Clinical trial NCT03472885
Conditions: Paroxysmal Nocturnal Hemoglobinuria (PNH)
Keywords: PNH Paroxysmal Nocturnal Hemoglobinuria ACH-0144471 Danicopan Eculizumab ALXN2040
Sponsor: Alexion Pharmaceuticals, Inc.
Start date: 2018-05-08; Completion date: 2023-01-05
Enrollment: 12 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
To determine the effectiveness of ACH-0144471 (also known as danicopan and ALXN2040) in improving anemia when given with eculizumab for 24 weeks in participants with PNH. Danicopan dose may be increased within each participant, to a maximum of 200 milligrams (mg) three times daily (TID) based on safety and efficacy at protocol-specified time points.

Detailed description:
The purpose of this study is to determine the effectiveness of danicopan in improving anemia, as measured by increased blood hemoglobin, when given with eculizumab (a drug commonly used for treatment of PNH) for 24 weeks in participants with PNH.

The 24-week treatment period was followed by a long-term extension phase. In the extension phase, participants received the same danicopan dose plus eculizumab as they were receiving at the end of 24-week treatment phase.

Results are reported for the 24-week treatment period.

Arms: arm 1: Starting dose of 100 mg danicopan TID in combination with eculizumab. arm 2: Starting dose of 100 or 150 mg danicopan TID in combination with eculizumab. arm 3: Starting dose of 100, 150, or 200 mg danicopan TID in combination with eculizumab. arm 4: Optimal dose (starting dose of either 100, 150, or 200 mg, as determined from Groups 1-3) of danicopan TID in combination with eculizumab.
Interventions: intervention 1: Danicopan intervention 2: Eculizumab
Intervention descriptions: intervention 1: Participants received a daily oral dose of danicopan TID during the treatment period. intervention 2: Participants received intravenous eculizumab administered at the participant's usual dose and schedule.

Protocol documents:
Prot_000.pdf: 
A Phase 2 Open-label Study of ACH-0144471 in Patients 
with Paroxysmal Nocturnal Hemoglobinuria (PNH) Who 
Have an Inadequate Response to Eculizumab Monotherapy 
 
Unique Protocol ID: 
ACH471-101 
NCT Number: 
NCT03472885 
EudraCT Number:  
2016-003526-16 
Date of Protocol:  
19 February 2019 
 


ACH-0144471 
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Clinical Protocol ACH471-101, Amendment 3.1  
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Clinical Trial Protocol 
ACH471-101 
 
Study Title: 
A Phase 2 Open-label Study of ACH-0144471 in Patients with Paroxysmal 
Nocturnal Hemoglobinuria (PNH) Who Have an Inadequate Response to 
Eculizumab Monotherapy 
Study Number: 
ACH471-101 
Study Phase:  
2 
Product Name: 
ACH-0144471 Tablets 
EudraCT Number: 2016-003526-16 
Universal Trial 
U1111-1209-4655 
Number (UTN): 
IND Number:  
127,367 
Indication: 
 
Paroxysmal Nocturnal Hemoglobinuria (PNH) 
Investigators:  
Multi-center 
Sponsor: 
 
Achillion Pharmaceuticals, Inc. 
Sponsor Contact: 
 
 
 
Medical Monitor: 
 
 
 
 
 
Date 
Original Protocol: 
14 September 2017 (Version 1.0) 
Amendment 1 
13 December 2017 (Version 2.0) 
Amendment 1.1 
17 January 2018 (Version 2.1) 
Amendment 2 
13 March 2018 (Version 3.0) 
Amendment 3 
15 February 2019 (Version 4.0) 
Amendment 3.1 
19 February 2019 (Version 4.1) 
 
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. 
PPD
PPD


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Sponsor Signature(s) 
 
Study Title: 
A Phase 2 Open-label Study of ACH-0144471 in Patients with Paroxysmal 
Nocturnal Hemoglobinuria (PNH) Who Have an Inadequate Response to 
Eculizumab Monotherapy 
Study Number: 
ACH471-101 
Protocol Date: 
19 February 2019 
This clinical study protocol has been approved by the sponsor.   
 
Achillion Pharmaceuticals, Inc. 
300 George Street 
New Haven, CT 06511 
Date 
 2/19/2019 | 1:19 PM EST
PPD
PPD


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Investigator’s Signature(s) 
 
Study Title: 
A Phase 2 Open-label Study of ACH-0144471 in Patients with Paroxysmal 
Nocturnal Hemoglobinuria (PNH) Who Have an Inadequate Response to 
Eculizumab Monotherapy 
 
Study Number: 
ACH471-101 
Protocol Date: 
19 February 2019 
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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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 
Ingredients: 
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 Study of ACH-0144471 in Patients with Paroxysmal Nocturnal 
Hemoglobinuria (PNH) Who Have an Inadequate Response to Eculizumab Monotherapy  
 
Study Number: 
ACH471-101 
 
Study Phase: 
Phase 2 
 
Primary Objective: 
To evaluate the efficacy of ACH-0144471 plus eculizumab based on the increase in 
hemoglobin (Hgb) relative to baseline during 24 weeks of treatment  
 
Secondary 
Objectives: 
• 
To evaluate the efficacy of ACH-0144471 plus eculizumab based on the reduction in 
the number of RBC units transfused during the 24 weeks of treatment with 
ACH-0144471 compared to the 24 weeks prior to initiation of treatment with ACH 
0144471 
• 
To evaluate the efficacy of ACH-0144471 plus eculizumab based on the percentage 
of patients who are RBC transfusion-independent during 24 weeks of treatment 
• 
To evaluate the efficacy of ACH-0144471 plus eculizumab based on the change from 
baseline in lactate dehydrogenase (LDH) during 24 weeks of treatment 
• 
To evaluate the safety and tolerability of 24 weeks of treatment with ACH-0144471 
plus eculizumab based on serious adverse events (SAEs), Grade 3 and Grade 4 
adverse events (AEs), and events leading to discontinuation of study drug 
Exploratory 
Objectives: 
• 
To explore the effect of ACH-0144471 plus eculizumab on complement biomarkers 
including alternative pathway (AP) activity, Bb, fD, and C3 fragment deposition 
during 24 weeks of treatment 
• 
To evaluate health-related quality of life (QOL) measures during 24 weeks of 
treatment  
• 
To explore the benefits of ACH-0144471 plus eculizumab 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, 
including prior treatment with eculizumab alone 
o Documenting the evolution of PNH over the course of treatment with 
ACH-0144471 plus eculizumab from a patient’s perspective 
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o Comparing patients' experience with eculizumab alone and ACH-0144471 plus 
eculizumab treatment 
• 
To explore patients’ expectations towards treatment with ACH-0144471 plus 
eculizumab 
Study Design: 
This is a multiple-center, open-label, multiple-dose Phase 2 study in patients with PNH 
who have inadequate response to eculizumab treatment.  This study will include up to 14 
patients who will receive 24 weeks of daily oral treatment with ACH-0144471 plus 
intravenous (IV) eculizumab administered at the patient’s usual dose and schedule.  This 
will be followed by a long-term extension phase.   
There will be 4 groups studied based on initial dose of ACH-0144471, which will be 
enrolled sequentially.  Group 1 will start at 100 mg three times daily (TID).  Group 2 will 
start at 150 mg TID.  Group 3 will start at 200 mg TID. Group 4 will start at the optimal 
dose determined from Groups 1-3.  The initial dose level of Groups 2 and 3 could be 
lower based on emerging safety data from the prior group(s).  The decision to enroll 
subsequent groups at initial lower dose levels than planned will be made by the Sponsor 
in collaboration with the investigators. 
There will be a minimum of 4 weeks of treatment required at each dose level before 
dosing of the subsequent group of patients at the next highest dose level.  The first three 
groups will include 2 patients per group to determine an optimal ACH-0144471 dose for 
the remaining 8 patients in the fourth group.  ACH-0144471 dose may be increased within 
each patient, to a maximum of 200 mg TID based on safety and Hgb values at protocol-
specified time points, after a minimum of 4 weeks of treatment at the lower dose level 
during the 24-week treatment phase.  All dose escalations will be made on a patient-by-
patient basis at the discretion of the PI, in consultation with the Sponsor. 
Upon completion of 24 weeks of treatment, patients will then enter a long-term extension 
phase of this study with the same ACH-0144471 dose plus eculizumab as they were 
receiving at the end of 24-week treatment phase.  
Patients 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 may receive vaccinations during 
this study, as described in Section 6.3.  Those who have been previously vaccinated may 
receive recommended boosters as described in Section 6.3.  
Patients who are not already on antibiotic prophylaxis when they enter the trial as part of 
Standard of Care (SOC) will be prescribed prophylactic penicillin V (or an appropriate 
alternative) from the start of dosing with ACH-0144471 (Day 1), plus eculizumab, 
through the end of dosing. 
Patients will return to the clinic for safety, PK, and other assessments at Week 1, Week 2, 
Week 4, Week 8 and Week 12, and then every 4 weeks until Week 24.  Patients will have 
local safety labs drawn at Week 3, Week 6, and Week 10.  Patients will also be asked to 
return to the clinic or a local lab 72-96 hours after any dose escalation.  At the Week 12 
visit, subjects will remain at the clinic for 8 hours for intensive PK/PD sampling and 
collection of a time-matched ECG at the maximum plasma concentration of 
ACH-0144471 (3 hours after dosing).   
After Week 24, if patients are receiving clinical benefit they will continue with treatment 
in an extension phase, during which they will return to the clinic every 8 weeks, with a 
local lab visit 4 weeks after every clinic visit starting at Week 28.  Clinical benefit will be 
assessed by the PI based on improvement in Hgb.  Additionally, patients must not have 
developed any comorbidity that might make it unsafe to continue on therapy, or any 


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safety concern related to treatment with ACH-0144471.  Patients will continue to receive 
the same dose of eculizumab on the same schedule that they were receiving prior to the 
start of the study.  Patients will be allowed to continue therapy in this study until: 
1) ACH-0144471 is commercially available in their country; 2) the development of 
ACH-0144471 as a potential therapy for PNH is terminated; or 3) the therapy is no longer 
tolerated or effective.  In addition, 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. 
 
If a patient discontinues from the study, dosing of ACH-0144471 will be tapered over 
6 days, as described in Section 5.3.1.3, and two follow-up visits will be conducted 
approximately 14 days and 28 days after the last dose of ACH-0144471.  Patients will 
continue to receive the same dose of eculizumab on the same schedule that they were 
receiving during the taper and follow-up periods and then resume therapy for their PNH 
as directed by their physician. 
Treatment Groups: 
All patients will receive ACH-0144471 administered orally TID over a period of 24 
weeks while patients continue to receive eculizumab at their usual dose and schedule.  
Four treatment groups are planned based on the starting dose of ACH-0144471: Group 1 
starting at 100 mg TID, Group 2 starting at 150 mg TID, Group 3 starting at 200 mg TID 
and Group 4, an expansion group starting at the optimal dose determined from Groups 1-
3.  For Groups 1 and 2, the starting dose of ACH-0144471 may be escalated within 
patient to a maximum dose of 200 mg TID based on accumulating safety data and Hgb 
response within that patient.  Additional groups of patients may be enrolled at each initial 
dose level based on emerging safety data from the prior group(s). At the end of 24 weeks, 
patients who are receiving clinical benefit in the opinion of the PI will continue extended 
dosing of ACH-0144471 plus eculizumab.  For patients not continuing on with long-term 
treatment, a taper of ACH-0144471over six days will be implemented, followed by 28 
days of follow-up.  
Study Population: 
Adult PNH patients with RBC-transfusion-dependent anemia (defined as having received 
at least one RBC transfusion within 12 weeks prior to screening) and who are receiving a 
stable dose of eculizumab (have been receiving eculizumab at approved or higher doses 
for at least 24 weeks prior to entry without change in dose or schedule for at least 
8 weeks). 
Number of Patients: 
Up to 14 patients are planned 
Inclusion Criteria: 
1. Diagnosed with PNH  
2. Have received at least one RBC transfusion within 12 weeks prior to screening 
3. Anemia (Hgb <10 g/dL) with adequate reticulocytosis (absolute reticulocyte count 
≥100 × 109/L) 
4. Must be on a stable regimen of eculizumab (have been on eculizumab for at least 
24 weeks without change in dose or schedule for at least the past 8 weeks) 
5. Platelet count ≥40,000/µL without the need for platelet transfusions 
6. Documentation of vaccination for N. meningitidis, H. influenzae, and S. pneumoniae, 
or willingness to receive vaccinations as described in Section 6.3 
7. Willingness to receive antibiotic prophylaxis if not already prescribed within standard 
of care, as described in Section 5.2.3 
8. Age 18 years to 65 years, inclusively (or ≥ minimum adult age in accordance with 
local legal requirements) 


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9. 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. 
10. 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. 
11. Must agree to provide written informed consent 
12. Must be willing and able, at all times, to have transportation and telephone access, 
and to be within 1 hour of an emergency medical center 
Exclusion Criteria 
1. Current evidence of bone marrow failure or aplastic anemia requiring treatment 
2. History of a major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic 
stem cell/marrow transplant (unless HSCT engraftment has failed) 
3. Received another investigational agent within 30 days or 5 half-lives of the 
investigational agent prior to study entry, whichever is greater  
4. Documented C5 mutations  
5. Known or suspected complement deficiency 
6. Contraindication to one or more of the required vaccinations 
7. Active bacterial infection or clinically significant active viral infection, a body 
temperature >38°C, or other evidence of infection on Day 1, or have a history of 
febrile illness within 14 days prior to first study drug administration 
8. History of meningococcal infection, or a first-degree relative or household contact 
with a history of meningococcal infection  
9. 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 PI would make it difficult to properly provide prophylactic antibiotic therapy or 
treat an active infection.  
10. 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) 
11. Laboratory abnormalities at screening, including: 
• 
Alkaline phosphatase (ALP) >1.5 × upper limit of normal (ULN) 
• 
Absolute neutrophil counts (ANC) <1,000/μL 
• 
Alanine aminotransferase (ALT) >1.5 × ULN 


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• 
Direct bilirubin >1.5 × ULN (unless due to extravascular hemolysis, in the 
opinion of the investigator) 
• 
Any other clinically significant laboratory abnormality that, in the opinion of the 
Principal Investigator (PI), would make the patient inappropriate for the study or 
put the patient at undue risk 
12. Females who are pregnant, nursing, or planning to become pregnant during the study 
or within 90 days of study drug administration  
13. Prior history or current evidence of biliary cholestasis 
14. Gilbert’s syndrome  
Patients with history or family history suggestive of Gilbert’s syndrome will be tested 
and excluded from study if positive for UGT1A1 genotyping polymorphism or 
missense change 
15. 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 
16. Taking medications known to prolong the QT/QTc interval (see Section 5.5.2), or 
have a family history of prolonged QT syndrome or with a screening QTcF 
>450 msec for males or >470 msec for females 
17. Have eGFR<30 mL/min/1.73 m2 and/or are on dialysis 
Criteria to Escalate to a 
Higher Dose of 
ACH-0144471: 
Decisions to change the dose of ACH-0144471 will be made by the site PI in consultation 
with the Sponsor after review of ongoing safety data and documented accordingly. 
• 
1st Dose Escalation Point (Week 4) 
On a patient-by-patient basis, if the starting dose for a group is well tolerated and the 
available safety data are satisfactory, a patient may be escalated to the next highest 
dose (to a maximum dose of 200 mg TID) if his/her Hgb level from Week 4 has not 
increased by ≥1.5 g/dL from their baseline value (Day 1), or the patient received a 
transfusion during the previous 4 weeks.  
• 
2nd Dose Escalation Point (Week 8) 
On a patient-by-patient basis, a patient may be escalated to the next highest dose, to a 
maximum of 200 mg TID, if his/her Hgb level from Week 8 has not increased by 
≥3 g/dL from their baseline value (Day 1), or the patient received a transfusion 
during the previous 4 weeks.  
• 
3rd Dose Escalation Point (Week 12) 
On a patient-by-patient basis, a patient may be escalated to the next highest dose, to a 
maximum dose of 200 mg TID, if his/her Hgb level from Week 12 has not 
normalized, or the patient received a transfusion during the previous 4 weeks. 
At each time point: 
o Patients currently taking 100 mg TID may escalate to 150 mg TID 
o Patients currently taking 150 mg TID may escalate to 200 mg TID 
o Patients taking 200 mg TID will stay on the same dose 


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Any patient who has not already been dose escalated up to 200 mg ACH-0144471 by 
his/her Week 12 visit, may be escalated in the same manner up to a maximum of 200 mg 
ACH-0144471 TID, if they have been on their previous dose for at least 4 weeks. 
Depending on when data are received and reviewed, if the patient is going to dose 
escalate, the site should contact the patient as soon as possible to provide new dosing 
instructions.  If necessary, the patient may be asked to return to the clinic for new drug 
supplies prior to their next clinic visit.  Patients should have blood drawn (locally or at the 
clinic) 72 to 96 hours after starting the new dose for measurement of LDH, Hgb, and liver 
function tests (ALT, aspartate aminotransferase [AST], gamma glutamyl transferase 
[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 dose of 200 mg TID has already been reached 
• 
Hgb level has increased from baseline and is in the normal range 
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 Achillion 
medical monitor. 
Individual Stopping 
Criteria: 
Any individual patient who meets any of the following criteria will be discontinued from 
further dosing of ACH-0144471: 
• 
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 6.19 
Discontinuation of ACH-0144471 treatment will also be considered for: 
• 
ALT or AST >8 × ULN  
• 
ALT or AST >5 × ULN for more than 2 weeks  
• 
ALT or AST >3 × ULN and clinically significant elevation in Total Bilirubin 
relative to baseline 
• 
ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
• 
If there is a marked prolongation of the QT/QTc interval during treatment with 
the study drug, especially if the measurement is obtained from more than one 
ECG 
• 
Development of a meningococcal infection or severe sepsis 
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 will evaluate LDH and Hgb levels, as well 


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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.   
Patients who discontinue from ACH-0144471 treatment will follow the procedures for 
early termination indicated in Appendix 1, but continue to receive their usual regimen of 
eculizumab. 
Study Stopping 
Criteria 
Dosing in the study will be terminated if one or more of the following occurs: 
• 
Two or more patients experience the same or similar study drug-related serious 
adverse event 
• 
Two or more patients experience the same or similar study drug-related Grade 4 or 
higher adverse events 
• 
Two or more patients discontinue study therapy due to liver function test 
abnormalities as detailed below 
o ALT or AST >8 × ULN 
o ALT or AST >5 × ULN for more than 2 weeks 
o ALT or AST >3 × ULN and total bilirubin >2 × ULN or INR >1.5, in the 
absence of warfarin anticoagulation 
o ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
• 
Two or more patients develop a meningococcal infection or severe sepsis 
Test Product, 
Dosage Form, and 
Strength: 
ACH-0144471, administered as 50, 75, or 100 mg tablets 
Mode of 
Administration: 
Oral 
Duration of 
Treatment, 
Confinement, and 
Total Study 
Participation 
The maximum screening period is 60 days. Each patient will receive daily oral doses of 
ACH-0144471 TID plus eculizumab according to the patient’s usual dose and schedule 
for a total of 24 weeks (168 days). If a patient is receiving clinical benefit, in the opinion 
of the PI, the patient will enter the long-term treatment extension phase of the study.  If a 
patient discontinues from the study there will be a 6-day taper at the end of treatment and 
follow-up for an additional 28 days after the end of the study period. Therefore the 
maximum duration for patient participation for those patients not continuing on to long-
term treatment could be up to 262 days (60 days screening, 168 days of treatment, 6 days 
of taper, and 28 days follow-up). For those patients entering the long-term treatment 
extension, patients will continue therapy in this study until: 1) ACH-0144471 is 
commercially available in their country; 2) the development of ACH-0144471 as a 
potential therapy for PNH is terminated; or 3) the therapy is no longer tolerated or 
effective. If patients discontinue during the extension phase, they will have ACH-0144471 
tapered and have follow-up visits. 
 
No overnight stays in the clinic are required.  
 
Safety Assessments: 
Safety will be evaluated by assessment of AEs, clinical laboratory tests, ECGs, and vital 
signs measurements at 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 prophylactic 
antibiotics, and will be carefully monitored for the development of fever 
(see Appendix 4). 
 


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Additionally, the site must report any Grade 3 or Grade 4 AEs which are possibly, 
probably, or definitely related to study drug (see Section 6.16.7) to the Sponsor within 24 
hours. 
  
Pharmacokinetic 
Assessments: 
Blood samples will be collected as described in Section 6.13, at the times indicated in the 
schedule of assessments in Appendix 1 to determine plasma concentrations of 
ACH-0144471.  At the Week 12 visit, patients will remain in the clinic for 8 hours post-
dose to collect additional PK samples.  PK parameters of ACH-0144471, including tmax, 
Cmax and AUC0-tau will be determined using validated bioanalytical methods.  Single 
trough PK samples will be taken at other time points.  Blood samples will be collected 
prior to dosing of ACH-0144471 at each visit throughout the study to determine trough 
concentrations of ACH-0144471.   
 
Pharmacodynamic 
and Efficacy 
Assessments: 
Pharmacodynamics will be evaluated as described in Section 6.14 using serum, plasma, or 
whole blood collected during the study. 
Samples will also be collected and retained for additional genetic and non-genetic 
complement-associated biomarker testing, as discussed in Section 6.11.2.   
Patient-reported 
Outcomes 
Assessments: 
Quality of Life (QoL) questionnaires will be administered at various time points as 
specified in the Schedule of Assessments in Appendix 1 using the tools in Appendix 2.  
The FACIT Fatigue scale (version 4) questionnaire and the EORTC-QLQ-C30 (version 
3.0) scale will be administered to patients to collect patients’ health-related QoL during 
screening (baseline) and after treatment with ACH-0144471, respectively. 
In addition, interviews by independent outcomes researchers chosen by the Sponsor will 
be conducted with patients enrolled in the trial prior to initiation of study treatment 
(during screening period), and follow-up interviews will be conducted during the trial at 
the time points specified in Appendix 1.  These interviews will be conducted to collect 
patients’ experience of PNH, its impact on everyday lives and the disease trajectory and 
patients’ experience of ACH-0144471 plus eculizumab 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. For patients that 
terminate early, a follow-up interview will be obtained at the time of termination.  
 
Statistical Methods: 
Summary statistics will be provided for the following efficacy, safety, PK, and PD 
parameters: 
• 
Primary efficacy parameter: 
o For the Optimal Dose Group: median Hgb during the 24-week treatment phase 
compared to the baseline (Day 1) Hgb  
o For the groups treated at doses lower than the optimal dose level: median Hgb 
over the time period that the patient received the highest dose level during the 
24-week treatment phase compared to baseline (Day 1) Hgb 
• 
Secondary efficacy parameters: 
o Number of units of RBCs transfused during 24 weeks of treatment 
o RBC transfusion status: number and percent of patients without RBC 
transfusions during 24 weeks of treatment  
o Change from baseline in LDH during 24 weeks of treatment 
• 
Safety parameters: 


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o SAEs 
o AEs leading to discontinuation of the study medication 
o AEs (related and regardless of relationship with study drugs) 
o Grade 3 and Grade 4 laboratory abnormalities 
• 
PK, PD, and biomarker parameters: 
o Selected blood chemistry, hematology, and urinalysis laboratory measurements 
o PK parameters (AUC, Cmax, and Tmax) at Week 12 visit, and trough 
concentrations at various time points  
o Complement biomarkers to evaluate alternative pathway activities: Bb, fD, and 
C3 fragments deposition. 
• 
Patient-reported outcomes: 
o FACIT-Fatigue (version 4) 
o EORTC QLQ-C30 (version 3) 
A statistical analysis plan (SAP) will be developed for analyses of data collected during 
the initial 24-week treatment phase to provide details of the data analysis procedures and 
presentations as patient data are emerging with progression of the dose optimization 
process. 


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Table of Contents 
Sponsor Signature(s) ..............................................................................................................................2 
Investigator’s Signature(s) .....................................................................................................................3 
Synopsis .................................................................................................................................................4 
List of Appendices ...............................................................................................................................17 
List of Tables .......................................................................................................................................17 
List of Abbreviations and Definitions of Terms ..................................................................................18 
1 
Introduction ..................................................................................................................................21 
1.1 
Results of Nonclinical Studies .............................................................................................21 
1.2 
Previous Human Experience with ACH-0144471 ...............................................................21 
1.3 
Rationale ..............................................................................................................................22 
1.3.1 Complement Factor D ......................................................................................................22 
1.3.2 Paroxysmal Nocturnal Hemoglobinuria (PNH) ...............................................................22 
1.3.3 Potential Advantages of Addition of ACH-0144471 to Standard of Care with 
Eculizumab in the Treatment of PNH ..............................................................................23 
1.3.4 Safety Considerations .......................................................................................................23 
2 
Study Objectives ...........................................................................................................................24 
2.1 
Primary Objective ................................................................................................................24 
2.2 
Secondary Objectives ..........................................................................................................24 
2.3 
Exploratory Objectives ........................................................................................................25 
3 
Investigational Plan ......................................................................................................................25 
3.1 
Overall Study Design and Plan ............................................................................................25 
3.2 
Rationale for Study Design ..................................................................................................28 
3.2.1 Justification of Design ......................................................................................................28 
3.2.2 Justification of Dose .........................................................................................................29 
3.2.3 Criteria to Escalate to a Higher Dose ...............................................................................29 
3.2.4 Individual Stopping Criteria .............................................................................................30 
3.2.5 Study Stopping Criteria ....................................................................................................31 
3.2.6 Study Duration and Dates .................................................................................................32 
4 
Study Population Selection ..........................................................................................................32 
4.1 
Study Population ..................................................................................................................32 
4.2 
Inclusion Criteria .................................................................................................................32 
4.3 
Exclusion Criteria ................................................................................................................33 


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5 
Study Treatment(s) .......................................................................................................................35 
5.1 
Study Drug - Investigational Drug ACH-0144471 ..............................................................35 
5.2 
Treatments Administered .....................................................................................................35 
5.2.1 ACH-0144471 and Background Therapy (Eculizumab) ..................................................35 
5.2.2 Vaccines ...........................................................................................................................35 
5.2.3 Prophylactic Antibiotics ...................................................................................................35 
5.3 
Selection of Timing and Dose for Each Patient ...................................................................36 
5.3.1 ACH-0144471 ..................................................................................................................36 
5.3.2 Eculizumab .......................................................................................................................37 
5.4 
Method of Assigning Patients to Treatment Groups ...........................................................37 
5.5 
Restrictions ..........................................................................................................................37 
5.5.1 Prior Therapy ....................................................................................................................37 
5.5.2 Concomitant Therapy .......................................................................................................37 
5.5.3 Fluid and Food Intake .......................................................................................................38 
5.5.4 Patient Activity and Other Restrictions ............................................................................38 
5.5.5 Contraception ...................................................................................................................39 
5.6 
Treatment Compliance .........................................................................................................40 
5.7 
Packaging and Labeling .......................................................................................................41 
5.8 
Storage and Accountability ..................................................................................................41 
5.9 
Investigational Product Retention at Study Site ..................................................................41 
6 
Study Procedures ..........................................................................................................................42 
6.1 
Informed Consent ................................................................................................................42 
6.2 
Medical History ...................................................................................................................42 
6.3 
Vaccination ..........................................................................................................................42 
6.4 
Prophylactic Antibiotics ......................................................................................................43 
6.5 
Physical Examination ..........................................................................................................43 
6.6 
Vital Signs ............................................................................................................................43 
6.7 
Body Temperature ...............................................................................................................44 
6.8 
Electrocardiography .............................................................................................................44 
6.9 
Clinical Laboratory Measurements ......................................................................................44 
6.10 
Pregnancy Testing ................................................................................................................46 
6.11 
Sample Collection, Storage, and Shipping ..........................................................................46 
6.11.1 Blood Collection for Complement Assays (AP Wieslab, CH50, C3, Bb, and fD) ..........46 


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6.11.2 Samples for Genetic and Additional Non-genetic Complement-associated Biomarker 
Testing, and for Determination of Vaccine Response ......................................................46 
6.11.3 Pharmacokinetic Plasma Samples ....................................................................................46 
6.11.4 Blood Volumes .................................................................................................................47 
6.12 
Dispensing Study Drug ........................................................................................................47 
Safety Assessments ..........................................................................................................................47 
6.13 
Pharmacokinetic Assessments .............................................................................................49 
6.14 
Pharmacodynamic and Efficacy Assessments .....................................................................49 
6.15 
Patient-Reported Outcomes Assessments ............................................................................50 
6.15.1 Quality of Life (QoL) Questionaires ................................................................................50 
6.15.2 Patient Reported Outcomes (PRO) Interviews .................................................................50 
6.16 
Adverse Events Assessments ...............................................................................................51 
6.16.1 Definitions ........................................................................................................................51 
6.16.2 Criteria for Assessing Seriousness ...................................................................................52 
6.16.3 Documentation and Reporting of Adverse Events ...........................................................53 
6.16.4 Treatment and Follow-up of Adverse Events ...................................................................54 
6.16.5 Timeframe for Collection of Adverse Events ..................................................................54 
6.16.6 Severity and Grading of Adverse Events .........................................................................54 
6.16.7 Assessment of Causality ...................................................................................................54 
6.16.8 Pregnancy .........................................................................................................................55 
6.16.9 Reporting Serious Adverse Events ...................................................................................56 
6.16.10 
Investigator Reporting Requirements for SAEs ......................................................57 
6.17 
Concomitant Medication Assessments ................................................................................57 
6.18 
Monitoring Patient Safety ....................................................................................................58 
6.19 
Removal of Patients from the Trial or Study Drug ..............................................................58 
7 
Study Activities ............................................................................................................................59 
7.1 
Screening Activities .............................................................................................................59 
7.1.1 Screening Visit (Day -60 to Day -1) ................................................................................59 
7.1.2 Vaccination Visit(s) (Day -42 to Day 1) ..........................................................................60 
7.1.3 Patient Reported Outcomes (PRO) Phone Interview – Screening ...................................60 
7.2 
Clinic Visits .........................................................................................................................60 
7.2.1 Weeks 1 Through 24 ........................................................................................................61 
7.2.2 ACH-0144471 Dosing Taper ...........................................................................................62 


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7.2.3 Follow-Up Visits ..............................................................................................................63 
7.2.4 Unscheduled Visits ...........................................................................................................63 
7.3 
Local Laboratory Visits – Weeks 1 through 24 ...................................................................63 
7.4 
Long-Term Treatment Extension .........................................................................................63 
7.4.1 Clinic Visits ......................................................................................................................64 
7.4.2 Local Laboratory Visits ....................................................................................................64 
7.4.3 Quality of Life Questionnaires and Patient-Reported Outcomes (PRO) Phone Interviews
 64 
8 
Quality Control and Assurance ....................................................................................................64 
8.1 
Routine Monitoring ..............................................................................................................64 
8.2 
Site Audits ............................................................................................................................65 
9 
Planned Statistical Methods .........................................................................................................65 
9.1 
General Considerations ........................................................................................................65 
9.2 
Determination of Sample Size .............................................................................................66 
9.3 
(Data) Analysis Sets .............................................................................................................66 
9.3.1 Full Analysis Set ..............................................................................................................66 
9.3.2 Optimal Dose Analysis Set ...............................................................................................66 
9.4 
Demographics and Baseline Characteristics ........................................................................66 
9.5 
Efficacy Analysis .................................................................................................................67 
9.6 
Safety Analysis ....................................................................................................................67 
9.7 
Pharmacokinetic (PK) Analysis ...........................................................................................68 
9.8 
Patient-Reported Outcome Measures Assessments .............................................................68 
9.8.1 Quality of Life Questionnaires .........................................................................................68 
9.8.2 Patient Reported Outcomes (PRO) Interviews .................................................................69 
10 Administrative Considerations .....................................................................................................69 
10.1 
Investigators and Study Administrative Structure ...............................................................69 
10.2 
Institutional Review Board or Independent Ethics Committee and Regulatory Approval ..69 
10.2.1 Ethics Approval ................................................................................................................69 
10.2.2 Regulatory Approval ........................................................................................................69 
10.2.3 Amendments .....................................................................................................................69 
10.3 
Ethical Conduct of the Study ...............................................................................................70 
10.4 
Patient Information and Consent .........................................................................................70 
10.5 
Patient Confidentiality .........................................................................................................70 


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10.6 
Study Monitoring .................................................................................................................71 
10.6.1 Access to Information for Monitoring ..............................................................................71 
10.6.2 Access to Information for Auditing or Inspections ..........................................................71 
10.7 
Case Report Forms and Study Records ...............................................................................71 
10.7.1 Recording of Data ............................................................................................................71 
10.7.2 Source Documentation and Medical/Study Records ........................................................71 
10.8 
Data Monitoring Committee ................................................................................................72 
10.9 
Protocol Violations/Deviations ............................................................................................72 
10.10 Access to Source Documentation ........................................................................................72 
10.11 Data Generation and Analysis .............................................................................................72 
10.12 Retention of Data .................................................................................................................72 
10.13 Final Report, Publication and Disclosure Policy .................................................................73 
11 References ....................................................................................................................................74 
12 Appendices ...................................................................................................................................76 
 
List of Appendices 
Appendix 1. 
Schedule of Assessments .............................................................................................76 
Appendix 2. 
Quality of Life Assessments ........................................................................................83 
Appendix 3. 
Grading the Severity of Adult Adverse Events ............................................................88 
Appendix 4. 
Fever Management Plan ..............................................................................................89 
 
List of Tables 
Table 1. 
Study Design ................................................................................................................27 
Table 2. 
ACH-0144471 Dosing Taper Schedule .......................................................................37 
Table 3. 
Clinical Laboratory Tests .............................................................................................45 
Table 4. 
Approximate Total Blood Volumes for First 24 Weeks of Treatment ........................48 
Table 5. 
Pharmacodynamic Markers .........................................................................................50 
Table 6. 
PK Analysis Parameters ...............................................................................................68 
Table 7. 
Screening Through Week 13 Visits .............................................................................76 
Table 8. 
Week 14 through Follow-up Visits and Long-Term Extension...................................79 
Table 9. 
PK and PD Sampling and ECG Collection at Week 12 Visit* ....................................82 
 


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List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
1A1 
Cytochrome P450 family 1 subfamily A member 1 
AA 
Aplastic anemia 
ACE 
Angiotensin converting enzyme 
ACIP 
Advisory Committee on Immunization Practices 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
AP 
Alternative Pathway (of complement)  
ARB 
Angiotensin receptor blocker 
AST 
Aspartate transaminase 
AUC  
Area under the curve 
BA 
Bioavailability 
Bb 
Bb fragment of complement factor B 
BID 
Twice daily 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
°C 
Degrees Celsius 
C3 
C3 complement protein 
C3G 
C3 glomerulopathy 
C5 
C5 complement protein 
CBC 
Complete blood count 
CH50 
An assay to measure overall activity of complement classical pathway 
CIOMS 
Council for International Organizations of Medical Sciences 
CK  
Creatine kinase 
Cmax 
Maximum plasma concentration 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP3A 
Cytochrome P-450 3A 
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 
GGT 
Gamma-glutamyl transferase 
GLP 
Good Laboratory Practices 
GPI 
glycosylphosphatidylinositol 
HBsAg 
Hepatitis B surface antigen 
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 
IC50 
50% Inhibitory concentration 
ICF 
Informed Consent Form 


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Abbreviation 
Definition 
ICH 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use 
IC-MPGN 
Immune-complex membranoproliferative glomerulonephritis 
IEC  
Independent Ethics Committee 
IM 
Intramuscular 
INR 
International normalized ratio 
IRB 
Institutional review board 
IV 
Intravenous 
kDa 
Kilodalton 
LDH 
Lactate dehydrogenase 
LFC 
Liquid filled capsule 
LFT 
Liver function test 
LLN 
Lower limit of normal 
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  
MMF 
Mycophenolate mofetil 
NOAEL 
No observed adverse effect level 
P450 
Cytochrome P450 
PD 
Pharmacodynamic(s) 
P-gp 
P-glycoprotein 
PI 
Principal investigator 
PIGA 
Phosphatidylinositol N-acetylglucosaminyltransferase subunit A 
PK 
Pharmacokinetic(s) 
PNH 
Paroxysmal Nocturnal Hemoglobinuria 
PO 
Per oral 
PR interval 
Period that extends from the beginning of the P wave until the beginning of the QRS complex 
PRO 
Patient Reported Outcomes 
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’s 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 
SMS 
Short message service 
TEAE 
Treatment-emergent adverse event 
TID 
Three times daily 
tmax 
Time after administration of a drug when the maximum plasma concentration is reached 
UGT  
Uridine diphosphate glucuronosyltransferase 
UGT1A1 
Uridine diphosphate glucuronosyltransferase family 1 member A1 
ULN 
Upper limit of normal 
µL 
Microliter 
µM 
Micromolar 


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Abbreviation 
Definition 
WBC  
White blood cells 


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1 Introduction 
This is a multiple-center, open-label study in patients with PNH who have inadequate response to 
eculizumab treatment. This study will enroll up to 14 patients who will receive 24 weeks of daily 
oral treatment with ACH-0144471 plus intravenous (IV) eculizumab administered at the patient’s 
usual dose and schedule.  Patients enter the study in sequential groups with escalating initial dose 
levels, with a minimum of 4 weeks before dosing for the subsequent group of patients.  The first 
three groups will include 2 patients per group to determine an optimal ACH-0144471 dose for use in 
combination with eculizumab for the remaining 8 patients in the fourth group.  The initial dose level 
of Groups 2 and 3 could be lower based on emerging safety data from the prior group(s).  
ACH-0144471 dose may be increased within each group of patients based on Hgb values at 
protocol-specified time points during the 24-week treatment phase.  All dose escalations will be 
made on a patient-by-patient basis at the discretion of the PI, in consultation with the Sponsor.  The 
decision to enroll subsequent groups at initial lower dose levels than planned will be made by the 
Sponsor in collaboration with the investigators.   
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 for 
treatment of 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 in healthy volunteers are complete and results reported in 
the IB [3]: ACH471-001 Single Ascending Dose Study (SAD), ACH471-002 Multiple Ascending 
Dose Study (MAD), and ACH471-006 Relative Bioavailability Study (Rel BA).   
A drug-drug interaction study (ACH471-010) was recently completed in healthy volunteers.  This 
study was conducted to assess the effect of ACH-0144471on CYP3A, P-glycoprotein (P-gp), and 
UDP-gluronosyltransferase (UGT).  The single-dose PK of each substrate was compared to 
administration alone versus when given in the presence of steady-state levels of ACH-0144471 (150 
mg TID administered for 4 days).  Preliminary results indicate that ACH-0144471 is a weak 
inhibitor of CYP3A, a moderate inhibitor of P-gp, and had no effect on UGT.  
A monotherapy study of ACH-0144471 in PNH patients without prior treatment for PNH (Study 
ACH471-100) and a long-term extension to this study (ACH471-103) are ongoing (see Section 
3.2.2). 


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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 alternative pathway (AP) activation [2, 4].  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, 4].  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 AP activity and inflammation [5, 6].  The biochemical, 
physiological, and functional features of fD make it an attractive target for pharmacological 
inhibition as this may prove useful in the treatment of a wide spectrum of complement-mediated 
diseases 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 is currently under way under the auspices of the PNH Registry 
[7]. 
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 [8]. 
PNH is caused by a somatic mutation in the phosphatidylinositol N-acetylglucosaminyltransferase 
subunit A (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 AP via tickover mechanism [9].  In 
addition to anemia that requires frequent red blood cell (RBC) transfusions, there are other serious 
sequelae related to the liberation of intracellular hemoglobin (Hgb) 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. 


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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.  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.   
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.  However, approximately 30% of patients on eculizumab continue to have 
ongoing extravascular hemolysis. 
1.3.3 Potential Advantages of Addition of ACH-0144471 to Standard of Care with 
Eculizumab 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 mechanistic advantage since it acts upstream of C3 cleavage and has been shown to 
block C3 fragment deposition. 
• 
Patients who only 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. 
 
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 available data from eculizumab therapy and individual case 
reports of congenital complement system deficiencies, including complement fD, inhibition of the 
complement system may result in an increased risk of infection, notably Neisseria meningitidis (N. 
meningitidis) [13, 14, 15] and other encapsulated organisms.   


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Because of this potential risk, special safety precautions will be taken for patients participating in 
ACH471-101.  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).   
Patients on an eculizumab regimen may already be taking a prophylactic antibiotic, according to 
standard of care in their region.  Those patients will continue receiving the antibiotic during the 
duration of this trial.  If a patient is not already on a prophylactic antibiotic when entering the study, 
penicillin V (or an appropriate alternative) will be prescribed from the beginning of dosing of 
ACH-0144471 to the end of dosing.  If a patient has an allergy to or cannot tolerate penicillin V, the 
use of an alternative antibiotic will be considered on a case-by-case basis in consultation with the PI 
and the Sponsor to determine an appropriate alternative. 
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 will also be asked to monitor themselves between clinic visits 
(Appendix 4).   
Additionally, the site must report any Grade 3 or Grade 4 AEs which are possibly, probably, or 
definitely related to study drug (see Section 6.16.7) to the Sponsor within 24 hours. 
1.3.4.2 Risk of Hepatic Injury 
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 (ALP), 
gamma-glutamyl transferase (GGT), total/direct/indirect bilirubin, aspartate aminotransferase (AST), 
and alanine aminotransferase (ALT) will be closely monitored in all clinical studies with 
ACH-0144471. 
In humans, elevations in ALT levels have been observed in healthy volunteers in the MAD study 
(ACH471-002) with the high doses of 500 mg twice daily and 800 mg twice daily for 14 days (see 
IB [3]).  These ALT elevations were not associated with signs or symptoms of hepatic failure, 
occurred after completion of dosing, and were self-limited.  One participant in the ongoing 
monotherapy PNH trials ACH471-100/ACH471-103 had elevated transaminases associated with 
breakthrough hemolysis and discontinued ACH-0144471.  All abnormal transaminase findings were 
transient, were not associated with evidence of hepatic decompensation, and resolved within a short 
time period.  
2 Study Objectives 
2.1 Primary Objective 
The primary objective of the study is to evaluate the efficacy of ACH-0144471 plus eculizumab 
based on the increase in hemoglobin (Hgb) relative to baseline during 24 weeks of treatment. 
2.2 Secondary Objectives  
The secondary objectives of this study are: 


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• 
To evaluate the efficacy of ACH-0144471 plus eculizumab based on the reduction in the number 
of RBC units transfused during the 24 weeks of treatment with ACH-0144471 compared to the 
24 weeks prior to initiation of treatment with ACH 0144471 
• 
To evaluate the efficacy of ACH-0144471 plus eculizumab based on the percentage of patients 
who are RBC transfusion-independent during 24 weeks of treatment 
• 
To evaluate the efficacy of ACH-0144471 plus eculizumab based on the change from baseline in 
lactate dehydrogenase (LDH) during 24 weeks of treatment 
• 
To evaluate the safety and tolerability of 24 weeks of treatment with ACH-0144471 plus 
eculizumab based on serious adverse events (SAEs), Grade 3 and Grade 4 adverse events (AEs), 
and events leading to discontinuation of study drug 
 
2.3 Exploratory Objectives 
The exploratory objectives of this study are: 
• 
To explore the effect of ACH-0144471 plus eculizumab on complement biomarkers including 
alternative pathway (AP) activity, Bb, fD, and C3 fragment deposition during 24 weeks of 
treatment 
• 
To evaluate health-related quality of life (QOL) measures during 24 weeks of treatment  
• 
To explore the benefits of ACH-0144471 plus eculizumab 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, including prior treatment 
with eculizumab alone 
o Documenting the evolution of PNH over the course of treatment with ACH-0144471 plus 
eculizumab from a patient’s perspective 
o Comparing patients' experience with eculizumab alone and ACH-0144471 plus eculizumab 
treatment 
• 
To explore patients’ expectations towards treatment with ACH-0144471 plus eculizumab 
 
3 Investigational Plan 
3.1 Overall Study Design and Plan 
This is a multiple-center, open-label, multiple-dose Phase 2 study in patients with PNH who have 
inadequate response to eculizumab treatment.  This study will include up to 14 patients who will 
receive 24 weeks of daily oral treatment with ACH-0144471 plus intravenous (IV) eculizumab 
administered at the patient’s usual dose and schedule.  This will be followed by a long-term 
extension phase.   
There will be 4 groups studied based on initial dose of ACH-0144471, which will be enrolled 
sequentially.  Group 1 will start at 100 mg TID.  Group 2 will start at 150 mg TID.  Group 3 will 


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start at 200 mg TID.  Group 4 will start at the optimal dose determined from Groups 1-3.  The initial 
dose level of Groups 2 and 3 could be lower based on emerging safety data from the prior group(s).  
The decision to enroll subsequent groups at initial lower dose levels than planned will be made by 
the Sponsor in collaboration with the investigators.  
There will be a minimum of 4 weeks of treatment required at each dose level before dosing of the 
subsequent group of patients at the next highest dose level.  The first three groups will include 2 
patients per group to determine an optimal ACH-0144471 dose for the remaining 8 patients in the 
fourth group.  ACH-0144471dose may be increased within each patient, to a maximum of 200 mg 
TID based on safety and Hgb values at protocol-specified time points, after a minimum of 4 weeks 
of treatment at the lower dose level during the 24-week treatment phase.  All dose escalations will be 
made on a patient-by-patient basis at the discretion of the PI, in consultation with the Sponsor.   
In order to be eligible, PNH patients must have RBC-transfusion-dependent anemia (defined as 
having received at least one RBC transfusion within 12 weeks prior to screening) and who are 
receiving a stable dose of eculizumab (have been receiving eculizumab at approved or higher doses 
for at least 24 weeks prior to entry without change in dose or schedule for at least 8 weeks).  Table 1 
provides a visual view of the study design. 
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 
may receive vaccinations during this study, as described in Section 6.3.  Those who have been 
previously vaccinated, depending on evolving recommendations in this patient population and/or the 
results of any testing that may be performed to examine the patient response to vaccines, may 
receive recommended boosters as described in Section 6.3.   
Patients will return to the clinic for safety, PK, and other assessments at Week 1, Week 2, Week 4, 
Week 8 and Week 12, and then every 4 weeks until Week 24.  Patients will have local safety labs 
drawn at Week 3, Week 6, and Week 10.  Patients will also be asked to return to the clinic or a local 
lab 72-96 hours after any dose escalation.  At the Week 12 visit, subjects will remain at the clinic for 
8 hours for intensive PK/PD sampling and collection of a time-matched ECG at the maximum 
plasma concentration of ACH 0144471 (3 hours after dosing). 
Quality of Life (QoL) Questionnaires (FACIT Fatigue Scale [version 4] and 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 during screening and after 
treatment with ACH-0144471 plus eculizumab, respectively. 
In addition, Patient Reported Outcomes (PRO) interviews by independent outcomes researchers 
chosen by the Sponsor will be conducted with patients enrolled in the trial at times indicated in 
Appendix 1 to collect patients’ experience of PNH, its impact on everyday lives and the disease 
trajectory. 


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Table 1. 
Study Design 
Group 
N 
Treatment 
Weeks 1 – 4 
Weeks 5 – 8 
Weeks 9 – 12 
Weeks 13 – 241 
Beyond Week 
24 
Group 1 
2 
100 mg 
ACH-0144471 
TID + 
eculizumab2 
If Week 4 Hgb 
is ≥1.5 g/dL 
increase from 
Baseline, 
Stay at current 
dose of 
ACH-0144471  
If Week 4 Hgb 
is <1.5 g/dL 
increase from 
Baseline, or 
patient received 
a transfusion in 
previous 4 
weeks, 
Escalate to next 
highest dose4 of 
ACH-0144471  
If Week 8 Hgb 
is ≥3 g/dL 
increase from 
Baseline, 
Stay at current 
dose of 
ACH-0144471  
If Week 8 Hgb 
<3 g/dL 
increase from 
Baseline, or 
patient received 
a transfusion in 
the previous 4 
weeks, 
Escalate to next 
highest dose4of 
ACH-0144471  
If Week 12 Hgb 
is in the normal 
range 
Stay at current 
dose of 
ACH-0144471  
If Week 12 Hgb 
is < normal, or 
if the patient 
received a 
transfusion in 
the previous 4 
weeks, 
Escalate to next 
highest dose4 of 
ACH-0144471  
Patients will 
enter the long-
term extension 
phase and 
remain on the 
same dose of 
ACH-0144471 
they were 
receiving at 
Week 24 + 
eculizumab2 
Group 23 
2 
150 mg 
ACH-0144471 
TID + 
eculizumab2 
Group 33 
2 
200 mg 
ACH-0144471 
TID + 
eculizumab2 
Group 4 
8 
Optimal dose of 
ACH-0144471 
identified from 
Groups 1 – 3 + 
eculizumab2 
Hgb = hemoglobin; TID = three times daily 
1 
Any patient who has not already been dose escalated up to 200 mg ACH-0144471 by his/her Week 12 visit, may be escalated in the same manner up to a maximum 
of 200 mg ACH-0144471 TID, if they have been on their previous dose for at least 4 weeks 
2 
Patients will continue to receive eculizumab at their usual dose and schedule throughout the trial 
3 
Patients in Groups 2 and 3 could start at 100 mg TID or 150 mg TID, respectively, based on emerging safety data from the prior group(s)  
4 
From 100 mg TID to 150 mg TID, or from 150 mg TID to 200 mg TID if patient has not already escalated to 200 mg TID 
 
 


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After Week 24, if patients are receiving clinical benefit, they will continue treatment in an extension 
phase and return to the clinic every 8 weeks, with a local lab visit 4 weeks after every clinic visit.  
Clinical benefit will be assessed by the Principal Investigator (PI) based on an improvement in Hgb.  
Additionally, patients must not have developed any comorbidity that might make it unsafe to 
continue on therapy, or any safety concern related to treatment with ACH-0144471.  Patients will 
continue to receive the same dose of eculizumab on the same schedule that they were receiving prior 
to the start of the study.  Patients will continue therapy in this study until: 1) ACH-0144471 is 
commercially available in their country; 2) the development of ACH-0144471 as a potential therapy 
for PNH is terminated; or 3) until the therapy is no longer tolerated or effective.  
Patients who do not enter the long-term extension phase, or discontinue from the study, will have the 
dose of ACH-0144471 tapered over 6 days, as described in Section 5.3.1.3, and two follow-up visits 
will be conducted approximately 14 days and 28 days after the last dose of ACH-0144471.  Patients 
will continue to receive the same dose of eculizumab on the same schedule that they were receiving 
during the taper and follow-up periods as directed by their physician. 
3.2 Rationale for Study Design 
3.2.1 Justification of Design 
The purpose is to evaluate whether patients with PNH who exhibit only a partial response to 
eculizumab (when administered a therapeutic dose) as evidenced by ongoing hemolysis and anemia, 
may benefit from the addition of ACH-0144471. 
C3 fragment deposition on PNH RBCs during eculizumab treatment is a likely cause for suboptimal 
response in the subset of PNH patients who experience extravascular clearance of PNH RBCs coated 
by C3 fragments [16].  ACH-0144471 inhibits the complement cascade upstream of C3 and also 
blocks the complement amplification loop.  ACH-0144471 has been shown to prevent deposition of 
C3 fragments on PNH erythrocytes ex vivo [17] and therefore is expected to reduce extravascular 
hemolysis.  
A recent report also showed that eculizumab failed to completely block terminal pathway activity in 
several clinically relevant situations ex vivo.  Terminal pathway inhibition by eculizumab became 
less effective the more that complement was activated.  The degree of residual terminal pathway 
activity in the presence of eculizumab correlated with the number of surface-deposited C3b 
molecules [18].  Addition of ACH-0144471 to reduce the density of C3b is expected to convert the 
incomplete terminal pathway inhibition by eculizumab into complete inhibition, leading to a 
synergistic effect.  To test this, Achillion has conducted an in vitro study to assess the synergy of 
ACH-0144471 combined with eculizumab.  The study of ACH-0144471 with eculizumab was 
performed in an AP-dependent hemolytic assay using RBCs from a PNH patient and 20% normal 
human serum in the presence of 10 mM Mg+++EGTA.  A strong synergy in protection of PNH RBCs 
from hemolysis was observed, suggesting the potential for a similar synergistic effect in the clinical 
setting.  This experiment indicates that ACH-0144471 doses of < 200 mg TID could contribute 
meaningfully in a combination regimen with eculizumab. 


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3.2.2 Justification of Dose 
In the SAD study, single doses of ACH-0144471 up to 1200 mg and 2400 mg (given as two 
1200 mg doses separated by 12 hours) were well tolerated in healthy subjects. In the MAD study, 
multiple doses of 200 mg twice daily (BID) for 14 days or 75 mg TID for 7 days were also well 
tolerated in healthy subjects.  However, Grade 3 or Grade 4 ALT elevations occurred in two subjects 
in the higher dose cohorts (500 mg BID and 800 mg BID for 14 days) following completion of 
dosing in the MAD study [3]. 
Achillion partnered with the DILIsym group to employ DILIsym® to assess the clinical relevance of 
the liver enzyme elevations as well as the risk of liver injury at doses planned in the patient studies. 
The simulations indicate that the maximal loss of hepatocytes that occurred with doses up to 
2400 mg daily would not have a significant effect on liver function and doses up to 200 mg TID 
were not predicted to increase ALT [19, 20]. 
The 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.  
Data to date on doses from 100 to 200 mg TID have demonstrated clinically significant 
improvements in Hgb, LDH, increase in PNH RBC Type III clone size, and patient reported well-
being.  Treatment has been generally well tolerated.  Continued monitoring over time to demonstrate 
maintenance and/or improvement of these responses is needed. 
These data from the ongoing monotherapy studies provide clinical evidence that addition of 
ACH-0144471, at a dose of 100 mg TID or greater, in combination with eculizumab, could provide 
additive or synergistic benefit to patients with sub-optimal response to eculizumab monotherapy. 
Therefore, in study ACH471-101, the starting dose for Group 1 of ACH-0144471 will be 100 mg 
TID daily (see Section 3.2.3).  Dose adjustments will be made based on safety monitoring and Hgb 
levels and will not exceed 200 mg TID.  Patients will continue to receive eculizumab according to 
their usual dose and schedule.  
3.2.3 Criteria to Escalate to a Higher Dose 
Decisions to change the dose of ACH-0144471 will be made by the site PI in consultation with the 
Sponsor after review of ongoing safety data.  
• 
1st Dose Escalation Point (Week 4) 
On a patient-by-patient basis, if the starting dose for a group is well tolerated and the available safety 
data are satisfactory, a patient may be escalated to the next highest dose (to a maximum dose of 
200 mg TID) if his/her Hgb level from Week 4 has not increased by ≥1.5 g/dL from their baseline 
value (Day 1), or the patient received a transfusion during the previous 4 weeks.  


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• 
2nd Dose Escalation Point (Week 8) 
On a patient-by-patient basis, a patient may be escalated to the next highest dose, to a maximum of 
200 mg TID, if his/her Hgb level from Week 8 has not increased by ≥3 g/dL from their baseline 
value (Day 1), or the patient received a transfusion during the previous 4 weeks.  
• 
3rd Dose Escalation Point (Week 12) 
On a patient-by-patient basis, a patient may be escalated to the next highest dose, to a maximum 
dose of 200 mg TID, if his/her Hgb level from Week 12 has not normalized, or the patient received a 
transfusion during the previous 4 weeks. 
At each time point: 
• 
Patients currently taking 100 mg TID may escalate to 150 mg TID 
• 
Patients currently taking 150 mg TID may escalate to 200 mg TID 
• 
Patients taking 200 mg TID will stay on the same dose 
 
Any patient who has not already been dose escalated up to 200 mg ACH-0144471 by his/her Week 
12 visit, may be escalated in the same manner up to a maximum of 200 mg ACH-0144471 TID, if 
they have been on their previous dose for at least 4 weeks. 
Depending on when data are received and reviewed, if the patient is going to dose escalate, the site 
should contact the patient as soon as possible to provide new dosing instructions.  If necessary, the 
patient may be asked to return to the clinic for new drug supplies prior to their next clinic visit.  
Patients should have blood drawn (locally or at the clinic) 72 to 96 hours after starting the new dose 
for measurement of LDH, Hgb, and liver function tests (ALT, aspartate aminotransferase [AST], 
gamma glutamyl transferase [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 dose of 200 mg TID has already been reached 
• 
Hgb level has increased from baseline and is in the normal range 
 
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 Achillion medical 
monitor. 
3.2.4  Individual Stopping Criteria 
The PI may stop dosing ACH-0144471 in any patient who meets an individual stopping rule.  
However, the Achillion medical monitor should be notified immediately, if possible, before dosing is 
terminated.  If dosing of ACH-0144471 is to be terminated, the taper schedule described in Section 


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5.3.1.3 will be implemented and treatment with eculizumab will continue at the patient’s usual dose 
and schedule.  If dosing of ACH-0144471 is terminated for safety-related reasons, the PI may 
discontinue dosing ACH-0144471 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.   
Any individual patient who meets any of the following criteria will be discontinued from further 
dosing of ACH-0144471: 
• 
The patient experiences any serious adverse event (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 6.19 
 
Discontinuation of ACH-0144471 treatment will also be considered for:  
• 
ALT or AST >8 × ULN  
• 
ALT or AST >5 × ULN for more than 2 weeks  
• 
ALT or AST>3 × ULN and clinically significant elevation in Total Bilirubin relative to baseline 
• 
 ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
• 
If there is a marked prolongation of the QT/QTc interval during treatment with the study drug, 
especially if the measurement is obtained from more than one ECG 
• 
Development of a meningococcal infection or severe sepsis 
 
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 will 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.  
Patients who discontinue from ACH-0144471 treatment will follow the procedures for early 
termination, taper, and follow-up indicated in Appendix 1, but continue to receive their usual 
regimen of eculizumab. 
3.2.5 Study Stopping Criteria 
Dosing in the study will be terminated if one or more of the following occurs: 
• 
Two or more patients experience the same or similar study drug-related SAE 
• 
Two or more patients experience the same or similar study drug-related Grade 4 or higher AEs 


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• 
Two or more patients discontinue study therapy due to liver function test abnormalities as 
detailed below 
o ALT or AST >8 × ULN 
o ALT or AST >5 × ULN for more than 2 weeks 
o ALT or AST >3 × ULN and TBL >2 × ULN or INR >1.5 in the absence of warfarin 
coagulation 
o ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
• 
Two or more patients develop a meningococcal infection or severe sepsis 
 
3.2.6 Study Duration and Dates 
The maximum screening period is 60 days. Each patient will receive daily oral doses of 
ACH-0144471 TID plus eculizumab according to the patient’s usual dose and schedule for a total of 
24 weeks (168 days). If a patient is receiving clinical benefit, in the opinion of the PI, the patient will 
enter the long-term treatment extension phase of the study.  If a patient discontinues from the study 
there will be a 6-day taper at the end of treatment and follow-up for an additional 28 days after the 
end of the study period. Therefore the maximum duration for patient participation for those patients 
not continuing on to long-term treatment could be up to 262 days (60 days screening, 168 days of 
treatment, 6 days of taper, and 28 days follow-up). For those patients entering the long-term 
treatment extension, patients will continue therapy in this study until: 1) ACH-0144471is 
commercially available in their country; 2) the development of ACH-0144471as a potential therapy 
for PNH is terminated; or 3) the therapy is no longer tolerated or effective.  In addition, 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. 
No overnight stays in the clinic are required.  
4 Study Population Selection 
4.1 Study Population 
The study population is adult PNH patients with RBC transfusion- dependent anemia (defined as 
having received at least at least one RBC transfusion within 12 weeks prior to screening) and are 
receiving a stable dose of eculizumab (have been receiving eculizumab at approved or higher doses 
for at least 24 weeks prior to entry and without change in dose or schedule for at least 8 weeks).  Up 
to fourteen patients are planned to be enrolled in the trial.  
4.2 Inclusion Criteria  
Each patient must meet the following criteria to be enrolled in this study. 
1. Diagnosed with PNH 
2. Received at least one RBC transfusion within 12 weeks prior to screening 


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3. Anemia (Hgb <10 g/dL) with adequate reticulocytosis (absolute reticulocyte count ≥100 × 109/L) 
4. Must be on a stable regimen of eculizumab (have been on eculizumab for at least 24 weeks 
without change in dose or schedule for at least the past 8 weeks)  
5. Platelet count ≥40,000/µL without the need for platelet transfusions 
6. Documentation of vaccination for N. meningitidis, H. influenzae, and S. pneumoniae, or 
willingness to receive vaccinations as described in Section 6.3 
7. Willingness to receive antibiotic prophylaxis if not already prescribed within standard of care, as 
described in Section 5.2.3 
8. Age 18 years to 65 years, inclusively (or ≥ minimum adult age in accordance with local legal 
requirements) 
9. Female participants of childbearing potential must agree to use an acceptable method of 
contraception (as defined in Section 5.5.5) from 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. 
10. 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. 
11. Must agree to provide written informed consent 
12. Must be willing and able, at all times, to have transportation and telephone access, and to be 
within 1 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. Current evidence of bone marrow failure or aplastic anemia requiring treatment 
2. History of a major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem 
cell/marrow transplant (unless HSCT engraftment has failed) 
3. Received another investigational agent within 30 days or 5 half-lives of the investigational agent 
prior to study entry, whichever is greater  
4. Documented C5 mutations  
5. Known or suspected complement deficiency 
6. Contraindication to one or more of the required vaccinations 


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7. Active bacterial infection or clinically significant active viral infection, a body temperature 
>38°C, or other evidence of infection on Day 1, or have a history of febrile illness within 14 days 
prior to first study drug administration 
8. History of meningococcal infection, or a first-degree relative or household contact with a history 
of meningococcal infection  
9. 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 PI would make it difficult to 
properly provide prophylactic antibiotic therapy or treat an active infection.  
10. 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) 
11. Laboratory abnormalities at screening, including: 
• 
Alkaline phosphatase (ALP) >1.5 × upper limit of normal (ULN) 
• 
Absolute neutrophil counts (ANC) <1,000/μL 
• 
Alanine aminotransferase (ALT) >1.5 × ULN 
• 
Direct bilirubin >1.5 × ULN (unless due to extravascular hemolysis, in the opinion of the 
investigator and in consultation with the sponsor) 
• 
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 
12. Females who are pregnant, nursing, or planning to become pregnant during the study or within 
90 days of study drug administration  
13. Prior history or current evidence of biliary cholestasis 
14. Gilbert’s syndrome  
Patients with history or family history suggestive of Gilbert’s syndrome will be tested and 
excluded from study if positive for UGT1A1 genotyping polymorphism or missense change 
15. 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 
16. Taking medications known to prolong the QT/QTc interval (see Section 5.5), or have a family 
history of prolonged QT syndrome or with a screening QTcF >450 msec for males and 
>470 msec for females  
17. Have eGFR< 30 mL/min/1.73 m2 and/or are on dialysis 
 


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5 Study Treatment(s) 
5.1 Study Drug - Investigational Drug ACH-0144471 
ACH-0144471 will be dosed as a tablet 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.  ACH-0144471 will be administered as 50, 
75, or 100 mg tablets. 
5.2 Treatments Administered 
5.2.1 ACH-0144471 and Background Therapy (Eculizumab) 
ACH-0144471 will be administered orally three times daily (TID) over a period of 24 weeks while 
patients continue to receive eculizumab at their usual dose and schedule.  If a patient discontinues 
from the study, a taper of ACH-0144471 will be implemented, according to the schedule in Section 
5.3.1.3, and patients will continue to be dosed with eculizumab according to their usual dose and 
schedule.  If dosing of ACH-0144471 is terminated for safety-related reasons, the PI may 
discontinue dosing ACH-0144471 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 patient who discontinues treatment with ACH-0144471 will have the 
assessments indicated for Follow-up in Appendix 1 and then terminate from the study. 
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.   
5.2.3 Prophylactic Antibiotics 
The prophylactic antibiotic specified in this study is penicillin V (or an appropriate alternative).  
Patients on an eculizumab regimen may already be taking a prophylactic antibiotic, according to 
standard of care in their region.  Continued use of antibiotics other than penicillin V will be 
considered on a case-by-case basis with decisions made jointly between the PI and Sponsor during 
screening to determine whether the patient's existing regimen is appropriate.   
If a patient is not already on a prophylactic antibiotic when entering the study, penicillin V 
(500 mg/day PO) or an appropriate alternative will be prescribed from the beginning of dosing of 
ACH-0144471 (Day 1) to the end of dosing.  If a patient has an allergy to penicillin V, the use of an 
alternative antibiotic will be considered on a case-by-case basis in consultation with the PI and the 
Sponsor to determine an appropriate alternative. 


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5.3 Selection of Timing and Dose for Each Patient 
5.3.1 ACH-0144471 
The starting dose of ACH-0144471 will be based upon Group assignment.  Two patients assigned 
Group 1 and will start treatment with 100 mg TID.  Four weeks later, if there are no safety signals, 
two patients assigned to Group 2 will start treatment with 150 mg TID.  Four weeks later, if there are 
no safety signals, two patients assigned to Group 3 will start treatment with 200 mg TID.  Four 
weeks later, 8 patients assigned to Group 4 will start treatment with the optimal dose determined 
from Groups 1-3.  In Groups 1 and 2, on an individual patient basis, the dose may be increased 
multiple times at 4-week intervals, each time to the next higher dose level allowed based on safety 
data and Hgb level as described in Section 3.2.3.  The initial dose level of Groups 2 and 3 could be 
lower based on emerging safety data from the prior group(s).  The decision to enroll subsequent 
groups at initial lower dose levels than planned will be made by the Sponsor in collaboration with 
the investigators. 
Patients will be dosed with ACH-0144471TID (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 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. 
5.3.1.1 Clinic Visit Dose Administration Instructions 
The morning doses of ACH-0144471on the days of each visit to the clinic will be administered in 
the clinic by study site personnel.  For Clinic Visit days, patients will be instructed to fast for at least 
8 hours overnight and to abstain from taking their ACH-0144471study medication on the mornings 
of their study visits so that they can be dosed in the clinic following safety and pharmacokinetic 
assessments.  At the next day’s Clinic Visit, patients will first have blood drawn for clinical 
laboratory and other evaluations as described in Appendix 1, then have breakfast, and then 
15-30 minutes later take the dose of study medication assigned for that day. Patients will be required 
to bring back all remaining study drug at each visit, so that study site personnel may perform a drug 
accountability assessment.   
5.3.1.2 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 will be instructed to keep their study medication at room temperature. 


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5.3.1.3 ACH-0144471 Taper Schedule 
If a patient discontinues from the study, a taper of ACH-0144471 will be implemented, according to 
the schedule Table 2, and patients will continue to be dosed with eculizumab according to their usual 
dose and schedule. 
Table 2. 
ACH-0144471 Dosing Taper Schedule 
Dose at Termination 
Taper Period 1 
(Taper Days 1-3) 
Taper Period 2 
(Taper Days 4-6) 
100 mg TID  
50 mg TID 
50 mg BID 
150 mg TID 
100 mg TID 
50 mg TID 
200 mg TID 
125 mg TID 
75 mg TID 
 
If a dosing regimen not specified in Table 2 is assigned to a patient, then the Sponsor’s medical 
monitor will define a taper schedule prior to dosing termination. 
5.3.2 Eculizumab 
On Day 1 (± 1) of the study, patients will receive their eculizumab treatment according to their usual 
procedure and dose.  The reason for the ± 1 day window is because the location where patients 
would receive ACH-0144471 may not be the same as the location where they regularly receive their 
eculizumab treatments.  Every attempt should be made to try to dose both drugs on the same day if 
possible.  Patients will continue to receive eculizumab according to their usual dose and schedule for 
the remainder of the study.  The dose and schedule of eculizumab should not be altered during the 
course of the study, except that patients may switch from eculizumab to an approved eculizumab 
biosimilar or ravulizumab after completion of the primary endpoint at Week 24. 
5.4 Method of Assigning Patients to Treatment Groups 
Patients will be enrolled to one of four treatment groups sequentially once the prior treatment group 
has completed enrollment and each patient has completed 4 weeks of treatment.  Each patient will be 
assigned a sequential patient identification number within the study site.  
5.5 Restrictions 
5.5.1 Prior Therapy 
Patients may not commence treatment with ACH-0144471 if they have had a transfusion of RBCs 
≤2 weeks prior to the start of dosing.  Therefore, the patient must remain in screening until at least 
2 weeks have passed from the time of their last transfusion to the start of study drug. 
5.5.2 Concomitant Therapy 
Based on in vitro data, ACH-0144471 has the potential to inhibit several CYP enzymes as well as 
some transporters.  In vitro results for ACH-0144471 interactions with various CYP enzymes and 
transporters are described in the IB [3].   


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As described in Section 1.2, a drug-drug interaction study in healthy volunteers with ACH-0144471 
has been conducted to determine the potential for ACH-0144471 to affect CYP3A, P-gp and UGT.  
Preliminary results indicate that ACH-0144471 is a weak inhibitor of CYP3A, a moderate inhibitor 
of P-gp, and had no effect on UGT.  Therefore, use of specific concomitant medications other than 
eculizumab will be considered on a case-by-case basis with decisions made jointly between the PI 
and Sponsor, based on available knowledge of ACH-0144471 as well as the characteristics of the 
potential concomitant medication.  Per protocol, all subjects are to be treated with study medication 
in combination with eculizumab background therapy (Section 5.2.1); for the purpose of data 
collection and analysis, eculizumab used in this manner will be considered a concomitant 
medication.  If patients switch from eculizimab to an approved eculizumab biosimilar or 
ravulizumab after completion of the primary endpoint at Week 24 (Section 5.3.2), this medication 
used in this manner will be also considered a concomitant medication.  
Although QT prolongation has not been observed in the studies with ACH-0144471 conducted to 
date, a Thorough QT/Qtc study has not been conducted.  Therefore, a conservative approach is being 
taken for drugs that are known to prolong the QT interval and their use is excluded in this study. 
Details of all concomitant medication use, including all medications administered for the treatment 
of AEs, must be recorded in the patient’s case report form (CRF).  The following are some general 
guidelines for concomitant medication use based on currently available data:  
• 
Concomitant administration of folic acid, and/or erythropoiesis-stimulating agents is permitted if 
on stable doses for at least 4 weeks prior to Day 1.  
• 
Concomitant administration of steroids or other immunosuppressants is permitted if the dosage 
regimen is stable for at least 12 weeks 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. 
• 
Concomitant administration of drugs with the potential to cause QTc prolongation is prohibited. 
These include antiarrhythmics such as disopyramide, flecainide, mexiletine, systemic lidocaine, 
propafenone, quinidine and amiodarone 
The use of concomitant medications during the trial will be assessed at the timepoints indicated in 
the Schedule of Assessments (Appendix 1). 
5.5.3 Fluid and Food Intake 
Patients will 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. 
5.5.4 Patient Activity and Other Restrictions 
Patients should refrain from heavy exercise 24 hours prior to blood drawing for laboratory 
evaluations.  Walking and light exercise are acceptable. 


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While the consumption of alcohol is not prohibited, patients will be counseled to avoid the 
consumption of alcohol while participating in this study. 
5.5.5 Contraception 
5.5.5.1 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: 
o Oral, intravaginal, or transdermal combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation 
o Oral, injectable, or implantable progestogen-only hormonal contraception associated with 
inhibition of ovulation 
o Intrauterine device (IUD) or Intrauterine hormone-releasing system (IUS) 
o 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 from the date of screening until 90 days 
after their last dose of study drug 
5.5.5.2 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 


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• 
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. 
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 child-bearing 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 for ACH-0144471 will be performed at each visit.  Patients will 
be required to bring back 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 may also receive automated reminders (e.g., via text or phone call) and they must respond to 
and record the time they take each daily dose of ACH-0144471 in an effort to ensure compliance.  
The site will be notified of any non-response or non-compliance to follow up and address with the 
patient directly. 


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5.7 Packaging and Labeling 
Labels for ACH-0144471 tablets will include, at a minimum, the following information: 
o Clinical Study Number 
o Sponsor Name and Address 
o Product Name and Strength 
o Dosage Form and Route of Administration 
o Direction for Use 
o Contents (Number of Tablets) 
o Lot Number (or Code) 
o Storage Instructions 
o Keep out of the reach of children 
o 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 to 25°C), with allowed excursion of 15 to 30°C.  Patients will be instructed to keep 
their study medications in the original container at room temperature. 
Patients will be required to bring back their study drug at each visit so that study site personnel may 
perform drug accountability.   
The PI or designee (e.g., pharmacist) is responsible for ensuring storage as per the label on the drug 
product at the site and adequate accountability of all used and unused study drug.  This includes 
acknowledgment of receipt of each shipment of study drug (quantity and condition) and patient 
dispensing records and returned or destroyed drug.  Dispensing records will document quantities 
received from Achillion Pharmaceuticals, Inc. (or designee) and quantities dispensed to patients, 
including lot number, date dispensed, patient identifier number, patient initials, and the initials of the 
person dispensing the medication.  All drug supplies and associated documentation will be 
periodically reviewed and verified by the Study Monitor over the course of the study. 
5.9 Investigational Product Retention at Study Site 
At study initiation, the Study Monitor will evaluate the site’s Standard Operating Procedure for 
study drug disposal/destruction in order to ensure that it complies with Achillion Pharmaceuticals, 
Inc. requirements.  Drug may be returned to the Sponsor (or designee) or destroyed on an ongoing 
basis during the study, if appropriate, after drug accountability has been verified by the Study 
Monitor.  At the end of the study, following final drug inventory reconciliation by the Study 
Monitor, the study site will dispose of and/or destroy all unused study drug supplies, including 
empty containers, according to these procedures.  If the site cannot meet Achillion Pharmaceuticals, 


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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. 
6 Study Procedures 
The required study procedures are detailed in this section.  The schedule for these procedures is 
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 to determine whether the patient meets the eligibility criteria.  The history will 
include all surgeries and past medical procedures, all past significant illnesses or current chronic 
conditions, all medication use currently and within the past 90 days (including over the counter 
medications, and use of herbal and nutrient supplements), all eculizumab use during the prior 
24 weeks, and any prior use of alcohol, illicit drugs and/or controlled substances.  The history will 
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 must also include at least 24 weeks and up to 
3 years (if available) of RBC transfusion history.  The medical history will be reviewed at screening 
and at each 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 case report 
form (CRF). 
6.3 Vaccination 
Inhibition by ACH-0144471 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 or boosters 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 or boosters against each organism and/or serotype.  Study participants who do not have 


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a sufficient history for some or all of these vaccines should be vaccinated or provided boosters as 
recommended in the applicable guidelines. 
For any vaccines or boosters 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 7) for possible evaluation of response to 
vaccines or boosters. 
If local practice dictates, vaccinations or boosters for N. meningitidis, S. pneumoniae and 
H. influenzae may all be administered on Day 1 of the treatment period.  The criteria for determining 
whether vaccinations or boosters are required will be the same as those described above, as will the 
guidance on the selection of specific vaccines.  
In addition, boosters may also be given during trial participation based on evolving vaccination 
guideline recommendation changes. 
6.4 Prophylactic Antibiotics 
As described in Section 5.2.3, participants who are not already on antibiotic prophylaxis will be 
prescribed penicillin V (or an appropriate alternative) from the start of dosing with ACH-0144471 
(Day 1) through the end of dosing. 
6.5 Physical Examination 
A complete physical examination will be conducted by the PI (or designee) at the times indicated in 
the Schedule of Assessments (Appendix 1).  This will include an examination of all major 
body/organ systems (including skin, head, eyes, ears, nose, throat, neck, thyroid, lungs, heart, 
abdomen, lymph nodes, and extremities), height, weight and calculation for BMI (height and BMI at 
Screening visit only).  Measurements of height and weight will 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 will 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. 


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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). 
6.8 Electrocardiography 
The PI or designee will obtain ECG measurements at the times indicated in Appendix 1 (Table 7, 
Table 8 and Table 9).  All ECG recordings will be 12-lead, and will 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 will also be noted by the PI or 
designee.  Please note, at the Week 12 visit, patients will remain at the clinic for an additional 8 
hours to collect intensive PK and PD samples.  An additional ECG will be collected at 3 hours post-
dose; this ECG should be in triplicate, with approximately 1 minute between tracings.  If patients 
have a dose escalation after Week 12, the time-matched ECG/PK assessments will be repeated (see 
Section 7.2.1.1). 
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 6.16 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 3, 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 3. 
Clinical Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Additional Tests 
only at Screening 
Other 
Assessments10 
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 (ALP) 
Aspartate aminotransferase 
(AST) 
Bicarbonate (HCO3) 
Bile acids 
Bilirubin(fractionated)1 
Blood urea nitrogen (BUN) 
Calcium 
Calculated eGFR2 
Chloride 
Creatine kinase (CK)3 
Creatinine 
Gamma-glutamyl transferase 
(GGT) 
Glucose4 
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 
Microscopic 
examinatio
n of 
sediment5 
Nitrite 
Leukocytes 
Occult blood 
pH 
Protein 
Specific 
gravity 
Urobilinogen 
Cr-1 Polymorphisms 
Erythropoietin 
FSH6 
HCV Ab 
HbsAg 
HIV Ab 
Sample for genetic 
biomarker testing 
(white blood cells)7 
Serum Pregnancy 
test8 
Urine drug screen9 
 
AP Wieslab 
Bb 
C3 
C3fragment 
deposition 
CH50 
D-dimer 
Direct Coombs 
Factor D  
Free hemoglobin 
Haptoglobin 
Plasma/Serum 
samples for 
additional non-
genetic biomarker 
testing7 
PNH Clone Size 
PT/PTT/INR  
Urine pregnancy 
test9 
Samples for potential 
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 
Provide estimated Glomerular Filtration Rate (eGFR) based on Modification of Diet in Renal Disease (MDRD) 
equation 
3 
Perform at Screening and Day 1, and then subsequently only as a reflex if AST > ULN 
4 
If glucose is > ULN, reflexively test HbA1c 
5 
Only if occult blood, protein, or leukocytes present on dipstick analysis 
6 
For postmenopausal women  
7 
See Section 6.11.2 


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8 
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. 
9 
Urine drug screen will be measured at screening.  Test will include, at a minimum, amphetamines, barbiturates, 
cocaine metabolites, opiates, benzodiazepines, and cannabinoids. 
10 
Refer to the Schedule of Assessments (Appendix 1) for times when these tests will be done 
 
6.10 Pregnancy Testing 
Females of child-bearing 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 receive vaccinations or boosters (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 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 AP hemolysis assay, and the 
plasma concentrations of fB, Ba, 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: 1) 
if a patient does not respond to the investigative drug; 2) if a patient experiences drug-related 
toxicity; or 3) to further characterize the underlying disease. Serum samples will be collected to 
potentially assess patient response to vaccinations at various time points in the study.  Achillion may 
store samples for future use. 
6.11.3 Pharmacokinetic Plasma Samples 
For samples collected for PK analysis, whole blood (2 mL) will be collected into vacutainers 
containing K2EDTA.  The vacutainers will be gently inverted 5 to 8 times to thoroughly mix the 
preservative with the blood and kept chilled in an ice bath.  The tubes will be centrifuged at 4°C for 


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15 minutes at 1300 g within 30 minutes of blood collection.  Approximately 400 µL of plasma will 
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 backup samples will remain at the clinic.  
Information on when and where to ship samples will be provided separately.   
6.11.4 Blood Volumes 
Approximate blood volumes are detailed in Table 4.  The total approximate planned blood volume to 
be collected per individual is 745.5 ml over 24 weeks plus the taper and follow-up periods.  During 
the extension phase, the planned maximum volume for blood collection for local laboratory visits is 
14.5 mL and 49.0 mL for clinic visits.  These volumes do 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. 
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. 
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).  Additionally, the site must report any Grade 3 or Grade 4 AEs which are possibly, 
probably, or definitely related to study drug (see Section 6.16.7) to the Sponsor within 24 hours. 
 


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Table 4. 
Approximate Total Blood Volumes for First 24 Weeks of Treatment  
 
 
24-Weeks Treatment and Follow-up 
Extension Phase 
Test 
Volume 
Drawn/ 
Test (mL) 
Screening 
24-weeks 
Treatment  
Taper & 
Follow-up 
Total 
Local Lab 
Visits 
Clinic 
Visits 
 
 
# Tests 
# Tests 
# Tests 
# Tests 
Blood 
Drawn 
(mL) 
Screening Visit Labs 
(chemistry, LDH, erythropoietin, 
hematology, serum pregnancy, FSH, 
Serology [HIV, HBsAg, HCV Ab] 
14.0 
1 
0 
0.0 
1 
14.0 
0.0 
0.0 
Clinical Labs (chemistry [including 
LDH & haptoglobin] & hematology) 
10.5 
0 
15 
4 
19 
199.5 
10.5 
10.5 
PT, PTT/INR 
4.5 
1 
7 
1 
9 
40.5 
0.0 
0.0 
Free hemoglobin 
4.0 
1 
12 
2 
15 
60.0 
4.0 
4.0 
D-dimer 
4.5 
1 
7 
1 
9 
40.5 
0.0 
4.5 
Direct Coombs 
2.0 
1 
5 
2 
8 
16.0 
0.0 
2.0 
Flow Cytometry: Clone Size 
2.0 
1 
7 
2 
10 
20.0 
0.0 
2.0 
Flow Cytometry: C3 Fragment 
Deposition  
4.0 
0 
7 
2 
10 
36.0 
0.0 
4.0 
AP Wieslab, AP Hemolysis, fD 
5.0 
1 
13 
4 
18 
90.0 
0.0 
5.0 
Bb 
2.0 
1 
9 
4 
14 
28.0 
0.0 
2.0 
CH50, C3 
4.0 
1 
9 
4 
14 
56.0 
0.0 
4.0 
Sample for assessment of patient 
response to vaccines 
3.5 
2 
4 
0 
6 
21.0 
0.0 
3.5 
Samples for non-genetic biomarkers  
5.5 
0 
11 
2 
13 
71.5 
0.0 
5.5 
Sample for CR1 polymorphisms 
test; potential genetic assessment of 
complement genes 
8.5 
1 
0 
0 
1 
8.5 
0.0 
0.0 
PK samples 
2.0 
0 
17 
3 
20 
40.0 
0.0 
2.0 
Total Volume  
 
 
 
 
 
741.5 
14.5 
49.0 
 


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6.13 Pharmacokinetic Assessments 
Serial blood samples will be collected at the Week 12 visit, at the times indicated in Table 9 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 as indicated in 
Table 7 and Table 8. 
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. 
6.14 Pharmacodynamic and Efficacy Assessments 
Pharmacodynamics will be evaluated using serum, plasma, and whole blood collected during the 
study with the assays outlined in Table 5 and the Schedule of Assessments (Appendix 1).  Please 
note, at the Week 12 visit, patients will remain at the clinic for an additional 8 hours to collect 
intensive PK and PD samples.  Additional information on sample collection and shipping 
instructions will be provided in a separate laboratory manual. 
Samples will also be collected and retained for potential additional genetic and non-genetic 
complement-associated biomarker testing, as described in Section 6.11.2. 
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 Hgb levels and other 
measures of hemolysis, as well as RBC transfusion requirements. 


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Table 5. 
Pharmacodynamic Markers 
Assay Identifier*  
Assay Descriptions 
CR1 polymorphisms 
Genetic test 
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 or immunoturbidity assay 
CH50 
MAC-mediated lysis of the antibody sensitized target; 
serial diluted serum  
AP Wieslab assay 
ELISA; LPS as activator; measurement of MAC 
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. 
 
6.15 Patient-Reported Outcomes Assessments 
6.15.1 Quality of Life (QoL) Questionaires 
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 assessments during screening (baseline) and after initiating treatment with 
ACH-0144471.  
6.15.2 Patient Reported Outcomes (PRO) Interviews 
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 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 will be interviewed during the screening period and at the times indicated in Appendix 1.  
For patients who enter the long-term treatment extension, an interview will be conducted at Week 48 
(± 1 week).  A single follow-up interview will be obtained for any patient that terminates early.1 
                                                 
1 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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Once the patient has qualified for the study, a Contact Order Form, including patient contact details, 
will be completed and sent to a dedicated independent unit in charge of scheduling and setting up the 
interviews.  The interviews will be conducted by a trained, experienced interviewer by telephone in 
the local language and will last approximately 30 minutes.  The interviewers will follow a semi-
structured interview guide, specifically developed for the study and the time-point (provided in a 
separate manual).  The guide summarizes the objectives of the study, and the methodology and 
process of the interviews.  It contains the themes to be covered during the interviews.  Amongst 
those, the main themes that will be explored will include patients’ experience of the disease and the 
disease trajectory, in order to document the symptoms and manifestations, and its impact on 
everyday lives.  This process will be followed for all scheduled interviews. 
6.16 Adverse Events Assessments 
6.16.1 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: 
o 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. 
o Any new disease or exacerbation of an existing disease. 
o Recurrence of an intermittent medical condition (e.g., headache) not present at baseline. 
o Any case of abuse of alcohol, illicit drugs, or prescription drugs; abuse of study drug(s) or 
protocol -specified drug(s); addiction. 
o A pregnancy that occurs or becomes confirmed during a clinical study (see Section 6.16.8). 
o Laboratory test or other clinical test (e.g., ECG or X-ray) with a clinically significant 
abnormality (as defined below). 
o An effect of the study medication, including comparator. 
o 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. 


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The following are not considered to be AEs: 
o Medical or surgical procedures (e.g., surgery, endoscopies, tooth extraction, transfusion, etc.) 
- the condition which leads to the procedure is the AE; 
o Preexisting diseases or conditions or laboratory abnormalities present or detected prior to the 
screening evaluation that do not worsen; 
o 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: 
o Associated with accompanying symptoms; and/or, 
o Require medical/surgical intervention; and/or, 
o Lead to a change in study drug dosing or discontinuation from the study; and/or 
o Lead to significant additional concomitant drug treatment, or other therapy; and/or, 
o Lead to any of the outcomes included in the definition of a serious adverse event; and/or 
o Considered clinically significant by the investigator. 
Whenever possible, the etiology of the abnormal findings (rather than the abnormal finding(s) itself) 
should be documented as the adverse event.  Repeated additional tests and/or other evaluations 
required to establish the significance and etiology of an abnormal result should be obtained when 
clinically indicated. 
Any abnormal test result that is determined to be an error does not require reporting as an adverse 
event. 
Surgical procedures themselves are not AEs, but are therapeutic measures for conditions that require 
surgery.  The condition for which the surgery is required may be an adverse event, if it occurs or is 
detected during the study period.  Planned surgical measures permitted by the clinical study protocol 
(if any) and the condition(s) leading to these measures are not adverse events, if the condition(s) was 
(were) known before the start of the study treatment and documented in the patient’s medical record.  
In the latter case, the condition should be reported as medical history. 
All patients who have AEs, whether considered to be associated with the use of the investigational 
product or not, must be monitored to determine the outcome of the event(s).  The clinical course of 
the AE will be followed according to accepted standards of medical practice, even after the end of 
the period of observation, until a satisfactory explanation is found or the investigator considers it 
medically justifiable to terminate follow-up. 
6.16.2 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: 
o Results in death 


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o 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.) 
o 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. 
o Is a persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions 
o Is a congenital anomaly/birth defect (in the child of a patient who was exposed to the study 
drug) 
o Is an important medical event or reaction 
 
6.16.3 Documentation and Reporting of Adverse Events 
AEs, including TEAEs, may be spontaneously reported by a patient or his/her representative, or 
elicited during questioning and examination of a patient.  All AEs will be assessed by the 
Investigator and documented regardless of apparent causality from use of the study treatment(s).  For 
each AE, the investigator will evaluate and report the date of onset and resolution, outcome, 
intensity, relationship to study treatment(s), action taken, additional treatments required to manage 
the event, and determination of seriousness.  All identified AEs occurring during the trial and 
follow-up period must be fully recorded and described on the appropriate CRF page.  The AE should 
be reported in standard medical terminology.  Whenever possible, the AE should be evaluated and 
reported as a diagnosis, rather than as individual signs or symptoms.  A cluster of signs and 
symptoms that results from a single cause should be reported as a single AE (e.g., fever, elevated 
WBC, cough, abnormal chest X-ray, etc. can all be reported as “pneumonia”). 
If a definitive diagnosis is not possible, the individual symptoms and signs should be recorded.  
Documentation must be supported by an entry in the patient’s medical record.  The relationship to 
study drug or study procedures should be assessed using the definitions in Section 6.16.7. 
Additionally, the site must report any Grade 3 or Grade 4 AEs which are possibly, probably, or 
definitely related to study drug (see Section 6.16.7) to the Sponsor within 24 hours. 


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6.16.4 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. 
6.16.5 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. 
6.16.6 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) [21].  The PI (or 
designee) should determine the severity of the AE based on the overall clinical importance or 
significance of the finding for that individual patient.  
If an AE that was reported during the study increases or decreases in severity, then that AE is given a 
resolution date and time and a new record initiated with the new severity.  If the severity of an AE 
remains the same, the AE will be kept open through to resolution. 
6.16.7 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: 
o Unrelated: In the opinion of the investigator, there is no association between the study drug and 
the adverse event 


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o Unlikely: In the opinion of the investigator, it is unlikely that there is an association between the 
study drug and the reported event 
o 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) 
o 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 
o 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’. 
6.16.8 Pregnancy 
Any pregnancy, including female partner pregnancies of male patients that occurs or becomes 
confirmed during a clinical study (time frames outlined in Section 6.16.5) 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 
• 
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. 


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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. 
 
6.16.9 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 6.16.5). 
The procedures for reporting all SAEs and/or pregnancies, regardless of causal relationship, are as 
follows: 
SAE 
o Record the SAE on the SAE reporting form provided by Achillion (or designee) 
o Send the SAE form (via email) to both
 AND to Achillion Pharmaceuticals within 24 
hours of becoming aware of the SAE 
Pregnancy 
o Record the pregnancy on the pregnancy form provided by Achillion (or designee) 
o 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. 
CCI
CCI


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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. 
6.16.10 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. 
6.17 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. 
CCI
PPD
PPD
PPD


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6.18 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.  Additionally, the site 
must report any Grade 3 or Grade 4 AEs which are possibly, probably, or definitely related to study 
drug (see Section 6.16.7) to the Sponsor within 24 hours. 
6.19 Removal of Patients from the Trial or Study Drug 
A patient is free to withdraw from the study at any time without jeopardizing future medical care.  In 
addition, the PI (or designee) may decide, for reasons of medical prudence or patient noncompliance, 
to discontinue dosing ACH-0144471 in a patient.  The PI will also stop dosing ACH-0144471 in any 
patient who meets an individual stopping rule (Section 3.2.4).  In either case, whenever possible, the 
Achillion medical monitor will be notified immediately, and if possible, before dosing is terminated.  
When dosing of ACH-0144471 is terminated, study participation is not necessarily also terminated.  
Instead, whenever possible, the patient will complete all the activities for the Week 24 or Early 
Termination Visit as described in Appendix 1, complete a dosing taper as described in Section 
5.3.1.3, and return for a Follow-up visit two weeks after the last dose of study drug.  Patients will 
continue to receive their eculizumab regimen, as per the PI’s judgment. 
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 
• 
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.  
• 
Physical examinations, assessment of vital signs, ECG measurements, all required safety 
laboratory testing, and collection of blood and urine samples for PK and PD evaluation will be 
performed at various time points throughout the study.  For patients not continuing on to an 
extension study, there will be a follow up visit approximately 2 weeks and 4 weeks after the last 
dose of study drug. 
• 
Dosing should be at approximately the same times each day 
• 
Transfusion information will be collected at every visit 
 
During the treatment periods when multiple assessments occur at the same time, they will be 
conducted in the following order (unless otherwise specified):  
1. ECG and vital signs prior to blood sampling  
2. PK samples will be taken prior to dosing 
3. Blood for laboratory safety tests will be taken prior to dosing  
 
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 (Day -60 to Day -1) 
Prospective patients will 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.  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 will 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 will be reviewed as described in Section 6.2, and a 
complete physical examination will be conducted as described in Section 6.5.  A urine drug screen 
will be performed during Screening.  The urine drug screen will include, at a minimum, 
amphetamines, barbiturates, cocaine metabolites, opiates, benzodiazepines, and cannabinoids.  The 
PI, in consultation with the Sponsor, will use professional judgment in allowing the patient to 
continue participation in the study when evaluating the results of the drug screen if any positive 
results are obtained.  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 and ALT), or if the patient has a history of unexplained jaundice, 
unexplained high bilirubin levels, or a history otherwise suggestive of Gilbert's syndrome, the patient 
will be tested for this condition. 


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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 will 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) (Day -42 to Day 1) 
As part of the screening process, participants will be evaluated to determine whether vaccination 
against N. meningitidis, S. pneumoniae, or H. influenzae is required, as described in Section 6.3.  
Any participant without sufficient history of these vaccines may be vaccinated or provided boosters, 
as appropriate.  For participants who receive vaccinations and/or boosters, they may be either 
administered during the screening period, after all other screening assessments have been completed, 
or may be administered on Day 1 of the treatment period.  For participants who will receive 
vaccinations, all other screening procedures must be completed, and patients must qualify for the 
study prior to vaccinations being administered.  Female participants 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.   
In addition, boosters may also be given during trial participation based on evolving vaccination 
guideline recommendation changes. 
7.1.3 Patient Reported Outcomes (PRO) Phone Interview – Screening 
Patient Reported Outcomes interviews will be conducted during the screening period, prior to 
initiation of study treatment.  Patients must pass all other screening tests and be considered eligible 
for the study prior to being scheduled for their interview.  The procedures indicated in Section 6.15.2 
will be followed. 
7.2 Clinic Visits 
During the Treatment Period, physical examinations, assessment of vital signs, ECG measurements, 
all required safety laboratory testing, pregnancy testing for women of child-bearing potential, QoL 
assessments, PRO interviews, and collection of blood and urine samples for PK and PD evaluation 


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will be performed at various time points as specified in Appendix 1.  The assessments listed in the 
Schedule of Assessments, including collection of blood for determination of trough levels of study 
drug and measurement of the listed complement markers will be performed prior to the 
administration of the first daily dose.   
Patients will be instructed to fast prior to coming to a clinic visit and to bring their supply of 
ACH-0144471 with them for administration at the site.   
Visits may take place within a window of ±1 day relative to the specified day. 
The site will need to administer a meal or snack (see Section 5.5.3) within 15 - 30 minutes prior to 
dosing with ACH-0144471. 
At the clinic, patients will be provided enough ACH-0144471 to last until their next visit.  Clinic 
staff will also instruct the patient how to take their medication at home (Section 5.3.1.2) and record 
the time they took each dose and whether or not the dose was taken with food.  The first dose of the 
day should be taken at the same time each morning; all doses should be taken approximately 15-30 
minutes after completion of a meal or snack.  (see Section 5.5.3).  Patients will be instructed to store 
their study drug at room temperature. 
Patients will continue to receive eculizumab at their usual location according to their usual dose and 
schedule for the entirety of the study. 
Patients will take penicillin V from Day 1 through the end of dosing in this trial (see Section 5.2.3).  
7.2.1 Weeks 1 Through 24 
On Day 1 (± 1) of the study, patients will receive their usual eculizumab treatment at their regular 
location.  Patients will continue to receive eculizumab at their usual location according to their usual 
dose and schedule for the remainder of the study. 
If a patient is not already on a prophylactic antibiotic when entering the study, penicillin V 
(500 mg/day PO) or an appropriate alternative will be prescribed starting on Day 1.  Patients will 
begin daily oral dosing on Day 1 with the dose of ACH-0144471 TID (depending on the group) as 
described in Section 3.1.  Patients will return to the clinic at Week 1, Week 2, Week 4, Week 8, and 
Week 12 for the assessments indicated in Appendix 1, Table 7, and then every 4 weeks until 
Week 24.  
QoL questionnaires (see Section 6.15.1) will be administered and a PRO Phone Interview (see 
Section 6.15.2) will be conducted at the times outlined in the Schedule of Assessments 
(Appendix 1). 
7.2.1.1 Dose Escalation Evaluations (Week 4, Week 8, and Week 12) 
After review of results of the patient’s Week 4, Week 8, and Week 12 Hgb level and safety data, 
depending on patient's assigned group and current dose level, a patient may be dose escalated during 
the study (see Section 3.2.3 and Table 1).  If the PI plans to dose escalate the patient, the site should 
contact the patient as soon as possible to provide new dosing instructions.  If necessary, the patient 


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may be asked to return to the clinic for new drug supplies.  Any patient who has not already been 
dose escalated up to 200 mg ACH-0144471 by his/her Week 12 visit, may continue to be escalated 
up to 200 mg ACH-0144471 TID, at the discretion of the PI if they have been on their previous dose 
for at least 4 weeks.  
In addition to the assessments indicated in Table 7, at the Week 12 visit, patients will remain in the 
clinic for 8 hours post-dose to have additional PK, PD and ECG assessments done as described in 
Table 9.  Patients will be instructed to fast prior to coming to the clinic visit and to bring their supply 
of ACH-0144471 with them for administration at the site.   
In the event a patient is further dose escalated after Week 12, the additional PK, PD, and ECG 
assessments in Table 9 should be repeated accordingly, and the patient should have blood drawn 
(locally or at the clinic) 72 to 96 hours after starting the new dose for measurement of LDH, Hgb, 
and liver function tests (ALT, AST, GGT, and ALP) (see Section 7.3).   
7.2.1.2 Week 24 Visit or Early Termination 
At the Week 24 visit, patients will have all assessments as indicated in Table 8.  Patients will also be 
evaluated for continuation of treatment with ACH-0144471.  Clinical benefit will be assessed by the 
PI based on an improvement in Hgb.  Additionally, patients must not have developed any 
comorbidity that might make it unsafe to continue on therapy, or any safety concern related to 
treatment with ACH-0144471.  Patients continuing treatment with ACH-0144471 plus eculizumab 
will continue on the same dose of ACH-0144471 they were receiving at the Week 24 visit.  The 
procedures outlined in Section 7.4 will be followed if a patient is continuing on to long-term 
treatment.  Patients will be provided with enough ACH-0144471 to last until their next visit.  Any 
patients continuing with treatment will not have the ACH-0144471 taper visits (Section 7.2.2) or 
follow-up visits (Section 7.2.3).  
Patients who do not continue to extended treatment will come back to the clinic for visits during the 
taper period (Section 7.2.2) and follow-up period (Section 7.2.3).  At Week 24, these patients will be 
provided with study drug and dosing instructions for their taper doses, and continue their standard of 
care eculizumab therapy as directed by their physician.  Patients will continue taking their 
medication at home in the same way as previously described (see Section 5.3.1.2).  
7.2.2 ACH-0144471 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 5.3.1.3.  On Days 3 (T1) and 6 (T2) of the taper period, 
patients will have assessments performed as indicated in Appendix 1.   
Patients will be instructed to fast prior to coming to the T1 and T2 clinic visits and to bring their 
study drug with them for administration at the site.  Patients will continue taking their medication at 
home in the same way as previously described (see Section 5.3.1.2).  Patients will continue to 
receive eculizumab at their usual dose and schedule. 
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7.2.3 Follow-Up Visits  
Patients who discontinue ACH-0144471 for any reason will have two follow-up visits approximately 
2 weeks and 4 weeks after the last dose of ACH-0144471.  The procedures indicated in Appendix 1 
will be followed.  Patients will continue their normal standard of care and receive eculizumab at 
their usual dose and schedule. 
7.2.4 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 will include at a minimum: 
• 
Assess for compliance with protocol restrictions 
• 
Assess for AEs and SAEs 
• 
Collect transfusion information 
• 
Record concomitant medications 
• 
Conduct a brief 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 3 
• 
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. 
7.3 Local Laboratory Visits – Weeks 1 through 24 
Patients will have local laboratory visits at Week 3, Week 6, and Week 10 for the assessments 
indicated in Appendix 1, Table 7. 
For dose escalations, patients should have blood drawn (locally or at the clinic) 72 to 96 hours after 
starting the new dose for measurement of LDH, Hgb, and liver function tests (ALT, AST, GGT, and 
ALP).   
7.4 Long-Term Treatment Extension 
Patients who enter the long-term extension will continue taking ACH-0144471 at the dose they were 
taking at Week 24 and will continue to receive eculizumab at their usual dose and schedule.  Patients 
will also continue taking penicillin V, 500 mg/day PO.  In the event a patient is further dose 
escalated after Week 24, the additional PK, PD, and ECG assessments in Table 9 should be repeated 
accordingly, and the patient should have blood drawn (locally or at the clinic) 72 to 96 hours after 
starting the new dose for measurement of LDH, Hgb, and liver function tests (ALT, AST, GGT, and 
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Patients will continue therapy in this study with ACH-0144471 plus eculizumab and be followed in 
the clinic until: 1) ACH-0144471 is commercially available in their country; 2) the development of 
ACH-0144471 as a potential therapy for PNH is terminated; or 3) the therapy is no longer tolerated 
or effective.  In addition, 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. 
If a patient discontinues during the extension phase, the procedures indicated in Sections 7.2.2 and 
7.2.3 will be followed. 
7.4.1 Clinic Visits 
After Week 24, patients who are continuing on to long-term treatment will return to the clinic every 
8 weeks starting at Week 32 and have the assessments described in Appendix 1.  Women of 
childbearing potential will receive urine pregnancy tests at each of these visits.  Patients will be 
instructed to fast prior to coming to a clinic visit and to bring their supply of ACH-0144471 with 
them for administration at the site.  Clinic visits during the long-term extension may take place 
within a window of ±3 days relative to the specified day for the first 24 weeks, and then within a 
window of ±7 days relative to the specified day for the duration of the study.   
At the clinic, patients will be provided enough ACH-0144471 to last until their next visit.  Clinic 
staff will also instruct the patient how to take their medication at home (Section 5.3.1.2) and record 
the time they took each dose and whether or not the dose was taken with food.  The first dose of the 
day will be taken at the same time each morning; all doses should be taken approximately 15-30 
minutes after completion of a meal or snack.  (see Section 5.5.3).  Patients will be instructed to store 
their study drug at room temperature. 
7.4.2 Local Laboratory Visits 
In between clinic visits, patients will have blood drawn at a local clinical laboratory every 8 weeks 
(starting at Week 28) for assessment of Hgb, free Hgb, and LDH levels (Appendix 1, Table 8). 
These visits should occur within a window of ±7 days relative to the specified day.  Women of 
childbearing potential will also receive a urine pregnancy test at these visits. 
7.4.3 Quality of Life Questionnaires and Patient-Reported Outcomes (PRO) Phone 
Interviews 
QoL questionnaires (see Section 6.15.1) will be administered and a PRO Phone Interview (see 
Section 6.15.2) will be conducted at Week 48 (± 1 week).  After Week 48, QoL questionnaires will 
be administered approximately every 6 months for the duration of the study. 
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, 


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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 will 
provide adequate time and space for monitoring visits. 
The monitor will query any missing or spurious data with the PI (or designee), which will 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. 
9 Planned Statistical Methods 
9.1 General Considerations 
Data from the initial 24-week treatment phase and the study extension phase will be presented and 
analyzed separately.  The planned analysis described in the following sections will focus on data 
from the 24-week treatment phase.  Planned analysis on data from the study extension phase will 
depend on the results of 24-week treatment phase. 
Subject (Patient) listings will be provided for all efficacy/PD, PK, and safety parameters for all 
patients receiving at least one dose of ACH-0144471. 
Data from the group of 8 (or more) patients who receive the optimal dose of ACH-0144471 for 
24 weeks, in combination with eculizumab, will be presented and summarized separately from the 


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other groups of patients whose dose levels of ACH-0144471 will be less than the optimal dose level 
for the full 24-week treatment phase.  This group of patients receiving the optimal dose will be 
referred to as the Optimal Dose Group.  The other 6 (or fewer) patients will form groups based on 
the initial ACH-0144471 dose: 100 mg TID, 150 mg TID, or 200 mg TID. 
As indicated above, the Optimal Dose Group may include more than 8 patients at the end of the dose 
optimization process if the optimal dose level of ACH-0144471 is achieved prior to the enrollment 
of patients in the Optimal Dose Group (e.g., 2 or more groups, all started with same optimum dose of 
ACH-0144471 plus eculizumab, may be combined for analyses of this dose). 
Summary tables on efficacy/PD and safety parameters will be presented for the Optimal Dose 
Group.  Inferential statistical procedures (e.g., confidence intervals, comparisons with baseline 
values, etc.) may be employed on selected efficacy parameters for group(s) of patients receiving less 
than the optimal dose level. 
A statistical analysis plan (SAP) will be developed for analyses of data collected during both the 
initial 24-week treatment phase and the long-term extension to this study, in order to provide details 
of the data analysis procedures and presentations as patient data are emerging with progression of 
the dose optimization process.  
9.2 Determination of Sample Size 
The sample size is based on the small number of PNH patients who have an inadequate response to 
eculizumab monotherapy and the goal of achieving an optimal dose level of ACH-0144471 in 
combination with eculizumab treatment.  It is estimated that 14 patients enrolling sequentially will 
be sufficient to identify an optimal dose level of ACH-0144471 plus eculizumab for use in future 
studies. 
9.3 (Data) Analysis Sets 
9.3.1 Full Analysis Set  
The full analysis set will include all patients who receive at least one dose of ACH-0144471, and 
will be used for the efficacy / PD, PK, and safety analysis. 
9.3.2 Optimal Dose Analysis Set 
The optimal dose analysis set includes data from patients receiving the identified optimal dose of 
ACH-0144471 in combination with eculizumab, starting on Day 1 of treatment (the Optimal Dose 
Group).  Other analysis sets may be developed if clinically deemed meaningful with emerging 
patient data. 
9.4 Demographics and Baseline Characteristics 
Demographic parameters (age, gender, race, weight, BMI) and baseline PNH disease characteristics, 
including RBC transfusion history, will be summarized for the full analysis set and the optimal dose 
analysis set to provide an overall description of the study population.  


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9.5 Efficacy Analysis 
The primary efficacy endpoint is: 
• 
For the Optimal Dose Group: median Hgb during the 24-week treatment phase compared to the 
baseline (Day 1) Hgb  
• 
For the groups treated at doses lower than the optimal dose level: median Hgb over the time 
period that the patient received the highest dose level during the 24-week treatment phase 
compared to baseline (Day 1) Hgb  
Summary statistics will be provided for the Optimal Dose Group for the primary efficacy endpoint 
of change in median Hgb over the 24-week treatment phase.  The ninety-five percent (95%) 
confidence interval for mean of median changes from baseline will be computed.  Other statistical 
analysis procedures may be applied if clinically deemed meaningful. 
The secondary efficacy endpoints are: 
• 
Number of units of RBCs transfused during 24 weeks of treatment 
• 
RBC transfusion status: number and percent of patients without RBC transfusions during 24 
weeks of treatment  
• 
Change from baseline in LDH during 24 weeks of treatment 
 
Similar to the primary efficacy endpoint, summary presentations will be provided for the Optimal 
Dose Group only. 
Summary statistics for continuous variables will be provided for the secondary efficacy endpoints, 
RBC transfusion units received during 24 weeks of dosing, and LDH change from baseline at 
protocol-specified time points.  Red blood cell transfusion status during the 24-week treatment phase 
will be summarized using frequency count and percentage.   
In addition, comparison in RBC transfusion units ‘24 weeks after’ and ‘24 weeks before’ the 
initiation of ACH-0144471 will be provided and summarized.  The time period ‘24 weeks after’ is 
defined as the period of time inclusive of Day 1 through Week 24 of the treatment phase. 
Hemoglobin levels and changes from baseline Hgb level over the 24-week treatment phase will be 
plotted for each patient.  Mean (or median) Hgb level and mean (or median) change from baseline 
over time will also be plotted.  
Details on analysis and presentations of efficacy endpoints will be described in the SAP. 
9.6 Safety Analysis 
The safety of ACH-0144471 in combination with eculizumab during the 24-week treatment phase 
will be assessed by measuring the frequency of SAEs, all AEs (and grades) regardless of relationship 
with study drugs, discontinuations due to AEs, and Grade 3 and 4 laboratory abnormalities.  
Summary tables will be provided for both the Optimal Dose Group and other groups of patients 


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started at other ACH-0144471 levels.  Note that 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 for the Optimal Dose Group.  Data on vital signs and ECGs will be 
examined either through patient listings or by summary statistics of selected parameters for the 
Optimal Dose Group. 
Other exploratory techniques, e.g., graphic presentations, may also be employed to facilitate clinical 
interpretations of the safety results. 
Details on analysis and presentations of safety parameters will be described in the SAP. 
9.7 Pharmacokinetic (PK) Analysis 
Pharmacokinetic analysis will be done using a validated computer program for the full analysis set.  
The PK characteristics of ACH-0144471 from patients, including, but not limited to, the standard PK 
parameters outlined in Table 6 below, will be derived from the individual plasma concentration time 
data at Week 12 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. 
Trough plasma concentrations will be listed and summarized to assess the amounts of ACH-144471 
at steady state prior to the first daily dose.  Graphic presentations will also be provided to depict PK 
profiles of ACH-0144471 from the patients. 
Table 6. 
PK Analysis Parameters 
AUC 
Area under the curve 
Cmax 
Maximum plasma concentration 
tmax 
Time after administration of a drug when the maximum plasma 
concentration is reached 
 
9.8 Patient-Reported Outcome Measures Assessments 
9.8.1 Quality of Life Questionnaires 
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 patient fatigue 
conditions. 
Similar analysis and presentations may be provided for each domain score of the EORTC QLQ-C30 
instrument.   


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9.8.2 Patient Reported Outcomes (PRO) Interviews 
De-identified transcripts of the patients’ interviews will be analyzed using a thematic analysis based 
on the grounded theory.  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.  A validated software package 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. 
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 will be 
recorded. 
10.2 Institutional Review Board or Independent Ethics Committee and 
Regulatory Approval 
10.2.1 Ethics 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 will 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 will 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.  


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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 will comply with the applicable 
regulatory requirements and will adhere to ICH GCP (E6).  Each patient must be adequately 
informed in a language that they can understand and read of the aims, methods, anticipated benefits, 
potential hazards and the discomfort the study may entail, as well as their right to abstain from 
participating in the study and to withdraw their consent at any time without affecting their medical 
care.  If important new information is incorporated into the ICF and approved by the EC, all patients 
still actively participating in the study must be re-consented. 
Written informed consent will 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 will supply all enrolled patients with a copy of their signed 
informed consent form.  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. 


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10.6 Study Monitoring 
10.6.1 Access to Information for Monitoring 
In accordance with ICH-GCP guidelines, the Study Monitor must have direct access to the 
investigator’s source documentation in order to verify the consistency of the data recorded in the 
CRFs. 
The Study Monitor is responsible for routine review of the CRFs at regular intervals throughout the 
study, to verify adherence to the protocol, and the completeness, consistency, and accuracy of the 
data being entered.  The Study monitor will have access to any patient records needed to verify the 
entries on the CRFs.  The investigator agrees to cooperate with the Study Monitor to ensure that any 
problems detected in the course of these monitoring visits are resolved. 
10.6.2 Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or Achillion Pharmaceuticals, Inc. may conduct inspections 
or audits of the clinical study.  If the investigator is notified of an inspection by a regulatory 
authority, the investigator agrees to notify the Achillion Pharmaceuticals, Inc. Medical Monitor 
immediately.  The investigator agrees to provide to representatives of a regulatory agency or 
Achillion Pharmaceuticals, Inc. access to records, facilities, and personnel for the effective conduct 
of any inspection or audit. 
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 will be completed by the investigator (or designee), who will 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 will 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, will be recorded in 
the patient’s medical/study records by the investigator (or designee).  The investigator (or designee) 
will 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. 


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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 will provide adequate time and space for monitoring visits. 
Patients will have access to safety laboratory results upon request at any time during the study.  PK 
levels will not be available until after all study analysis is completed 
10.11 Data Generation and Analysis 
Data generation and analysis will be specified and detailed in the SAP. 
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 
will be classified into at least two separate categories as follows: 
o Investigator study file, and 
o 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 


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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 will 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 will be made for storage outside of the site. 
The interviews will be audio recorded in a de-identified way.  The audio files will serve as source 
documents and will be archived in Trial Master File.  Any additional copy of audio recordings 
temporarily retained by interviewers and / or transcription unit will be destroyed after transcription 
process completion.  The audio recordings will be transcribed word by word for the analysis. 
10.13 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 4.0. New Haven (CT): Achillion 
Pharmaceuticals, Inc.; 2016. 57 p. 
4. 
Figueroa JE, Densen P. Infectious diseases associated with complement deficiencies. Clinical 
microbiology reviews. 1991;4(3):359-95. 
5. 
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. 
6. 
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. 
7. 
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. 
8. 
Pramoonjago P, Pakdeesuwan K, Siripanyaphinyo U, Chinprasertsuk S, Kinoshita T, 
Wanachiwanawin W. Genotypic, immunophenotypic and clinical features of Thai patients 
with paroxysmal nocturnal haemoglobinuria. Br J Haematol. 1999 May;105(2):497-504. 
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. 
1 
 


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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. 
Risitano AM, Notaro R, Marando L, Serio B, Ranaldi D, Seneca E, Ricci P, Alfinito F, 
Camera A, Gianfaldoni G, Amendola A, Boschetti C, Di Bona E, Fratellanza G, Barbano F, 
Rodeghiero F, Zanella A, Iori AP, Selleri C, Luzzatto L, Rotoli B. Complement fraction 3 
binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal 
hemoglobinuria patients treated by eculizumab. Blood. 2009 Apr 23;113(17):4094-100. doi: 
10.1182/blood-2008-11-189944. Epub 2009 Jan 29. 
17. 
Yuan X, Gavriilaki E, Thanassi JA, Yang G, Baines AC, Podos SD, Huang Y, Huang M, 
Brodsky RA. Small-molecule factor D inhibitors selectively block the alternative pathway of 
complement in paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic 
syndrome. Haematologica. 2017 Mar;102(3):466-75. doi: 10.3324/haematol.2016.153312. 
Epub 2016 Nov 3. 
18. 
Harder MJ, Kuhn N, Schrezenmeier H, Höchsmann B, von Zabern I, Weinstock C, Simmet T, 
Ricklin D, Lambris JD, Skerra A, Anliker M, Schmidt CQ. Incomplete inhibition by 
eculizumab: mechanistic evidence for residual C5 activity during strong complement 
activation. Blood. 2017 Feb 23;129(8):970-80. doi: 10.1182/blood-2016-08-732800. Epub 
2016 Dec 27. 
19. 
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. 
20. 
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 April 14, 2017. 
21. 
U.S. Department of Health and Human Services, National Institutes of Health, National 
Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. 
[CTCAE 4.03 June 2010]. Downloaded from 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
01 April 2017. 
 


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12 Appendices 
Appendix 1. 
Schedule of Assessments  
Table 7. 
Screening Through Week 13 Visits 
Test 
Screening 
ACH-0144471 + Eculizumab 
Visit 
Day -60 
to -1 
Day 
-42 
Day 
-14 
Day 1 
(B/L) 
Wk 1 
(Day 7) 
Wk 2 
Wk 3 
Wk 41 
Wk 6 
Wk 81 
Wk 10 
Wk 
121 
Post-
Escalation 
Clinic Visit Days 
X 
X2 
X2 
X 
X 
X 
 
X 
 
X 
 
X 
 
Local Laboratory Visit 
 
 
 
 
 
 
X3 
 
X3 
 
X3 
 
X4 
Screening Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History  
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
FSH5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HCV Ab, HbsAg, HIV Ab 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CR1 Polymorphism Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Erythropoietin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height, BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Sample for other genetic 
testing (white blood cells) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccinations 
 
X2 
X2 
X7,8 
 
Vaccination Boosters8 
See Section 6.3 
Patient Reported Outcomes 
Interviews9 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Dosing and Drug Distribution 
Eculizumab Dosing10 
 
 
 
X 
Administered according to the patient’s usual dose and schedule 
ACH-0144471 Dosing10 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ACH-0144471 Dispensing11 
 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
Clinical Assessments 
Physical Exam12 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
Vital Signs 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
 


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Test 
Screening 
ACH-0144471 + Eculizumab 
Visit 
Day -60 
to -1 
Day 
-42 
Day 
-14 
Day 1 
(B/L) 
Wk 1 
(Day 7) 
Wk 2 
Wk 3 
Wk 41 
Wk 6 
Wk 81 
Wk 10 
Wk 
121 
Post-
Escalation 
Body Temperature13 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
Weight 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
12-lead ECG (single) 
X 
 
 
 
 
X 
 
X 
 
X 
 
X14 
 
QoL Questionnaires 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
RBC Transfusion Review 
X 
X2 
X2 
X 
X 
X 
 
X 
 
X 
 
X 
 
AE/SAE 
 
X2 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant 
Medications/Protocol 
Restrictions 
X 
X2 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Laboratory Assessments15 
Hematology, Chemistry, 
and Urinalysis16 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X4 
Pregnancy Test17 
X 
X8 
X8 
X8 
 
 
 
X 
 
X 
 
X 
 
PT/PTT/INR, D-Dimer18 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Free Hemoglobin, 
haptoglobin 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Direct Coombs 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
PK Samples19 
 
 
 
X 
X 
X 
 
X 
 
X 
 
X14 
 
AP Wieslab, Bb, fD, C3, 
CH50, AP hemolysis 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
X14 
 
Flow cytometry: Clone Size 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Flow cytometry: 
C3 fragment deposition 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Plasma/Serum samples for 
additional non-genetic 
biomarker testing (fB, Ba, 
C5a, and soluble C5b-9) 
 
 
 
X 
 
X 
 
X 
 
X 
 
X14 
 
Sample for potential 
assessment of patient 
response to vaccines20 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
1 
Weeks 4, 8, and 12 are dose escalation timepoints.  See Section 3.2.3 for dose escalation information 
2 
Only for patients who need to receive vaccinations during the screening period (see Section 6.3 for guidance) 


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Test 
Screening 
ACH-0144471 + Eculizumab 
Visit 
Day -60 
to -1 
Day 
-42 
Day 
-14 
Day 1 
(B/L) 
Wk 1 
(Day 7) 
Wk 2 
Wk 3 
Wk 41 
Wk 6 
Wk 81 
Wk 10 
Wk 
121 
Post-
Escalation 
3 
At Weeks 3, 6, and 10, hematology, chemistry, and urinalysis, as described in Section 6.9 will be collected at the local laboratory.  Site will call patient within 1 
day to confirm that local laboratory visit occurred.  Site will also assess AEs, SAEs, and concomitant medications. 
4 
If a dose escalation occurs, measurement of LDH, Hgb, and liver function tests (ALT, AST, GGT, ALP), should be drawn locally or at the clinic 72-96 hours after 
escalation 
5 
FSH for postmenopausal women at screening only. 
6 
Urine drug screen will be measured at screening. For all patients, test will include, at a minimum, amphetamines, barbiturates, cocaine metabolites, opiates, 
benzodiazepines, and cannabinoids. 
7 
If local practice dictates, vaccinations for N. meningitidis, S. pneumoniae and H. influenzae may all be administered on Day 1 of the treatment period.  (see 
Section 6.3 for guidance) 
8 
Female patients of childbearing potential receiving vaccinations or boosters (see Section 6.3) must have a negative urine pregnancy test on the days of 
vaccination, before any vaccine or booster is administered. 
9 
Interview could be scheduled ± 1 week 
10 
Refer to section 5.3 for dosing of ACH-0144471 and eculizumab 
11 
Patients will be provided with sufficient study drug to last until their next appointment. Treatment compliance assessments will be performed at each visit.  
Depending on when subjects are dose escalated (see Section 3.1), patients may need to return to the clinic in between visits to be dispensed ACH-0144471 and 
new dosing instructions. 
12 
Full physical exam at Screening and Day 1.  Brief physical exam at all other timepoints. 
13 
Patients will be monitored for fever at every clinic visit and will monitor themselves in between visits.  See Appendix 4 for instructions on fever management. 
14 
For PK, PD, and ECG schedule at this visit, refer to Table 9 
15 
Blood and urine samples will be collected prior to dosing 
16 
Hematology, chemistry, and urinalysis, as described in Section 6.9 
17 
Serum pregnancy test at screening.  Urine pregnancy test at baseline and every 4 weeks for the duration of the study including follow-up 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 follow-up serum pregnancy test. 
18 
D-Dimer only assessed at Screening, Week 4, and Week 12. 
19 
Except at Week 12, PK trough samples only; collected prior to first daily dose 
20 
Samples for vaccine response will be required only if vaccination(s) were administered during the Screening period.  If required, a sample will be collected during 
screening, pre-dose and 2 hours after dosing ACH-0144471 on Day 1 and Week 12.  A pre-dose sample should also be collected at the next scheduled clinic visit 
after any dose escalation beyond Week 12. 
 


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Table 8. 
Week 14 through Follow-up Visits and Long-Term Extension 
Test 
ACH-0144471 + Eculizumab 
Follow-up7 
Wk 16 
Wk 20 
Wk 24 
or ET1 
Post-
Escalation2 
Long-term 
Extension3 
Un-
scheduled6 
Taper7 
Local 
Laboratory 
Visit4 
Clinic 
Visit5 
 
T18 
T28 
F/U19 
F/U29 
Clinic Visits 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Patient Reported Outcomes Interviews 
 
 
X10 
 
 
X11 
 
 
 
 
 
Dosing and Drug Distribution 
Eculizumab Dosing12 
Administered according to the patient’s usual dose and schedule 
ACH-0144471 Dosing13 
X 
X 
X 
 
 
X 
 
X 
X 
 
 
ACH-0144471 Dispensing13 
X 
X 
X 
 
 
X 
 
X 
 
 
 
Clinical Assessments 
Vaccination Boosters15 
See Section 6.3 
Physical Exam16 
X 
X 
X 
 
 
X 
X 
 
 
X 
X 
Vital Signs 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Body Temperature17 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Weight 
 
 
X 
 
 
X 
 
 
 
 
X 
12-lead ECG (single) 
 
X 
X 
 
 
X18 
X 
 
 
 
X 
QoL Questionnaires 
 
 
X 
 
 
X11 
 
 
 
 
 
RBC Transfusion Review  
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
AE/SAE 
X 
Concomitant Medications/  
Protocol Restrictions 
X 
Laboratory Assessments19 
Hematology, Chemistry, and 
Urinalysis20 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Pregnancy Test21 
X 
X 
X 
 
X 
X 
 
 
 
 
X 
PT/PTT/INR, D-Dimer22 
X 
X 
X 
 
 
 
 
 
 
 
X 
Free Hemoglobin, haptoglobin 
X 
X 
X 
 
 
X 
X 
 
 
X 
X 
Local Lab tests: Hgb, free Hgb, and 
LDH 
 
 
 
 
X 
 
 
 
 
 
 
Direct Coombs 
 
X 
X 
 
 
X 
 
 
 
X 
X 
PK Samples (Trough) 
X 
X 
X 
 
 
X 
X 
X 
X 
 
X 


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Test 
ACH-0144471 + Eculizumab 
Follow-up7 
Wk 16 
Wk 20 
Wk 24 
or ET1 
Post-
Escalation2 
Long-term 
Extension3 
Un-
scheduled6 
Taper7 
Local 
Laboratory 
Visit4 
Clinic 
Visit5 
 
T18 
T28 
F/U19 
F/U29 
AP Wieslab, Bb, CH50, AP hemolysis 
assay 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
fD, C3 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
Flow cytometry: Clone Size, C3 
fragment deposition 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
Plasma/Serum samples for additional 
non-genetic biomarker testing (fB, Ba, 
C5a, and soluble C5b-9) 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
Sample for potential assessment of 
patient response to vaccines 
 
 
 
 
 
X23 
 
 
 
 
 
1 
At the Week 24 visit, patients will be evaluated for continuation of treatment with ACH-0144471 plus eculizumab as described in Section 3.1 
2 
For any patients who have a dose escalation beyond Week 12 (See section 3.2.3), measurement of LDH, Hgb, and liver function tests (ALT, AST, GGT, ALP), 
should be drawn locally or at the clinic 72-96 hours after escalation 
3 
If a patient discontinues from ACH-0144471 during the long-term treatment phase, the taper and follow-up procedures will be performed. 
4 
Patients who enter the long-term extension will have local laboratory visits every 8 weeks, starting at Week 28. These visits should occur within a window of ±7 
days relative to the specified day. 
5 
Patients who enter the long-term extension will return to the clinic every 8 weeks, starting at Week 32.  Clinic visits during the long-term extension may take 
place within a window of ±3 days relative to the specified day for the first 24 weeks, and then within a window of ±7 days relative to the specified day for the 
duration of the study (see Section 7.4). 
6 
See Section 7.2.4 
7 
For patients who discontinue from the study. 
8 
T1 = Day 3 of the taper; T2 = Day 6 of the taper 
9 
F/U 1 = follow-up visit 1 will be 14 days after the last dose of study drug (including taper) F/U 2 = follow-up visit will be 28 days after the last dose of study drug 
(including taper). 
10 
Interview could be scheduled ± 1 week 
11 
QoL questionnaires and Patient Reported Outcomes Interview will be administered at Week 48 ± 1 week.  After Week 48, QoL questionnaires will be 
administered approximately every 6 months for the duration of the study.  
12 
Eculizumab will be administered following the usually prescribed procedures for the patient. 
13 
Patients will take ACH-0144471 as described in Section 3.2.3. 


ACH-0144471 
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Clinical Protocol ACH471-101, Amendment 3.1  
19 February 2019, Version 4.1 
 
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Test 
ACH-0144471 + Eculizumab 
Follow-up7 
Wk 16 
Wk 20 
Wk 24 
or ET1 
Post-
Escalation2 
Long-term 
Extension3 
Un-
scheduled6 
Taper7 
Local 
Laboratory 
Visit4 
Clinic 
Visit5 
 
T18 
T28 
F/U19 
F/U29 
14 
Patients will be provided with sufficient study drug to last until their next visit. Patients will be instructed on how to take their medication at home (see Section 
5.3.1.2). Treatment compliance assessments will be performed at each visit. 
15 
Female patients of childbearing potential receiving vaccination boosters (see Section 6.3) must have a negative urine pregnancy test on the days of vaccination, 
before any vaccine or booster is administered. 
16 
Full physical exam at Week 24.  Brief physical exam at all other timepoints. 
17 
Patients will be monitored for fever at every clinic visit and will monitor themselves in between visits.  See Appendix 4 for instructions on fever management. 
18 
Every other visit (Weeks 32, 48, 64 etc.) 
19 
Blood and urine samples will be collected prior to dosing 
20 
Hematology, chemistry, and urinalysis, as described in Section 6.9 
21 
For women of childbearing potential, urine pregnancy tests will be performed every 4 weeks. Any positive urine pregnancy test will be confirmed by a follow-up 
serum pregnancy test. 
22 
PTT/PT/INR assessed at Weeks 16, 20, 24 and Follow-Up visit 2.  D-Dimer to be assessed at Weeks 16, 20, 24, and every 8 weeks during the long-term 
extension. 
23 
A sample will be collected prior to administration of a booster and at the next clinic visit.  A sample should also be collected at the next scheduled clinic visit after 
any dose escalation beyond Week 12. 
 


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Clinical Protocol ACH471-101, Amendment 3.1  
19 February 2019, Version 4.1 
 
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Table 9. 
PK and PD Sampling and ECG Collection at Week 12 Visit* 
Test 
Time After Dosing (hr) 
0a 
1 
1.5 
2 
2.5 
3 
4 
6 
8 
PK plasma samples 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AP Wieslab, AP hemolysis, Bb 
X 
 
 
X 
 
 
X 
X 
X 
fD, C3, CH50 
X 
 
 
 
 
 
 
 
 
Plasma/Serum samples for additional non-genetic 
biomarker testing (fB, Ba, C5a, and soluble C5b-9) 
X 
 
 
X 
 
 
X 
X 
X 
Samples for potential assessment of patient response 
to vaccines 
X 
 
 
X 
 
 
 
 
 
Triplicate 12-lead ECGs 
Xb 
 
 
 
 
Xb 
 
 
 
*In the event a patient is further dose escalated after Week 12, the additional PK, PD, and ECG assessments described above should be repeated accordingly 
a 
Prior to dosing 
b 
Tracings should be separated by approximately 1 minute 
 


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Clinical Protocol ACH471-101, Amendment 3.1  
19 February 2019, Version 4.1 
 
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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. 
 
 


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19 February 2019, Version 4.1 
 
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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 
An16 
I have to limit my social activity because I am tired
0 
1 
2 
3 
4 
 
English (Universal) 
16 November 2007 


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Clinical Protocol ACH471-101, Amendment 3.1  
19 February 2019, Version 4.1 
 
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Copyright 1987, 1997 
Page 1 of 1 
 
 


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Clinical Protocol ACH471-101, Amendment 3.1  
19 February 2019, Version 4.1 
 
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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 
 
 


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19 February 2019, Version 4.1 
 
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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 
 
 


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Clinical Protocol ACH471-101, Amendment 3.1  
19 February 2019, Version 4.1 
 
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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 


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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 
patients for signs and symptoms of infection.   
Minimum Requirements 
The points mentioned below are to be considered as a minimum diagnostic and management 
procedure.  These are not meant to replace or bypass a systematic and thorough assessment of the 
patient; instead, they are intended to facilitate rapid initiation of assessment and management of 
fever. 
A. General Management for Outpatients 
 
All patients in this study will: 
  
1. Be educated and counseled by site staff regarding the potential for serious, rapidly progressive 
bacterial infections which may be life threatening and therefore understand the need to identify 
fever rapidly and seek emergency medical evaluation without delay 
 
2. Be educated and counseled by site staff regarding high risk behaviors, which include drinking 
from the same beverage containers, sharing eating utensils with others, avoiding large crowds, 
and smoking (including second-hand exposure) 
 
3. Be provided a thermometer and taught how to use it. All patients need to take these 
thermometers with them at all times. They need to be able to take their temperature if feeling 
warm or unwell 
 
4. Be instructed to contact the investigator immediately and/or seek emergency medical attention 
for any temperature >38.0°C /100.4°F 
 
5. They will be advised not to wait for site staff to return their phone call before seeking emergency 
medical attention. They should go to the nearest emergency medical facility for evaluation. 
 
6. Be taught to be alert to the signs of possible serious infections, which are often flu-like 
symptoms 
 
7. At all times, have immediate access to transportation and telephone, and be within one hour of an 
emergency medical center 
 
8. Be provided with a study contact card and instructed to carry this with them at all times. The 
study contact card should be provided to the emergency medical personnel who should be asked 
to contact the study site 
 
B. General Management for Any Fever Detected in the Clinic  
For Any Fever, the site needs to: 


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1. Assess for symptoms - Consider meningococcal disease as a diagnosis. When meningococcal 
disease is suspected, early treatment is critical 
2. Repeat and confirm all temperature measurements >38.0°C 
3. Notify the PI and Sponsor for all confirmed temperature measurements >38.0°C 
4. Consider if referring to an emergency medical facility is appropriate. If so, refer. Otherwise: 
a. PI or designee to perform a complete physical examination (including assessing if fever is 
accompanied by a severe headache, stiff neck, or other signs of meningeal irritation, 
shortness of breath, skin rashes, or other unusual signs or symptoms), document a plan based 
on her/his clinical judgment, and possibly an ID consult depending on assessment 
b. CBC (if not done in the last 12 hours) and blood culture  
c. Treat any suspicion of meningococcal infection aggressively; consider initiation of empirical 
antimicrobial therapy (assuming there are no other obvious sources of fever) at least until 
culture results become available and/or an alternative etiology is found 
d. Infectious disease consult is required once the PI or designee initiates empiric antibiotic 
treatment 
e. Measure temperature hourly until <38.0°C 
f. All cases of fever will be assessed by the Investigator, regardless of apparent causality from 
use of the study treatment(s) 
g. All activities performed as part of the Fever Management Plan will be documented 
 
Acute Meningococcal Disease 
Intravenous (IV) antibiotics should be given as soon as meningococcal disease is suspected.  The 
choice of antibiotics should be selected to provide adequate coverage for N. meningitidis - 
suggestions are 2 g of ceftriaxone IV after basic blood draws for CBC and blood culture are 
completed, or 2 g Meropenem IV every 8 hours.  Cefotaxime IV may be used as well.  If 
unavailable, penicillin G IV could be used (the recommended dose in persons with normal renal 
function is 2 million units every 2 h, or 4 million units every 4 hours [24 million units/day]).  As far 
as possible, 2 sets of blood cultures should be collected prior to antibiotic administration.  Other 
investigations should not delay antimicrobial therapy. 
Normal body temperature varies over the course of the day.  The normal daily temperature variation 
is typically 0.5°C (0.9°F).  During a febrile illness, daily low and high temperature readings are 
maintained but at higher levels.  However, this daily variation can be as high as 1.0°C in some 
individuals recovering from a febrile illness. 

SAP_001.pdf: 
A Phase 2 Open-label Study of ACH-0144471 in Patients 
with Paroxysmal Nocturnal Hemoglobinuria (PNH) Who 
Have an Inadequate Response to Eculizumab Monotherapy 
 
Unique Protocol ID: 
ACH471-101 
NCT Number: 
NCT03472885 
EudraCT Number:  
2016-003526-16 
Date of SAP:  
09 March 2020 
 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Trial Protocol ACH471-101 
V1 09MAR2020 
 
 
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STATISTICAL ANALYSIS PLAN 
ACH471-101 
 
Study Title: 
A Phase 2 Open-label Study of ACH-0144471 in Patients with Paroxysmal 
Nocturnal Hemoglobinuria (PNH) Who Have an Inadequate Response to 
Eculizumab Monotherapy  
 
Study Number: 
ACH471-101 
Study Phase: 
2  
Product Name: 
ACH-0144471 Tablet 
 
 
 
Version Number: 
v.1 
Effective Date: 
09MAR2020 
 
 
 
 
Protocol Version: 
Amendment 3.1 (Version 4.1), dated 19 February 2019 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document, particularly unpublished data, is the property or under the 
control of Achillion Pharmaceuticals, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant for review by you, your staff and an applicable Institutional Review 
Board.  The information is only to be used by you and in connection with authorized clinical studies of 
the investigational drug described in the protocol.  You will not disclose any of the information to others 
without written authorization from Achillion Pharmaceuticals, Inc., except to the extent necessary to 
obtain informed consent from those persons to whom the drug may be administered. 


ACH-0144471 
Achillion Pharmaceuticals, Inc. 
Clinical Trial Protocol ACH471-101 
V1 09MAR2020 
 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................2 
1 
ABBREVIATIONS ..............................................................................................................................4 
2 
OVERVIEW .........................................................................................................................................5 
3 
OBJECTIVES ......................................................................................................................................5 
3.1 
Primary Objectives ......................................................................................................................5 
3.2 
Secondary Objectives ..................................................................................................................5 
3.3 
Exploratory Objectives ................................................................................................................6 
4 
ENDPOINTS ........................................................................................................................................6 
4.1 
Primary Endpoint .........................................................................................................................6 
4.2 
Secondary Endpoints ...................................................................................................................6 
4.3 
Exploratory Endpoints .................................................................................................................7 
5 
STUDY DESCRIPTION ......................................................................................................................8 
5.1 
Study Design ................................................................................................................................8 
5.2 
Treatment Assignment .................................................................................................................9 
5.3 
Blinding and Unblinding .............................................................................................................9 
5.4 
Protocol Amendments ..................................................................................................................9 
6 
SAMPLE SIZE ...................................................................................................................................10 
7 
POPULATIONS FOR ANALYSIS ...................................................................................................11 
8 
STATISTICAL ANALYSES .............................................................................................................11 
8.1 
General Methods and Baseline Considerations .........................................................................11 
8.2 
Study Population ........................................................................................................................12 
8.2.1 Subject Disposition and Discontinuation ...............................................................................12 
8.2.2 Demographic and Baseline Characteristics ............................................................................12 
8.2.3 Medical History ......................................................................................................................13 
8.2.4 Prior Treatments .....................................................................................................................13 
8.3 
Extent of Exposure .....................................................................................................................13 
8.4 
Concomitant Therapies ..............................................................................................................14 
8.5 
Efficacy Assessment ..................................................................................................................14 
8.5.1 Primary Outcome Measure .....................................................................................................14 
8.5.2 Secondary Outcome Measures ...............................................................................................14 


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8.5.3 Exploratory Outcome Measures .............................................................................................15 
8.6 
Safety Assessment .....................................................................................................................16 
8.6.1 Treatment-Emergent Adverse Events (TEAE) .......................................................................16 
8.6.2 Clinical Laboratory Parameters ..............................................................................................17 
8.6.3 12-lead ECG ...........................................................................................................................18 
8.6.4 Vital Signs, Temperatures, and Weights ................................................................................19 
8.6.5 Physical Exam ........................................................................................................................19 
8.7 
Pharmacokinetic (PK) Assessments ..........................................................................................19 
8.7.1 PK Parameters and Analysis ..................................................................................................19 
8.7.2 PK Analysis ............................................................................................................................20 
8.8 
Pharmacodynamic (PD) Assessment .........................................................................................21 
8.9 
PK/PD Assessment ....................................................................................................................21 
9 
CHANGES FROM PROTOCOL SPECIFIED ANALYSIS .............................................................21 
10 DOCUMENT HISTORY ...................................................................................................................21 
 


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V1 09MAR2020 
 
 
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1 ABBREVIATIONS 
 
AE 
Adverse event 
AP 
Alternative Pathway (Complement) 
AUC 
Area under the plasma concentration-time curve 
BLQ 
Below the lower limit of quantification 
Cmax 
Maximum plasma concentration 
CRF 
Case Report Form 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
Plasma trough (pre-dose) concentration over the dosing interval for the 
first daily dose 
CV% 
Coefficient of variation 
ECG 
Electrocardiogram 
EORTC-QLQ-
C30 
European Organisation for Research and Treatment of Cancer, 30-
item Quality of Life questionnaire 
FACIT 
Functional Assessment of Chronic Illness Therapy 
Hgb 
Hemoglobin 
LDH 
Lactate dehydrogenase 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
ULN 
Upper limit of normal 
PD 
Pharmacodynamic 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PNH 
Paroxysmal Nocturnal Hemoglobinuria 
QoL 
Quality of Life 
QTcF 
QT interval corrected using Fridericia’s formula 
PRO 
Patient Reported Outcomes 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SD 
Standard deviation 
TE 
Treatment Emergent 
TEAE 
Treatment-Emergent Adverse Event 
TID 
Three times daily 
Tmax 
Time after administration of a drug when the maximum plasma 
concentration is reached 
 


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V1 09MAR2020 
 
 
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2 OVERVIEW 
This statistical analysis plan (SAP) describes data presentations and the statistical procedures to be 
implemented for the data from Study ACH471-101.   
There will be 4 groups studied based on initial dose of ACH-0144471, which will be enrolled 
sequentially.  Group 1 will start at 100 mg three times daily (TID).  Group 2 will start at 150 mg TID.  
Group 3 will start at 200 mg TID. Group 4 will start at the optimal dose determined from Groups 1-3.  
The initial dose level of Groups 2 and 3 could be lower based on emerging safety data from the prior 
group(s).  
A minimum of 4 weeks of treatment are required at each dose level before dosing of the subsequent 
group of patients at the next highest dose level.  The first three groups include 2 patients per group to 
determine an optimal ACH-0144471 dose for the remaining 8 patients in the fourth group.  
ACH-0144471 dose may be increased within each patient, to a maximum of 200 mg TID based on 
safety and Hgb values at protocol-specified time points, after a minimum of 4 weeks of treatment at the 
lower dose level during the 24-week treatment phase.   
Since all subjects receive the same treatment, ACH-0144471, the terms ‘study drug’, ‘treatment’, or 
‘ACH-0144471’ are interchangeable in this document. Note also that the expressions ‘subject’ and 
‘patient’ are used interchangeably throughout this document. The analysis and summary presentations of 
study results will, therefore, combine data from 4 groups into one grouping regardless of initial dose 
regimens. 
At the writing of this SAP, the enrollment to the study has been completed.  All patients have reached 24 
weeks of treatment with ACH-0144471 plus eculizumab.  Most of them are participating in the long-
term extension phase of the study.  
 
3 OBJECTIVES 
3.1 Primary Objectives 
The primary objective of this study is to evaluate the efficacy of ACH-0144471 plus eculizumab based 
on the increase in hemoglobin (Hgb) relative to baseline during 24 weeks of treatment. 
  
3.2 Secondary Objectives 
The secondary objectives of this study are: 
• 
to evaluate the efficacy of ACH-0144471 plus eculizumab based on the reduction in the number of 
RBC units transfused during the 24 weeks of treatment with ACH-0144471 compared to the 24 
weeks prior to initiation of treatment with ACH 0144471 


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• 
to evaluate the efficacy of ACH-0144471 plus eculizumab based on the percentage of patients who 
are RBC transfusion-independent during 24 weeks of treatment 
• 
to evaluate the efficacy of ACH-0144471 plus eculizumab based on the change from baseline in 
lactate dehydrogenase (LDH) during 24 weeks of treatment  
• 
to evaluate the safety and tolerability of 24 weeks of treatment with ACH-0144471 plus eculizumab 
based on serious adverse events (SAEs), Grade 3 and Grade 4 adverse events (AEs), and events 
leading to discontinuation of study drug. 
 
3.3 Exploratory Objectives 
The exploratory objectives of this study are: 
• 
to explore the effect of ACH-0144471 plus eculizumab on complement biomarkers including 
alternative pathway (AP) activity, Bb, fD, and C3 fragment deposition during 24 weeks of treatment 
• 
to evaluate health-related quality of life (QOL) measures during 24 weeks of treatment  
• 
To explore the benefits of ACH-0144471 plus eculizumab 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, including prior treatment with 
eculizumab alone 
o documenting the evolution of PNH over the course of treatment with ACH-0144471 plus 
eculizumab from a patient’s perspective 
o comparing patients' experience with eculizumab alone and ACH-0144471 plus eculizumab 
treatment 
• 
to explore patients’ expectations towards treatment with ACH-0144471 plus eculizumab. 
4 ENDPOINTS 
4.1 Primary Endpoint 
• Change in hemoglobin (Hgb) level from baseline at Week 24. 
4.2 Secondary Endpoints 
• Reduction in the number of red blood cell (RBC) units transfused and transfusion instances 
during the 24 weeks of treatment with ACH-0144471 compared to the 24 weeks prior to 
initiation of treatment with ACH-0144471; 
• Number and proportion of patients who are RBC transfusion independent at 24 weeks of 
treatment; 


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V1 09MAR2020 
 
 
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• Change in lactate dehydrogenase (LDH) level from baseline at Week 24; 
• Safety, as measured by frequency of SAEs, AEs ≥ Grade 3, laboratory abnormalities ≥ Grade 3, 
and AEs leading to discontinuation of study drug. 
4.3 Exploratory Endpoints 
• PNH type III RBC clone size at Week 24; 
• Complement components: C3, C3 fragments, Bb, and AP-Wieslab at scheduled time points; 
• Total score and change from baseline total score on the FACIT Fatigue scale instrument at 
scheduled time points; 
• Change from baseline in EORTC QLQ-C30 scores at scheduled time points. 


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V1 09MAR2020 
 
 
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5 STUDY DESCRIPTION 
5.1 Study Design 
This is a multiple-center, open-label, multiple-dose Phase 2 study in patients with PNH who have 
inadequate response to eculizumab treatment.  Eligible PNH patients must have RBC-transfusion-
dependent anemia and are receiving a stable dose of eculizumab. 
This study plans to include up to 14 patients who will receive 24 weeks of daily oral treatment with 
ACH-0144471 plus intravenous (IV) eculizumab administered at the patient’s usual dose and schedule. 
Four groups, based on initial dose of ACH-0144471, are to be enrolled sequentially.  Initial dose for 
Group 1 plans to be 100 mg TID.  Group 2 plans to start at 150 mg TID.  Group 3 plans to start at 200 
mg TID.  Group 4 start at the optimal dose determined from Groups 1-3.  The initial dose level of 
Groups 2 and 3 could be lower based on emerging safety data from the prior group(s).  
A minimum of 4 weeks of treatment are required at each dose level before dosing of the subsequent 
group of patients at the next highest dose level.  The first three groups include 2 patients per group to 
determine an optimal ACH-0144471 dose for the remaining 8 patients in the fourth group.  
ACH-0144471 dose may be increased within each patient, to a maximum of 200 mg TID based on 
safety and Hgb values at protocol-specified time points, after a minimum of 4 weeks of treatment at the 
lower dose level during the 24-week treatment phase.  Refer to Section 3.1 of the protocol for details of 
study design and dose escalation criteria. 
In addition to meeting the study eligibility criteria, patients will also 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.  Those who have been previously vaccinated will receive recommended 
boosters, depending on evolving recommendations in this patient population.  Vaccination procedures 
during the study are described in Section 6.3 of the protocol. 
Patients return to the clinic for safety, PK, and other assessments at protocol-specified time points. At 
the Week 12 visit, subjects remain at the clinic for 8 hours for intensive PK/PD sampling and collection 
of a time-matched ECG at the maximum plasma concentration of ACH 0144471 (3 hours after dosing).  
The FACIT Fatigue Scale (Version 4) questionnaire and the EORTC-QLQ-C30 (Version 3) are 
administered to collect patients’ health-related quality of life at baseline and after treatment with ACH-
0144471 plus eculizumab. 
In addition, Patient Reported Outcomes (PRO) interviews by independent outcomes researchers chosen 
by the Sponsor will be conducted with patients enrolled in the trial at pre-determined time points to 
collect patients’ experience of PNH, its impact on everyday lives and the disease trajectory. 
 


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After Week 24, if patients are receiving clinical benefit, they continue treatment in a (long-term) 
extension phase with ACH-0144471 and the same dose and schedule of eculizumab that they have been 
receiving prior to the start of extension phase.  Patients not entering the extension phase, or discontinue 
from the study, will have the dose of ACH-0144471 tapered over 6 days, and two follow-up visits will 
be conducted approximately 14 days and 28 days after the last dose of ACH-0144471. 
5.2 Treatment Assignment 
All patients receive ACH-0144471 (plus eculizumab) and will be assigned to one of the four sequential 
groups as described above.  Each patient will be assigned a subject identification number within each 
study center. 
Note that patients receive the same eculizumab regimens as they have received prior to initiation of 
ACH-0144471.  Eculizumab is considered as a concomitant / background medication, as opposed to a 
study therapy. 
5.3 Blinding and Unblinding 
Not applicable for this single arm trial. 
5.4 Protocol Amendments 
There are five amendments to the original protocol. 


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Amendment 
No. 
Amendment 
Date 
Main Purposes of Amendment 
1 
13-DEC-2017 
1. Update the contraception section to include definitions requested by 
Health Authorities.   
2. Update the contact information for SAE reporting. 
1.1 
17-JAN-2018 
1. Add wording to permit the conducting of patient reported outcomes 
interviews as questionnaires where required. 
2 
13-MAR-2018 
1. Specify that vaccination against bacterial infections should be performed, 
when necessary based on vaccination history, according to national 
and/or local guidelines. 
2. Update and clarify the requirements for “acceptable” and “highly 
effective” methods of contraception.  
3. The time window for definition of a missed dose has been reduced from 
6 hours to 4 hours. 
3 
15-FEB-2019 
1. Amend the exclusion criteria to allow enrollment of participants with a 
history of hematopoietic stem cell transplant if HSCT engraftment has 
failed. 
2. Amend the exclusion criteria to allow enrollment of participants with 
direct bilirubin > 1.5 × ULN if the elevated bilirubin is due to 
extravascular hemolysis, in the opinion of the investigator. 
3. Permit participants to switch from eculizumab to an approved 
eculizumab biosimilar or ravulizumab after completion of the primary 
endpoint at Week 24. 
4. Expands potential enrolment to a maximum of 14 participants. 
3.1 
19-FEB-2019 
1. Shorten the time (from 12 to 8 weeks) for which participants must be 
receiving a stable dose of eculizumab prior to study entry.  
 
6 SAMPLE SIZE 
The sample size is based on the small number of PNH patients who have an inadequate response to 
eculizumab monotherapy and the goal of achieving an optimal dose level of ACH-0144471 in 
combination with eculizumab treatment.  It is estimated that 14 patients enrolling sequentially will be 
sufficient to identify an optimal dose level of ACH-0144471 plus eculizumab for use in future studies. 


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7 POPULATIONS FOR ANALYSIS 
There are three study populations for analysis. 
• Enrolled population consists of subjects who signed an informed consent form and were assigned a 
subject identification number. This cohort is used to assess subject status and deaths. 
• Treated population includes Enrolled subjects who receive at least 1 dose of study medication, ACH-
0144471.  Data from treated subjects are used for safety analyses.  
• The modified intent-to-treat (mITT) population includes Treated subjects who receive at least 4 
weeks of study medication, ACH-0144471.  Data from mITT subjects are used for efficacy, PK, and 
selected PD biomarkers analyses.  Note that there are a total of 11 patients completing 24 weeks of 
study medication. 
 
8 STATISTICAL ANALYSES 
As noted in the Overview (Section 2) of this document, the protocol indicated 4 sequentially enrolled 
groups with subjects in Group 4 starting at the optimal dose determined from Groups 1-3.  Since the 
majority of subjects have received a similar dose regimen, safety and efficacy summary tables will 
summarize data from all subjects together as one treatment group.  
The primary analysis and summary presentations will focus on data from 24 weeks of ACH-0144471 
treatment period, unless otherwise specified.  Subject listings will include data from the entire study, 
including the long-term extension of the study.  Presentations and discussions on the data from long-
term extension phase will be undertaken in a separate report.   
Note that results from PRO interviews will be presented in a separate report. 
8.1 General Methods and Baseline Considerations 
Data listings by subject identification will be provided for all data collected during the study.  Efficacy, 
PK/PD, and safety parameters for which summary results will be provided are detailed in following 
sections.  As stated above, safety and efficacy summary tables will be presented with all subjects 
combined as one treatment group and will only include data from 24-week treatment period.  
To summarize continuous data, descriptive statistics will include: number of subjects, mean, standard 
deviation, median, minimum, and maximum.  For the calculation of summary statistics and analysis, 
unrounded data points will be used. 
To summarize categorical data, frequency counts and percentages will be presented.  
Longitudinal summaries of efficacy and safety parameters use protocol pre-defined visit Week as 
described in Appendix 1, schedule of assessments, of the protocol.   
For longitudinal summaries of data, windows around planned measurement times are based on the 
midpoint between planned study visits unless specified otherwise.  If there are multiple measurements 


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within the same window, use the value in the visit window closest to the day of the planned visit for 
each time point (as determined by the absolute difference in days between the planned visit and the 
collection date, and the absolute difference in days between the planned visit and the assay date). 
For laboratory test results, when both local and central laboratory values are collected on the same date, 
the central laboratory value will be used.  
Baseline values for efficacy / PD and safety parameters are defined as the last measurement, including 
unscheduled visits, prior to first dose of ACH-0144471. 
Since subjects are allowed to have RBC transfusions between screening and first day of dosing of ACH-
014471, the baseline Hgb is determined according to the following rules: 
• If no RBC transfusions are given between screening and dosing, the baseline Hgb is the last 
measurement prior to the first dose of ACH-0144471, as described above. 
• If RBC transfusions are given between screening and dosing, the baseline Hgb will be 
determined as follows, 
o if the Hgb measurement prior to the first dose of ACH-0144471 after transfusions (Day 1 
pre-dose) is within 3 g/dL of the screening Hgb value, then the Day 1 pre-dose 
measurement will be the baseline for the subject; 
o  if the Hgb measurement prior to the first dose of ACH-0144471 after transfusions (Day 1 
pre-dose) is more than 3 g/dL higher than the screening Hgb value, the baseline Hgb will 
be the screening Hgb measurement for the subject. 
The value of 3 g/dL is chosen because more than 3 g/dL increase in Hgb immediately after RBC 
transfusions is biologically and clinically implausible.   
 
8.2 Study Population 
8.2.1 Subject Disposition and Discontinuation 
The summary table(s) will include the following:  
• Number of patients (enrolled / treated) 
• Number of patients who completed 24 weeks of treatment 
• Reasons for not completing 24 weeks of treatment 
• Number of patients entering long-term extension phase 
 
8.2.2 Demographic and Baseline Characteristics  
The following demographic and baseline characteristics will be summarized: 
• 
Age (in years)  
• 
Gender  
• 
Race  
• 
Ethnicity 


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• 
Weight (kg) 
• 
Height (cm) 
• 
Body mass index (BMI, kg/m2) 
• 
Transfusion history  
o Number and unit of RBC transfusions 52 weeks prior to screening 
o Number of patients with RBC transfusions between screening and first dose of ACH-0144471  
• 
Hemoglobin (g/dL) 
• 
LDH (U/L) 
• 
Reticulocyte counts (103/uL) 
• 
Direct Coombs (positive / negative) 
• 
Total Bilirubin (mg/dL) 
• 
Indirect bilirubin (mg/dL) 
• 
Direct bilirubin (mg/dL) 
• 
C3 fragment (%) 
• 
PNH type III RBC clone size (%) 
• 
Platelet counts (103/uL) 
• 
Absolute neutrophil counts (103/uL) 
• 
ALT (IU/L) 
• 
AST  (IU/L) 
• 
ALP  (IU/L) 
• 
GGT  (IU/L) 
 
8.2.3 Medical History 
Medical history terms will be coded with the most current version of Medical Dictionary for Regulatory 
Activities (MedDRA®) and will be summarized by preferred term and system organ class and listed by 
subject.   
 
8.2.4 Prior Treatments 
Prior medications will be listed and summarized. These are medications taken before the first dose of 
ACH-0144471. Medications will be summarized by preferred term and system organ class using the 
most recent version of WHO dictionary.  All patients should have received stable dose regimen of 
eculizumab at least 8 weeks prior to first dose of ACH-0144471.  Separate listing will be provided for 
eculizumab. 
 
Data from transfusions 52 weeks before first dose of ACH-0144471 will also be listed by subject.  Note 
that the transfusion summary results are presented as part of baseline characteristics described in section 
8.2.2 above. 
 
8.3 Extent of Exposure 
Note that all treated patients, except for one patient, completed 24-week treatment period.  Treatment 
durations, therefore, will be computed for each patient as (last date of dose – first date of dose + 1) 
during the study.  The last date of dose will be the date prior to any tapering period or database lock date 
when patients are in long-term extension phase.  In addition, a contingency table will be provided to 


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display the number of patients with exposure in the following categories: 1-4 weeks, 5-12 weeks, 13-24 
weeks, 25-48 weeks, and >48 weeks.  
Number of doses at different dose regimen and length of each dose regimen taken during the entire 
treatment period, including dose regimen taken during long-term extension phase, will also be provided 
and listed for each patient. 
Compliance with study drug will be estimated and listed for each patient as: (number of tablets actually 
taken / number of tablets should have been taken) *100.  The tablet counts are collected in the case 
report form (CRF) form “Study Drug Dispensing/Accountability Record”.   
8.4 Concomitant Therapies 
Concomitant medications will be listed. These are medications taken any time on or after the first dose 
of ACH-0144471 and on or before the last dose of ACH-0144471. Medications will be summarized by 
preferred term and system organ class using the most recent version of WHO dictionary. 
Concomitant medications will be summarized only for the duration of 24-week treatment period. 
As eculizumab is considered a concomitant medication, a separate listing will be provided which also 
includes other approved C5 inhibitors that patients are allowed to switch to during long-term extension 
phase. 
Transfusions received while taking the study drug, ACH-0144471, will also be listed by subject. 
8.5 Efficacy Assessment 
All efficacy analysis will be carried out on data from mITT subjects.  A total of 11 subjects are included 
in the mITT analysis. 
8.5.1 Primary Outcome Measure 
The primary efficacy endpoint is Hgb change from baseline value at Week 24.  Summary statistics will 
be provided for the changes from baseline for all patients (one treatment group). 
Reductions in Hgb values over time are the primary parameter used to evaluate the efficacy of ACH-
0144471.  Observed and change from baseline values will be listed and summarized at protocol pre-
defined time points (Weeks) during 24 weeks of treatment period. 
Observed and change from baseline values versus time will also be plotted to depict Hgb reduction 
profiles over the course of the 24-week treatment period.  
8.5.2 Secondary Outcome Measures 
The secondary efficacy endpoints are listed in Section 4.2.  
Similar to primary efficacy endpoints, only descriptive statistics will be provided for the secondary 
outcome measures. 


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• Mean, median, minimum, and maximum reduction in the number of RBC units transfused 
during the 24 weeks of treatment compared to the 24 weeks prior to first dose of ACH-0144471 
will be presented; 
• Mean, median, minimum, and maximum reduction in the number of RBC transfusion instances 
during the 24 weeks of treatment compared to the 24 weeks prior to first dose of ACH-0144471 
will be displayed; 
• Number and percentage of patients who are RBC transfusion independent at 24 weeks of 
treatment will be presented; 
• Mean, standard deviation, median, minimum and maximum of change in LDH level from 
baseline at protocol pre-specified visits, including Week 24, will be presented.  Similar 
presentation may be available for the observed LDH levels and LDH relative to upper limit of 
normal (ULN).  Observed and change from baseline values and LDH relative to ULN versus 
time may also be plotted for LDH measurements over the course of the 24-week treatment 
period. 
8.5.3 Exploratory Outcome Measures 
PNH type III RBC clone size will be presented at protocol pre-specified time points, including Week 24.  
Similarly, observed and change from baseline values of the complement components of C3, C3 
fragments, Bb, and AP-Wieslab will be summarized at protocol pre-specified time points. 
The analysis and summarization of the FACIT Fatigue scale instrument and EORTC QLQ-C30 scores 
are described as below. 
FACIT Fatigue Scale (Version 4) 
There are 13 items in the FACIT Fatigue scale questionnaire.  Each item includes 5 possible responses, 
0-4, with 0 being “Not at all” and 4 being “Very much”.  Total score from these 13 items will be 
provided for each patient at each protocol pre-defined time points. 
Negatively stated items must be reversed before being added to obtain the scale total score.  Therefore, 
the negatively stated items will be reversed by subtracting the response from “4”.  Note that all items, 
except for items #7 and #8, are negatively stated. 
The FACIT Fatigue scale and the calculation of total score are presented in Appendix 2 of this 
document.  Note that the total score range is 0 to 52, with higher total scored indicating better quality of 
life. 
Summary statistics for total score and change from baseline in total score will be provided at protocol 
pre-specified time points up to and including Week 24.  Subject listings for total score and change from 
baseline in total score will be provided for all protocol pre-specified time points. 
EORTC QLQ-C30 (version 3) 


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There are 30 items in the EORTC QLQ-C30 questionnaire which is composed of both multi-item scales 
and single-item measures (refer to Appendix 2 of the protocol). These include 5 functional scales, 3 
symptom scales, a global health status / QoL scale, and 6 single items.  The items which form the scales 
and global health status are listed in Table 1 of Appendix 3 of this document.  The 2 global health status 
items have 7 possible responses, with 1 being poor and 7 being excellent.  All the other 28 items have 4 
possible responses, with 1 being “Not at All” and 4 being “Very Much”. 
All of the scales and single-item measures are transformed into scores from 0 to 100.  The procedures of 
computing the scores for each functional scales, single-item measures, and global health status /QoL are 
presented in Appendix 3 of this document.  A high scale score represents a higher response level: 
• a high score for a functional scale represents a high / healthy level of functioning, 
• a high score for the global health status / QoL represents a high QoL, 
• but a high score for a symptom scale / item represents a high level of symptomatology / 
problems. 
For each functional scale, single-item measure, and global health status / QoL, score and change from 
baseline score will be provided for each patient at all protocol pre-specified time points. 
Summary statistics for the scale / score and change from baseline in the scale / score will be provided at 
protocol pre-specified time points up to and including Week 24. 
8.6  Safety Assessment 
Evaluation of safety includes assessment of the following clinical parameters and will be described in 
detail in the subsequent subsections.  All patients receiving at least one dose of ACH-0144471 (Treated 
population) will be included in the safety assessment.  Note that there are 11 patients treated with ACH-
0144471 for this study.   
Summary tables will be provided for selected clinical parameters.  All summary tables will include data 
points during 24-week treatment period and dose tapering period.  By-subject listings will provide all 
data points throughout the entire study, including long-term extension phase. 
1. TEAEs, including discontinuation due to adverse even 
2. Clinical laboratory parameters 
3. 12-lead ECG parameters 
4. Vital signs, including body temperatures 
5. Physical findings. 
 
8.6.1 Treatment-Emergent Adverse Events (TEAE) 
Adverse events (AEs) will be coded with the most current version of Medical Dictionary for Regulatory 
Activities (MedDRA®). 


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A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during treatment with 
ACH-0144471, including the 6-day dose tapering period, having been absent pre-treatment, or worsens 
relative to the pre-treatment state.   
If an AE that was reported during treatment increases in severity, then that AE is given a resolution date 
and time and a new record initiated with the new severity.  If the severity of an AE remains the same or 
decreases, the AE will be kept open through to resolution, reflecting the maximum severity.  
AEs will be listed by subject including preferred term, verbatim term, system organ class (SOC), days 
from first dosing date, onset and resolution dates/times, duration, frequency, severity, seriousness, 
outcome, action taken, and relationship to ACH-0144471.  
TEAEs will be summarized by preferred term and SOC for the number of subjects reporting the TEAE, 
the number of TEAEs reported, and the number of events by severity and relationship to study drug.  
Summaries of AEs include both non-serious and SAEs as defined in the protocol.  AEs with missing 
severity are included only in summaries of all severity grades (related or regardless of relationship to 
study drug).  If a subject had an AE with different severities during treatment, then only the greatest 
severity is reported, unless otherwise specified.  In addition, a TEAE summary table with decreasing 
frequencies in terms of MedDRA® preferred terms, based on safety population, will also be provided. 
Note that there could be two separate summary tables for the number of subjects reporting the TEAE 
and the number of TEAEs reported.   
It is not anticipated to encounter AE with missing start date in this study.  Any AE with missing start 
time will be treated as TEAE.  For subjects having discontinued from the study, AEs that are missing 
resolution dates will be considered to be lost-to-follow-up.  
All events captured in the database will be listed in by-subject data listings.  However, only TEAEs will 
be summarized.  Separate subject listings may be provided for pre-treatment AEs, TEAEs, and AEs 
occurred during the long-term extension phase of the study. 
Should any serious adverse events (SAEs) or discontinuation of ACH-0144471 due to adverse events 
(TEAE or SAE) occur, subject listings for such adverse events will be displayed in a tabulated format 
and narratives will be included in the study report.  If no such event occurs during the study, the tables 
should provide a statement clearly indicating as such, e.g. ‘No SAE reported’, ‘No TEAE led to 
discontinuation of study drug’. 
8.6.2 Clinical Laboratory Parameters 
Descriptive statistics at protocol pre-specified visits up to and including Week 24, will be provided, at a 
minimum, for the laboratory test results of hematology, serum chemistry, and urinalysis as listed in 
Table 3 of the protocol.  Descriptive statistics may be provided for additional laboratory parameters, if 
warranted.  


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Levels and changes from baseline in the laboratory measurements will be summarized at baseline and at 
protocol pre-specified visits.  Baseline is the last assessment before the first dose of ACH-0144471, 
including unscheduled assessments, unless otherwise specified (refer to Section 8.1).  
As noted in Section 8.1, when both local and central laboratory values are collected on the same date, 
the central laboratory value will be used. Selected lab parameters may be converted to SI or US standard 
units, as clinically deemed appropriate.  Laboratory abnormalities are determined from laboratory 
measurements analyzed at the central or local laboratories, and are graded using Common Terminology 
Criteria for Adverse Events (CTCAE), as presented in Appendix 1 of this document. 
For laboratory tests with CTCAE toxicity grades available, laboratory abnormalities are summarized by 
worst treatment-emergent grade [treatment emergent (TE) lab abnormalities].  For tests that have 
CTCAE toxicity grades in both high and low directions, e.g. serum glucose, etc., the summary table 
should specify separately for the TE abnormalities as being high or being low in toxicity grades.  Note 
that the post-baseline laboratory value with the highest treatment-emergent toxicity grade is reported for 
each test. 
Laboratory abnormalities during 24-week treatment period will be further summarized by baseline 
toxicity grade and worst grade during treatment period (shift tables). Shift tables will be provided for 
liver function test (LFT) results and other selected laboratory test results based on CTCAE grades.  The 
other selected laboratory tests may include: hemoglobin, platelet counts, total bilirubin, and others as 
clinically deemed meaningful.   
Unscheduled values will be labeled as unscheduled in the listings. 
Exploratory graphic presentations may be provided when data indicate that such analyses are 
appropriate and clinically meaningful. 
8.6.3 12-lead ECG 
Subject listing will be provided for ECG parameters: HR, RR, PR interval, QRS interval, QT interval, 
and QTcF.  Abnormal and clinically significant findings will also be included in the listing. 
Values and changes from baseline in ECG measurements are summarized at baseline and at each 
scheduled time points up to and including visit Week 24.  Baseline ECG is the last assessment before 
first dose of ACH-0144471. 
ECG results will also be classified as normal, abnormal (not clinically significant), and abnormal 
(clinically significant).  Summary table will be provided for clinically significant abnormalities.  If no 
clinically significant abnormalities are found, the table should state ‘No clinically significant ECG 
abnormality reported’. 
The frequency of subjects with a maximum increase from baseline in QTcF interval will be summarized 
according to the following categories: >30, >60, and ≤30 ms.  All incidences of >30 and >60 ms will be 
flagged in the listing. 


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The treatment-emergent (TE) ECG events indicate that the abnormality / prolongations were not present 
at baseline.  TE abnormalities will be summarized for the following parameters.  Note that TE QTcF 
interval abnormalities are based on CTCAE criteria.  
• Treatment-emergent (TE) PR interval  > 200 msec; 
• TE QTcF interval: 
o Grade 1: 450 – 480 msec  
o Grade 2: 481 – 500 msec 
o Grade 3: ≥ 501 msec on at least 2 separate ECG readings 
o Grade 4: ≥ 501 msec or > 60 msec change from baseline and Torsade de pointes, 
polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia 
The maximum interval (or increase from baseline) during 24-week treatment period is reported for each 
ECG parameter 
Unscheduled readings will be labeled as unscheduled in the listings. 
8.6.4 Vital Signs, Temperatures, and Weights 
Subject listing will be provided for vital signs parameters: systolic and diastolic blood pressures, pulse 
rate, respiration rate and temperature.  In addition, the same listing will also include weight 
measurements.  
8.6.5 Physical Exam 
Data collected from physical exams, both complete and brief, will be listed by patient and by time 
points, including unscheduled visit time points. 
8.7 Pharmacokinetic (PK) Assessments 
PK assessments will be performed based on plasma concentrations from mITT subjects receiving ACH-
0144471 during 24 weeks of treatment period. 
 
8.7.1 PK Parameters and Analysis 
PK parameters from plasma concentrations for ACH-0144471 will be calculated using a non-
compartmental approach based on the concentration vs time data.  The standard PK parameters outlined 
below, will be derived from the individual plasma concentration time data at Week 12 with intensive PK 
sampling, using Phoenix WinNonlin® Version 6.4 or higher, as data permit.  
Subjects for whom there is insufficient data to calculate the PK parameters will have available data 
included in the concentration tables with descriptive statistics only. 


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For the calculation of the PK parameters, concentrations that are below the lower limit of quantification 
(BLQ) prior to the Tmax will be set to 0 and those thereafter as missing. Concentrations that are missing 
or not reportable will be treated as missing values. For concentration summary statistics, concentrations 
that are BLQ will be set to 0.  At least 3 time points with measurable concentration will be required for 
the calculation of AUC. 
Trough plasma concentrations will be listed and summarized to assess the amounts of ACH-144471 at 
steady state prior to the first daily dose.  Graphic presentations will also be provided to depict PK 
profiles of ACH-0144471 from the patients. 
PK Analysis Parameters 
AUC 
Area under the curve 
Cmax 
Maximum observed plasma concentration 
tmax 
Time after administration of a drug when the maximum plasma concentration is 
reached 
Ctrough 
Observed plasma concentration prior to the first daily dose 
 
AUC values will be estimated using the linear trapezoidal rule. Actual sampling times relative to dosing 
will be used in the computation.   
 
Unless otherwise specified below, missing sampling or concentration values should not be imputed, but 
left missing in the calculation of derived PK parameters. If the actual sampling time is missing, but a 
valid concentration value has been measured, the scheduled protocol time will be used for the 
calculation of derived PK parameters. 
On a case by case basis, it may be necessary to exclude individual PK concentration values for the 
calculation of derived PK parameters because they are erroneous, abnormal or appear implausible to the 
pharmacokineticist in charge of the analysis. Any excluded data will be flagged in the individual data 
listings. The reason for exclusion will also be documented. If the exclusion has a meaningful impact on 
the overall interpretation of the results, then it will be discussed. 
 
Actual post-dose time will be used in calculation of PK parameters and in the generation of individual 
concentration-time profiles. Scheduled (nominal) sampling times will be used as a replacement for 
unknown or missing actual times and will be used for the pre-dose values. Nominal sampling times will 
be used in the generation of summary concentration-time profiles and the concentration-time listings. 
 
8.7.2 PK Analysis 
Individual PK parameters will be listed. Descriptive statistics (number of non-missing observations (N), 
arithmetic mean, SD, median, coefficient of variation (CV%), minimum, maximum, geometric mean 
and geometric CV%) will be used to summarize the calculated PK parameters of ACH-0144471 by dose 
group, if data allow. 


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Individual concentration profiles with actual post-dose time will be listed. Descriptive summary 
statistics (N, arithmetic mean, SD, median, CV%, minimum, maximum, geometric mean and geometric 
CV%) will be used to summarize the concentration profiles by dose group, if data allow. 
Individual time-concentration graphs will be provided for each subject in both linear and semi-log 
scales. Mean time-concentration graphs will also be provided by dose group, if data allow. 
8.8 Pharmacodynamic (PD) Assessment  
PD assessment will be based on data from mITT subjects receiving ACH-0144471 during 24 weeks of 
treatment period. 
PD markers include selected laboratory tests to assess the effects of ACH-0144471 (plus eculizumab) on 
complement alternative pathway activity.  Analyses on data from Hgb, LDH measurements and various 
biomarkers in Section 8.5.1 to 8.5.3 above have provided detailed description on PD assessment of 
ACH-0144471.  Other PD parameters may be explored, if clinically deemed meaningful.  
8.9 PK/PD Assessment 
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. If a PK/PD relationship assessment is warranted, details 
on the assessment will be provided in the clinical study report (CSR). 
9 CHANGES FROM PROTOCOL SPECIFIED ANALYSIS 
There are changes from protocol specified analysis: 
• Since the majority of subjects have received a similar dose regimen, safety and efficacy 
summary tables will summarize data from all subjects together as one treatment group. The 
primary efficacy endpoint measure is mean change from baseline, rather than median change 
from baseline as specified in the protocol. 
• No 95% confidence intervals will be provided as there are only 11 patients completing 24 weeks 
of treatment.  Summary statistics and longitudinal presentations for Hgb and other efficacy 
parameters would be sufficient to describe the effectiveness of ACH-0144471 in addition to 
eculizumab. 
• The protocol uses ‘analysis sets’ (Section 9.3 of the protocol) to identify groupings of subjects.  
The SAP uses simple word ‘populations’ to identify various groupings of subjects in the study. 
10 DOCUMENT HISTORY 
Version No. 
Author(s) 
Descriptions 
Draft 
Original dated 13JAN2020 
v.1 
Minor edits from draft 
 
PPD
PPD


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


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Clinical Trial Protocol ACH471-101 
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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
LIFE-THREATING 
eGFR or CrCl 
<LLN - 60 
ml/min/1.73 m2 or 
proteinuria 2+ 
present; urine 
protein/creatinine 
>0.5 
59 - 30 
ml/min/1.73 m2 
eGFR or CrCl 29 - 15 
ml/min/1.73 m2 
eGFR or CrCl <15 
ml/min/1.73 m2 
Glucose,  
   Fasting , High 
>ULN - 160 mg/dL; 
>ULN - 8.9 mmol/L 
>160 - 250 mg/dL; 
>8.9 - 13.9 mmol/L 
>250 - 500 mg/dL; 
>13.9 - 27.8 mmol/L; 
>500 mg/dL; >27.8 
mmol/L 
Glucose, Low  
<LLN - 55 mg/dL; 
<LLN - 3.0 mmol/L 
<55 - 40 mg/dL; 
<3.0 - 2.2 mmol/L 
<40 - 30 mg/dL; <2.2 
- 1.7 mmol/L 
<30 mg/dL; <1.7 
mmol/L 
GGT, High 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
Lipase, High 
>ULN – 1.5 x ULN 
>1.5 – 2.0 x ULN 
>2.0 – 5.0 x ULN 
>5.0 x ULN 
Lipid Disorders, 
    Cholesterol, High  
>ULN - 300 mg/dL; 
>ULN - 7.75 mmol/L 
>300 - 400 mg/dL; 
>7.75 - 10.34 
mmol/L 
>400 - 500 mg/dL; 
>10.34 - 12.92 
mmol/L 
>500 mg/dL; >12.92 
mmol/L 
    Triglycerides, 
High 
150 mg/dL - 300 
mg/dL; 1.71 
mmol/L - 3.42 
mmol/L 
>300 mg/dL - 500 
mg/dL; >3.42 
mmol/L - 5.7 
mmol/L 
>500 mg/dL - 1000 
mg/dL; >5.7 mmol/L 
- 11.4 mmol/L 
>1000 mg/dL; >11.4 
mmol/L 
Magnesium, High 
>ULN - 3.0 mg/dL; 
>ULN - 1.23 
mmol/L 
- 
>3.0 - 8.0 mg/dL; 
>1.23 - 3.30 
mmol/L 
>8.0 mg/dL; >3.30 
mmol/L 
Magnesium, Low 
<LLN - 1.2 mg/dL; 
<LLN - 0.5 
mmol/L 
<1.2 - 0.9 mg/dL; 
<0.5 - 0.4 
mmol/L 
<0.9 - 0.7 mg/dL; 
<0.4 - 0.3 
mmol/L 
<0.7 mg/dL; <0.3 
mmol/L 
Phosphate, Low 
<LLN - 2.5 mg/dL; 
<LLN - 0.8 
mmol/L 
<2.5 - 2.0 mg/dL; 
<0.8 - 0.6 
mmol/L 
<2.0 - 1.0 mg/dL; 
<0.6 - 0.3 
mmol/L 
<1.0 mg/dL; <0.3 
mmol/L; 
Potassium, High 
>ULN - 5.5 mmol/L 
>5.5 - 6.0 mmol/L 
>6.0 - 7.0 mmol/L 
>7.0 mmol/L 
Potassium, Low 
<LLN - 3.0 mmol/L 
- 
<3.0 - 2.5 mmol/L;  
<2.5 mmol/L 
SODIUM, High 
>ULN - 150 mmol/L 
>150 - 155 mmol/L 
>155 - 160 mmol/L 
>160 mmol/L 
SODIUM, Low 
<LLN - 130 mmol/L 
 -      
<130 - 120 mmol/L 
<120 mmol/L 
URICACID 
>ULN - 10 mg/dL 
(0.59 mmol/L)  
 -      
- 
>10 mg/dL; >0.59 
mmol/L 
HEMATOLOGY 
CD4 Lymphocytes  
decreased 
<LLN - 500/mm3; 
<LLN - 0.5 x 109 /L 
<500 - 200/mm3; 
<0.5 - 0.2 x 109 /L 
<200 - 50/mm3; <0.2 
- 0.05 x 109 /L 
<50/mm3; <0.05 x 
109 /L 


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


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Clinical Trial Protocol ACH471-101 
V1 09MAR2020 
 
 
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APPENDIX 2 . 
FACIT Fatigue Scale and Calculation of Total Score 
 
Below is a list of statements that other people with your illness have said are important. Please circle or 
mark one number per line to indicate your response as it applies to the past 7 days. 
Not At All 
A Little Bit 
Somewhat 
Quite a Bit 
Very Much 
1 
I feel fatigued 
0 
1 
2 
3 
4 
2 
I feel weak all over 
0 
1 
2 
3 
4 
3 
I feel listless (“washed out”) 
0 
1 
2 
3 
4 
4 
I feel tired 
0 
1 
2 
3 
4 
5 
I have trouble starting things 
0 
1 
2 
3 
4 
because I am tired 
6 
I have trouble finishing things 
0 
1 
2 
3 
4 
because I am tired 
7 
I have energy 
0 
1 
2 
3 
4 
8 
I am able to do my usual activities 
0 
1 
2 
3 
4 
9 
I need to sleep during the day 
0 
1 
2 
3 
4 
10 
I am too tired to eat 
0 
1 
2 
3 
4 
11 
I need help doing my usual activities 
0 
1 
2 
3 
4 
12 
I am frustrated by being too tired 
0 
1 
2 
3 
4 
to do the things I want to do 
13 
I have to limit my social activity 
0 
1 
2 
3 
4 
because I am tired 
 
Scoring: Items are scored as follows: 4=Not At All; 3=A Little Bit; 2=Somewhat; 1=Quite A Bit; 
0=Very Much, EXCEPT items #7 and #8 which are reversed scored. Total score range 0-52. 
Item Number 
Reverse Item? 
Item Response 
Item Score 
1 
4 
- 
= 
2 
4 
- 
= 
3 
4 
- 
= 
4 
4 
- 
= 
5 
4 
- 
= 
6 
4 
- 
= 
7 
0 
+ 
= 
8 
0 
+ 
= 
9 
4 
- 
= 
10 
4 
- 
= 
11 
4 
- 
= 
12 
4 
- 
= 
13 
4 
- 
= 
 
Sum individual item scores:   
  
 


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Clinical Trial Protocol ACH471-101 
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Appendix 3. EORTC QLQ-C30 Scoring Procedure 
 
For information about terms and conditions for using the questionnaire, please contact the Quality 
of Life Unit, EORTC Data Center.1 
 
Scoring procedures 
 
 
 
1 From EORTC QLQ-C30 Scoring Manual, third edition, 2001, pages 5-7.  


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General principles of scoring 
The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five 
functional scales, three symptom scales, a global health status / QoL scale, and six single items. 
Each of the multi-item scales includes a different set of items - no item occurs in more than one 
scale. 
All of the scales and single-item measures range in score from 0 to 100. A high scale score 
represents a higher response level. 
Thus a high score for a functional scale represents a high / healthy level of functioning, a high 
score for the global health status / QoL represents a high QoL, but a high score for a symptom 
scale / item represents a high level of symptomatology / problems. 
The principle for scoring these scales is the same in all cases: 
1. Estimate the average of the items that contribute to the scale; this is the raw score. 
2. Use a linear transformation to standardize the raw score, so that scores range from 0 to 100; a 
higher score represents a higher ("better") level of functioning, or a higher ("worse") level of 
symptoms. 
Coding of the scoring procedure is presented in Appendix 3 for three major statistical packages. 


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Technical Summary 
In practical terms, if items I 1 , I 2 ,... I n are included in a scale, the procedure is as follows: 
Raw score 
Calculate the raw score 
RawScore = 
( 
) n 
I 
I 
I 
RS 
n 
+ 
+ 
+ 
= 
... 
2 
1 
Linear transformation 
Apply the linear transformation to 0-100 to obtain the score S, 
Functional scales: 
) 
( 
100 
1 
1 
× 
 
 
 
 
 
 
− 
− 
= 
range 
RS 
S 
Symptom scales / items: 
( 
) 
{ 
} 100 
1 
× 
− 
= 
range 
RS 
S 
Global health status / QoL: 
) 
( 
} 
{ 
100 
1 
× 
− 
= 
range 
RS 
S 
Range is the difference between the maximum possible value of  RS and the minimum possible  
The QLQ-C30 has been designed so that all items in any scale take the same range of  
value. 
Therefore, the range of 
values. 
RS Equals the range of the item values. 
Most items are 
scored 1 to 4, giving range 
The exceptions are the items contributing to the global 
=3. 
Health status / QoL, which are 7-point questions with range =6 , and the initial yes/no items 
on the earlier versions of the QLQ-C30 which have    
 range =1. 


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Scoring the EORTC QLQ-C30 version 3.0 
 
Table 1: Scoring the QLQ-C30 version 3.0 
Scale 
Number 
of items 
Item 
range* 
Version 
3.0 
Item numbers 
Function 
scales 
Global health status / QoL 
Global health status/QoL (revised)† 
QL2 
2 
6 
29, 30 
Functional scales 
Physical functioning (revised)† 
PF2 
5 
3 
1 to 5 
F 
Role functioning (revised)† 
RF2 
2 
3 
6, 7 
F 
Emotional functioning 
EF 
4 
3 
21 to 24 
F 
Cognitive functioning 
CF 
2 
3 
20, 25 
F 
Social functioning 
SF 
2 
3 
26, 27 
F 
Symptom scales / items 
Fatigue 
FA 
3 
3 
10, 12, 18 
Nausea and vomiting 
NV 
2 
3 
14, 15 
Pain 
PA 
2 
3 
9, 19 
Dyspnoea 
DY 
1 
3 
8 
Insomnia 
SL 
1 
3 
11 
Appetite loss 
AP 
1 
3 
13 
Constipation 
CO 
1 
3 
16 
Diarrhoea 
DI 
1 
3 
17 
Financial difficulties 
FI 
1 
3 
28 
* Item range is the difference between the possible maximum and the minimum response to individual items; most 
items take values from 1 to 4, giving range = 3. 
† (revised) scales are those that have been changed since version 1.0, and their short names are indicated in this 
manual by a suffix “2” – for example, PF2. 
For all scales, the RawScore, RS, is the mean of the component items: 
RawScore = RS = (I1 + I2 +...+ In) n 
Then for Functional scales: 
 (RS −1) 
Score =1− ×100 
 
range  
and for Symptom scales / items and Global health status / QoL:  


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Score ={(RS −1) range}×100 
 
Examples: 
Emotional 
functioning 
RawScore = (Q21 + Q22 + Q23 + Q24 ) 4 
EF Score ={1−(RawScore −1) 3}×100 
Fatigue 
RawScore = (Q10 + Q12 +Q18 ) 3 FA 
Score ={(RawScore −1) 3}×100 


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Clinical Trial Protocol ACH471-101 
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STATISTICAL ANALYSIS PLAN 
 
APPROVAL PAGE 
 
 
A Phase 2 Open-label Study of ACH-0144471 in Patients with Paroxysmal Nocturnal Hemoglobinuria 
(PNH) Who Have an Inadequate Response to Eculizumab Monotherapy 
 
 
 
Protocol ACH471-101 
 
 
Prepared by: 
 
 
 
 
 
 
Signature 
 
Date 
 
 
 
Approved by: 
 
 
 
 
 
Signature 
 
Date 
 
 
 
 
 
Signature 
 
Date 
 
 
 
PPD
PPD
PPD
PPD