALT, AST, GGT, and ALP).  
Dosing will not be escalated for a patient if one or more of the following occurs: 
• Patient experiences a study drug-related Grade 4 AE 
• It is determined that the limit of safety and/or tolerability has been reached.  This decision will be 
made following discussions between the sponsor Medical Monitor and the site PI 
• The maximum allowed dose of 250 mg TID has already been reached 
• LDH level, as measured locally, is reduced to ≤50% relative to baseline by Day 6, or to ≤20% 
relative to baseline by Day 13 
If a patient has been dose escalated, he/she may be dose reduced to a lower dose for safety or tolerability 
reasons following consultation between the investigator and the with Achillion medical monitor. 
Based on Day 20 LDH results, if a patient’s LDH level is less than or equal to 20% of his/her baseline 
value and remains <1.5× ULN for LDH, then the patient will be permitted to continue dosing after Day 
28 by entering Part 2 of the study without further approval from the sponsor.  
For patients who do not meet the preceding definition, the investigator will discuss with the sponsor 
about progressing the patient to Part 2 of the study if they believe that there has been clinically 
significant improvement in Part 1.  This discussion and the resulting decision and rationale will be 
documented in the site file. 
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3.2.4 Individual Stopping Criteria 
The PI may stop dosing in any patient who meets one of the stopping criteria described below; however, 
the Achillion medical monitor should be notified immediately and if possible, before dosing is 
terminated.  If dosing is to be terminated for any reason other than safety, it is recommended that a taper 
be implemented as described in Section 5.2.1.  If dosing is terminated for safety-related reasons, the PI 
may discontinue dosing immediately if they feel it is in the best interest of the patient.  Whenever 
possible, this decision should be discussed with the Achillion medical monitor prior to dosing 
termination. 
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 (exceptions 
may be considered at the request of the investigator if the event can be managed by dose reduction or 
interruption); 
• 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: 
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 clinically significant elevation in Total Bilirubin* relative to baseline 
* Because patients may have ongoing hemolysis which may result in increased bilirubin and AST, 
increases in bilirubin and/or AST during the study must be evaluated in the context of any continuing 
hemolysis.  The PI should evaluate LDH and Hgb levels as well as baseline bilirubin and AST levels to 
determine if the increases observed are due to an effect on liver function or are secondary to hemolysis.  
In addition to the individual stopping criteria described above, the sponsor reserves the right to close any 
study site or terminate the study at any time for any reason at the sole discretion of the sponsor.  
3.3 Study Duration and Dates 
Each patient will receive multiple doses of ACH-0144471 for a total of 28 days during Part 1, and may 
be treated for an additional 8 weeks if they participate in Part 2.  Additionally, there will be a 6-day taper 
at the end of treatment, for a total treatment duration of up to 90 days.  Including the taper, the total 
study duration for patients who complete Part 1 but do not participate in Part 2 will be 48 days, not 
including screening.  For patients who participate in both Part 1 and Part 2, the total study duration will 
be up to 104 days, not including screening.  There are no overnight stays in this study.  The maximum 
screening period is up to 60 days. 
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4 Study Population Selection 
4.1 Study Population 
This study will be conducted in currently untreated PNH patients meeting eligibility criteria. 
4.2 Inclusion Criteria 
Each patient must meet the following criteria to be enrolled in this study. 
1. Currently untreated PNH patients with PNH Type III erythrocyte and/or granulocyte clone size 
≥10% and anemia (Hgb <12 g/dL) with adequate reticulocytosis (as determined by the 
investigator) 
2. LDH ≥1.5× upper limit of normal (ULN) 
3. Platelet count ≥50,000/µL in the absence of platelet transfusion 
4. Documentation of vaccination for Neisseria meningitidis, Haemophilus influenzae, and 
Streptococcus pneumoniae, or willingness to receive vaccinations as described in Section 6.3 
5. Age ≥18 years (or ≥ minimum adult age in accordance with local legal requirements) 
6. Female participants of childbearing potential must agree to use an acceptable method of 
contraception (as defined in Section 5.5.5) from the date of signing the informed consent to the 
first day of dosing (Day 1), and must agree to use a highly effective method of contraception (as 
defined in Section 5.5.5) from the first day of dosing to 30 days after their last dose of study 
drug.  Female participants of childbearing potential must also have a negative serum pregnancy 
test during Screening and negative urine pregnancy test on Day 1. 
Female participants of non-childbearing potential need not employ a method of contraception. 
7. Non-sterile male participants must agree to use a highly effective method of contraception (as 
defined in Section 5.5.5) with their partner(s) of childbearing potential from the first day of 
dosing to 90 days after their last dose of study drug. 
Males who are surgically sterile need not employ additional contraception.   
Males must agree not to donate sperm while enrolled in this study and for 90 days after their last 
dose of study drug. 
8. Must agree to provide written informed consent 
9. Must be willing, at all times, 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 hematopoetic stem 
cell/marrow transplant 
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2. History of dosing with another investigational agent within 30 days or 5 half-lives of the 
investigational agent prior to study entry, whichever is greater 
3. History of dosing with eculizumab at any dose or interval within the past 75 days before study 
drug administration 
4. Known or suspected complement deficiency 
5. Contraindication to one or more of the required vaccinations 
6. Active bacterial infection or clinically significant active viral infection, a body temperature 
>38°C, or other evidence of infection on Day 1, or with a history of febrile illness within 14 days 
prior to first study drug administration 
7. History of meningococcal infection, or a first-degree relative or household contact with a history 
of meningococcal infection 
8. History of hypersensitivity reactions to commonly used antibacterial agents, including beta-
lactams, penicillin, aminopenicillins, fluoroquinolones (specifically including ciprofloxacin), 
cephalosporins, and carbapenems, which in the opinion of the investigator would make it 
difficult to properly provide either empiric antibiotic therapy or treat an active infection 
9. 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) 
10. Laboratory abnormalities at screening, including: 
• Alkaline phosphatase (ALP) >1.5× ULN 
• Absolute neutrophil count (ANC) <1,000/μL 
• Alanine aminotransferase (ALT) > ULN 
• Any other clinically significant laboratory abnormality that, in the opinion of the PI, would 
make the patient inappropriate for the study or put the patient at undue risk 
11. 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 
12. Prior history or current evidence of biliary cholestasis 
13. Gilbert’s syndrome 
Patients with history or family history suggestive of Gilbert’s syndrome should be tested and 
excluded from study if positive for UGT1A genotyping polymorphism or missense change 
14. Evidence of human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection (positive 
serology for HIV-1 antibody (HIV Ab), positive hepatitis B surface antigen (HbsAg), or positive 
anti-HCV antibody (HCV Ab) at Screening or historically 
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5 Study Treatment(s) 
5.1 Study Drug 
ACH-0144471 will be dosed as a tablet formulation containing the drug substance, lactose, 
microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulphate, magnesium stearate, 
colloidal silicon dioxide and hypromellose acetate succinate.  The coating components are: polyvinyl 
alcohol, titanium dioxide, macrogol/polyethylene glycol and talc. 
5.2 Treatment(s) Administered 
5.2.1 ACH-0144471 
A single treatment group is planned.  The expected enrollment is approximately 4 to 12 patients.  
ACH-0144471 will be administered as multiple doses over a period of at least 28 days.  The starting 
dose, dosing interval and maximum dose is based on data from the Phase 1 SAD, MAD, Rel BA studies, 
and emerging data from the first two patients in this study.  The starting dose will be 150 mg TID, and 
the maximum dose will be 250 mg TID. 
If patients do not go on to an extension study, it is recommended that a taper of ACH-0144471 be 
implemented, according to the schedule in Table 1.  If dosing is terminated for safety-related reasons, 
the PI may discontinue dosing immediately if they feel it in the best interest of the patient.  Whenever 
possible, this decision should be discussed with the Achillion medical monitor prior to dosing 
termination.  
Table 1. 
Dosing Taper Schedule 
Dose at Termination 
Taper Period 1 
(Taper Days 1-3) 
Taper Period 2 
(Taper Days 4-6) 
150 mg TID 
100 mg TID 
50 mg TID 
175 mg TID 
100 mg TID 
50 mg TID 
200 mg TID 
125 mg TID 
75 mg TID 
225 mg TID 
150 mg TID 
75 mg TID 
250 mg TID 
175 mg TID 
75 mg TID 
 
5.2.2 Vaccines 
Depending on the patient’s vaccination history, the vaccines described in Section 6.3 may need to be 
administered to patients according to the schedule described.  Since these are commercially available 
products, information about the specific vaccines can be found on the package inserts/product labels for 
those products. 
5.3 Selection of Timing and Dose for Each Patient 
Patients will be dosed three times daily (TID) (a dose in the morning, a second dose approximately 
8 hours later, and a third dose approximately 8 hours after the second dose).  Doses should be taken at 
approximately the same time each day and as close as possible to 8 hours apart.  All doses should be 
taken approximately 15-30 minutes after completion of a meal or snack.  If a dose is missed, it should be 
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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. 
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.  For Clinic Visit days, patients should be instructed 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.  In addition, patients should be instructed to fast for at least 8 hours prior 
to coming to the clinic on Days 1, 13, and 28.  Patients will be required to bring their study drug at each 
visit so that study site personnel may perform drug accountability. 
5.3.2 Home Dose Administration Instructions 
Patients will take ACH-0144471 three times daily (TID) (a dose in the morning, a second dose 8 hours 
later, and a third dose 8 hours after the second dose).  Doses should be taken at approximately the same 
time each day.  All doses should be taken approximately 15-30 minutes after completion of a meal or 
snack.  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 keep their study medications at room temperature. 
5.4 Method of Assigning Patients to Treatment Groups 
All patients will receive ACH-0144471 and will be assigned to the same treatment group.  Each patient 
will be assigned a sequential subject identification number within each study center. 
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 study drug administration, whichever is greater.  Patients must not have 
received eculizumab at any dose or interval within the past 75 days before study drug administration. 
5.5.2 Concomitant Therapy 
Based on in vitro data, ACH-0144471 has the potential to inhibit several cytochrome (CYP) enzymes as 
well as some transporters.  In contrast, the PK profile of ACH-0144471 is not likely to be affected by 
other drugs.  Specific in vitro results for various CYP enzymes and transporters are described in the IB 
[3]. 
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.  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 steroids or other immunosuppressants is permitted if the dosage 
regimen is stable for at least 3 months before Day 1. 
• Oral, injectable, implantable, transdermal, or intravaginal hormonal therapies are allowed for either 
contraception or hormonal replacement therapy. 
• If it is necessary to treat a fever (see Appendix 4), 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. 
• Administration of eculizumab or any other complement inhibitor is not permitted during this study. 
 
The use of concomitant medications during the trial should be assessed at each visit, as indicated in the 
Schedule of Assessments (Appendix 1). 
5.5.3 Fluid and Food Intake 
Patients should be instructed to take each dose of ACH-0144471 with food.  All doses should be taken 
approximately 15-30 minutes after completion of a meal or snack.  Patients should be instructed to fast 
for at least 8 hours prior to coming to the clinic on Days 1, 13, and 28, and before the local safety lab 
sample collections on Days 49 and 77 to allow collection of fasting samples for determination of bile 
acids as described in Table 2. 
5.5.4 Patient Activity and Other Restrictions 
Patients should refrain from heavy exercise 24 hours prior to having blood drawn for laboratory 
evaluations.  Walking and light exercise are acceptable. 
While the consumption of alcohol is not prohibited, patients should be counseled to avoid the 
consumption of alcohol while participating in this study. 
5.5.5 Contraception 
5.5.5.1 Contraception for Male Participants 
All non-sterile male participants must use highly effective contraception with their partner(s) of 
childbearing potential from the first day of dosing (Day 1) through 90 days after their last dose of study 
drug.   
Sterile is defined as having bilateral orchiectomy. 
Highly effective contraception for males is defined as any of the following:  
• Vasectomy with confirmed medical assessment of surgical success 
• Condom plus use of one of the following by partner(s) of child-bearing potential: 
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 Oral, intravaginal, or transdermal combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation 
 Oral, injectable, or implantable progestogen-only hormonal contraception associated with 
inhibition of ovulation 
 Intrauterine device (IUD) or Intrauterine hormone-releasing system (IUS) 
 Bilateral tubal occlusion 
• Sexual abstinence, defined as refraining from heterosexual intercourse during the entire period 
from the first day of dosing (Day 1) through 90 days after their last dose of study drug.  Periodic 
abstinence (e.g., calendar, symptothermal, post-ovulation methods) is not an acceptable method 
of contraception.  The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the participant.  If a 
participant is usually not sexually active but becomes active, they, with their partner(s), must 
comply with the contraceptive requirements described in this section.  
Male participants must agree to refrain from sperm donation while enrolled in this study and for 90 days 
after their last dose of study drug 
5.5.5.2 Contraception for Female Participants 
Female participants of childbearing potential must use an acceptable method of contraception from the 
date of signing the informed consent to the first day of dosing (Day 1), and must use a highly effective 
method of contraception from the first day of dosing (Day 1) through 30 days after their last dose of 
study drug.   
Highly effective contraception for females is defined as any of the following: 
• Oral, intravaginal, or transdermal combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated with 
inhibition of ovulation 
• Intrauterine device (IUD) or Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomised partner(s) with confirmed medical assessment of surgical success 
• Sterile partner(s) (bi-lateral orchiectomy) 
• Sexual abstinence, defined as refraining from heterosexual intercourse during the entire period 
from the first day of dosing (Day 1) through 30 days after their last dose of study drug.  Periodic 
abstinence (e.g., calendar, symptothermal, post-ovulation methods) is not an acceptable method 
of contraception.  The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the participant.  If a 
participant is usually not sexually active but becomes active, they, with their partner(s), must 
comply with the contraceptive requirements described in this section.  
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Acceptable contraception for females is defined as any of the following: 
• Any of the methods of highly effective contraception listed above 
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary 
mode of action 
• Male or female condom with or without spermicide.  Combinations of a male condom with either 
cap, diaphragm or sponge with spermicide (double barrier methods) are also considered 
acceptable, but not highly effective, birth control methods. 
• Cap, diaphragm or sponge with spermicide 
Female participants of childbearing potential must have a negative serum pregnancy test at screening 
and a negative urine pregnancy test at baseline in order to enter the study, and must have urine 
pregnancy tests throughout the study at the intervals defined in the Schedule of Assessments 
(Appendix 1). 
Female participants of non-childbearing potential, as defined by one of the following, need not employ a 
method of contraception: 
• Surgical sterilization by hysterectomy, bilateral salpingectomy, or bilateral oophorectomy 
• Postmenopausal with amenorrhea for at least 1 year prior to dosing and FSH serum levels 
consistent with postmenopausal status 
 
5.6 Treatment Compliance 
Treatment compliance assessments shall be performed at each visit.  Patients will be required to bring 
their ACH-0144471 drug supply at 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 receive automated reminders (e.g., via SMS text or phone call) and must respond to record 
the time they take each daily dose of ACH-0144471 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: 
• Clinical Study Number 
• Sponsor Name and Address 
• Product Name and Strength 
• Dosage Form and Route of Administration 
• Direction for Use 
• Contents (Number of Tablets) 
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• Lot Number (or Code) 
• Storage Instructions 
• 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. 
 
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 in the original container at room temperature. 
Patients will be required to bring 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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6 Study Procedures 
The required study procedures are detailed in this section. The timeline for the 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. 
6.2 Medical History 
At Screening, the PI or designee will interview each patient and obtain a complete medical and 
medication history, including information related to the diagnosis, disease history, and management of 
the patient’s PNH, to determine whether the patient meets the eligibility criteria. The history should 
include 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), and any prior use of alcohol, illicit drugs 
and/or controlled substances. The history should also include a full vaccination history. Patients must 
not require any treatment or medication for concurrent illnesses as specified by the inclusion and 
exclusion criteria or anticipate the need for any excluded concomitant medications. The history should 
also include up to 3 years of transfusion history, if available. The medical/medication history will be 
reviewed at each visit and at the final 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 Vaccination 
Inhibition by ACH-4471 of factor D, and of the complement alternative pathway, may be associated 
with an increased risk of infection by N. meningitidis, H. influenza, and S. pneumoniae. Vaccination is 
an important means to mitigate this theoretical risk. Additional information regarding the risk of 
infection can be found in Section 6.5.1 of the Investigator's Brochure. 
As discussed in Section 6.2, a full vaccination history will be gathered. Based on the vaccination history, 
the need for vaccinations against N. meningitidis, S. pneumoniae, and H. influenzae in this study will be 
evaluated according to national and/or local guidelines. If local and/or national guidelines do not exist or 
do not fully address vaccination against these organisms, investigators should consider consulting the 
Advisory Committee on Immunization Practices (ACIP) guidelines (available at https://www.cdc.gov/ 
vaccines/acip/index.html). Based on the available guidelines and each subject's vaccination history, the 
Investigator will assess the need for vaccinations against each organism and/or serotype. Study 
participants who do not have a sufficient history for some or all of these vaccines should be vaccinated 
or provided boosters as recommended in the applicable guidelines. 
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For any vaccines given as part of this study, full identifying information, including the brand, will be 
recorded in the participant’s CRF.  Samples will be collected from participants at the times indicated in 
the Schedule of Assessments (Table 5) for possible evaluation of response to vaccines. 
6.4 Prophylactic Antibiotics 
Antibiotic prophylaxis is allowed if deemed appropriate by local clinical practice and/or guidelines for 
treatment with a complement inhibitor.  For example, if the vaccination series for N. meningitidis has 
not been completed at least 2 weeks prior to dosing with ACH-0144471, antibiotic prophylaxis with oral 
penicillin or an appropriate alternative (as described in Appendix 4) could be implemented in 
accordance with local practice on prevention of meningococcal infection.  In such instances, consider 
continuing prophylaxis until at least two weeks after completion of the vaccination series.   
6.5 Physical Examination 
A complete physical examination will be conducted by the PI (or designee) at Screening and Day 1.  
This will include an examination of all major body/organ systems (including skin, head, eyes, ears, nose, 
throat, neck, thyroid, lungs, heart, abdomen, lymph nodes, and extremities), height, weight and 
calculation for BMI (height and BMI at Screening visit only).  Measurements of height and weight 
should be taken with the patients in light clothing or underwear and without shoes. 
Brief physical examinations, to include general appearance and examination of cardiovascular and 
respiratory systems, abdomen, extremities/skin, and additional organs or systems targeted to any new 
signs or symptoms, will be performed by the PI (or designee) at the times specified in the Schedule of 
Assessments (Appendix 1) or at the discretion of the Investigator or designee, and/or when patients 
present with AEs.  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.  All vital sign measurements for an individual should be taken on the 
dominant arm (if possible) throughout the study.  Vital signs may be measured using an automated vital 
signs machine.  Vital sign values 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 4) 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 4). 
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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 by the PI or designee. 
In some cases it may be appropriate to repeat an abnormal ECG to rule out improper lead placement as 
contributing to the ECG abnormality.  It is important that the leads are placed in approximately the same 
positions each time in order to achieve precise ECG recordings. 
All ECGs must be read by the PI or designee.  The PI/designee needs to evaluate the finding of ECG 
abnormalities promptly (refer to Section 6.17.1 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. 
6.9 Clinical Laboratory Measurements 
Blood and urine samples will be collected according to Table 2, at times listed in Appendix 1. 
Patients will be in a seated or supine position during the blood collection.  Specific instructions for 
sample collection, processing, and shipping will be provided in a separate laboratory manual. 
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Table 2. 
Clinical Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Additional 
Screening Tests 
Other 
Assessments11 
Complete blood count 
(CBC), including: 
- Red blood cell 
(RBC) count 
- White blood cell 
(WBC) count 
- WBC differential 
(absolute and 
percent): 
- neutrophils 
- lymphocytes 
- monocytes 
- eosinophils 
- basophils 
- Hematocrit (Hct) 
- Hemoglobin (Hgb) 
- Mean corpuscular 
volume (MCV) 
- Mean corpuscular 
hemoglobin 
(MCH) 
- Mean corpuscular 
hemoglobin 
concentration 
(MCHC) 
- Mean platelet 
volume (MPV) 
- Platelet count 
- Red cell 
distribution width 
(RDW) 
- Reticulocyte count 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase (AST) 
Bicarbonate (HCO3) 
Bilirubin (fractionated)1 
Bile Acids2 
Blood urea nitrogen (BUN) 
Calcium 
Calculated eGFR3 
Chloride 
Creatine kinase4 
Creatinine 
C-reactive protein (CRP) 
Gamma-glutamyl transferase 
(GGT) 
Glucose5 
Lactate dehydrogenase (LDH) 
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) 
Potassium 
Sodium 
Total protein 
Uric acid 
Bilirubin 
Color 
Glucose 
Ketones 
Hemosiderin 
Leukocytes 
Microscopic 
examination of 
sediment6 
Nitrite 
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
Erythropoietin 
FSH7 
HCV Ab 
HBsAg 
HIV Ab 
Sample for 
genetic 
biomarker 
testing (white 
blood cells)8 
Serum Pregnancy 
test9 
Urine drug 
screen10 
 
AP Wieslab 
Bb 
C3 
CH50 
C3fragment 
deposition 
D-dimer 
Direct Coombs 
Factor D 
Free hemoglobin 
Haptoglobin 
Plasma/Serum 
samples for 
additional non-
genetic 
biomarker 
testing8 
PNH Clone Size 
PT/PTT/INR 
Urine pregnancy 
test9 
Samples for 
assessment of 
patient 
response to 
vaccines 
All tests to be performed as per the schedule outlined in Appendix 1. 
1 
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 
2 
Days 1, 13, 28, 49, and 77 only; samples must collected under fasting conditions on these days  
3 
Provide estimated Glomerular Filtration Rate (eGFR) based on Modification of Diet in Renal Disease (MDRD) 
equation 
4 
Perform at Screening and Day 1, and then subsequently only as a reflex if AST > ULN 
5 
If glucose is > ULN, reflexively test HbA1c 
6 
Only if occult blood, protein, or leukocytes present on dipstick analysis 
7 
For postmenopausal women 
8 
See Section 6.11.2 
9 
Serum pregnancy test at Screening and urine pregnancy tests as per the schedule in Appendix 1 for women of 
childbearing potential only.  See Section 6.10. 
10 Urine drug screen will be measured at screening.  For all patients, test should include, at a minimum, amphetamines, 
barbiturates, cotinine, cocaine metabolites, opiates, benzodiazepines, and cannabinoids 
11 Check the Schedule of Assessments (Appendix 1) for times when these tests should be done  
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6.10 Pregnancy Testing 
All females of childbearing potential (as determined at screening) will have a serum pregnancy test 
during screening, a urine pregnancy test on Day 1 (prior to the start of drug administration), and a urine 
pregnancy test every 4 weeks for the duration of the study including follow-up.  On Day 1, the urine 
pregnancy test must be done pre-dose and be negative to continue on to dosing. 
Female patients of childbearing potential who require vaccinations (see Section 6.3) 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 (AP Wieslab, CH50, C3, Bb, and fD) 
Depending on the type of complement test, either serum or plasma will be used.  It is important that 
serum 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 PD Samples for Genetic and Additional Non-genetic Complement-associated 
Biomarker Testing, and for Determination of Vaccine Response 
Samples will be collected and retained for potential assessment of non-genetic complement-associated 
biomarkers as per the schedule in Appendix 1 including: hemolysis assay, and the plasma concentrations 
of fB, Ba, iC3b, C5a, and soluble C5b-9.  Subject to patient consent, a sample will also be collected at 
screening for potential genetic analysis.  Genetic analyses may be conducted if a patient does not 
respond to the investigative drug, if a patient experiences drug-related toxicity, or to further characterize 
the underlying disease.  Serum samples will be collected to assess patient response to vaccinations at 
various time points in the study. 
Samples used for PD analyses will be stored from the beginning of this clinical study to one year after 
the clinical study report is finished. 
6.11.3 PK Plasma Samples 
For samples collected for pharmacokinetic analysis, whole blood (2 mL) will be collected into 
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 in a laboratory manual. 
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6.11.4 Blood Volumes 
Approximate blood volumes for each cohort are detailed in Table 3 below.  The total planned blood 
volume to be collected per individual is approximately 776.9 mL over 3 months.  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.  Please refer to the 
laboratory manual for specific instructions regarding blood and urine volume, collection, processing and 
handling. 
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Table 3. 
Approximate Total Blood Volumes 
Test  
Volume/
Test 
(mL) 
Screening 
Part 1 
Part 2 
(Including Taper 
and Follow-up) 
Total 
Tests 
Blood 
Drawn 
(mL) 
Tests 
Blood 
Drawn 
(mL) 
Tests 
Blood 
Drawn 
(mL) 
Tests 
Blood 
Drawn 
(mL) 
Screening Visit Labs 
(chemistry, LDH, 
erythropoietin, 
hematology, serum 
pregnancy, FSH, 
Serology [HIV, 
HBsAg, HCV Ab] 
14.0 
1 
14.0 
0 
0 
0 
0 
1 
14.0 
Clinical Labs 
(chemistry 
[including LDH & 
haptoglobin] & 
hematology) 
10.5 
0 
0 
8 
84 
11 
115.5 
19 
199.5 
PT/PTT/INR 
2.7 
1 
2.7 
2 
5.4 
1 
2.7 
4 
10.8 
Free Hemoglobin 
6.0 
1 
6.0 
5 
30.0 
5 
30.0 
11 
66.0 
LDH (Local) 
3.5 
0 
0 
2 
7.0 
2 
7.0 
4 
14.0 
D-dimera 
2.7 
0 
0 
2 
5.4 
1 
2.7 
3 
8.1 
Direct Coombs 
2.0 
1 
2.0 
1 
2.0 
2 
4.0 
4 
8.0 
Flow Cytometry: 
Clone Size 
2.0 
1 
2.0 
1 
2.0 
4 
8.0 
6 
12.0 
Flow Cytometry: C3 
Fragment Deposition  
4.0 
0 
0 
2 
8.0 
3 
12.0 
5 
20.0 
AP Wieslab 
3.5 
0 
0 
20 
70 
5 
17.5 
25 
87.5 
Bb 
2.0 
0 
0 
20 
40.0 
5 
10.0 
25 
50.0 
CH50, C3, fD 
7.5 
0 
0 
3 
22.5 
3 
22.5 
6 
45.0 
Samples for non-
genetic biomarkers  
5.5 
0 
0 
20 
110.0 
3 
16.5 
23 
126.5 
Sample for genetic 
biomarker testing 
8.5 
1 
8.5 
0 
0 
0 
0 
1 
8.5 
Sample for 
assessment of patient 
response to vaccines 
7.0 
1 
7.0 
3 
21.0 
1 
7.0 
5 
35.0 
PK samples 
2.0 
0 
0.0 
31 
62.0 
5 
10.0 
36 
72.0 
Total Volume  
 
 
42.2 
 
469.3b 
 
265.4 
 
776.9 
For each test, the number of tests is the maximum described in the Schedule of Assessments (Appendix 1). 
a 
Shared sample with PT/PTT/INR when appropriate; only D-dimer-specific samples listed 
b 
Drawn over 1 month 
c 
Drawn over 3 months 
 
6.12 Dispensing Study Drug 
ACH-0144471 will be supplied as tablets.  The site will dispense study drug as required to provide 
patients with sufficient study drug to last until the next visit.  If the information necessary to support a 
dose escalation decision is not available during the time the patient is in the clinic, the patient may be 
required to return for new drug supplies following dose escalation. 
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6.13 Safety Assessments 
Safety will be evaluated by monitoring and assessment of AEs, clinical laboratory tests, ECG findings, 
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 6, 13, and 20, at the times indicated in the Schedule of 
Assessments (Appendix 1) to determine plasma and/or serum concentrations of ACH-0144471.  
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 and Efficacy Assessments 
Pharmacodynamics will be evaluated using serum, plasma, and whole blood collected during the study 
with the assays outlined in Table 4 and the Schedule of Assessments (Appendix 1).  Additional 
information on sample collection and shipping instructions will be provided in a separate laboratory 
manual.   
Table 4. 
Pharmacodynamic Markers 
Assay Identifier*  
Assay Descriptions 
LDH 
Blood test 
CBC components 
Blood test 
Free hemoglobin 
Blood test 
Haptoglobin 
Blood test 
D-dimer 
Blood test 
PNH clone size 
Flow cytometry 
C3  
ELISA 
CH50 
MAC-mediated lysis of the anti-body sensitized target; serial 
diluted serum  
AP Wieslab assay 
ELISA; LPS as activator; measurement of TCC 
fD  
ELISA 
Bb  
ELISA 
C3 fragment deposition 
Flow cytometry 
Direct Coombs test 
Blood test 
Additional complement-associated 
biomarkers  
ELISA or other 
*The schedule for when these tests are to be done can be found in Appendix 1 
 
Samples will also be collected and retained for genetic and non-genetic complement-associated 
biomarker testing, as described in Section 6.11.2. 
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While multiple tests of the complement system will be performed to assess effect of ACH-0144471 on 
complement activity, clinical efficacy will be assessed using changes in LDH and Hgb levels and other 
measures of hemolysis, as well as RBC transfusion requirements. 
6.16 Patient-Reported Outcomes Assessments 
The FACIT Fatigue scale and the EORTC-QLQ-C30 will be administered to patients at the schedule 
indicated in Appendix 1 using the tools provided in Appendix 2 to collect patients’ health-related quality 
of life at baseline and after treatment with ACH-0144471, respectively. 
In addition, patients will be interviewed by an outcomes researcher chosen by the Sponsor to collect 
their experience of PNH, its impact on everyday lives and the disease trajectory, and, following 
treatment, to collect patients’ experience of ACH-0144471 treatment and their perception of the 
evolution of their condition.  The interviews will be conducted over the phone by a trained, experienced 
interviewer and will last approximately 30 minutes. 
Patients who have not been included in the prescreening study (protocol ACH471-102) will be 
interviewed during the screening period (no more than 1 week prior to the first dose of ACH-0144471).  
At the end of Part 1 (Day 28 ± 1 week), follow-up phone interviews will be conducted with all patients 
to collect patients’ experience of ACH-0144471 treatment and their perception of the evolution of their 
condition.  Patients continuing in Part 2 will also be interviewed at the end of Part 2 (Day 84 ± 1 week).  
Patients who terminate early may be interviewed at the time of termination.a 
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 
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. 
                                                 
a If interviews are not permitted by local regulations or EC requirements, the PI may administer these as questionnaires.  If 
this is necessary, the questionnaires will be provided by Achillion  
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• 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.); or, 
 
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 
• 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 
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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. 
• 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 
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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).  Achillion Pharmaceuticals may request that certain AEs be followed until resolution or 
stabilization. 
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 
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 Common Terminology Criteria for 
Adverse Events (CTCAE) Adverse Event Severity Grading Table (Appendix 3) [18].  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.  
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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’. 
6.17.8 Pregnancy 
Any pregnancy, including female partner pregnancies of male patients that occurs or becomes confirmed 
during a clinical study (time frames outlined in Section 6.17.5) must be reported to Achillion (or 
designee) within one business day of first knowledge of the pregnancy.  The report should be provided 
on the pregnancy form.  While pregnancy itself is not considered an AE, for the purposes of tracking, it 
should be captured as an AE as well as reported on the pregnancy forms. 
All pregnancies should be followed and discussed with the medical monitor as follows: 
• The investigator will follow up with the patient every 3 months throughout the pregnancy and 
report to Achillion (or designee) using the pregnancy forms 
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• Following the estimated date of delivery, the investigator will follow up with the patient and 
report to Achillion (or designee) using the pregnancy forms 
• The final outcome of the delivery will be reported to Achillion (or designee) using the pregnancy 
forms 
Any SAEs related to the pregnancy (see below), or occurring during the patient’s pregnancy, or after 
delivery, must be documented and reported to Achillion (or designee) on both the SAE Form and the 
pregnancy forms.  SAEs occurring in the child (e.g., congenital anomalies or other conditions present at 
birth, whether genetically inherited or occurring in utero) must also be documented on both the SAE 
form and the pregnancy forms. 
Reportable SAEs associated with pregnancy include, but are not limited to: 
• Pregnancy losses (e.g., spontaneous abortion, late fetal death, elective termination) 
• Life-threatening developments (e.g., placental abruption, fetal distress) 
• Congenital anomalies 
• Neonatal or maternal death, or 
• Any event resulting in maternal or neonatal hospitalization/prolonged hospitalization. 
 
6.17.9 Reporting Serious Adverse Events 
Achillion Pharmaceuticals, Inc. has requirements for the expedited reporting of safety events meeting 
specific requirements to worldwide regulatory authorities; therefore, Achillion Pharmaceuticals must be 
notified immediately regarding the occurrence of any SAE and/or pregnancy that occurs during the 
study (time frames outlined in Section 6.17.5). 
The procedures for reporting all SAEs and/or pregnancies, regardless of causal relationship, are as 
follows: 
SAE 
• Record the SAE on the SAE reporting form provided by Achillion (or designee) 
• Send the SAE form (via email) to both
AND to Achillion Pharmaceuticals within 24 hours 
of becoming aware of the SAE 
Pregnancy 
• Record the pregnancy on the pregnancy form provided by Achillion (or designee) 
• Send the pregnancy form (via email) to both
AND to Achillion Pharmaceuticals within one 
business day of becoming aware of the pregnancy 
Contact information is provided below.  Local telephone contact numbers will be provided in the SAE 
Reporting Form Completion Guidelines. 
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SAE CONTACT 
Pharmacovigilance 
 
SAE Reporting email Addresses: 
 
 
 
SAE Telephone Numbers: 
 
In the event of email failure, report by telephone via the 
Safety Hotline: 
 
 
 
Achillion Pharmaceuticals 
 
 
For fatal or life-threatening events, provide copies of hospital discharge reports, autopsy reports, and 
other documents, as applicable.  Achillion Pharmaceuticals may request additional information from the 
PI to ensure the timely completion of accurate safety reports. 
Any follow-up information collected on any report of an SAE and/or pregnancy must be reported by the 
investigator within one business day. 
A copy of the submitted SAE form must be retained on file by the investigator.  If required, the 
investigator must submit copies of the SAE forms to the IRB or EC and retain documentation of these 
submissions in the site study file. 
In the case of a medical emergency, please use the contact provided on the title page of the protocol. 
6.17.10 Investigator Reporting Requirements for SAEs 
Achillion is responsible for ensuring that Investigators and central ECs/IRBs are notified of all AEs that 
are serious, unexpected and considered related, probably related, or possibly related to the 
investigational product.  A CRO may be designated to perform this notification.  This notification will 
be in the form of a MedWatch/CIOMS report.  The PI will notify the local ECs or IRB as per EC or IRB 
requirements.  Upon receiving such notices, the PI must review and retain the notice.  The Sponsor, 
Investigator, and EC or IRB will determine if the informed consent requires revision.  The PI should 
also comply with EC or IRB procedures for reporting any other safety information. 
6.18 Concomitant Medication Assessments 
Details of all prior (within 30 days of the screening evaluation) and concomitant medication use, 
including all medications administered for the treatment of AEs, will be recorded in the patient’s CRF at 
each study visit. 
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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 4) 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 
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 3.2.4).  In either case, whenever possible, the Achillion medical monitor should 
be notified immediately, and if possible, before dosing is terminated.  When dosing is terminated, study 
participation is not necessarily also terminated.  Instead, whenever possible, the patient should complete 
all the activities for the Day 84 or Early Termination Visit as described in Appendix 1, complete a 
dosing taper as described in Section 5.2.1, and return for a Follow-up visit two weeks after the last dose 
of study drug. 
Reasons for patient withdrawal include (but are not limited to): 
• 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 (see Section 3.2.4 for individual patient stopping rules) 
• Patient request to discontinue for any reason 
• A female patient becomes pregnant or wishes to become pregnant, or the female partner of a male 
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 efficacy, PK, and PD 
evaluation will be performed at various time points throughout the study.  There will be a follow-up visit 
approximately 2 weeks after the last dose of study drug. 
Dosing should be at approximately the same time(s) each day. 
Transfusion history should be collected at every visit.   
During the treatment 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 precisely at the specified times 
• 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 Activities 
7.1.1 Screening Visit (Days –60 to -1) 
Prospective patients should be screened within 60 days of first administration of study drug.  A window 
of up to 60 days is permitted to allow screening followed by any required vaccinations; if a patient is 
participating in the preliminary screening study (ACH471-102), vaccinations may already have been 
administered, and tests performed as part of that study within 30 days of first administration of study 
drug may fulfill screening requirements for this study.  During the screening period, informed consent 
will be obtained and patient eligibility determined according to the criteria specified in this protocol.  
The screening clinic and laboratory 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.  A urine drug screen will be performed during screening, and must be negative 
to allow dosing.  The urine drug screen should include, at a minimum, amphetamines, barbiturates, 
cotinine, cocaine metabolites, opiates, benzodiazepines, and cannabinoids.  For women of childbearing 
potential, a serum pregnancy test will be done during screening and must be negative to be eligible for 
the study. 
If screening laboratory assessments show elevated indirect bilirubin levels in conjunction with normal 
liver function tests (AST, ALT, Alkaline phosphatase), or if the patient has a history of unexplained 
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jaundice, unexplained high bilirubin levels, or a history of dark urine, the patient should be tested for 
Gilbert’s syndrome. 
Screening procedures may be spread over more than one visit.  All evaluations must be completed 
before the patient is accepted into the study. 
If the patient is unable to receive study drug within 60 days of screening, the patient may be re-screened 
once.  The repeating of individual screening laboratory results that fall outside the reported normal 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. 
Patients who meet all eligibility criteria will be educated about the restrictions on concomitant 
medication usage and other substances. 
Once the patient is entered into the study, all protocol deviations should be reported to the Achillion 
Pharmaceuticals, Inc. Medical Monitor or designee.  The Medical Monitor (or designee) will assess all 
protocol deviations to determine if any impacted patient safety or data integrity.  Any protocol deviation 
which is deemed to impact patient safety or data integrity will be considered a significant protocol 
deviation, and the rationale for considering a protocol deviation significant will be documented. 
7.1.2 Vaccination Visit(s) (Days -42 to Day -14, if required) 
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 6.3.  All other screening procedures must be 
completed, and patients must qualify for the study prior to any vaccinations being administered.  Female 
patients of childbearing potential who require vaccinations (see Section 6.3) must also have a negative 
urine pregnancy test on the days of vaccination, before any vaccine or booster is administered. 
7.1.3 Patient Reported Outcomes Interview - Screening 
Patients who did not participate in the prescreening study (protocol ACH471-102) will be interviewed as 
part of quality of life assessments during the screening period, no more than 1 week prior to the first 
dose of ACH-0144471 (see Section 6.16).  Patients must pass all other screening tests and be considered 
eligible for the study prior to being scheduled for their interview.  Patients who participated in ACH471-
102 will have had this first interview during that study and do not need to repeat this activity. 
7.2 On-Study Activities 
7.2.1 Clinic Visits 
During the study period, physical examinations, assessment of vital signs, ECG measurements, all 
required safety laboratory testing, pregnancy testing for women of child-bearing potential, and collection 
of blood and urine samples for PK and PD evaluation will be performed at various time points between 
as specified in Appendix 1.  On days when patients will remain at the clinic for intensive PK sampling 
(Days 6, 13, and 20), all doses of ACH-0144471 should be administered at the clinic. 
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At clinic visits, patients should be instructed how to take their medication at home, as described in 
Section 5.3. 
During Part 1 (Days 1 to 28), all visits should occur on the specified day.  During Part 2 (Days 29 
through the end of follow-up), visits may take place within a window of ±1 day relative to the specified 
day. 
7.2.2 Safety Follow up at Local Laboratory 
On the days indicated in Appendix 1 (Schedule of Assessments) the patients will have blood drawn for 
safety assessments at their local laboratories.  Patients should be instructed to fast for at least 8 hours 
prior to the local safety lab sample collections on Days 49 and 77 to allow collection of fasting samples 
for determination of bile acids as described in Table 2. 
7.2.3 Safety Follow up After Escalation 
As described in Section 3.2.3, the PI, in consultation with the Sponsor, may escalate dosing at times 
other than the dose escalation evaluation points in Part 1 of the study after evaluating the clinical benefit 
and the available safety, PK, and PD data (including laboratory test results) for a patient.  Patients 
should have blood drawn (locally or at the clinic) 72 to 84 hours after starting the new dose for 
measurement of LDH and liver function tests (ALT, AST, GGT, and ALP).  
7.2.4 Patient Reported Outcomes Interview – Day 28 (± 1 week) and Day 84 (± 1 week) 
Follow-up interviews for all patients will be conducted as described in Section 6.16 at the end of Part 1 
(Day 28 ± 1week); patients continuing in Part 2 will also be interviewed at the end of Part 2 (Day 84, ± 
1 week).  For patients who terminate early, a follow-up interview will be obtained at the time of 
termination. 
7.2.5 Dosing Taper 
It is recommended that patients who discontinue ACH-0144471 for any reason have study drug tapered 
over 6 days, as described in Section 5.2.1.  On Days 3 and 6 of the taper period, patients will have blood 
drawn for local determination of chemistry and hematology parameters as indicated in Appendix 1 
(Schedule of Assessments). 
If a long-term extension study is available at the end of the patient’s participation in this study, and the 
patient chooses to enroll in it, the dosing taper will not be required. 
7.2.6 Follow-Up Visit 
Patients will have a follow-up visit approximately 2 weeks after the last dose of study drug.  The 
procedures indicated in Appendix 1 should be followed. 
If a long-term extension study is available at the end of the patient’s participation in this study, and the 
patient chooses to enroll in it, this visit will not be required. 
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7.2.7 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 
• Conduct a physical exam and obtain resting supine vital signs (BP, HR, RR) 
• Measure body temperature 
• Collect blood samples for laboratory safety analysis as described in the Hematology and 
Chemistry columns of Table 2 and for determination of LDH 
• 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, PK and PD, and safety parameters.  Summary statistics 
will be computed for selected efficacy and safety parameters so that meaningful clinical interpretations 
can be made.  Graphic presentations will also be produced for selected efficacy and safety parameters. 
Data from Part 1 and Part 2 will be analyzed together.  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 untreated PNH patients and 
exploratory nature of this study to evaluate effectiveness of ACH-0144471. 
9.3 Analysis Populations 
All patients who receive at least one dose of ACH-0144471 will be included in the efficacy and safety 
analysis. 
9.4 Demographics and Baseline Characteristics 
Demographic parameters (age, gender, race, weight, BMI) and baseline PNH disease characteristics will 
be summarized to provide an overall description of study population. 
9.5 Efficacy Analysis 
The primary efficacy endpoint will be change in LDH level from baseline on Day 28. 
Summary statistics will be provided for the primary efficacy endpoint.  Ninety-five percent (95%) 
confidence interval for mean change from baseline will be computed. 
Summary statistics will also be provided for secondary efficacy endpoints: change from baseline in 
hemoglobin level on Day 28 and, if data from patients continuing into Part 2 of the study are deemed 
clinically meaningful, Day 84.  Data on transfusions due to low hemoglobin levels will also be 
summarized. 
LDH levels and changes from baseline LDH levels over time will be plotted for each patient.  Mean (or 
median) LDH level and mean (or median) change from baseline over time will also be plotted. 
Graphic presentations for hemoglobin endpoints may also be provided. 
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9.6 Safety Analysis 
Treatment-emergent AEs (TEAEs) will be summarized and listed by system-organ-class and preferred 
term using the most current version of the Medical Dictionary for Regulatory Activities (MedDRA®).  
All SAEs and discontinuation due to AEs will be listed in tabulated format. 
All clinical laboratory data (hematology, serum chemistry, and urinalysis) with normal ranges, out-of-
range flags, and toxicity grades will be listed by patient.  Descriptive summary statistics may be 
provided for selected lab tests. 
Data on vital signs and ECGs 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 population.  The 
PK characteristics of ACH-0144471 from untreated PNH patients, including, but not limited to, the 
standard PK parameters outlined in the table below, will be derived from the individual plasma 
concentration time data on study Days with intensive PK sampling.  Descriptive statistics (number of 
patients, mean / geometric mean, SD, median, minimum, and maximum) will be used to summarize the 
calculated PK parameters by appropriate study Days. 
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-144471 in 
the body at steady state prior to daily dose.  Graphic presentations will also be provided to depict PK 
profiles of ACH-0144471 from untreated PNH 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 pathway activity.  Analysis on data from LDH measurements 
is described in Section 9.5 above.  Analyses for the remaining markers are either secondary or 
exploratory. 
Except for results from AP-Wieslab assay, change from baseline values at various time points will be 
computed for the PD markers.  Summary statistics may be provided for 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.  The relationship 
between LDH levels and other endpoints with alternative pathway markers may also be explored. 
9.9 PK/PD Assessments 
The relationships between 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 Outcomes Assessments 
9.10.1 Quality of Life Scales 
Total score and change from baseline total score on the FACIT Fatigue scale instrument will be 
computed for each patient at each time point.  Both mean change total scores and individual patients’ 
change total scores may be plotted over time to provide visual examination on the improvement of 
fatigue condition. 
Similar analysis and presentations may be provided for each domain score of the EORTC QLQ-C30 
instrument. 
9.10.2 Patient Interviews 
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 [19].  A validated 
software package [20] will be used to facilitate the storage, coding, analysis, and retrieval of qualitative 
data. 
Other analysis procedures relevant to interview data may also be explored.  A separate analysis plan 
and/or report will be provided for the 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 amendments to the protocol will require IRB/IEC approval before implementation of changes made 
to the study design, except for changes necessary to eliminate an immediate hazard to study participants.  
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. 
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 
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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 date of birth, subject number, 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. 
Audio files of the interviews will be transcribed and de-identified (any identifying information such as 
dates, names, locations will be removed).  The de-identified transcripts will be delivered for analysis and 
a single audio file will be kept as a source document in the Trial Master File.  Any copies of the audio 
file will be destroyed immediately upon confirmation of receipt of the transcript. 
Data protection and privacy regulations will be observed in capturing, forwarding, processing, and 
storing patient contact details and data.  Patients will be informed accordingly and will be requested to 
give their consent on contact details data handling procedures in accordance with national regulations.  
In order to secure data privacy protection, patient contact details will be sent to a dedicated unit in 
charge of scheduling and setting up the interviews independently from study sponsor, monitor, data 
management and data analysis structures and other study stakeholders.  The specific information about 
patient contact details management will be provided on a Contact Order Form to be completed by 
Investigator and patient, signed by the patient and sent to the unit in charge of scheduling and setting up 
the interviews.  This form will not include health data. 
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. 
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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. 
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 Violations/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. 
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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. 
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. 
The interviews will be audio recorded in a de-identified way.  The audio files will serve as source 
documents and will be archived in Trial Master File.  Any additional copy of audio recordings 
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temporarily retained by interviewers and / or transcription unit will be destroyed after transcription 
process completion.  The audio recordings will be transcribed word by word for the analysis. 
10.13 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 
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.
Merle NS, Noe R, Halbwachs-Mecarelli L, et al. Complement System Part II: Role in Immunity.
Front Immunol. 2015;6:257.
2.
Volanakis JE, Narayana SV. Complement factor D, a novel serine protease. Protein Science.
1996;5(4):553-64.
3.
Apelian D. ACH-0144471 Investigator’s Brochure Version 5.0. New Haven (CT): Achillion
Pharmaceuticals, Inc.; 2016. 95 p.
4.
Yang G. Comparative Evaluation of ACH-0144471 and Eculizumab in Functional CAP Assays
and in a Physiological Hemolysis Assay with PNH Patient Cells.  New Haven, CT: Achillion
Pharmaceuticals, Inc.; 2017. DRAFT IN PREPARATION Report No.: ACH-17-074.
5.
Figueroa JE, Densen P. Infectious diseases associated with complement deficiencies. Clinical
microbiology reviews. 1991;4(3):359-95.
6.
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.
7.
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.
8.
Späth-Schwalbe E, Schrezenmeier H, Heimpel SH. [Paroxysmal nocturnal hemoglobinuria.
Clinical experiences with 40 patients at one center over 25 years]. Dtsch Med Wochenschr
120:1027-1033, 1995. PMID: 7628314.
9.
Schubert J, Roth A. Update on paroxysmal nocturnal haemoglobinuria: on the long way to
understand the principles of the disease. Eur J Haematol. 2015;94(6):464-73.
10.
Hill A, Rother RP, Arnold L, et al. Eculizumab prevents intravascular hemolysis in patients with
paroxysmal nocturnal hemoglobinuria and unmasks low-level extravascular hemolysis occurring
through C3 opsonization. Haematologica. 2010;95(4):567-73.
11.
Rondelli T, Risitano AM, Peffault de Latour R, et al. Polymorphism of the complement receptor 1
gene correlates with the hematologic response to eculizumab in patients with paroxysmal
nocturnal hemoglobinuria. Haematologica. 2014;99(2):262-6.
12.
Nishimura J, Yamamoto M, Hayashi S, et al. Genetic variants in C5 and poor response to
eculizumab. The New England Journal of Medicine. 2014;370(7):632-9.
13.
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.
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14.
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.
15.
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.
16.
Siler S, Howell B. DILIsym Services Final Report “Assessment of Clinical Biomarkers and
Prediction of Hepatocyte Loss for ACH4471 Clinical Trials.” Research Triangle Park, NC, USA.
January 12, 2017.
17.
Yang, K, Siler S, Howell B, DILIsym Services Final Report “Prediction of Hepatotoxicity Risk
for ACH4471 Based on Mechanistic Modeling with DILIsym®” Research Triangle Park, NC,
USA August 29, 2017.
18.
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.
19.
Bowen GA. Grounded theory and sensitizing concepts. International Journal of Qualitative
Methods. September 2006; 5 (3). http://www.ualberta.ca/~iiqm/backissues/5_3/PDF/bowen.pdf.
20.
Friese S. ATLAS.ti 7.0. User Guide and Reference. http://atlasti.com/wp-
content/uploads/2014/05/atlasti_v7_manual_201312.pdf?q=/uploads/media/atlasti_v7_manual_20
1312.pdf Gmbh, Berlin: ATLAS.ti Scientific Sofware Development; 2013.
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12 Appendices 
 
 
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Appendix 1. Schedule of Assessments 
Table 5. 
Schedule of Assessments 
Screening 
Part 1 
Part 21 
Taper and 
Follow-up 
Unscheduled 
Day 
-60
to -1 -42 -14
1 
(B/L) 3 
6
7 
13 
14 17 20 24 28 35 42 49 56 63 70 77 84 or 
E/T4
T35 T65 F/U6 
Dose 
Esc2 
Other3 
Clinic Visit Days 
X 
X7
X7
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dose Escalation Day8
X 
X 
Screening Assessments 
Informed Consent 
X 
Inclusion/ Exclusion 
Criteria 
X 
Protocol restrictions 
X 
Medical History 
(including transfusion 
history)  
X 
Vaccination History 
X 
Demographics 
X 
Pregnancy Test10 
X X11 X11 
X9
X 
X 
X 
X 
FSH12
X 
Urine Drug Screen13
X 
HCV Ab, HbsAg, HIV Ab X 
Erythropoietin 
X 
Vaccinations14
X 
X 
Patient-Reported 
Outcomes Assessment 
Interviews
X15
X16 
X16 
Dosing and Drug 
Distribution 
ACH-0144471 Dosing17
X 
X X17 X18 X17 X18
X17
X 
X19
X19
X19
X19
X 
X 
Study Drug Dispensing20 
X 
X 
X 
X 
X 
X19 
X19
X19
X19
X 
Clinical Assessments 
Physical Exam 
X 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Temperature 
X 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height, BMI 
X 
Weight 
X 
X9 
X 
X 
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Screening 
Part 1 
Part 21 
Taper and 
Follow-up 
Unscheduled 
Day 
 
-60 
to -1 -42 -14 
1 
(B/L) 3 
6 
7 
13 
14 17 20 24 28 35 42 49 56 63 70 77 84 or 
E/T4 T35 T65 F/U6 
Dose 
Esc2 
Other3 
Patient-Reported 
Outcome Measures 
Assessments (QoL 
Questionnaires) 
X 
 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
12-Lead ECGs (single) 
X 
 
 
X9 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
AEs/SAEs 
X 
X7 X7 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
Concomitant Medications 
including Transfusions 
X 
X7 X7 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, Chemistry, 
and Urinalysis21 
X 
 
 
X9,22 X 
X 
 
X22 
 
 
X 
 
X22 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
PT, PTT, INR 
X 
 
 
X9,22 
 
 
 
 
 
 
 
 
X22 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Haptoglobin 
X 
 
 
X9,22 
 
X 
 
X22 
 
 
X 
 
X22 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Free Hemoglobin 
X 
 
 
X9,22 
 
X 
 
X22 
 
 
X 
 
X22 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
LDH (local) 
 
 
 
 
 
X23 
 
X23 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Safety Labs (local) 
 
 
 
 
 
 
 
 
 
X24 
 
X24 
 
X24 
 
X24 
 
X24 
 
X24 
 
X24 X24 
 
X25 
 
D-dimer 
X 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
PK samples26 
 
 
 
 
 
X27 
 
X27 
 
 
X27 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
Direct Coombs 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
PNH Clone Size 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
C3 fragment deposition 
 
 
 
X9 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
AP Wieslab26  
 
 
 
X9 
 
X27 
 
X27 
 
 
X27 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
Bb26 
 
 
 
X9 
 
X27 
 
X27 
 
 
X27 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
fD, C3, CH50 
 
 
 
X9 
 
 
 
 
 
 
X27 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
Plasma/Serum Samples 
for Additional Non-
genetic Biomarker 
Testing 
 
 
 
X9 
 
X27 
 
X27 
 
 
X27 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
Sample for genetic 
Biomarker testing (white 
blood cells) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sample for assessment of 
patient response to 
vaccines28 
X 
 
 
X9 
 
 
 
 
 
 
X27 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
ACH-0144471 
Clinical Study Report – ACH471-100
Achillion Pharmaceuticals, Inc. 
30 Oct 2019
Confidential
Page 916 of 944

ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-100, Amendment 7 
13 March 2018 (Version 8.0) 
Confidential 
Page 71 of 81 
Screening 
Part 1 
Part 21 
Taper and 
Follow-up 
Unscheduled 
Day 
-60
to -1 -42 -14
1 
(B/L) 3 
6
7 
13 
14 17 20 24 28 35 42 49 56 63 70 77 84 or 
E/T4
T35 T65 F/U6 
Dose 
Esc2 
Other3 
AE = Adverse Event; AP = alternative pathway; B/L = Baseline; BMI = Body Mass Index; ECG = Electrocardiogram; E/T = Early Termination; fD = Factor D; F/U = Follow-up Visit; INR 
= International Normalized Ratio; LDH = Lactate Dehydrogenase; PK = Pharmacokinetic; PT = Prothrombin time; PTT = Partial thromboplastin time; SAE = Serious Adverse Event 
Note that ALT and other liver function tests are included in the clinical laboratory safety tests conducted on Days 1, 3, 6, 13, 17, 20, 24, and 28 in Part 1, weekly on Days 35, 42, 49, 56, 63, 
70, 77, and 84 in Part 2, and on Days 3 and 6 of the taper. 
1 
During Part 2, visits may take place within a window of ±1 day relative to the specified day. 
2 
Measurement of LDH and liver function tests (ALT, AST, GGT, ALP), to be drawn locally or at the clinic 72-84 hours after escalation, as described in Section 7.2.3. 
3 
See Section 7.2.5 for activities. 
4 
For patients who terminate early in either Part 1 or Part 2, these assessments should be conducted. 
5 
T3 = Day 3 of the taper; T6 = Day 6 of the taper. 
6 
The follow-up visit should be 14 days after the last dose of study drug (including taper).  For patients who complete Part 1 but do not participate in Part 2 this will be Day 48; for 
patients who participate in both Part 1 and Part 2 this will be Day 104.  If a long-term extension study is available at the end of the patient’s participation in this study, and the patient 
chooses to enroll in it, this visit will not be required. 
7 
Only for patients who need to receive vaccinations.  See Section 6.3. 
8 
Unless the PI feels a clinic visit is required, dose escalation decisions and modified dosing instructions may be provided by phone.  Information on concomitant medications, AEs, and 
SAEs should be collected. 
9 
Prior to dosing. 
10 Serum pregnancy test at Screening and urine pregnancy tests at other timepoints 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. 
11 Female patients of childbearing potential requiring vaccinations (see Section 6.3) must have a negative urine pregnancy test on the days of vaccination, before any vaccine or booster is 
administered. 
12 FSH for postmenopausal women at screening only. 
13 For all patients, urine drug screen should include, at a minimum, amphetamines, barbiturates, cotinine, cocaine metabolites, opiates, benzodiazepines, and cannabinoids. 
14 Vaccinations should be given if needed, per the guidance in Section 6.3. 
15 The patient reported outcomes assessment interview during screening should be conducted no more than 1 week prior to the first dose of ACH-0144471, and will only be conducted for 
those patients who did not participate in the prescreening study ACH471-102. 
16 Interview may be scheduled ± 1 week.  Patients who terminate before Day 28 will receive an interview at the time of their termination.  Patients who enter Part 2 but terminate before 
Day 84 will receive an interview at the time of their termination. 
17 Patients will take ACH-0144471 three times daily (TID) (a dose in the morning, a second dose 8 hours later, and a third dose 8 hours after the second dose).  On Clinic Visit Days, 
patients will be instructed to abstain from taking their study medication on the mornings of their study visits so that they can be dosed in the clinic See Section 5.3 for details of the 
timing of dosing both in the clinic and at home. 
18 Doses taken at home.  Patients will take ACH-0144471 three times daily (TID) (a dose in the morning, a second dose 8 hours later, and a third dose 8 hours after the second dose). 
Patients should record the times they take their doses.  Doses should be taken at approximately the same time each day. 
19 Only for patients continuing on to Part 2. 
20 As discussed in Section 6.12, patients should be provided with sufficient study drug for 1 week of dosing during Part 1 or 2 weeks of dosing during Part 2.  Treatment compliance 
assessments should be performed at each visit. 
21 Hematology, chemistry, and urinalysis, as described in Table 2. 
ACH-0144471 
Clinical Study Report – ACH471-100
Achillion Pharmaceuticals, Inc. 
30 Oct 2019
Confidential
Page 917 of 944

ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-100, Amendment 7 
13 March 2018 (Version 8.0) 
 
Confidential 
Page 72 of 81 
 
 
 
Screening 
Part 1 
Part 21 
Taper and 
Follow-up 
Unscheduled 
Day 
 
-60 
to -1 -42 -14 
1 
(B/L) 3 
6 
7 
13 
14 17 20 24 28 35 42 49 56 63 70 77 84 or 
E/T4 T35 T65 F/U6 
Dose 
Esc2 
Other3 
22 Day 1, 13 and 28 samples should be drawn under fasting conditions. 
23 On Days 6 and 13 only, a sample should be drawn for local determination of LDH for dose escalation decisions.  Other analytes should not be reported.  Values will be reviewed 
according to the procedures outlined in Section 3.2.2.  Depending on when the data is received and reviewed, if the patient is going to dose escalate, the site should call the patient as 
soon as possible (Days 6-9 or Days 13-15) to provide new dosing instructions.  
24 On Days 17, 24, 35, 49, 63, and 77, and Days 3 and 6 of the taper, samples should be drawn for local determination of chemistry and hematology parameters as described in Table 2.  
Day 49 and 77 samples should be drawn under fasting conditions. 
25 Liver function tests (ALT, AST, GGT, ALP) only. 
26 Except on Days 6, 13, and 20 these are trough samples only; collect prior to first daily dose. 
27 For PK or PD schedule on these days, refer to Table 6.  
28 Samples for vaccine response will be required only if vaccination(s) were administered during the Screening period.  If required, samples will be collected during screening, pre-dose 
and 2 hours after dosing ACH-0144471 on Day 1, Day 20, and Day 84.  
 
ACH-0144471 
Clinical Study Report – ACH471-100
Achillion Pharmaceuticals, Inc. 
30 Oct 2019
Confidential
Page 918 of 944

ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-100, Amendment 7 
13 March 2018 (Version 8.0) 
 
Confidential 
Page 73 of 81 
 
 
Table 6. 
PK and PD Sampling on Days 6, 13, and 20 
 
Time After Dosing (hr) 
 
0a 
1 
1.5 
2 
2.5 
3 
4 
6 
8 
12 
PK plasma samples 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AP Wieslab, Bb 
X 
 
 
X 
 
 
X 
X 
X 
X 
fD, C3, CH50b 
Xb 
 
 
 
 
 
 
 
 
 
Plasma/Serum Samples 
for Biomarker Testing 
X 
 
 
X 
 
 
X 
X 
X 
X 
Sample for assessment of 
patient response to 
vaccinesb 
Xb 
 
Xb 
 
 
 
 
 
 
 
a 
Prior to dosing. 
b 
Day 20 only. 
 
ACH-0144471 
Clinical Study Report – ACH471-100
Achillion Pharmaceuticals, Inc. 
30 Oct 2019
Confidential
Page 919 of 944

ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-100, Amendment 7 
13 March 2018 (Version 8.0) 
 
Confidential 
Page 74 of 81 
 
 
Appendix 2. 
Quality of Life Assessments 
FACIT Fatigue Scale (Version 4) 
EORTC QLQ-C30 (Version 3) 
These QoL assessments will be done at the clinic visits specified in Appendix 1. 
 
 
ACH-0144471 
Clinical Study Report – ACH471-100
Achillion Pharmaceuticals, Inc. 
30 Oct 2019
Confidential
Page 920 of 944

ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-100, Amendment 7 
13 March 2018 (Version 8.0) 
 
Confidential 
Page 75 of 81 
 
 
FACIT Fatigue Scale (Version 4) 
 
Below is a list of statements that other people with your illness have said are important.  Please 
circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
 
 
Not 
at all 
A little 
bit 
Some
-what 
Quite 
a bit 
Very 
much 
HI7 
I feel fatigued
 ...................................................................................... 
0 
1 
2 
3 
4 
HI12 
I feel weak all over
 ...................................................................................... 
0 
1 
2 
3 
4 
An1 
I feel listless (“washed out”)
 ...................................................................................... 
0 
1 
2 
3 
4 
An2 
I feel tired
 ...................................................................................... 
0 
1 
2 
3 
4 
An3 
I have trouble starting things because I am tired
 ...................................................................................... 
0 
1 
2 
3 
4 
An4 
I have trouble finishing things because I am tired
 ...................................................................................... 
0 
1 
2 
3 
4 
An5 
I have energy
 ...................................................................................... 
0 
1 
2 
3 
4 
An7 
I am able to do my usual activities
 ...................................................................................... 
0 
1 
2 
3 
4 
An8 
I need to sleep during the day
 ...................................................................................... 
0 
1 
2 
3 
4 
An12 
I am too tired to eat
 ...................................................................................... 
0 
1 
2 
3 
4 
An14 
I need help doing my usual activities
 ...................................................................................... 
0 
1 
2 
3 
4 
An15 
I am frustrated by being too tired to do the things I 
want to do
 ...................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
ACH-0144471 
Clinical Study Report – ACH471-100
Achillion Pharmaceuticals, Inc. 
30 Oct 2019
Confidential
Page 921 of 944

ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-100, Amendment 7 
13 March 2018 (Version 8.0) 
Confidential 
Page 76 of 81 
An16 
I have to limit my social activity because I am tired
0 
1 
2 
3 
4 
English (Universal) 
16 November 2007 
Copyright 1987, 1997 
Page 76 of 1 
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Clinical Study Report – ACH471-100
Achillion Pharmaceuticals, Inc. 
30 Oct 2019
Confidential
Page 922 of 944

ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-100, Amendment 7 
13 March 2018 (Version 8.0) 
 
Confidential 
Page 77 of 81 
 
 
 
EORTC QLQ-C30 (Version 3) 
 
We are interested in some things about you and your health.  Please answer all of the questions yourself by 
circling the number that best applies to you.  There are no "right" or "wrong" answers.  The information that you 
provide will remain strictly confidential. 
Please fill in your initials: 
 
Your birthdate (Day, Month, Year): 
 
Today's date (Day, Month, Year):  
 
_____________________________________________________________________________________ 
 
 
 
 
 
 
 
 
 
 
Not at A 
Quite Very 
 
 
 
 
 
 
 
 
 
 
All 
Little a Bit 
Much 
1. 
Do you have any trouble doing strenuous activities, 
 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
 
3. 
Do you have any trouble taking a short walk outside of the house? 
1 
2 
3 
4 
 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
 
5. 
Do you need help with eating, dressing, washing 
 
yourself or using the toilet? 
1 
2 
3 
4 
 
During the past week:   
 
 
 
 
 
Not at A 
Quite Very 
 
 
 
 
 
 
 
 
 
 
All 
Little a Bit 
Much 
6. 
Were you limited in doing either your work or other daily activities? 
1 
2 
3 
4 
 
7. 
Were you limited in pursuing your hobbies or other 
 
leisure time activities? 
1 
2 
3 
4 
 
8. 
Were you short of breath? 
1 
2 
3 
4 
 
9. 
Have you had pain? 
1 
2 
3 
4 
 
10. Did you need to rest? 
1 
2 
3 
4 
 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
 
12. Have you felt weak? 
1 
2 
3 
4 
 
13. Have you lacked appetite? 
1 
2 
3 
4 
 
14. Have you felt nauseated? 
1 
2 
3 
4 
 
15. Have you vomited? 
1 
2 
3 
4 
 
16. Have you been constipated? 
1 
2 
3 
4 
 
Please go on to the next page 
ACH-0144471 
Clinical Study Report – ACH471-100
Achillion Pharmaceuticals, Inc. 
30 Oct 2019
Confidential
Page 923 of 944

ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-100, Amendment 7 
13 March 2018 (Version 8.0) 
 
Confidential 
Page 78 of 81 
 
 
During the past week:   
 
 
 
 
 
Not at A 
Quite Very 
 
 
 
 
 
 
 
 
 
 
All 
Little a Bit 
Much 
 
17. Have you had diarrhea? 
1 
2 
3 
4 
 
18. Were you tired? 
1 
2 
3 
4 
 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
 
20. Have you had difficulty in concentrating on things, 
 
like reading a newspaper or watching television? 
1 
2 
3 
4 
 
21. Did you feel tense? 
1 
2 
3 
4 
 
22. Did you worry? 
1 
2 
3 
4 
 
23. Did you feel irritable? 
1 
2 
3 
4 
 
24. Did you feel depressed? 
1 
2 
3 
4 
 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
 
26. Has your physical condition or medical treatment 
 
interfered with your family life? 
1 
2 
3 
4 
 
27. Has your physical condition or medical treatment 
 
interfered with your social activities? 
1 
2 
3 
4 
 
28. Has your physical condition or medical treatment 
 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
For the following questions please circle the number between 1 and 7 that  
best applies to you 
 
29. How would you rate your overall health during the past week? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 Very poor 
 
 
 
 
 
Excellent 
 
 
30. How would you rate your overall quality of life during the past week? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 Very poor 
 
 
 
 
 
                            Excellent 
 
© Copyright 1995 EORTC Quality of Life Group.  All rights reserved.  Version 3.0 
 
ACH-0144471 
Clinical Study Report – ACH471-100
Achillion Pharmaceuticals, Inc. 
30 Oct 2019
Confidential
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ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-100, Amendment 7 
13 March 2018 (Version 8.0) 
Confidential 
Page 79 of 81 
Appendix 3. 
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) 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
ACH-0144471 
Clinical Study Report – ACH471-100
Achillion Pharmaceuticals, Inc. 
30 Oct 2019
Confidential
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ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-100, Amendment 7 
13 March 2018 (Version 8.0) 
Confidential 
Page 80 of 81 
Appendix 4. 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 subject; 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
ACH-0144471 
Clinical Study Report – ACH471-100
Achillion Pharmaceuticals, Inc. 
30 Oct 2019
Confidential
Page 926 of 944

ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Protocol ACH471-100, Amendment 7 
13 March 2018 (Version 8.0) 
 
Confidential 
Page 81 of 81 
 
 
2. Repeat and confirm all temperature measurements >38.0°C 
3. Notify the PI and Sponsor for all confirmed temperature measurements >38.0°C 
4. Consider if referring to an emergency medical facility is appropriate.  If so, refer.  Otherwise: 
a. PI or designee to perform a complete physical examination (including assessing if fever is 
accompanied by a severe headache, stiff neck, or other signs of meningeal irritation, shortness of 
breath, skin rashes, or other unusual signs or symptoms), document a plan based on her/his 
clinical judgment, and possibly an ID consult depending on assessment 
b. CBC (if not done in the last 12 hours) and blood culture 
c. Treat any suspicion of meningococcal infection aggressively; consider initiation of empirical 
antimicrobial therapy (assuming there are no other obvious sources of fever) at least until culture 
results become available and/or an alternative etiology is found 
d. Infectious disease consult is required once the PI or designee initiates empiric antibiotic 
treatment 
e. Measure temperature hourly until <38.0°C 
f. All cases of fever will be assessed by the Investigator, regardless of apparent causality from use 
of the study treatment(s) 
g. All activities performed as part of the Fever Management Plan should be documented 
 
Acute Meningococcal Disease 
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. 
  
ACH-0144471 
Clinical Study Report – ACH471-100
Achillion Pharmaceuticals, Inc. 
30 Oct 2019
Confidential
Page 927 of 944