A Phase 1/2 Single-ascending and Multiple-ascending Dose, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of Subcutaneously Administered ALN-CC5 in Healthy Adult Volunteers and Patients With Paroxysmal Nocturnal Hemoglobinuria
Phase: PHASE1
Conditions: Paroxysmal Nocturnal Hemoglobinuria (PNH)
Sponsor: Alnylam Pharmaceuticals

 
 
Official Title: 
 
A Phase 1/2 Single‐ascending and Multiple‐ascending Dose, Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics Study of 
Subcutaneously Administered ALN‐CC5 in Healthy Adult Volunteers and 
Patients with Paroxysmal Nocturnal Hemoglobinuria 
 
NCT Number:    
NCT02352493 
Document Date:   
Amendment 5,  
12 June 2017 

ALN-CC5                                                                                                            Clinical Study Protocol ALN-CC5-001 
 
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The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without expressed written 
authorization of Alnylam Pharmaceuticals, Inc. 
The study will be completed according to guidelines of Good Clinical Practice.  Compliance 
with this practice provides public assurance that the rights, safety, and well-being of study 
subjects are protected consistent with the principles that have their origin in the Declaration of 
Helsinki. 

ALN-CC5                                                                                                            Clinical Study Protocol ALN-CC5-001 
 
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MENT 
 
I have read the protocol for study ALN-CC5-001 and agree to conduct the study as outlined.  I 
agree to maintain the confidentiality of all information received or developed in connection with 
this protocol. 
 
 
                         
Printed Name of Investigator 
 
                         
Signature of Investigator 
 
             
Date 

ALN-CC5         
 Clinical Study Protocol ALN-CC5-001 
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Methodology: This study is designed to evaluate the safety, tolerability, PK, and PD of ALN-CC5 in a 
randomized, double-blind, placebo-controlled manner in healthy adult subjects and in an open-label 
manner in patients with PNH.  A Safety Review Committee (SRC) will perform regular reviews (at 
predefined decision-making time points) of safety, tolerability, and available PD data collected during 
the study with the primary purpose of protecting the safety of subjects and patients participating in the 
study.  The study will be conducted in the following parts:   
Part A:  SAD phase in healthy adult subjects
Part B:  MAD phase in healthy adult subjects
Part C:  multiple dose phase in patients with confirmed PNH who are either naïve to, or on
a stable dose of, eculizumab (as assessed by the Investigator)
Part A:  Subjects will be screened from -90 to -2 days before study drug administration.  Eligible 
subjects will be admitted to the clinical study site on Day -1 to determine continued eligibility and for 
pretreatment assessments.  Subjects will be randomized on Day 0 and will receive a single dose of study 
drug.  Subjects will be discharged from the clinical study site after completing the 24 hour postdose 
follow-up assessments.   
Subjects will return to the clinical study site on an outpatient basis for safety, tolerability, PK, and PD 
monitoring at specified time points through the last postdose follow-up visit (Day 70).  For subjects 
with serum complement activity below normal range at Day 70, monitoring visits will occur every 
28±7 days until serum complement activity is within the normal reference range as assessed by 
complement alternative pathway (CAP) enzyme-linked immunosorbent assay (ELISA) or until the SRC 
makes a decision on a case-by-case basis to discontinue follow-up, whichever is sooner.  The decision 
cannot be made until after completion of the last postdose follow-up visit. 
Subjects in each cohort will be randomized in a 3:1 ratio (ALN-CC5:placebo) in a double-blind, 
placebo-controlled manner.  Study drug will be administered according to a sentinel dosing strategy.  
The first sentinel subject in each cohort will receive study drug (ALN-CC5 or placebo) followed by an 
approximately 24 hour safety follow-up.  The second sentinel subject in each cohort will then receive 
study drug (ALN-CC5 or placebo) followed by an approximately 24 hour safety follow-up, after which 
remaining subjects in the cohort will be dosed. 
The starting dose for subjects in Cohort 1 will be 50 mg of study drug (ALN-CC5 or placebo).  The 
following are planned dose levels for subsequent cohorts in Part A; however, the actual dose 
administered will be determined by the SRC: 
Cohort 2:  200 mg
Cohort 3:  400 mg
Cohort 4:  600 mg
Cohort 5:  900 mg
The highest dose of study drug proposed for Part A will not exceed 900 mg. 
Part B:  Subjects will be screened from -90 to -2 days before dose administration.  Eligible subjects 
will be admitted to the clinical study site on Day -1 to determine continued eligibility and for 
pretreatment assessments.  Subjects will be randomized on Day 0 and will receive an initial dose of 
study drug.  Subjects will be discharged from the clinical study site following the completion of the 
24 hour postdose follow-up assessments.  Subjects will return to the clinical study site for study drug 
administration and safety, tolerability, PK, and PD monitoring over the treatment period and for 
postdose follow-up.  For subjects with serum complement activity below normal range at the last 
postdose follow-up visit, monitoring visits will occur every 28±7 days until serum complement activity 

ALN-CC5                                                                                                            Clinical Study Protocol ALN-CC5-001 
 
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is within the normal reference range as assessed by CAP ELISA or until the SRC makes a decision on a 
case-by-case basis to discontinue follow-up, whichever is sooner.  The decision cannot be made until 
after completion of the last postdose follow-up visit. 
Dose levels for Part B will be selected after SRC review of safety, tolerability, and available PD data 
from Part A.  Dosing in each Part B cohort will begin at a dose that is no greater than the highest safe 
and tolerated dose explored in Part A.  If recommended by the SRC, weekly, once every 2 weeks, or 
monthly dosing regimens to assess safety and PD parameters, and corresponding PK sampling 
schedules may be investigated.  Subjects in each cohort will be randomized in a 3:1 ratio 
(ALN-CC5:placebo) in a double-blind, placebo-controlled manner.  The following are planned dose 
levels for subsequent Part B cohorts; however, the actual dose administered will be determined by the 
SRC: 
 Cohort 1:  50 mg 
 Cohort 2:  200 mg 
 Cohort 3:  400 mg 
 Cohort 4:  600 mg 
The highest dose of study drug proposed for Part B will not exceed 600 mg. 
Part C:  The start of Part C and the study drug dose will depend on SRC review of safety, tolerability, 
and available PD data from Part A and Part B.  A maximum of 3 cohorts comprised of at least 4 patients 
each will be enrolled in Part C.   
Patients will be screened from -90 to -2 days before dose administration.  Patients will have a 
consultation at the clinical study site on Day -1 to determine continued eligibility and for pretreatment 
assessments.  Patients will be admitted and dosed on Day 0.  Patients will be discharged from the 
clinical study site following the completion of the 24 hour postdose follow up assessments.  Patients 
will return to the clinical study site for study drug administration and for safety, tolerability, PK, and 
PD monitoring over the treatment period and for postdose follow-up.  For patients with serum 
complement activity below normal range at the last postdose follow-up visit, monitoring visits will 
occur every 28±7 days until serum complement activity is within the normal reference range as assessed 
by CAP ELISA or until the SRC makes a decision on a case-by-case basis to discontinue follow-up, 
whichever is sooner.  The decision cannot be made until after completion of the last postdose follow-up 
visit. 
During the dosing period, the SRC will meet at regular intervals to recommend cohort initiation and the 
dose and regimen to be administered to all patients in a cohort or all patients in Part C.  Dosing will 
begin at a dose no greater than the highest safe and tolerated dose explored in Part B.  During the dosing 
period, the SRC may recommend the ALN-CC5 dose and regimen be modified for all patients, based on 
safety, tolerability, and available PD, including the degree of complement inhibition and clinically 
meaningful suppression of intravascular hemolysis as evaluated by LDH.  Weekly, once every 2 weeks, 
or monthly dosing regimens may be investigated.  The SRC may recommend de-escalation to a lower 
dose and regimen or re-escalation to a higher dose and regimen. 
Optional Cohorts:  Based on the evaluation of safety, tolerability, and available PD data, it may be 
decided by the SRC that optional cohorts may be enrolled and dosed according to the same eligibility 
criteria, corresponding randomization scheme, and sentinel dosing strategy detailed in Part A and 
Part B.  In both Part A and Part B, up to 3 exploratory cohorts (exploring additional dosing and/or dose 
regimen) may be added.  The dose levels for optional cohorts may be at intermediate dose levels 
compared to those administered in Part A and Part B, but will not exceed 900 mg and 600 mg, 
respectively, provided the dose is considered safe and tolerable. 
Number of subjects (planned):  Up to 76 subjects will be enrolled in the study. 

ALN-CC5                                                                                                            Clinical Study Protocol ALN-CC5-001 
 
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 Part A:  Up to 32 healthy adult subjects (including optional cohorts) 
 Part B:  Up to 28 healthy adult subjects (including optional cohorts) 
 Part C:  Up to 16 patients with confirmed PNH (approximately 8 patients on a stable dose 
of eculizumab as assessed by the Investigator) 
Diagnosis and eligibility criteria for Part A and Part B:  Adult healthy subjects meeting the 
following eligibility criteria will be enrolled in Part A or Part B. 
Inclusion Criteria: 
1. Male and female subjects aged 18 to 45 years, inclusive. 
2. 12-lead electrocardiogram (ECG) within normal limits or with no clinically significant 
abnormalities in the opinion of the Investigator. 
3. Body mass index ≥18.0 kg/m2 and ≤30 kg/m
2. 
4. Systolic blood pressure ≤140 mmHg and a diastolic blood pressure of ≤90 mmHg after 
10 minutes supine rest. 
5. Female subjects of childbearing potential agreeing to use one of the acceptable methods of 
contraception listed below from the time of signing the informed consent until 5 months 
following administration of the last dose of study medication: 
 The subject’s male partner has undergone documented vasectomy with documentation of 
azoospermia (male sterilization) and the use of a barrier method (condom or occlusive cap 
[diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository). 
 A documented placement of an intrauterine device (IUD) or intrauterine system (IUS) and 
the use of a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] 
used with spermicidal foam/gel/film/cream/suppository). 
 Oral contraceptives (combination estrogen/progesterone pills), injectable progesterone, or 
subdermal implants and the use of a barrier method (condom or occlusive cap [diaphragm 
or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository]). 
 Documented tubal ligation (female sterilization).  In addition, a barrier method (condom or 
occlusive cap [diaphragm or cervical/vault caps] used with spermicidal 
foam/gel/film/cream/suppository). 
 True abstinence:  when this is in line with the preferred and usual lifestyle of the subject, 
including female subjects with same sex partners. Periodic abstinence (eg, calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.  Abstinent subjects have to agree to use one of the 
above-mentioned contraceptive methods, if they start sexual relationships during the study 
and for up to 5 months after the last dose of study drug. 
6. Male subjects agreeing to use acceptable methods of contraception if the male subject’s partner 
could become pregnant from the time of the first administration of study medication until 
5 months following administration of the last dose of study medication.  One of the following 
acceptable methods of contraception must be utilized: 
 Surgical sterilization (vasectomy with documentation of azoospermia) and a barrier method 
(condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal 
foam/gel/film/cream/suppository). 

ALN-CC5                                                                                                            Clinical Study Protocol ALN-CC5-001 
 
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 The subject’s female partner uses oral contraceptives (combination estrogen/progesterone 
pills), injectable progesterone, or subdermal implants and a barrier method (condom or 
occlusive cap [diaphragm or cervical/vault caps] used with spermicidal 
foam/gel/film/cream/suppository). 
 The subject’s female partner uses medically prescribed topically-applied transdermal 
contraceptive patch and a barrier method (condom or occlusive cap [diaphragm or 
cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository). 
 The subject’s female partner has undergone documented tubal ligation (female 
sterilization).  In addition, a barrier method (condom or occlusive cap [diaphragm or 
cervical/vault caps] with spermicidal foam/gel/film/cream/suppository) must be used. 
 The subject’s female partner has undergone documented placement of an IUD or IUS and 
the use of a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] 
used with spermicidal foam/gel/film/cream/suppository). 
 True abstinence: when this is in line with the preferred and usual lifestyle of the subject, 
including male subjects with same sex partners.  Periodic abstinence (eg, calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.  Abstinent subjects have to agree to use one of the 
above-mentioned contraceptive methods, if they start sexual relationships during the study 
and for up to 5 months after the last dose of study drug. 
7. Vaccinated against Neisseria meningitides with meningococcal group A, C, W-135, and Y 
(ACWY) conjugate vaccine and meningococcal group B vaccine and confirmed seroconversion 
to ACWY on Day -1. 
8. Willing to comply with protocol-required visit schedule and visit requirements and provide 
written informed consent. 
9. Light smokers and users of nicotine (defined as the equivalent of 10 cigarettes per day) or 
nonsmokers and non-users of nicotine. 
Exclusion Criteria for all Subjects in Part A and Part B: 
1. Any uncontrolled or serious disease, or any medical or surgical condition, that may either 
interfere with participation in the clinical study and/or put the subject at significant risk 
(according to Investigator’s judgment) if he/she participates in the clinical study. 
2. A known underlying disease, or surgical or medical condition that, in the opinion of the 
Investigator, may interfere with interpretation of the clinical study results. 
3. Active serious mental illness or psychiatric disorder, including, but not limited to, 
schizophrenia, bipolar disorder, or severe depression requiring current pharmacological 
intervention. 
4. Clinically significant illness within the 7 days before administration of the first dose of study 
drug. 
5. Alanine aminotransferase (ALT) or aspartate aminotransferase above the normal range; total 
bilirubin, alkaline phosphatase, or albumin outside the reference range and considered clinically 
relevant in the opinion of the Investigator at screening and Day -1. 
6. Complete blood count (CBC) laboratory results that are considered clinically relevant and 
unacceptable by the Investigator at screening and Day -1. 
7. International normalized ratio above the reference range at the Screening visit. 

ALN-CC5                                                                                                            Clinical Study Protocol ALN-CC5-001 
 
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8. Complement activity below normal reference range as evaluated by CAP ELISA. 
9. Known or suspected hereditary asymptomatic complement deficiency. 
10. 
Any other clinical safety laboratory test result considered clinically significant and 
unacceptable by the Investigator. 
11. 
Clinical laboratory evidence or clinical diagnosis of human immunodeficiency virus (HIV) 
infection, hepatitis C virus (HCV) infection, or chronic hepatitis B virus (HBV) infection (as 
shown by hepatitis B surface antigen [HBsAg] positivity). 
12. 
Positive screen for alcohol or drugs of abuse at screening and Day -1 and consume more than 
14 (female) or 21 (male) units of alcohol a week (unit: 1 glass of wine [125 mL] = 1 measure of 
spirits = ½ pint of beer). 
13. 
History or clinical evidence of alcohol abuse, within the 12 months before screening.  Alcohol 
abuse is defined as regular weekly intake of more than 21 units for males and 14 units for 
females (using alcohol tracker http://www.nhs.uk/Tools/Pages/NHSAlcoholtracker.aspx). 
14. 
History or clinical evidence of drug abuse, within the 12 months before screening.  Drug abuse 
is defined as compulsive, repetitive, and/or chronic use of drugs or other substances with or 
without problems related to their use and/or where stopping or a reduction in dose will lead to 
withdrawal symptoms. 
15. 
Donated more than 500 mL of blood within 90 days before the first dose of study drug. 
16. 
Received an investigational agent (including complement C5 inhibitors) within 90 days before 
the first dose of study drug or are in follow-up of another clinical study. 
17. 
Used prescription medications within 14 days or 7 half-lives (whichever is longer) of 
administration of the first dose of study drug. 
18. 
Used over-the-counter medication, excluding routine vitamins, within 7 days before the first 
dose of study drug, unless determined by the Investigator and Sponsor to be not clinically 
relevant, and unlikely to impact on study outcomes. 
19. 
History of intolerance to subcutaneous (SC) injection or relevant abdominal scarring (surgical, 
burns, etc.). 
20. 
History of meningococcal infection. 
21. 
History of vaccinations with evidence of insufficient immunizations. 
22. 
History of significant recurrent infections in the opinion of the Investigator or delegate. 
23. 
Presence or suspicion of active viral, bacterial, fungal, or parasitic infection including herpes, 
herpes zoster, or cold sores within 14 days before the first study drug administration (patients 
may be rescreened). 
24. 
Subjects who have had their spleen removed for any reason. 
25. 
History of multiple drug allergies or history of allergic reaction to an oligonucleotide or 
N-acetylgalactosamine (GalNAc). 
26. 
Known hypersensitivity or contraindication to any medication, including any vaccine 
component, or current manifestation of any significant allergic disorder. 
27. 
Clinically significant allergic reactions to antibiotics in the opinion of the Investigator and not 
willing to use antibiotic prophylaxis as specified in protocol. 
28. 
Legal incapacity or limited legal capacity. 
29. 
Any other conditions which, in the opinion of the Investigator, would make the subject 
unsuitable for enrollment or could interfere with the subject’s participation in or completion of 
the study. 
30. 
Travelled to Saudi Arabia or Africa within 90 days of screening, or who plan to do so during 
the study (patients may be rescreened). 

ALN-CC5                                                                                                            Clinical Study Protocol ALN-CC5-001 
 
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31. 
Women who are pregnant or breastfeeding. 
Diagnosis and Eligibility Criteria for Part C:  Adult patients with PNH meeting the following 
eligibility criteria will be enrolled in Part C. 
Inclusion Criteria 
1. Adults aged minimum 18 years at screening. 
2. Granulocyte and monocyte PNH clone >1% as documented by medical records. 
3. LDH ≥1.5 upper limit of normal (ULN) in the absence of eculizumab.  If on stable eculizumab 
therapy, as assessed by the Investigator, patients must have historical laboratory values 
documenting elevated LDH levels before administration of the first dose of eculizumab. 
4. Female patients of childbearing potential agreeing to use one of the acceptable methods of 
contraception listed below from the time of signing the informed consent until 5 months 
following administration of the last dose of study medication: 
 The subject’s male partner has undergone documented vasectomy with documentation of 
azoospermia (male sterilization) and the use of a barrier method (condom or occlusive cap 
[diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository). 
 A documented placement of an IUD or IUS and the use of a barrier method (condom or 
occlusive cap [diaphragm or cervical/vault caps] used with spermicidal 
foam/gel/film/cream/suppository). 
 Oral contraceptives (combination estrogen/progesterone pills), injectable progesterone, or 
subdermal implants and the use of a barrier method (condom or occlusive cap [diaphragm 
or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository). 
 Documented tubal ligation (female sterilization). In addition, a barrier method (condom or 
occlusive cap [diaphragm or cervical/vault caps] used with spermicidal 
foam/gel/film/cream/suppository). 
 True abstinence: when this is in line with the preferred and usual lifestyle of the patient, 
including female subjects with same sex partners. Periodic abstinence (eg, calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.  Abstinent patients have to agree to use one of the 
above-mentioned contraceptive methods, if they start sexual relationships during the study 
and for up to 5 months after the last dose of study drug. 
5. Male patients agreeing to use acceptable methods of contraception if the male patient’s partner 
could become pregnant from the time of the first administration of study medication until 5 
months following administration of the last dose of study medication.  One of the following 
acceptable methods of contraception must be utilized: 
 Surgical sterilization (vasectomy with documentation of azoospermia) and a barrier method 
(condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal 
foam/gel/film/cream/suppository). 
 The patient’s female partner uses oral contraceptives (combination estrogen/progesterone 
pills), injectable progesterone, or subdermal implants and a barrier method (condom or 
occlusive cap [diaphragm or cervical/vault caps] used with spermicidal 
foam/gel/film/cream/suppository). 

ALN-CC5                                                                                                            Clinical Study Protocol ALN-CC5-001 
 
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 The patient’s female partner uses medically prescribed topically-applied transdermal 
contraceptive patch and a barrier method (condom or occlusive cap [diaphragm or 
cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository). 
 The patient’s female partner has undergone documented tubal ligation (female 
sterilization).  In addition, a barrier method (condom or occlusive cap [diaphragm or 
cervical/vault caps] with spermicidal foam/gel/film/cream/suppository) must be used. 
 The patient’s female partner has undergone documented placement of an IUD or IUS and 
the use of a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] 
used with spermicidal foam/gel/film/cream/suppository). 
 True abstinence: when this is in line with the preferred and usual lifestyle of the patient, 
including male subjects with same sex partners.  Periodic abstinence (eg, calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.  Abstinent patients have to agree to use one of the 
above-mentioned contraceptive methods, if they start sexual relationships during the study 
and for up to 5 months after the last dose of study drug. 
6. Willing to comply with protocol-required visit schedule and visit requirements and provide 
written informed consent. 
7. Vaccinated against Neisseria meningitides according to standard practice at the clinical study 
site. 
Exclusion Criteria: 
1. History of venous or arterial thromboembolic events within the past 12 months. 
2. Active serious mental illness or psychiatric disorder, including, but not limited to, 
schizophrenia, bipolar disorder, or severe depression requiring current pharmacological 
intervention. 
3. ALT > 2 × ULN and considered clinically relevant in the opinion of the Investigator. 
4. CBC laboratory results that are considered clinically relevant and unacceptable by the 
Investigator. 
5. Any other clinical safety laboratory test result considered clinically significant and 
unacceptable by the Investigator. 
6. Known or suspected hereditary asymptomatic complement deficiency. 
7. Known clinical laboratory evidence or clinical diagnosis of HIV infection, HCV infection, or 
chronic HBV infection (as shown by HBsAg positivity). 
8. History or clinical evidence of alcohol abuse, within the 12 months before screening.  Alcohol 
abuse is defined as regular weekly intake of more than 21 units for males and 14 units for 
females (using alcohol tracker http://www.nhs.uk/Tools/Pages/NHSAlcoholtracker.aspx). 
9. History of multiple drug allergies or history of allergic reaction to an oligonucleotide or 
GalNAc. 
10. 
History of intolerance to SC injection or relevant abdominal scarring (surgical, burns, etc.). 
11. 
History of meningococcal infection. 
12. 
Presence or suspicion of active viral, bacterial, fungal, or parasitic infection including herpes, 
herpes zoster, or cold sores within 14 days before the first study drug administration (patients 
may be rescreened). 
13. 
Legal incapacity or limited legal capacity at screening. 
14. 
Any other conditions which, in the opinion of the Investigator, would make the patient 

ALN-CC5                                                                                                            Clinical Study Protocol ALN-CC5-001 
 
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unsuitable for enrollment or could interfere with the subject’s participation in or completion of 
the study. 
15. 
Travelled to Saudi Arabia or Africa within 90 days of screening, or who plan to do so during 
the study (patients may be rescreened). 
16. 
Women who are pregnant or breastfeeding. 
Investigational product, dosage, and mode of administration:  
ALN-CC5 is a synthetic, chemically modified small interfering RNA targeting CC5 messenger RNA 
with a covalently attached triantennary GalNAc ligand.  ALN-CC5 will be supplied as a sterile 
200-mg/mL solution for SC injection. 
Duration of treatment: 
A single SC dose of study drug will be administered in Part A.  In Part B and Part C, respectively, study 
drug will be administered over a maximum of a 13 or a 39 week period. 
Reference therapy, dosage and mode of administration:  
Subjects randomized to placebo treatment in Part A or Part B will be administered placebo, which will 
be supplied by the clinical study site as sterile normal saline 0.9% solution for SC injection. 
Criteria for evaluation: 
Safety:  Safety evaluation will include clinical laboratory safety tests (hematology, biochemistry, 
coagulation, and urinalysis), vital signs (oral body temperature, blood pressure, heart rate, and 
respiration rate), physical examinations, 12-lead ECGs, concomitant medications, and adverse event 
monitoring.  
 will be measured in subjects and patients 
Pharmacodynamics:  PD analysis will include assessment of the impact of ALN-CC5 administration 
on plasma levels of C5 protein (assessed by ELISA and/or mass spectrometry-based methods) and 
serum complement activity (assessed by CAP ELISA and complement classical pathway ELISA 
assays). 
Pharmacokinetics:  Blood and urine samples will be collected for assessment of ALN-CC5 PK 
parameters and possible metabolite analysis.  PK parameters include, but are not limited to, maximum 
plasma concentration, time to reach maximum plasma concentration, area under the plasma 
concentration versus time curve, and apparent terminal elimination half-life.   
Exploratory:  Exploratory assessments include inhibition of hemolytic activity (assessed by sensitized 
sheep red blood cell [RBC] and
)
 will be assessed only in subjects 
consenting to the procedure.  Exploratory assessments in patients with PNH include, but are not limited 
to, LDH levels,
 
 eculizumab levels (patients on stable doses of eculizumab 
only),
, 
 
 
Statistical Methods:  Statistical analyses will be primarily descriptive; no formal hypotheses will be 
tested.  Data will be analyzed separately for Part A and Part B by ALN-CC5 dosing cohorts versus 
placebo.  Descriptive statistics will be presented for continuous variables, and frequencies and 
percentages will be presented for categorical and ordinal variables.  Percentages will be based on the 
number of non-missing values in a dose group.  All study data will be also presented in a listing for 
each subject/patient.   
In Part C, data will be analyzed by cohort for patients on the same dose and dose regimen.  
Additionally, analysis may be based on patients who are either naïve to eculizumab treatment or on 
stable doses of eculizumab (as assessed by the Investigator). 
 

ALN-CC5                                                                                                                                                                                   Clinical Study Protocol ALN-CC5-001 
 
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n. C5 levels will be measured by ELISA and/or mass spectrophotometry in a central laboratory. 
o. Serum complement activity includes:  CAP ELISA and CCP ELISA. 
p. 
 
 
q. For patients in the optional cohorts, consenting to the procedure, a blood sample for 
 will be collected anytime during the study.  Samples 
will be analyzed at a central laboratory. 
r. See Section 10.4.2.1 for handling of ISRs. 
 
 

ALN-CC5                                                                                                                                                                                   Clinical Study Protocol ALN-CC5-001 
 
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k. Collect blood samples for biochemistry and hematology only. 
l. SC injection of study drug per the Study Drug Administration Manual. 
m. Details regarding time points for collection of blood and urine samples for full PK analysis are outlined in Table 11 in the appendix (Section 18). 
n. Collect blood samples for PK analysis predose (-60 minutes) and 60±30 minutes postdose only.  Collect urine samples PK analysis predose (-60 minutes) only. 
o. C5 levels will be measured by ELISA and/or mass spectrophotometry in a central laboratory. 
p. Serum complement activity includes:  CAP ELISA and CCP ELISA. 
q. 
 
 
 
r. See Section 10.4.2.1 for handling of ISRs. 
 
 

ALN-CC5                                                                                                                                                                                   Clinical Study Protocol ALN-CC5-001 
 
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d. For patients with serum complement activity below normal range at the last postdose follow-up visit, monitoring visits will occur until serum complement activity is 
within the normal reference range as assessed by CAP ELISA or until the SRC makes a decision on a case-by-case basis to discontinue follow-up, whichever is 
sooner (see Section 3.5.3). 
e. Patients will have been or will be vaccinated against Neisseria meningitides (see Section 10.1.8.2 for vaccination specifications). 
f. See Section 10.1.4 for assessments to be performed during a full and directed medical examination. 
g. Vital signs include blood pressure, heart rate, oral body temperature, and respiratory rate.  Vital signs will be measured in the supine position after the subject has 
rested comfortably for 10 minutes.  On Day 0, vital signs should be collected predose (-60 minutes); and 30±5 minutes and 4 hours (±15 minutes) postdose.  After 
Day 0, vital signs should be collected predose (-60 minutes); and up to 12±1 hours postdose on days when study drug is administered. 
h. 12-lead ECGs will be measured in the supine position after the subject has rested comfortably for 10 minutes.  On Day 0, the ECG should be performed predose (-
60 minutes); and ±4 hours postdose.  After Day 0, the ECG should be performed predose (-60 minutes); and up to 12 hours postdose on days when study drug is 
administered. 
i. See Section 10.1.7.4 for viral serology parameters. 
j. Biochemistry, hematology, coagulation, and urinalysis parameters to be measured are described in Section 10.1.7. 
k. Collect blood samples for biochemistry and hematology only. 
l. For patients receiving treatment with eculizumab, a blood sample for the measurement of eculizumab levels will be collected before and 60±30 minutes after each 
treatment with eculizumab.  Single weekly samples will be taken on the weeks between eculizumab treatments on the days that ALN-CC5 is administered.  If 
eculizumab treatment is stopped, weekly samples will be taken, thereafter. 
m. SC injection of study drug per the Study Drug Administration Manual.  Patients on stable doses of eculizumab will continue receiving treatment concomitantly with 
ALN-CC5; patients will receive their last dose of eculizumab when at least 2 consecutive measurements of C5 levels demonstrate a degree of suppression consistent 
with complement inhibition.  Patients who are naïve to eculizumab treatment may begin ALN-CC5 administration.  ALN-CC5 may be administered at home 
between visits to the clinical study center by a home healthcare provider trained in the administration of ALN-CC5. 
n. Details regarding time points for collection of blood and urine samples for full PK analysis are outlined in Table 13 in the appendix (Section 18). 
o. C5 levels will be measured by ELISA and/or mass spectrophotometry in a central laboratory. 
p. Serum complement activity includes:  CAP ELISA and CCP ELISA. 
q. Exploratory 
 are described in Section 9.3. 
r. See Section 10.4.2.1 for handling of ISRs. 
 
 
 

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TABLE OF CONTENTS  
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS 
...............................................................................................................22 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
................................................29 
1. 
INTRODUCTION 
......................................................................................................32 
1.1. 
Background Information on the Disease to be Treated 
..............................................32 
1.2. 
Background Information on the Product ....................................................................33 
1.3. 
Mechanism of RNA Interference 
................................................................................33 
1.4. 
Rationale for ALN-CC5 for the Treatment of Complement-Mediated 
Disease 
........................................................................................................................33 
1.5. 
Nonclinical Development 
...........................................................................................34 
1.5.1. 
Nonclinical Pharmacology 
..........................................................................................34 
1.5.2. 
Single-dose Pharmacology in Nonhuman Primates ...................................................34 
1.5.3. 
Repeat-dose Pharmacology in Nonhuman Primates 
...................................................35 
1.6. 
Clinical Development 
.................................................................................................35 
1.7. 
Study Rationale 
...........................................................................................................36 
1.8. 
Rationale for Dose Selection 
......................................................................................36 
1.9. 
Potential Risks and Benefits 
.......................................................................................37 
1.9.1. 
Potential Benefits 
........................................................................................................37 
1.9.2. 
Potential Risks 
............................................................................................................37 
1.9.2.1. 
Serious Meningococcal Infections 
..............................................................................37 
1.9.2.2. 
Allergic Reactions and Injection Reactions 
................................................................38 
1.9.2.3. 
Vaccinations ...............................................................................................................39 
1.9.2.4. 
Prophylactic Antibiotics 
.............................................................................................39 
1.9.3. 
Risk Mitigation Strategy 
.............................................................................................40 
2. 
STUDY OBJECTIVES ..............................................................................................42 
2.1. 
Primary Objective 
.......................................................................................................42 
2.2. 
Secondary Objectives 
.................................................................................................42 
2.3. 
Exploratory Objectives 
...............................................................................................42 
3. 
INVESTIGATIONAL PLAN 
.....................................................................................43 
3.1. 
Overall Study Design 
..................................................................................................43 
3.1.1. 
Single-ascending Dose Phase (Part A) 
.......................................................................43 

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3.1.2. 
Multiple-ascending Dose Phase (Part B) 
....................................................................44 
3.1.3. 
Multiple Dose Phase (Part C) 
.....................................................................................44 
3.1.4. 
Optional Cohorts 
.........................................................................................................45 
3.1.5. 
Treatment and Study Duration 
....................................................................................46 
3.2. 
Number of Subjects and Patients 
................................................................................46 
3.3. 
Treatment Assignment 
................................................................................................46 
3.4. 
Adaptive Study Design Feature 
..................................................................................46 
3.5. 
Safety Review Committee 
..........................................................................................50 
3.5.1. 
Primary Responsibility 
...............................................................................................50 
3.5.2. 
Membership 
................................................................................................................50 
3.5.3. 
Timing and Purpose of Review Meetings ..................................................................50 
3.5.4. 
Data Requirements 
......................................................................................................51 
3.5.4.1. 
Safety Data 
..................................................................................................................51 
3.5.4.2. 
Pharmacodynamic Data 
..............................................................................................51 
3.5.4.3. 
Pharmacokinetic Data 
.................................................................................................51 
4. 
CRITERIA FOR STUDY DRUG DOSING AND DOSE 
PROGRESSION/ESCALATION 
...............................................................................52
 
4.1. 
Study Drug Dosing and Progression/Escalation in Part A .........................................52 
4.2. 
Study Drug Dosing and Progression/Escalation in Part B 
..........................................52 
4.3. 
Study Drug Dosing and Regimen Modifications in Part C 
........................................53 
4.3.1. 
Management of Breakthrough Hemolytic Events ......................................................54 
4.4. 
Study Progression/Escalation and Dose Suspension/Stopping Rules ........................54 
4.4.1. 
Cohort Progression/Escalation and Suspension/Stopping Rules 
................................56 
4.4.2. 
Individual Patient Progression/Escalation and Suspension/Stopping Rules in 
Part C 
..........................................................................................................................59 
5. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
..............................................60 
5.1. 
Inclusion Criteria 
........................................................................................................60 
5.1.1. 
Inclusion Criteria for all Subjects in Part A and Part B 
..............................................60 
5.1.2. 
Inclusion Criteria for all Patients in Part C 
.................................................................61 
5.2. 
Exclusion Criteria 
.......................................................................................................63 
5.2.1. 
Exclusion Criteria for all Subjects in Part A and Part B 
.............................................63 
5.2.2. 
Exclusion Criteria for All Patients in Part C ..............................................................65 
5.3. 
Withdrawal Criteria 
....................................................................................................65 

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5.3.1. 
Reason for Withdrawal 
...............................................................................................66 
5.3.2. 
Handling of Withdrawals 
............................................................................................66 
5.3.3. 
Replacements 
..............................................................................................................67 
6. 
TREATMENT OF SUBJECTS 
..................................................................................68 
6.1. 
Description of Study Drug 
..........................................................................................68 
6.2. 
Concomitant Medications 
...........................................................................................68 
6.2.1. 
Permitted Concomitant Medications ..........................................................................68 
6.2.2. 
Prohibited Concomitant Medications 
.........................................................................68 
6.3. 
Subject Restrictions 
....................................................................................................69 
6.4. 
Treatment Compliance 
................................................................................................69 
6.5. 
Assignment to Dose Cohort and Subject Number 
......................................................69 
6.6. 
Randomization and Blinding 
......................................................................................69 
6.6.1. 
Breaking the Blind 
......................................................................................................70 
7. 
STUDY DRUG MATERIALS AND MANAGEMENT 
...........................................72 
7.1. 
Study Drug 
..................................................................................................................72 
7.1.1. 
Antibiotic Prophylaxis 
................................................................................................72 
7.1.2. 
Study-specific Vaccinations 
.......................................................................................72 
7.2. 
Study Drug Packaging and Labeling 
..........................................................................72 
7.3. 
Study Drug Storage 
.....................................................................................................72 
7.4. 
Study Drug Preparation 
..............................................................................................73 
7.5. 
Study Drug Administration.........................................................................................73 
7.5.1. 
Injection Site Examinations 
........................................................................................73 
7.6. 
Study Drug Accountability 
.........................................................................................73 
7.7. 
Study Drug Handling and Disposal 
............................................................................73 
8. 
PHARMACOKINETIC ASSESSMENTS 
.................................................................74 
8.1. 
Blood Sample Collection 
............................................................................................74 
8.2. 
Urine Sample Collection 
.............................................................................................74 
8.3. 
Sample Analysis 
.........................................................................................................74 
9. 
PHARMACODYNAMIC AND EXPLORATORY ASSESSMENTS 
......................75 
9.1. 
Pharmacodynamic Blood Sample Collection 
.............................................................75 
9.2. 
 
9.3. 
 

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9.3.1. 
 
9.3.2. 
 
9.3.3. 
  
 
9.3.4. 
 
10. 
ASSESSMENT OF SAFETY 
.....................................................................................77 
10.1. 
Safety Parameters 
.......................................................................................................77 
10.1.1. 
Demographics and Medical History 
...........................................................................77 
10.1.2. 
Vital Signs ..................................................................................................................77 
10.1.3. 
Weight, Height, and Body Mass Index 
.......................................................................77 
10.1.4. 
Physical Examination 
.................................................................................................77 
10.1.5. 
Electrocardiogram 
.......................................................................................................78 
10.1.6. 
Maximum Blood Volume 
...........................................................................................78 
10.1.7. 
Laboratory Assessments 
.............................................................................................78 
10.1.7.1. Biochemistry, Hematology, Coagulation, and Cytokine Panel 
..................................78 
10.1.7.2. Urinalysis 
....................................................................................................................80 
10.1.7.3. Immunogenicity 
..........................................................................................................80 
10.1.7.4. Viral Serology 
.............................................................................................................80 
10.1.7.5. Drugs of Abuse and Alcohol Screening (Part A and Part B only) 
.............................80 
10.1.7.6. Pregnancy Screening ..................................................................................................81 
10.1.7.7. Follicle-Stimulating Hormone Assessment 
................................................................81 
10.1.8. 
Study-specific Vaccinations 
.......................................................................................81 
10.1.8.1. Vaccination Specifications for Part A and Part B ......................................................81 
10.1.8.2. Vaccination Specifications for Part C 
.........................................................................82 
10.1.9. 
Prophylactic Antibiotic Administration and Compliance Check ...............................82 
10.2. 
Adverse and Serious Adverse Events 
.........................................................................83
 
10.2.1. 
Definition of Adverse Events 
.....................................................................................83 
10.2.1.1. Adverse Event 
.............................................................................................................83
 
10.2.1.2. Serious Adverse Event 
................................................................................................83 
10.2.1.3. Suspected Unexpected Serious Adverse Reactions 
....................................................83 
10.2.1.4. Other Adverse Events 
.................................................................................................83 
10.3. 
Eliciting Adverse Event Information 
..........................................................................84 
10.4. 
Adverse Event Reporting 
............................................................................................84 

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10.4.1. 
Assessment of Causality 
.............................................................................................84 
10.4.2. 
Assessment of Toxicity 
...............................................................................................85 
10.4.2.1. Injection Site Signs or Symptoms 
...............................................................................85 
10.5. 
Serious Adverse Event Reporting 
...............................................................................86 
10.6. 
Suspected Unexpected Serious Adverse Reactions Reporting 
...................................86 
10.6.1. 
Pregnancy Reporting ..................................................................................................87 
11. 
STATISTICS 
..............................................................................................................88 
11.1. 
Sample Size and Randomization 
................................................................................88 
11.2. 
Analysis Sets 
...............................................................................................................88 
11.3. 
Statistical Methodology 
..............................................................................................88 
11.3.1. 
Baseline Evaluations 
...................................................................................................89 
11.3.2. 
Safety Data Analysis 
...................................................................................................89 
11.3.2.1. Safety Parameters 
.......................................................................................................89 
11.3.2.2. Adverse Events 
...........................................................................................................89 
11.3.2.3. Clinical Laboratory Safety Parameters, Vital Signs, Physical Examinations, 
and 12-lead Electrocardiograms 
.................................................................................89 
11.3.3. 
Pharmacokinetic Analysis ..........................................................................................90 
11.3.3.1. Pharmacokinetic Parameters 
.......................................................................................90 
11.3.3.2. Analysis 
......................................................................................................................90 
11.3.4. 
Pharmacodynamic Analysis........................................................................................90 
11.3.5. 
Exploratory Analysis 
..................................................................................................90 
11.4. 
Interim Analysis 
..........................................................................................................90 
11.5. 
Handling of Missing and Incomplete Data 
.................................................................91 
12. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................92 
12.1. 
Quality Assurance and Quality Control 
......................................................................92 
12.2. 
Monitoring 
..................................................................................................................92 
13. 
STUDY REPORTING REQUIREMENTS 
................................................................93 
14. 
ETHICS 
......................................................................................................................94 
14.1. 
Informed Consent 
.......................................................................................................94 
14.2. 
Research Ethics Committee Approval 
........................................................................94 
14.3. 
Confidentiality 
............................................................................................................94 
15. 
DATA HANDLING AND RECORD KEEPING 
......................................................96 
15.1. 
Inspection of Records 
.................................................................................................96 

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15.2. 
Retention of Records 
..................................................................................................96 
16. 
PUBLICATION POLICY 
..........................................................................................97 
17. 
LIST OF REFERENCES 
............................................................................................98 
18. 
APPENDICES 
..........................................................................................................100 
Appendix 1:  Pharmacokinetic Assessment Time Points ............................................................100 
Appendix 2:  Schedules of Assessments for Alternative Dosing Regimens for Part B 
...............103
 
Appendix 3:  Schedules of Assessments for Alternative Dosing Regimens for Part C 
...............119 
 
LIST OF TABLES 
Table 1: Schedule of Assessments for Single-ascending Dose Cohorts (Part A) 
.....................13 
Table 2: Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B)  5 
Weekly Doses 
.............................................................................................................16 
Table 3: Schedule of Assessments for Multiple-dose Cohorts (Part C)  13 Weekly 
Doses (Cohort 1) 
.........................................................................................................19 
Table 4: Estimated NOAEL and Starting Dose Safety Margins...............................................37 
Table 5: Adaptive Study Design Areas, Features, and Limits 
..................................................47 
Table 6: Study Progression/Escalation Flow Chart 
..................................................................55 
Table 7: Cohort Progression/Escalation and Suspension/Stopping Rules for Part A 
and Part B ...................................................................................................................57 
Table 8: Individual Progression Rules for Part C Only 
............................................................59 
Table 9: Investigational Product 
...............................................................................................68 
Table 10: Pharmacokinetic Time Points for Single-ascending Dose Cohorts (Part A) 
............100
 
Table 11: Pharmacokinetic Time Points for Multiple-ascending Dose Cohorts (Part B) 
 Weekly Dosing 
......................................................................................................101
 
Table 12: Pharmacokinetic Time Points for the Multiple-ascending Dose Phase 
(Part B)  Other Dosing Schedules 
...........................................................................101 
Table 13: Pharmacokinetic Time Points for the Multiple Dose Phase (Part C)  13 
Weekly Doses (Cohort 1) 
.........................................................................................102 
Table 14: Pharmacokinetic Time Points for the Multiple Dose Phase (Part C)  5 
Weekly Doses Followed by Once Every 2 Weeks Dosing or Followed by 
Monthly Dosing (Cohort 2 and Cohort 3) 
................................................................102 
Table 15: Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B)  13 
Weekly Doses 
...........................................................................................................104 
Table 16: Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B)  
Once Every 2 Weeks Dosing 
....................................................................................107
 

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Table 17: Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B)  
Monthly Dosing 
........................................................................................................110 
Table 18: Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B)  5 
Weekly Doses Followed by Once Every 2 Weeks Dosing 
.......................................113 
Table 19: Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B)  5 
Weekly Doses Followed by Monthly Dosing 
...........................................................116 
Table 20: Schedule of Assessments for Multiple-dose Cohorts (Part C)  5 Weekly 
Doses Followed by Once Every 2 Weeks Dosing (Cohort 2 and Cohort 3) ............120 
Table 21: Schedule of Assessments for Multiple-dose Cohorts (Part C)  5 Weekly 
Doses Followed by Monthly Dosing (Cohort 2 and Cohort 3) ................................124 
Table 22: Schedule of Assessments for Multiple-dose Cohorts (Part C)  All Cohorts 
(Day 91 through PD Follow-up) 
...............................................................................127 
 
LIST OF FIGURES 
Figure 1: Single-ascending Dose Phase (Part A) Flow Diagram 
...............................................44 
Figure 2: Multiple-ascending Dose Phase (Part B) Flow Diagram 
............................................44 
Figure 3: Multiple-dose Phase (Part C) Flow Diagram 
..............................................................45 
Figure 4: Study Drug Dosing in the Multiple-dose Phase (Part C) 
............................................54 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition 
ACWY 
Neisseria meningitides serogroups A, C, W-135, and Y 
ADL 
activities of daily living 
AE 
adverse event 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AUC 
area under the plasma concentration-time curve 
BMI 
body mass index 
C5 
complement component 5 
CAP 
complement alternative pathway 
CBC 
complete blood count 
CCP 
complement classical pathway 
Cmax  
maximum (peak) plasma drug concentration 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOA 
drugs of abuse 
DSS 
Drug Safety Services (Covance) 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
ELISA 
enzyme-linked immunosorbent assay 
 
 
 
 
ET 
early termination 
 
  
FSH 
follicle-stimulating hormone 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
GPI 
Glycosylphosphatidylinositol 

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Abbreviation  
Definition 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HED 
human equivalent dose 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ISR 
injection site reaction 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
Intravenous 
LDH 
lactate dehydrogenase 
MAC 
membrane attack complex 
MAD 
multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
messenger RNA 
NHP 
non-human primate 
NOAEL 
no observed adverse effect level 
OAE 
other adverse events 
OTC 
over-the-counter 
PD 
pharmacodynamics(s) 
PIGA 
phosphatidylinositol glycan complementation class A 
PK 
pharmacokinetic(s) 
PNH 
paroxysmal nocturnal hemoglobinuria 
PT 
prothrombin time 
PV 
Pharmacovigilance (Covance) 
 
 
QTcB 
Bazett-corrected QT interval 
RBC 
red blood cell 
REC 
Research Ethics Committee 
RNA 
ribonucleic acid 

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Abbreviation  
Definition 
RNAi 
ribonucleic acid interference 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
siRNA 
small interfering ribonucleic acid 
SRC 
Safety Review Committee 
SOC 
System Organ Class 
SUSAR 
suspected unexpected serious adverse reaction 
t
½ 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse events 
t
max 
time to reach maximum plasma concentration 
TMF 
Trial Master File 
 
 
TTR 
Transthyretin 
UK 
United Kingdom 
ULN 
upper limit of normal 

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1. 
INTRODUCTION 
1.1. 
Background Information on the Disease to be Treated 
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal hematopoietic stem cell disorder of 
the blood characterized by the destruction of red blood cells (RBCs) by the complement system.  
The incidence is approximately 1.3 per million per year and the prevalence is 13-20 cases per 
million [1].  The etiology is an acquired somatic mutation in the phosphatidylinositol glycan 
class A (PIGA) gene that results in a clone of mature RBCs lacking glycosylphosphatidylinositol 
(GPI) anchored membrane proteins from their surface (PNH clone).  Deficiency of the 
GPI-anchored complement regulatory glycoproteins, CD55 and CD59, which normally protect 
cells from the complement system, results in unrestrained complement activation, culminating in 
the assembly of the membrane attack complex (MAC) and RBC lysis.  
The disorder is clinically characterized by intravascular hemolysis, bone marrow failure, and 
thrombosis.  Intravascular hemolysis causes anemia, increased levels of free hemoglobin, and 
chelation of nitric oxide.  Uncontrolled complement activation ultimately results in a variety of 
symptoms and complications such as thrombosis, extreme fatigue, dysphagia, abdominal pain, 
pulmonary hypertension, and renal impairment.  The magnitude of intravascular hemolysis is a 
key determinant for the frequency and severity of symptoms.  Elevated lactate dehydrogenase 
(LDH) is reflective of hemolysis and patients with LDH levels greater than 1.5 times the upper 
limit of normal (ULN) have a higher risk of thrombosis and experience more frequent and more 
severe symptoms [2, 3].  Up to 50% of patients with PNH have clinically evident bone marrow 
failure syndromes such as aplastic anemia or myelodysplastic syndrome [4].   
The 10-year survival rate in patients with PNH ranges from 63% for diagnoses before 1985 to 
92% for diagnoses after 1996; the increased survival rate is presumably attributed to improved 
standard of care [5].  The most common cause of death is thrombotic events [6].  A small 
proportion (5 to 15%) of PNH patients may undergo spontaneous remission of their disease [5]. 
The current gold-standard diagnostic test for PNH is flow cytometry of granulocytes and 
erythrocytes to detect the presence of CD55, CD59, and other GPI-anchored proteins [7]. 
Clinical management of PNH is guided by the disease-specific presentations.  The majority of 
patients are offered supportive treatment aiming to mitigate anemia, bone marrow failure, and to 
treat and prevent thromboembolic events.  Bone marrow transplant is considered curative of 
classical PNH; however, it is associated with significant morbidity and mortality [8].  
Approximately 20 to 25% of patients with a PNH clone receive intravenous (IV) treatment with 
eculizumab (Soliris
®), a humanized monoclonal antibody that specifically binds the terminal 
complement component 5 (C5) and blocks its cleavage to C5a and C5b, and thereby, the 
initiation of MAC formation, which is the key precursor of hemolysis.  The safety and 
pharmacodynamics (PD) of eculizumab were established in multiple clinical studies [6, 9, 10, 
11], leading to its approval for the treatment of PNH in 2007. 
Management of PNH has been improved during the past 10 years; however, significant clinical 
challenges remain and justify further treatment optimization.  Despite treatment with 
eculizumab, patients still experience breakthrough hemolysis caused by inflammatory increase in 
C5 [12, 13, 14].  Furthermore, eculizumab is administered every 2 weeks via IV infusion 
affecting the overall quality of life (QOL) of patients [6]. 

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1.2. 
Background Information on the Product 
Alnylam Pharmaceuticals, Inc. is developing ALN-CC5, a synthetic RNA interference (RNAi) 
therapeutic designed to suppress liver production of C5 protein, for the treatment of PNH.  
ALN-CC5 comprises a small interfering RNA (siRNA) targeting C5 messenger RNA (mRNA) 
that is covalently linked to a triantennary N-acetylgalactosamine (GalNAc) ligand.   
1.3. 
Mechanism of RNA Interference 
RNAi is a naturally occurring cellular mechanism for regulating gene expression that is mediated 
by siRNAs.  Synthetic siRNAs are short (19-25 base pairs), double-stranded oligonucleotides in 
a staggered duplex with an overhang at one or both of the 3-prime ends.  Such siRNAs can be 
designed to target the mRNA transcript of a given gene.  When formulated for tissue delivery 
and introduced into cells, the guide (or antisense) strand of the siRNA loads into an enzyme 
complex called the RNA-induced silencing complex.  This enzyme complex subsequently binds 
to its complementary mRNA sequence, mediating cleavage of the mRNA and the suppression of 
the target protein encoded by the mRNA [15].  Since unmodified siRNAs are rapidly eliminated 
and do not achieve significant tissue distribution upon systemic administration [16], various 
formulations are currently used to target their distribution to tissues, and to facilitate uptake of 
siRNAs into the relevant cell type.  One approach that has been used successfully in vivo, in 
animal models (including in rodents and nonhuman primates [NHP]) and humans employs IV 
delivery of siRNA in lipid nanoparticle formulations [16, 17].  Another approach for liver-
specific gene silencing is subcutaneously administered siRNA conjugated to a GalNAc 
carbohydrate ligand [18].  Conjugation of a triantennary GalNAc ligand to an siRNA enables 
hepatocyte binding and subsequent cellular uptake via the asialoglycoprotein receptor, resulting 
in engagement of the RNAi pathway and downregulation of hepatic proteins. 
1.4. 
Rationale for ALN-CC5 for the Treatment of Complement-Mediated 
Disease 
ALN-CC5 (containing siRNA drug substance, 
 targeting C5 mRNA) is a synthetic 
investigational RNAi therapeutic designed to suppress liver production of C5 protein, when 
administered via subcutaneous (SC) injection.  C5 is encoded by a single gene and is expressed 
and secreted predominantly by hepatocytes.  Through the mechanism of RNAi, the ALN-CC5 
siRNA enables the downregulation of C5 mRNA in the liver, thereby reducing levels of 
circulating C5 protein and resulting in inhibition of terminal complement pathway activity that 
prevents the formation of MAC, and in PNH, reduces intravascular hemolysis of RBCs.  The 
safety of reducing C5 is supported by clinical precedence of C5 inhibition with eculizumab 
treatment and the absence of any phenotypic consequences in subjects with known genetic C5 
deficiencies [20]. 
ALN-CC5 is intended for SC injection.  Subcutaneous dosing will reduce the risk of 
infusion-related complications such as infections and thrombophlebitis.  In particular, this 
consequent reduced risk of pathogen penetration is crucial in PNH patients due to a 
predisposition for infections.  Nonclinical data have shown that reducing C5 with ALN-CC5 has 
the potential to nullify natural and inflammatory triggered fluctuations in C5.  The duration of 
effect anticipated with ALN-CC5 based on nonclinical data may further reduce the risk of 
breakthrough hemolytic events.  Finally, given the mechanism for regulation of complement 

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activity, ALN-CC5 may be used as an alternative treatment or in combination with C5 
neutralizing agents. 
1.5. 
Nonclinical Development 
 
 
 
  
 
 
  
 
 
   
 
 
 
  
 
 
 
 
  
 
 
1.5.1. 
Nonclinical Pharmacology 
 
 
 
 
 
 
 
 
 
 
 
 
   
1.5.2. 
Single-dose Pharmacology in Nonhuman Primates   
 
 

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mRNA for the treatment of TTR-mediated amyloidosis.  ALN-TTRSC has been found to be 
generally safe and well tolerated in Phase 1 and Phase 2 clinical trials in >40 healthy subjects 
and 18 patients with familial amyloidotic cardiomyopathy and senile systemic amyloidosis 
(ALN-TTRSC-001; EudraCT 2012-004203-12; and ALN-TTRSC-002; EudraCT 
2013-002856-33).  Consistent and durable reduction in serum TTR levels of greater than 85% 
have been observed in healthy subjects and patients with TTR cardiomyopathy following SC 
administration with ALN-TTRSC.  An additional GalNAc siRNA conjugate-based study drug, 
ALN-AT3SC, is under investigation for the treatment of hemophilia A and B in an ongoing 
Phase 1 study (ALN-AT3SC-001, EudraCT 2013-003135-29).  Part A in healthy subjects has 
been completed.  ALN-AT3SC was considered safe and well tolerated and a dose of 0.03 mg/kg 
showed an approximately 25% reduction of antithrombin.  Part B of this study is ongoing. 
1.7. 
Study Rationale 
The objective of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), and PD 
of subcutaneously administered ALN-CC5 as a single-ascending dose (SAD) and 
multiple-ascending dose (MAD) to healthy adult subjects, and multiple doses (MD) to patients 
with PNH.  ALN-CC5 is comprised of an siRNA formulated in water for injection.  The siRNA 
is a chemically synthesized double-stranded oligonucleotide covalently linked to a ligand 
containing GalNAc residues.  This synthetic investigational RNAi therapeutic has been designed 
to downregulate the C5 mRNA in the liver, thereby reducing levels of circulating C5 protein and 
resulting in inhibition of terminal complement pathway activity and prevention of the formation 
of the MAC.  As a result, complement-mediated intravascular hemolysis of RBCs in PNH may 
be reduced.  Cumulatively, literature data regarding treatment of PNH with eculizumab, robust 
nonclinical data with ALN-CC5, and prior and ongoing clinical experience with other RNAi 
therapeutics in humans, suggests ALN-CC5 will have a favorable risk profile in the intended 
populations and supports the initial clinical development of ALN-CC5. 
1.8. 
Rationale for Dose Selection 
 
 
 
   
 
 
 
 
 
  
 
 
 

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Table 4:  
Estimated NOAEL and Starting Dose Safety Margins 
Species 
Estimated 
NOAEL 
Safety margin for planned starting 
 
Based on Body 
Weight 
Based on Body 
Surface Area
a 
 
 
 
 
 
 
 
 
 
Abbreviation:  NOAEL = no observed adverse effect level. 
a Body surface area margin calculated using species scaled conversion assumptions outlined in 
Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for 
Therapeutics in Adult Healthy Volunteers 
[http://wwwfda.gov/downloads/Drugs/Guidances/UCM078932.pdf].  
 
 
 
 
 
 
 
 
 
 
 
1.9. 
Potential Risks and Benefits 
1.9.1. 
Potential Benefits 
In the blinded part of the study, study drug will be administered to healthy subjects for research 
and development purposes.  Subjects receiving study drug will experience no medical benefit 
except for a health examination and a vaccination program against meningococcal infection.  The 
open-label multiple-dose part of the study will include PNH patients, either naïve to 
complement-directed treatment or currently on stable eculizumab treatment who may benefit 
from ALN-CC5 treatment. 
1.9.2. 
Potential Risks 
1.9.2.1. Serious Meningococcal Infections 
The potential clinical risks associated with administration of ALN-CC5 related to reduction of 
C5 activity can be extrapolated from the known safety profile of eculizumab [20].  ALN-CC5 is 
considered to have a similar clinical impact as that observed with eculizumab in that a reduction 
in C5 activity in plasma is anticipated.  Clinical study evidence with eculizumab has shown that 
meningococcal infections are the most common adverse reactions experienced by patients 
receiving treatment for complement-mediated diseases. 

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Administration of a C5 inhibitor increases susceptibility to meningococcal infections (septicemia 
and/or meningitis).  Life-threatening and fatal meningococcal infections have occurred in 
patients treated with eculizumab.  As of November 2011, there have been 18 reported cases of 
Neisseria meningitides among patients treated with eculizumab, 3 from clinical studies and 
15 during post-marketing experience [22]; however, the rate of meningococcal infections has not 
changed from clinical study experience and throughout post-marketing experience (less than 
0.5 cases per 100 patients) [22].  
The first case in a clinical study occurred in an unvaccinated, non-PNH patient before the 
initiation of the current risk management plan.  All other 17 patients who developed a 
meningococcal infection were vaccinated with a meningococcal vaccine according to local 
availability.  Eight of these patients received a tetravalent vaccine (Menactra
®, Menomune®, or 
Meningovax®), 6 received a vaccine covering either Neisseria subtype C or A/C, and 3 patients 
received an unknown vaccine type.  Thirteen of the 18 patients who developed infections 
underwent subtyping of Neisseria meningitides.  The predominant subtype was B (7 patients), a 
serotype not covered by the vaccines available at that time.  One patient had an infection caused 
by subtype C.  Another patient had an infection caused by subtype Y.  These 2 infections 
occurred in patients who were vaccinated with Menactra
®, which includes both serotypes in the 
target coverage [22].  
Fourteen of these 18 patients with meningococcal infection fully recovered.  One patient who 
was not vaccinated recovered with neurological sequelae and there were 3 meningococcal 
infection-related fatalities in patients with PNH.  Two of these patients had received a bivalent 
meningococcal vaccine and 1 patient had received a tetravalent vaccine.  Fatal infections were 
due to Neisseria meningitides type B in 2 patients and type X in 1 patient.  (In this study, the risk 
of infection by serotype X is minimized by excluding patients who travelled to Saudi Arabia or 
Africa within 90 days of screening, or who plan to do so during the study.)  The time from the 
beginning of eculizumab treatment to the start of infection was 5 months in 2 patients and 
10.5 months in 1 patient.  Of the 18 patients who developed meningococcal infection, 6 remained 
on eculizumab without further adverse reactions, 9 discontinued eculizumab, and information is 
unavailable for the remaining 3 patients [22].   
Vaccination against Streptococcus pneumonia (ie, pneumococcal polysaccharide vaccine 
[pnuemovax II®]) is not required for patients in this study.  Terminal complement deficiency 
(eg, C5 deficiency) is associated with susceptibility to Neisseria meningitides infections; 
whereas, risk of infections with encapsulated bacteria is not increased.  In contrast, deficiency of 
complement proteins more proximal in the complement cascade (eg, complement C3) are known 
to be associated with increased frequency of infections with encapsulated bacteria. 
1.9.2.2. Allergic Reactions and Injection Reactions  
Administration of ALN-CC5 may result in hypersensitivity reactions and/or injection site 
associated reactions.  Subjects will be closely monitored during and after study drug 
administration for symptoms of anaphylaxis and other hypersensitivity reactions, including 
circulatory arrest and/or respiratory changes, urticaria, arthralgias, myalgias, and other signs of 
related reactions.  Adequate treatment will be immediately available.  Injection-associated 
adverse events (AEs) may occur; depending on type and severity, discontinuation of further 
injection(s) may be required.  Subjects will be informed of early symptoms and signs of 

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hypersensitivity reactions, including hives; swollen face, eyelids, lips, or tongue; or trouble with 
breathing, and instructed to contact the study physician immediately if they develop any of these 
symptoms. 
1.9.2.3. Vaccinations 
As with any vaccine, an anaphylactic event following administration of the vaccine may rarely 
occur.  Subjects will be closely monitored for allergic or any other reactions following 
vaccination.  Any signs of injection reactions and other hypersensitivity reactions will be treated 
according to the anaphylaxis algorithm [23].  For the full list of all side effects reported with the 
following products, refer to the individual summary of product characteristics. 
1.9.2.3.1. Meningococcal Group A, C, W-135, and Y Conjugate Vaccine 
The most common adverse reactions (≥10%) among adults who received Menveo® were
headache, nausea, myalgia, injection site reactions (ISRs; including injection site pain, injection 
site erythema, injection site induration), and malaise (refer to the product SmPC).  
1.9.2.3.2. Meningococcal Group B Vaccine 
The most common adverse reactions (≥10%) among adults who received Bexsero® were
headache, nausea, ISRs (including injection site pain, injection site swelling, injection site 
induration, and injection site erythema), malaise, myalgia, and arthralgia (refer to the product 
SmPC). 
1.9.2.4. Prophylactic Antibiotics 
Meningitis can be caused by 13 Neisseria meningitides serotypes.  The most common serotypes 
associated with this disease are:  A, C, W-135, Y, (ACWY) and B [20].  To mitigate the risk of 
infection beyond the 5 most common serotypes, healthy subjects will be treated with 
ciprofloxacin prophylaxis as in previously completed Phase 1 studies (ClinicalTrials.gov 
Identifier:  NCT02083666). 
Ciprofloxacin is a broad-spectrum antibiotic active against both gram-positive and gram-negative 
bacteria.  The safety of fluoroquinolones, including ciprofloxacin, is similar to that of other 
antibiotics.  Most adverse reactions are mild to moderate, but serious adverse events (SAEs) have 
occurred.  Fluoroquinolones became the most commonly prescribed class of antibiotics to adults 
in 2002 [21]. 
The most frequently reported drug-related events were nausea (2.5%), diarrhea (1.6%), abnormal 
liver function tests (1.3%), vomiting (1%), and rash (1%).  Other AEs occurred at rates of <1%.  
A United Kingdom (UK) medical care database reported that fluoroquinolone use was associated 
with a 1.9-fold increase in tendonopathy.  Resistance to ciprofloxacin and other fluoroquinolones 
may evolve rapidly, even during a course of treatment, although resistance to this antimicrobial 
drug in Neisseria meningitides is still rare.  In the United States, Neisseria meningitides seldom 
shows resistance to commonly used antibiotics [24].  Two cases of meningococcal disease 
caused by ciprofloxacin-resistant Neisseria meningitides have been reported in North America 
[25].  In addition, 3 Neisseria meningitides clinical isolates showing resistance to ciprofloxacin 
have been reported in France (1999), Australia (2000), and Spain (2003), and sporadic cases of 
resistance to ciprofloxacin have also been reported [26]. 

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Subjects who do not tolerate ciprofloxacin or develop persistent AEs considered related to the 
use of ciprofloxacin can be switched to another type of antibiotic at the discretion of the 
Investigator. 
1.9.3. 
Risk Mitigation Strategy 
Potential risks will be closely monitored as part of safety evaluations performed during the study.  
Risks to subjects will also be minimized by a maximum 4-fold increase in dose levels and the 
use of a sentinel dosing strategy at each dose level.  Additionally, a Safety Review Committee 
(SRC) will perform regular reviews (at predefined decision-making time points) of safety, 
tolerability, and available PD data collected during the study with the primary purpose of 
protecting the safety of subjects and patients participating in the study.   
The following additional risk mitigation strategies will be used in this study: 
Subjects and patients will be informed in detail of the early signs of infections, both
orally and in writing.
Healthy subjects will be closely monitored for early signs and symptoms of infections
and will be evaluated immediately if an infection is suspected.  Treatment with the
study drug will be discontinued if a serious infection is suspected.
Subjects and patients will be monitored every 28±7 days until serum complement 
activity is within the normal reference range as assessed by CAP ELISA if serum 
complement activity is below normal range at the last postdose follow-up visit or 
until the SRC makes a decision on a case-by-case basis to discontinue follow-up, 
whichever is sooner (see Section 3.5.3).  The decision cannot be made until after 
completion of the last postdose follow-up visit.
Subjects and patients will be issued a safety information card stating that they are
enrolled in a clinical trial involving ALN-CC5, which can lower the ability of the
immune system to fight infections, especially meningococcal infection, which
requires immediate medical attention.
Subjects and patients will be immunized against Neisseria meningitides
(see Section 10.1.8).
Subjects and patients (as specified in the protocol) will be treated with prophylactic
ciprofloxacin (according to standard practice at the clinical study sites; see
Section 10.1.9).
The following instructions for early recognition and management of meningitis will be included 
in the Informed Consent Form (ICF) and in the Study Manual/Procedures: 
Meningitis, and associated septicemia, is usually associated with fever, vomiting,
severe headache, non-blanching rash, dislike of bright light, confusion, and
somnolence.  Not all of these signs and symptoms will show at once and the illness
may progress over 1 or 2 days; however, they can develop rapidly, sometimes in a
matter of hours.  Subjects will be informed in detail about these signs and symptoms
in the ICF.

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 Rapid admission to hospital is the highest priority when meningococcal disease is 
suspected.  Chemoprophylaxis of IV/intramuscular broad spectrum antibiotic that 
crosses the blood-brain barrier for suspected meningococcal infections should be 
started immediately.  Detailed early recognition and management algorithms (such as 
those published by the British Infection Society and the Meningitis Research 
Foundation (http://www.meningitis.org/news-media/download-resources) will be 
included in the Study Manual/Procedures. 

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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
 To evaluate the safety and tolerability of SAD or MAD of ALN-CC5 when 
administered to healthy adult subjects and of MD in patients with PNH  
2.2. 
Secondary Objectives 
 To characterize the PK of ALN-CC5  
 To assess the PD effect of ALN-CC5 on levels of C5 protein and complement activity 
2.3. 
Exploratory Objectives 
 To assess the PD effect of ALN-CC5 on inhibition of hemolysis in subjects and in 
patients with PNH 
 
 
 
 
 To explore the PD effect of ALN-CC5 on lactate dehydrogenase (LDH) levels in 
patients with PNH 
 
 
 
 
 
 
 
 
 
 
 Eculizumab levels 
 
 
 
 
 
 
 

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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This study is designed to evaluate the safety, tolerability, PK, and PD of ALN-CC5 in a 
randomized, double-blind, placebo-controlled manner in healthy adult subjects and in an 
open-label manner in patients with PNH.  This multinational study will be conducted at up to 
6 clinical study centers in the following parts:   
Part A:  SAD phase in healthy adult subjects
Part B:  MAD phase in healthy adult subjects
Part C:  multiple-dose phase in patients with confirmed PNH, either naïve to
eculizumab treatment or on stable doses of eculizumab (as assessed by the
Investigator)
An SRC will perform regular reviews (at predefined decision-making time points) of safety, 
tolerability, and available PD data collected during the study with the primary purpose of 
protecting the safety of subjects and patients participating in this clinical study (see Section 3.5).  
Additionally, the planned study design may be modified in accordance with the adaptive features 
of the clinical study protocol (see Section 3.4). 
3.1.1. 
Single-ascending Dose Phase (Part A) 
Part A of the study will be performed in a randomized (3:1), placebo-controlled, double-blind 
design to assess SAD of ALN-CC5 in healthy subjects (Figure 1).  Study drug will be 
administered according to a sentinel dosing strategy (Section 4.1). 
Subjects will be screened from -90 to -2 days before study drug administration.  Eligible subjects 
will be admitted to the clinical study site on Day -1 to determine continued eligibility and for 
pretreatment assessments.  Subjects will be randomized on Day 0 and will receive a single dose 
of study drug.  Subjects will be discharged from the clinical study site following completion of 
the 24 hour postdose follow-up assessments.   
Subjects will return to the clinical study site on an outpatient basis at the time points in the 
Schedule of Assessments (Table 1) and PK table (Table 10) for safety, tolerability, PK, and PD 
monitoring through Day 70.  For subjects with serum complement activity below normal range at 
the last postdose follow up visit (Day 70), monitoring visits will occur until serum complement 
activity is within the normal reference range as assessed by CAP ELISA or until the SRC makes 
a decision on a case-by-case basis to discontinue follow-up, whichever is sooner (see 
Section 3.5.3).  The decision cannot be made until after completion of the last postdose 
follow-up visit.  The duration of follow up is based on PD data from nonclinical studies in NHP 
that demonstrated 
 
 

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Figure 1:  
Single-ascending Dose Phase (Part A) Flow Diagram 
3.1.2. 
Multiple-ascending Dose Phase (Part B) 
Part B of the study will be performed in a randomized (3:1), placebo-controlled, double-blind 
design to assess MAD of ALN-CC5 in healthy subjects (Figure 2).   
Subjects will be screened from -90 to -2 days before dose administration.  Eligible subjects will 
be admitted to the clinical study site on Day -1 to determine continued eligibility and for 
pretreatment assessments.  Subjects will be randomized on Day 0 and will receive an initial dose 
of study drug.  Subjects will be discharged from the clinical study site following the completion 
of the 24 hour postdose follow-up assessments.  Subjects will return to the clinical study site at 
the time points in the Schedules of Assessments (Table 2, Table 15, Table 16, Table 17, 
Table 18, and Table 19) and PK tables (Table 11 and Table 12) for study drug administration and 
safety, tolerability, PK, and PD monitoring over the treatment period and for postdose follow-up.  
For subjects with serum complement activity below normal range at the last postdose follow-up 
visit, monitoring visits will occur until serum complement activity is within the normal reference 
range as assessed by CAP ELISA or until the SRC makes a decision on a case-by-case basis to 
discontinue follow-up, whichever is sooner (see Section 3.5.3).  The decision cannot be made 
until after completion of the last postdose follow-up visit. 
Figure 2:  
Multiple-ascending Dose Phase (Part B) Flow Diagram 
3.1.3. 
Multiple Dose Phase (Part C) 
Part C of the study will be conducted in patients with PNH in an open-label design to assess 
multiple doses of ALN-CC5.  The start of Part C and the study drug dose will depend on SRC 
review of safety, tolerability, and available PD data from Part A and Part B (Figure 3
S c
 
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Safety and Tolerability Assessments
Pharmacokinetic Assessments
Pharmacodynamic Assessments
Pharmacodynamic Follow-up
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maximum of 3 cohorts, comprised of at least 4 patients each, will be enrolled in Part C.  Overall, 
patients in Part C will undergo a maximum of 39 weeks of ALN CC5 dosing.  
Patients will be screened from -90 to -2 days before dose administration.  Patients will have a 
consultation at the clinical study site on Day -1 to determine continued eligibility and for 
pretreatment assessments.  Patients will be admitted and dosed on Day 0.  Patients will be 
discharged from the clinical study site following the completion of the 24 hour postdose 
follow-up assessments.  Patients will return to the clinical study site at the time points in the 
Schedules of Assessments (Table 3, Table 20, Table 21, and Table 22) and PK tables (Table 13 
and Table 14) for study drug administration and for safety, tolerability, PK, and PD monitoring 
over the treatment period and for postdose follow-up.  For patients with serum complement 
activity below normal range at the last postdose follow-up visit, monitoring visits will occur until 
serum complement activity is within the normal reference range as assessed by CAP ELISA or 
until the SRC makes a decision on a case-by-case basis to discontinue follow-up, whichever is 
sooner (see Section 3.5.3).  The decision cannot be made until after completion of the last 
postdose follow-up visit. 
In Part C, ALN-CC5 may be administered at home between visits to the clinical study center by 
a home healthcare provider trained in the administration of ALN-CC5.  Patients will return to the 
clinical study center every other month for assessments; however, in between, visits can be 
completed by a home healthcare provider. 
After the last dose of study drug, eligible patients may transition to an open-label extension study 
immediately after administration of the last dose of study drug or obtain standard of care 
treatment. 
Figure 3:  
Multiple-dose Phase (Part C) Flow Diagram 
3.1.4. 
Optional Cohorts 
Screening and Consultation 
Period
(Day -90 to Day -1)
Dosing Period
Safety and Tolerability Assessments
Pharmacokinetic Assessments
Pharmacodynamic Assessments
Postdose Follow-up
Pharmacodynamic Follow-up
Based on the evaluation of safety, tolerability, and available PD data, it may be decided by the 
SRC that optional cohorts may be enrolled and dosed according to the same eligibility criteria 
and corresponding randomization scheme and sentinel dosing strategy detailed in Part A and 
Part B.  In both Part A and Part B, up to 3 exploratory cohorts (exploring additional dosing and 
dose regimens) may be added.  The dose levels for optional cohorts may be at intermediate dose 
levels compared to those administered in Part A and Part B, but will not exceed 900 mg and 
600 mg, respectively, provided the dose is considered safe and well-tolerated.   

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3.1.5. 
Treatment and Study Duration 
A single SC dose of study drug will be administered in Part A.  In Part B and Part C, 
respectively, study drug will be administered over a maximum of a 13 or a 39 week period.  It is 
anticipated that this study will last for a maximum of 3 years from screening through the last 
subject/patient, last visit.  End of study is defined as last subject/patient, last visit.  It is 
anticipated that the duration of study participation for a subject/patient will be 665 days (1 year 
and 10 months). 
3.2. 
Number of Subjects and Patients 
Up to 76 subjects will be enrolled in the study. 
 
Part A:  Up to 32 healthy adult subjects (including optional cohorts) 
 
Part B:  Up to 28 healthy adult subjects (including optional cohorts) 
 
Part C:  Up to 16 patients with PNH (approximately 8 patients on a stable dose of 
eculizumab as assessed by the Investigator) 
3.3. 
Treatment Assignment 
Study treatment will be assigned in a randomized, double-blind manner in a 3:1 ratio (ALN-CC5 
or placebo) in Part A and in Part B.  Part C is an open-label study design. 
3.4. 
Adaptive Study Design Feature 
The use of adaptive study design features will allow for the continuing development of the study 
as new data emerges; therefore, the study can be adjusted in accordance with the pre-specified 
areas, features, and limits listed in Table 5. 

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Table 5: Adaptive Study Design Areas, Features, and Limits 
Areas 
Features 
Limits 
A Dosing 
regimen 
1. Dosing regimens may be determined or 
adapted in accordance with safety and 
tolerability data collected up to the 
decision-making time point. 
2. The term dosing regimen includes: (1) the 
dose level administered, (2) the frequency 
of dosing, and (3) the duration of dosing 
(ie, number of doses administered).  
Accordingly, these can be adjusted 
individually or in combination. 
I. The starting dose for subjects in 
Part A will not exceed 50 mg. 
II. The starting dose for subjects in 
Part B will not exceed doses already 
evaluated and considered safe and 
tolerable in the Part A. 
III. Based on data from GLP toxicology 
studies (see Section 1.5) and provided 
no safety or tolerability concerns 
have occurred, a maximum single 
dose level of 900 mg may be 
administered. 
IV. The interval between doses in Part B 
may be increased or decreased, but 
the interval between doses will not be 
shorter than 7 days and not longer 
than 30 days. 
V. The Part B dosing regimen may 
include a higher first dose, and 
subsequent doses administered at a 
lower dose level.  The maximum dose 
level in Part B will not exceed 
600 mg. 
VI. Different dosing regimens may be 
investigated, but the total number of 
planned study subjects/patients 
cannot be exceeded. 
B Sentinel/ 
sub-
groups 
1. The number and size of 
sentinel/sub-groups within a dosing 
regimen may be adaptable.  
2. Dose levels may be split into additional 
sub-groups. 
I. Mandatory sentinel dosing will be 
performed in Part A.   
II. The sentinel group will consist of 
2 subjects on ALN-CC5 or placebo 
(applicable to Feature 1). 
III. The remainder of the doses at a given 
level during Part A can be 
administered after a minimum of 
24 hours has elapsed since dosing of 
the sentinel group. 
IV. The sentinel dosing strategy applied 
in Part A can be applied in Part B if 
deemed necessary by the SRC.  
C Overlap 
1. Dosing regimens may overlap. 
I. Protocol-specific minimum study 
progression/escalation requirements 
must be met before dose 
progression/escalation (see 
Section 4). 

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Table 5: Adaptive Study Design Areas, Features, and Limits 
Areas 
Features 
Limits 
D Flexible 
cohort 
sizes 
1. Withdrawn subjects can be replaced at the 
discretion of the Sponsor and Investigator 
if not withdrawn for safety reasons (see 
Section 5.3). 
2. Replacement subjects may be enrolled in 
an ongoing cohort, or dosed together as a 
group or separately. 
I. Protocol-specific minimum 
requirements must be met before dose 
escalation (see Section 4). 
II. No more than 10 subjects in total at 
the same site on the same day will be 
dosed at 1 time per clinical study site. 
E Optional 
cohorts 
1. Optional cohorts may be included to 
explore additional dosing regimens 
(applicable to Part A and Part B). 
I. Up to 3 optional cohorts may be 
included in Part A. 
II. Up to 3 optional cohorts may be 
included Part B. 
III. Cohort sizes will not exceed 
4 subjects for each optional cohort in 
Part A and Part B, not including 
replacement subjects. 
IV. Dosing in optional cohorts will 
follow the same randomization 
scheme as that in Part A and Part B. 
V. Safety, tolerability, PD, and/or PK 
may also be explored under the 
following scenarios in optional 
cohorts: 
 
Escalate or de-escalate to a lower 
and/or to an intermediate dose 
level(s) for administration 
 
Provided suspension or stopping 
rules have not been met, the SRC 
may permit a dose level to be 
repeated to further characterize the 
PD and/or PK of the study drug 
F Samples 
and 
assess-
ments 
1. The inpatient period may be prolonged for 
subjects/patients in all dose levels in all 
cohorts if considered by the Investigator 
clinically necessary.  Prolonged inpatient 
periods will be decided on a 
subject/patient, case-by-case basis and/or 
if the SRC considers it necessary for 
determining safety and tolerability for a 
future dose level cohort. 
I. A maximum extended inpatient 
period due to clinical concerns cannot 
be defined as the extension will be as 
long as necessary to ensure the safety 
of the subjects/patients. 
1. Additional blood and urine samples for 
safety analysis may be obtained. 
I. A maximum number of blood 
samples cannot be defined as 
investigations will be performed as 
necessary to ensure the safety of the 
individual subjects; however, the 
maximum blood volume stated in this 
protocol will not be exceeded (see 
Section 10.1.6). 
2. Timing of safety assessments (eg, vital 
I. Changes to the timing of safety 

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Table 5: Adaptive Study Design Areas, Features, and Limits 
Areas 
Features 
Limits 
signs, 12-lead ECGs, etc.) may be 
adjusted in accordance with evolving 
data. 
3. Additional safety assessments (eg, vital 
signs, 12-lead ECGs, etc.) may be 
performed in accordance with evolving 
data and dosing schedule. 
assessments must be a reflection of 
the established safety and tolerability 
profile up to the decision-making 
time point (applicable to Features 1 
and 2) 
II. Changes to the timing of safety 
assessments must be made in the 
spirit of the current study protocol (ie, 
focus on the capture of essential and 
useful data) and not affect the risk 
profile of the study drug (applicable 
to Features 1 and 2). 
1. Specialist referrals (eg, hematologist, 
immunologist, etc.) may be made if 
considered clinically necessary by the 
Investigator, delegate, Sponsor, or SRC 
for subjects/patients on a case-by-case 
basis. 
I. A maximum number of specialist 
referrals for subjects/patients will be 
determined on a case-by-case basis 
and cannot be defined as the 
evaluations will be performed as 
necessary to ensure the safety of 
subjects/patients. 
1. Timing of PK and/or PD samples (blood 
and/or urine) may be adjusted in 
accordance with evolving data and 
dosing schedule/regimen. 
2. Additional or fewer PK and/or PD 
samples (blood and/or urine) may be 
obtained in accordance with evolving data 
and dosing schedule. 
I. Maximum blood volume stated in the 
protocol will not be exceeded (see 
Section 10.1.6). 
II. Optional PK and/or PD analysis can 
be performed at any stage during or 
after the study to facilitate 
decision-making and/or to increase 
understanding of the compound (ie, 
samples will be obtained, but not 
necessarily analyzed) (applicable to 
Features 1 and 2). 
III. The optional analysis is limited to the 
protocol-specified purpose 
(applicable to Features 1 and 2). 
1. Except for subjects that have been 
randomized, screening assessments 
performed at the clinical study center on 
subjects for another study can be used 
for this study to avoid unnecessary tests. 
I. The assessments must meet protocol 
criteria (eg, the method to be used). 
II. The assessments must be performed 
within the protocol screening 
window. 
Abbreviations:  ECG = electrocardiogram; GLP = Good Laboratory Practice; PD = pharmacodynamic; 
PK = pharmacokinetic; SRC = Safety Review Committee. 
 

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3.5. 
Safety Review Committee 
3.5.1. 
Primary Responsibility 
An SRC will perform regular reviews (at predefined decision-making time points) of safety, 
tolerability, and available PD data collected during the study with the primary purpose of 
protecting the safety of subjects and patients participating in the study.  The planned study design 
may be modified in accordance with the adaptive features of the clinical study protocol (see 
Section 3.4). 
3.5.2. 
Membership 
To ensure timely safety, tolerability, and available PD information exchange across the 
participating clinical study sites, the SRC will be comprised of the following members: 
 Investigator(s) or designee(s) at each clinical study site  
 Alnylam Medical Monitor 
 Study Medical Monitor 
 Independent hematologist 
Further internal or external experts may be consulted by the SRC as necessary.  The membership 
of the SRC and reporting structure are defined in the SRC Charter.   
3.5.3. 
Timing and Purpose of Review Meetings 
The SRC will convene to review safety, tolerability, and available PD data at predefined 
decision-making time points (see Section 4) or when progression/escalation and dose 
suspension/stopping rules are met to ensure the acceptability of continued dosing, and/or dose 
escalation to subsequent cohorts, and/or the transition from Part A to Part B, or from Part B to 
Part C.  In addition, there is an option for ad hoc SRC meetings to discuss safety and tolerability 
issues. 
If any progression/escalation and dose suspension/stopping rules are met and deemed to have a 
reasonable possibility of causal relationship with the study drug (see Section 10.4.1), the SRC 
will act in accordance with the rules stipulated in Section 4.4. 
The SRC will determine dose escalations, dose de-escalation, and/or cohort progressions 
according to the clinical study protocol, planned doses, and adaptive study features (see 
Section 3.4). 
To balance the health risks of slightly reduced complement activity with the risks of long-term 
ciprofloxacin use, the SRC will also determine whether study follow-up and prophylactic 
ciprofloxacin treatment will be discontinued in subjects or patients with complement activity 
below the normal range.  The decision cannot be made until after completion of the last postdose 
follow-up visit. 
Decision of the SRC should reflect unanimity wherever possible.  SRC decisions will be 
documented and archived in the Trial Master File (TMF).  The minutes will document clearly 
any questions posed and decisions reached. 

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All data and reports provided to and reviewed by the SRC, including minutes and decisions from 
the meetings will be archived in the TMF.  
3.5.4. 
Data Requirements 
Before SRC review, clinical study site Investigators or designees will prepare a report presenting 
the following safety, tolerability, and available PD data.  More detailed information on the 
content of such reports can be found in the SRC Charter. 
3.5.4.1. Safety Data 
The following data will be provided and reviewed: 
 AEs (including ISRs) 
 Concomitant medications 
 Vital signs (oral body temperature, blood pressure, heart rate, and respiration rate)  
 12-lead ECGs 
 Physical examinations (full and directed)  
 Clinical laboratory parameters (hematology, biochemistry, coagulation, and 
urinalysis) 
3.5.4.2.  Pharmacodynamic Data 
When available, the plasma concentration of C5 protein and serum complement activity will also 
be evaluated for assessment of PD effect (see Section 9.1) 
3.5.4.3. Pharmacokinetic Data 
Dose progression/escalation will be based on the evaluation of safety, tolerability, and available 
PD data, for dose levels administered in previous cohorts, rather than exposure to study drug (see 
Section 4.4). 

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4. 
CRITERIA FOR STUDY DRUG DOSING AND DOSE 
PROGRESSION/ESCALATION 
4.1. 
Study Drug Dosing and Progression/Escalation in Part A 
Subjects in each cohort will be randomized in a 3:1 ratio (ALN-CC5:placebo) in a double-blind, 
placebo-controlled manner.  Study drug will be administered according to a sentinel dosing 
strategy.  The first sentinel subject in each cohort will receive study drug (ALN-CC5 or placebo) 
followed by an approximately 24 hour safety follow-up.  The second sentinel subject in each 
cohort will then receive study drug (ALN-CC5 or placebo) followed by an approximately 24 
hour safety follow-up, after which the remaining subjects in the cohort will be dosed. 
After dosing all subjects in the cohort, the SRC will review a minimum of 21 days postdose 
safety, tolerability, and available PD data from all subjects in that cohort before dose escalation 
to the following cohort.  Based on nonclinical evaluation of ALN-CC5 PD, pharmacologic 
toxicity and on-target PD effect can be evaluated 21 days after single dose administration of 
ALN-CC5. 
The starting dose for subjects in Cohort 1 will be 50 mg of study drug (ALN-CC5 or placebo).  
The following are the planned dose levels for subsequent cohorts in Part A; however, the actual 
dose administered will be determined by the SRC: 
 Cohort 2:  200 mg  
 Cohort 3:  400 mg  
 Cohort 4:  600 mg  
 Cohort 5:  900 mg  
 Optional cohorts 6, 7, and 8:  Exploring additional dose and/or dose regimens 
The highest dose administered in Part A will not exceed 900 mg. 
4.2. 
Study Drug Dosing and Progression/Escalation in Part B 
Dosing in Part B, Cohort 1 may initiate 48 hours after SRC confirmation of safety, tolerability, 
and available PD data from the fourth subject dosed in Part A, Cohort 3.  Dosing in each cohort 
in Part B will begin at a dose that is no greater than the highest safe and tolerated dose explored 
in Part A.   
Subjects in each cohort will be randomized 3:1 (ALN-CC5:placebo) in a double-blind, 
placebo-controlled manner.  All subjects in a cohort may be dosed on the same day.  After 
dosing all subjects in the cohort, the SRC will review a minimum of 35 days postdose safety, 
tolerability, and available PD data from all subjects in that cohort before dose escalation to the 
following cohort.  Based on nonclinical evaluation of ALN-CC5 PD, pharmacologic toxicity and 
on-target PD effect can be evaluated 35 days after multiple-dose administration of ALN-CC5. 

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The following are the anticipated dose levels for subsequent cohorts in Part B; however, the 
actual dose administered will be determined by the SRC: 
 Cohort 1:  50 mg 
 Cohort 2:  200 mg 
 Cohort 3:  400 mg 
 Cohort 4:  600 mg 
 Optional cohorts 5, 6, and 7:  Exploring additional dose and/or dose regimens 
The highest dose administered in Part B will not exceed 600 mg.  If recommended by the SRC, 
weekly, once every 2 weeks, or monthly dosing regimens may be investigated.  Patients in Part B 
will receive a maximum of 13 weeks of study drug dosing. 
4.3. 
Study Drug Dosing and Regimen Modifications in Part C 
Part C will be initiated if the SRC, based on their expert clinical experience in treating PNH 
patients, determines that the safety, tolerability, and available PD (C5 levels and complement 
activity) data derived from Part A and Part B is clinically meaningful and the risk-benefit 
assessment is favorable. 
Figure 4 illustrates the cohort enrollment and dose and dosing regimen modification plan for 
Part C.  A maximum of 3 cohorts, comprised of at least 4 patients each, will be enrolled.  The 
SRC will meet at regular intervals (approximately every 8 weeks) to review ongoing safety, 
tolerability, and available PD data from Part B and Part C to recommend cohort initiation and to 
determine the dose and dosing regimen to be administered to all patients in a cohort or all 
patients in Part C.  During the dosing period, the SRC may also recommend the ALN-CC5 dose 
and regimen be modified for all patients, based on the degree of complement inhibition and 
clinically meaningful suppression of intravascular hemolysis as evaluated by LDH (Part C only).  
Part C does not include sentinel dosing.   
Dosing in Cohort 1 may initiate after SRC review of data from Part A and Part B at a dose no 
greater than the highest safe and tolerated dose explored in Part B.  Initially, 13 weekly doses of 
ALN-CC5 will be administered.  After completing the 13 week dosing period, patients in 
Cohort 1 may transition to extended dosing on a modified regimen provided the Day 140/ET 
study visit has not been completed; these patients will resume ALN-CC5 administration at a dose 
and regimen recommended by the SRC. 
Dosing in Cohort 2 may initiate after SRC review of data from subjects in Part B, Cohorts 4, 5, 
and 6, who completed ≥10 weeks of dosing.  Additionally, dosing in Cohort 2 may initiate after 
SRC confirmation that clinically meaningful suppression of intravascular hemolysis (evaluated 
by LDH levels) has occurred in at least 4 patients in Part C, Cohort 1, who completed ≥8 weeks 
of dosing.  Initially, ALN-CC5 will be administered once weekly for 5 doses. 
Dosing in Cohort 3 may initiate to further explore dose and dosing regimens after ≥4 patients in 
Part C, Cohort 2 complete ≥13 weeks of dosing data have been evaluated by the SRC.  Initially, 
ALN-CC5 will also be administered once weekly for 5 doses. 

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For the purpose of this protocol, the term ‘dose escalation’ is defined as progression or escalation 
to the next consecutive dose in line with the dose progression/escalation rules and minimum data 
requirements described in Section 4.4.1. 
For the purpose of this protocol, the term ‘suspension’ is defined as no further study drug will be 
administered at the dose level and that further dose escalation/progression will be suspended.  If 
a dose level is suspended, an ad hoc SRC meeting will be held.  Any resumption at the same or a 
higher dose level will require a substantial amendment, which will need to be approved by the 
Regulatory Authority and the Research Ethics Committee (REC).   
For the purpose of this protocol, the term ‘extension’ is defined as increasing the number of 
subjects or patients in a cohort; however, the overall total number of planned subjects in the 
study will not increase. 
Dose progression/escalation will be based on dose levels administered in previous cohorts with 
an acceptable safety and tolerability profile, rather than exposure, and no PK exposure limit has 
been set for this study.  This is based on the following rationale: 
 There is no expected on-target toxicity associated with C5 reduction.  Following 
vaccination of study participants, use of antibiotic prophylaxis and additional safety 
precautions; the risk of Neisseria infections is considered manageable (see 
Section 1.9.3). 
 PK data will not be used to justify dose escalation or to select dose levels for 
administration during the study.  There have not been any PK-related toxicities 
observed during nonclinical studies.  Additionally, nonclinical studies indicate that 
ALN-CC5 is rapidly eliminated from plasma (see IB). 
Table 6:  
Study Progression/Escalation Flow Chart 
Decision-making time points 
 
Part A: 
21 days after the last subject in a cohort is dosed with study drug 
 
Part B: 
35 days after the last subject in the cohort received the first dose of 
study drug 
Decision-making process 
 
SRC 
 
Double-blind data (blinded review) 
 
Documentation of decision via meeting minutes 
Minimum data reviewed at each decision-making time point 
 
4 subjects per cohort 
 
Safety data 
 
PD data (available) 

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Dependencies following data reviewed at each decision-making time point 
 
Part A to Part B:  Dosing in Part B, Cohort 1 may initiate 48 hours after 
confirmation of safety, tolerability, and available PD data from 
the fourth subject dosed in Part A, Cohort 3 
 
Part B to Part C: C5 shows a degree of suppression consistent with complement 
inhibition (as determined by SRC in Part A and Part B) 
4.4.1. 
Cohort Progression/Escalation and Suspension/Stopping Rules 
Cohort progression/escalation and study suspension/stopping rules are described in Table 7.  
Dose progression/escalation will proceed according to the adaptive study design features 
described in Table 5 and will be limited by whether progression/escalation and dose 
suspension/stopping rules are met. 
Standard toxicity grading according to the Common Terminology Criteria for Adverse Events 
(CTCAE; Version 4.0) will be used to grade AEs (see Section 10.4.2).  These are the most 
comprehensive criteria available and have proven useful in early phase studies.   
Abnormal laboratory and other tests should always be repeated before grading in order to ensure 
consistency and to exclude technical errors.  If applicable, diurnal variations in laboratory 
parameters and other measurements as well as baseline status should be taken into account when 
assessing whether abnormal laboratory values constitute a drug-related AE and when grading 
AEs. 

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Table 7: Cohort Progression/Escalation and Suspension/Stopping Rules for Part A and 
Part B 
AE 
Grade 
Severity/ 
Seriousness Reversibility 
Number of 
Subjects Affected Action 
Effect on Dose 
Progression or 
Escalation 
I 
Mild 
N/A 
N/A 
Next dose 
determined by 
SRC 
N/A 
II 
Moderate 
Showing signs 
of reversibility  
≤2 subjects in 
different SOC 
Next dose 
determined by 
SRC 
N/A 
2 subjects in same 
SOC 
Dose level may 
continue or be 
extended  
Following 
continuation or 
extension, dose 
escalation may 
proceed as per 
clinical study 
protocol 
≤3 subjects in 
different SOC 
Dose escalation  
on hold until 
results of 
continuation or 
extension are 
available 
≥3 subjects in same 
SOC 
Dose level 
suspended 
A lower 
(intermediate) dose 
level may be 
administered in the 
next cohort  
≥4 subjects in 
different SOC 
Dose continuation, 
extension, or 
escalation requires 
substantial 
amendment 
Showing no 
signs of 
reversibility  
≥2 subjects 
Dose level 
suspended 
A lower 
(intermediate) dose 
level may be 
administered in the 
next cohort  
Dose continuation, 
extension or 
escalation requires 
substantial 
amendment 
III 
Severe, not 
serious 
Showing 
signs of 
reversibility  
1 subject 
Dose level may 
continue or be 
extended 
Following 
continuation or 
extension, dose 
escalation may 
proceed as per the 
clinical study 
protocol 
Dose escalation on 
hold until results 
of continuation or 
extension are 
available 

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Table 7: Cohort Progression/Escalation and Suspension/Stopping Rules for Part A and 
Part B 
AE 
Grade 
Severity/ 
Seriousness Reversibility 
Number of 
Subjects Affected Action 
Effect on Dose 
Progression or 
Escalation 
 
Showing 
signs of 
reversibility  
≥2 subjects 
 
Dose level 
suspended 
A lower 
(intermediate) dose 
level may be 
administered in the 
next cohort  
Dose continuation, 
extension or 
escalation requires 
substantial 
amendment 
Showing no 
signs of 
reversibility 
≥1 subject 
Dose level 
suspended 
A lower 
(intermediate) dose 
level may be 
administered in the 
next cohort 
Dose continuation, 
extension or 
escalation requires 
substantial 
amendment 
Severe, 
serious 
N/A 
≥1 subject 
Dose level 
suspended 
A lower 
(intermediate) dose 
level may be 
administered in the 
next cohort 
Dose continuation, 
extension or 
escalation requires 
substantial 
amendment 
IV 
Life-
threatening N/A 
≥1 subject 
Study suspended 
Study 
continuation 
requires 
substantial 
amendment 
V 
Fatal 
N/A 
≥1 subject 
Study suspended 
Study 
continuation 
requires 
substantial 
amendment 
Abbreviations:  AE = adverse event; N/A = not applicable; SOC = System, Organ, Class; SRC = Safety Review 
Committee. 
 

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4.4.2. 
Individual Patient Progression/Escalation and Suspension/Stopping Rules in 
Part C 
Individual progression rules for Part C are presented in Table 8.  These rules apply to study 
drug-related AEs and SAEs in individual patients enrolled in Part C only; rules do not apply to 
subjects in Part A and Part B of the study. 
Table 8:  
Individual Progression Rules for Part C Only 
AE Grade Severity/Seriousness Action 
I 
Mild 
No action required. 
II 
Moderate 
Study drug administration may continue at the same 
or a lower (intermediate) dose if the SRC considers it 
safe for the patient. 
III 
Severe, not serious 
Study drug administration may continue at a lower 
(intermediate) dose if the SRC considers it safe for the 
patient. 
Severe, serious 
Study drug administration will be discontinued. 
IV 
Life-threatening 
V 
Fatal 
Abbreviations:  AE = adverse event; SRC = Safety Review Committee. 

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5. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1. 
Inclusion Criteria 
5.1.1. 
Inclusion Criteria for all Subjects in Part A and Part B 
1. Male and female subjects aged 18 to 45 years, inclusive. 
2. 12-lead ECG within normal limits or with no clinically significant abnormalities in the 
opinion of the Investigator. 
3. Body mass index (BMI) ≥18.0 kg/m2 and ≤30 kg/m2. 
4. Systolic blood pressure ≤140 mmHg and a diastolic blood pressure of ≤90 mmHg after 
10 minutes supine rest. 
5. Female subjects of childbearing potential agreeing to use one of the acceptable methods 
of contraception listed below from the time of signing the informed consent until 
5 months following administration of the last dose of study medication: 
 The subject’s male partner has undergone documented vasectomy with 
documentation of azoospermia (male sterilization) and the use of a barrier method 
(condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal 
foam/gel/film/cream/suppository). 
 A documented placement of an intrauterine device (IUD) or intrauterine system (IUS) 
and the use of a barrier method (condom or occlusive cap [diaphragm or 
cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository). 
 Oral contraceptives (combination estrogen/progesterone pills), injectable 
progesterone, or subdermal implants and the use of a barrier method (condom or 
occlusive cap [diaphragm or cervical/vault caps] used with spermicidal 
foam/gel/film/cream/suppository). 
 Documented tubal ligation (female sterilization).  In addition, a barrier method 
(condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal 
foam/gel/film/cream/suppository). 
 True abstinence:  When this is in line with the preferred and usual lifestyle of the 
subject, including female subjects with same sex partners.  Periodic abstinence (eg, 
calendar, ovulation, symptothermal, post ovulation methods) and withdrawal are not 
acceptable methods of contraception.  Abstinent subjects have to agree to use one of 
the above-mentioned contraceptive methods, if they start sexual relationships during 
the study and for up to 5 months after the last dose of study drug. 
6. Male subjects agreeing to use acceptable methods of contraception if the male subject’s 
partner could become pregnant from the time of the first administration of study 
medication until 5 months following administration of the last dose of study medication.  
One of the following acceptable methods of contraception must be utilized: 

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 Surgical sterilization (vasectomy with documentation of azoospermia) and a barrier 
method (condom or occlusive cap [diaphragm or cervical/vault caps] used with 
spermicidal foam/gel/film/cream/suppository). 
 The subject’s female partner uses oral contraceptives (combination 
estrogen/progesterone pills), injectable progesterone, or subdermal implants and a 
barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used 
with spermicidal foam/gel/film/cream/suppository). 
 The subject’s female partner uses medically prescribed topically-applied transdermal 
contraceptive patch and a barrier method (condom or occlusive cap [diaphragm or 
cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository). 
 The subject’s female partner has undergone documented tubal ligation (female 
sterilization).  In addition, a barrier method (condom or occlusive cap [diaphragm or 
cervical/vault caps] with spermicidal foam/gel/film/cream/suppository) must be used. 
 The subject’s female partner has undergone documented placement of an IUD or IUS 
and the use of a barrier method (condom or occlusive cap [diaphragm or 
cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository). 
 True abstinence:  When this is in line with the preferred and usual lifestyle of the 
subject, including male subjects with same sex partners.  Periodic abstinence (eg, 
calendar, ovulation, symptothermal, post ovulation methods) and withdrawal are not 
acceptable methods of contraception.  Abstinent subjects have to agree to use one of 
the above-mentioned contraceptive methods, if they start sexual relationships during 
the study and for up to 5 months after the last dose of study drug. 
7. Vaccinated against Neisseria meningitides with meningococcal group ACWY conjugate 
vaccine and meningococcal group B vaccine and confirmed seroconversion to ACWY on 
Day -1. 
8. Willing to comply with protocol-required visit schedule and visit requirements and 
provide written informed consent. 
9. Light smokers and users of nicotine (defined as the equivalent of 10 cigarettes per day) or 
nonsmokers and non-users of nicotine for at least 90 days before screening. 
5.1.2. 
Inclusion Criteria for all Patients in Part C 
1. Adults aged minimum 18 years at screening. 
2. Granulocyte and monocyte PNH clone >1% as documented by medical records. 
3. LDH ≥1.5 ULN in the absence of eculizumab.  If on stable eculizumab therapy, as 
assessed by the Investigator, patients must have historical laboratory values documenting 
elevated LDH levels before administration of the first dose of eculizumab. 
4. Female patients of childbearing potential agreeing to use one of the acceptable methods 
of contraception listed below from the time of signing the informed consent until 
5 months following administration of the last dose of study medication: 

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 The subject’s male partner has undergone documented vasectomy with 
documentation of azoospermia (male sterilization) and the use of a barrier method 
(condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal 
foam/gel/film/cream/suppository). 
 A documented placement of an IUD or IUS and the use of a barrier method (condom 
or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal 
foam/gel/film/cream/suppository). 
 Oral contraceptives (combination estrogen/progesterone pills), injectable 
progesterone, or subdermal implants and the use of a barrier method (condom or 
occlusive cap [diaphragm or cervical/vault caps] used with spermicidal 
foam/gel/film/cream/suppository). 
 Documented tubal ligation (female sterilization).  In addition, a barrier method 
(condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal 
foam/gel/film/cream/suppository). 
 True abstinence:  When this is in line with the preferred and usual lifestyle of the 
patient, including female subjects with same sex partners.  Periodic abstinence (eg, 
calendar, ovulation, symptothermal, post ovulation methods) and withdrawal are not 
acceptable methods of contraception.  Abstinent patients have to agree to use one of 
the above-mentioned contraceptive methods, if they start sexual relationships during 
the study and for up to 5 months after the last dose of study drug. 
5. Male patients agreeing to use acceptable methods of contraception if the male patient’s 
partner could become pregnant from the time of the first administration of study 
medication until 5 months following administration of the last dose of study medication.  
One of the following acceptable methods of contraception must be utilized: 
 Surgical sterilization (vasectomy with documentation of azoospermia) and a barrier 
method (condom or occlusive cap [diaphragm or cervical/vault caps] used with 
spermicidal foam/gel/film/cream/suppository). 
 The patient’s female partner uses oral contraceptives (combination 
estrogen/progesterone pills), injectable progesterone, or subdermal implants and a 
barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used 
with spermicidal foam/gel/film/cream/suppository). 
 The patient’s female partner uses medically prescribed topically-applied transdermal 
contraceptive patch and a barrier method (condom or occlusive cap [diaphragm or 
cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository). 
 The patient’s female partner has undergone documented tubal ligation (female 
sterilization).  In addition, a barrier method (condom or occlusive cap [diaphragm or 
cervical/vault caps] with spermicidal foam/gel/film/cream/suppository) must be used. 
 The patient’s female partner has undergone documented placement of an IUD or IUS 
and the use of a barrier method (condom or occlusive cap [diaphragm or 
cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository). 

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 True abstinence:  When this is in line with the preferred and usual lifestyle of the 
patient, including male subjects with same sex partners.  Periodic abstinence (eg, 
calendar, ovulation, symptothermal, post ovulation methods) and withdrawal are not 
acceptable methods of contraception.  Abstinent patients have to agree to use one of 
the above-mentioned contraceptive methods, if they start sexual relationships during 
the study and for up to 5 months after the last dose of study drug. 
6. Willing to comply with protocol-required visit schedule and visit requirements and 
provide written informed consent. 
7. Vaccinated against Neisseria meningitides according to standard practice at the clinical 
study site. 
5.2. 
Exclusion Criteria 
5.2.1. 
Exclusion Criteria for all Subjects in Part A and Part B 
1. Any uncontrolled or serious disease, or any medical or surgical condition, that may either 
interfere with participation in the clinical study and/or put the subject at significant risk 
(according to Investigator
's judgment) if he/she participates in the clinical study. 
2. A known underlying disease, or surgical or medical condition that, in the opinion of the 
Investigator, may interfere with interpretation of the clinical study results. 
3. Active serious mental illness or psychiatric disorder, including, but not limited to, 
schizophrenia, bipolar disorder, or severe depression requiring current pharmacological 
intervention. 
4. Clinically significant illness within the 7 days before administration of the first dose of 
study drug. 
5. Alanine aminotransferase (ALT) or aspartate aminotransferase above normal range; total 
bilirubin, alkaline phosphatase, or albumin outside the reference range and considered 
clinically relevant in the opinion of the Investigator at screening and Day -1. 
6. Complete blood count (CBC) clinical laboratory results that are considered clinically 
relevant and unacceptable by the Investigator at screening and Day -1. 
7. International normalized ratio above the reference range at the Screening visit. 
8. Complement activity below normal reference range as evaluated by CAP ELISA. 
9. Known or suspected hereditary asymptomatic complement deficiency. 
10. Any other clinical safety laboratory result considered clinically significant and 
unacceptable by the Investigator. 
11. Clinical laboratory evidence or clinical diagnosis of human immunodeficiency virus 
(HIV) infection, hepatitis C virus (HCV) infection, or chronic hepatitis B virus (HBV) 
infection (as shown by hepatitis B surface antigen [HBsAg] positivity). 
12. Positive screen for alcohol or drugs of abuse at screening and Day -1 and consume more 
than 14 (female) or 21 (male) units of alcohol a week (unit: 1 glass of wine [125 mL] = 
1 measure of spirits = ½ pint of beer). 

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13. History or clinical evidence of alcohol abuse, within the 12 months before screening.  
Alcohol abuse is defined as regular weekly intake of more than 21 units for males and 14 
units for females (using alcohol tracker 
http://www.nhs.uk/Tools/Pages/NHSAlcoholtracker.aspx). 
14. History or clinical evidence of drug abuse, within the 12 months before screening.  Drug 
abuse is defined as compulsive, repetitive, and/or chronic use of drugs or other 
substances with or without problems related to their use and/or where stopping or a 
reduction in dose will lead to withdrawal symptoms. 
15. Donated more than 500 mL of blood within 90 days before the first dose of study drug. 
16. Received an investigational agent (including complement C5 inhibitors) within 90 days 
before the first dose of study drug or are in follow-up of another clinical study. 
17. Used prescription medications within 14 days or 7 half-lives (whichever is longer) of 
administration of the first dose of study drug. 
18. Used over-the-counter (OTC) medication, excluding routine vitamins, within 7 days 
before the first dose of study drug, unless determined by the Investigator and Sponsor to 
be not clinically relevant, and unlikely to impact on study outcomes. 
19. History of intolerance to SC injection or relevant abdominal scarring (surgical, burns, 
etc.). 
20. History of meningococcal infection. 
21. History of vaccinations with evidence of insufficient immunizations. 
22. History of significant recurrent infections in the opinion of the Investigator or delegate. 
23. Presence or suspicion of active viral, bacterial, fungal, or parasitic infection including 
herpes, herpes zoster, or cold sores within 14 days before the first study drug 
administration (patients may be rescreened). 
24. Subjects who have had their spleen removed for any reason. 
25. History of multiple drug allergies or history of allergic reaction to an oligonucleotide or 
GalNAc. 
26. Known hypersensitivity or contraindication to any medication, including any vaccine 
component, or current manifestation of any significant allergic disorder. 
27. Clinically significant allergic reactions to antibiotics in the opinion of the Investigator 
and not willing to use antibiotic prophylaxis as specified in protocol. 
28. Legal incapacity or limited legal capacity at screening. 
29. Any other conditions which, in the opinion of the Investigator, would make the subject 
unsuitable for enrollment or could interfere with the subject’s participation in or 
completion of the study. 
30. Travelled to Saudi Arabia or Africa within 90 days of screening, or who plan to do so 
during the study (patients may be rescreened). 
31. Women who are pregnant or breastfeeding. 

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5.2.2. 
Exclusion Criteria for All Patients in Part C 
1. History of venous or arterial thromboembolic events within the past 12 months. 
2. Active serious mental illness or psychiatric disorder, including, but not limited to, 
schizophrenia, bipolar disorder, or severe depression requiring current pharmacological 
intervention. 
3. ALT >2 × ULN and considered clinically relevant in the opinion of the Investigator. 
4. CBC laboratory results that are considered clinically relevant and unacceptable by the 
Investigator. 
5. Any other clinical safety laboratory result considered clinically significant and 
unacceptable by the Investigator. 
6. Known or suspected hereditary asymptomatic complement deficiency. 
7. Known clinical laboratory evidence or clinical diagnosis of HIV infection, HCV 
infection, or chronic HBV infection (as shown by HBsAg positivity). 
8. History or clinical evidence of alcohol abuse, within the 12 months before screening.  
Alcohol abuse is defined as regular weekly intake of more than 21 units for males and 
14 units for females (using alcohol tracker 
http://www.nhs.uk/Tools/Pages/NHSAlcoholtracker.aspx). 
9. History of multiple drug allergies or history of allergic reaction to an oligonucleotide or 
GalNAc. 
10. History of intolerance to SC injection or relevant abdominal scarring (surgical, burns, 
etc.). 
11. History of meningococcal infection. 
12. Presence or suspicion of active viral, bacterial, fungal, or parasitic infection including 
herpes, herpes zoster; or, for cold sores within 14 days before the first study drug 
administration (patients may be rescreened). 
13. Legal incapacity or limited legal capacity at screening. 
14. Any other conditions which, in the opinion of the Investigator, would make the patient 
unsuitable for enrollment or could interfere with the patient’s participation in or 
completion of the study. 
15. Travelled to Saudi Arabia or Africa within 90 days of screening, or who plan to do so 
during the study (patients may be rescreened). 
16. Women who are pregnant or breastfeeding. 
5.3. 
Withdrawal Criteria 
In accordance with the Declaration of Helsinki, subjects/patients will be free to withdraw from 
the study at any time if they wish so, for any reason specified or unspecified, without penalty to 
their continuing medical care. 

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5.3.1. 
Reason for Withdrawal 
The Investigator, or designee, may withdraw a subject/patient from the study if the 
subject/patient: 
 Is in violation of the protocol 
 Has an AE 
 Meets individual stopping criteria 
 Requires the use of/need for a prohibited medication, which in the opinion of the 
Sponsor or Investigator, may jeopardize the study results or represent a risk to the 
participant 
 Requests to be withdrawn from the study (subject/patient withdrawal of consent) 
 Is found to be considerably non-compliant with the protocol-required study drug 
dosing visits 
 In the Investigator’s opinion, is unable to continue study participation 
 Is withdrawn from the study upon the request of Sponsor or the SRC, including 
Sponsor termination of the study 
Where a subject/patient meets withdrawal criteria for the study, no further study drug will be 
administered and, wherever possible, such study participants will continue to be followed for 
safety (see Section 5.3.2). 
5.3.2. 
Handling of Withdrawals 
In the event that a subject/patient withdraws or is withdrawn from the study, the Investigator will 
inform the Medical Monitor and Sponsor immediately.  If a subject/patient is withdrawn because 
individual stopping criteria have been met, the subject/patient requires the use of a prohibited 
medication, which in the opinion of the Sponsor or Investigator, may jeopardize the study results 
or represent a risk to the participant, or there is another medical reason for withdrawal, no further 
study drug will be administered and the subject/patient will remain under the supervision of the 
Investigator for protocol specified safety follow-up procedures.  The SRC will be notified.  
When a subject/patient withdraws or is withdrawn from the study, every effort should be made to 
conduct the Early Termination (ET) visit as soon as possible following withdrawal. 
A subject/patient who fails to return for ET evaluations will be contacted by the site in an 
attempt to have the subject/patient comply with the protocol.  The site will follow-up by 
telephone at least twice and send a letter to the subject/patient who fails to return for the ET visit. 
If a subject/patient is withdrawn for an AE, appropriate medical care should be provided and, if 
possible, the AE should be followed until resolution.  
When a subject/patient withdraws from the study, the primary reason for discontinuation must be 
recorded in the appropriate section of the electronic case report form (eCRF) and all efforts will 
be made to complete and report the observations as thoroughly as possible. 

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5.3.3. 
Replacements 
Subjects/patients who voluntarily withdraw or are withdrawn are termed dropouts.  
Subjects/patients who withdraw or are withdrawn from the study due to an AE that does not meet 
progression/escalation and dose suspension/stopping rules may be replaced with confirmation by 
the SRC.  Subjects/patients who withdraw from the study for reasons other than experiencing an 
AE may be replaced following discussion between the Sponsor and the Investigator. 
 

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6. 
TREATMENT OF SUBJECTS 
6.1. 
Description of Study Drug 
Table 9:  
Investigational Product 
 
Investigational Product 
Product Name: 
ALN-CC5 
Dosage Form: 
Solution for injection 
Route of Administration 
SC injection 
Physical Description 
Clear, colorless to pale yellow solution  
6.2. 
Concomitant Medications 
6.2.1. 
Permitted Concomitant Medications 
The following medications/treatments are permitted for all subjects/patients during the study: 
 
Oral contraceptives (combination estrogen/progesterone pills), injectable, progesterone, or 
subdermal implants 
 
Study applicable vaccinations 
 
Hormone replacement therapy  
 
Acetaminophen (maximum 2 g daily) for treatment of AEs 
 
Ciprofloxacin or other penicillin antibiotics 
 
At the discretion of the Investigator, prescription or nonprescription medications may be 
permitted when necessary to treat an AE.  Before the subject/patient uses any prescription 
or nonprescription medications, the Investigator or delegate must be consulted. 
6.2.2. 
Prohibited Concomitant Medications 
The following medications/treatments are not permitted for subjects in Part A and Part B of the 
study: 
 
Any OTC medications, except routine vitamins from 7 days before the first dose of study 
drug, unless considered not clinically relevant by the Investigator and the Sponsor 
 
Prescription medications not specified in Section 6.2.1 from 14 days or 7 half-lives 
(whichever is longer) before the first dose of study drug 
There are no prohibited concomitant medications for patients in Part C. 

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6.3. 
Subject Restrictions 
Subjects in Part A and Part B will be required to comply with the following restrictions during 
the study:  
 
When subjects are confined to the clinical study site, only the drinks and meals provided 
by the study site personnel will be allowed. 
 
Intake of alcohol will not be allowed for 24 hours before all study visits. 
 
Subjects can be light smokers/users of nicotine products (including snuff and chewing 
tobacco, and other nicotine-containing products). 
 
Intake of caffeine will not be allowed 24 hours before screening and all study visits. 
 
Blood donation will not be allowed at any time during the study and for up to 90 days after 
postdose follow-up is completed. 
 
Subjects must refrain from unaccustomed strenuous physical exercise for 48 hours before 
screening, study visits, and until postdose follow-up is completed. 
 
Subjects must not consume poppy seeds 48 hours before screening, before study drug 
administration, and until postdose follow-up is completed.  
 
Subjects must abstain from the consumption of energy drinks containing taurine or 
glucuronolactone 24 hours before screening, before study drug administration, until 
discharge, and before study visits and postdose follow-up. 
There are no restrictions for patients in Part C. 
6.4. 
Treatment Compliance 
Subject/patient compliance with study drug use is not relevant because all doses will be 
administered by qualified clinical study site personnel; any missed doses will be reported. 
6.5. 
Assignment to Dose Cohort and Subject Number 
The assignment of number and code for subject/patient identification is based on the requirement 
for anonymity.  Subjects/patients will be assigned a study identification number at screening.  In 
Part A and Part B, after confirmation of eligibility, during screening, and upon admission to the 
clinical study site, subjects will be assigned to a dose level cohort.  No subject will be a member 
of more than one cohort.  A unique subject identification number, incorporating the site number, 
will be assigned sequentially after the subject/patient has completed all of the screening 
procedures and is determined to be eligible and dosed for the study. 
6.6. 
Randomization and Blinding 
Part A and Part B will be conducted in a randomized 3:1 (ALN CC5:placebo), double-blinded, 
placebo-controlled manner.   
The study subjects, Investigators, Medical Monitors, and members of the study team at the 
Sponsor and at the Contract Research Organization(s) (CROs), clinical study site personnel, and 
members of the SRC will remain blinded to the treatment assignment for a minimum of 9 months 

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after a subject receives his or her last dose of study drug.  If an individual subject’s complement 
functional activity as measured by CAP ELISA is within the reference range, prophylactic 
antibiotics will be stopped after unblinding and that subject will have completed the study.  If an 
individual subject who received ALN-CC5 has a CAP ELISA result that has not returned to 
within the reference range after unblinding, then prophylactic antibiotics will continue and the 
subject will be required to attend follow-up visits until the CAP ELISA result returns to within 
the reference range or until the SRC makes a decision on a case-by-case basis to discontinue 
follow-up and prophylactic antibiotics, whichever is sooner (see Section 3.5.3).   
A biostatistician at the CRO, who is not related to the conduct of the study, and the 
pharmacokineticist at the Sponsor will be unblinded.  The biostatistician at the Sponsor, who is 
related to the conduct of the study, will not be unblinded.  Dummy identifiers will be assigned to 
PK, PD, and safety data by the unblinded statistician at the CRO to maintain double-blind status 
of the study. 
The clinical study site pharmacist will receive a cohort-specific randomization list and will 
prepare and dispense the study drug according to that list.  The clinical study site pharmacist will 
be unblinded, but will maintain the blind according to site-specific procedures and the Pharmacy 
Manual.  ALN-CC5 may be visually distinguishable from placebo; therefore, syringes will be 
masked in the pharmacy before transfer to the clinic for dose administration. 
For optional cohorts (Part A and Part B) the same randomization procedures will be applied.  
Part C of the study will be conducted as an open-label portion of the study.  No blinding 
procedures will be needed. 
The information provided to the Sponsor for subject identification will be the assigned subject 
identification number, the randomization number (for subjects admitted to the study), age and 
gender.  The subject identification number will appear on all documents relating to that subject 
and will be cross-referenced by the randomization number for the enrolled subjects. 
Further details will be included in the Study Manual/Procedures and in the Statistical Analysis 
Plan (SAP). 
6.6.1. 
Breaking the Blind 
In case of emergency, the clinical study site pharmacist will have access to the randomization 
list, which contains the study drug assignment for subjects.   
The coding system in the blinded part of the study includes a mechanism permitting rapid 
unblinding.  If the blind is prematurely broken, the investigator will promptly document and 
explain any unblinding to the sponsor.  In emergency situations, the investigator may need to 
break the treatment code immediately, or as quickly as possible, if it is in the best interest of the 
subject; thus, the investigator will have unrestricted and immediate access to break the treatment 
code via the randomization list held by the site pharmacist. 
If a subject becomes pregnant or seriously ill during the study or follow-up period, the blind 
should be broken only if knowledge of the treatment administered will affect treatment options 
available for the subject.  If possible, before breaking the blind, the Investigator, or designee, 
should attempt to contact the Medical Monitor and the Sponsor.  If there is a requirement to 
unblind subjects at the cohort level, only the subjects in that cohort will be unblinded.  

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A record of when the blind was broken, who broke the blind, and why it was broken, will also be 
maintained in the TMF.  Should unblinding occur, it will not have an impact on the planned 
study analyses. 

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7. 
STUDY DRUG MATERIALS AND MANAGEMENT 
7.1. 
Study Drug 
ALN-CC5 is a synthetic, chemically modified siRNA targeting CC5 mRNA ( 
) with 
a covalently attached triantennary GalNAc ligand.  ALN-CC5 will be supplied as a sterile 
200-mg/mL solution for SC injection.  In Part A and Part B, study drug is defined as ALN-CC5 
or placebo.  In Part C, study drug is defined as ALN-CC5. 
Placebo will be administered to subjects participating in Part A and Part B of the study and will 
be supplied by the clinical study site as sterile normal saline 0.9% for SC injection. 
7.1.1. 
Antibiotic Prophylaxis 
Ciprofloxacin will be supplied by the clinical study sites. 
7.1.2. 
Study-specific Vaccinations 
Meningococcal group ACWY conjugate vaccine and meningococcal group B vaccine will be 
supplied by the clinical study sites. 
7.2. 
Study Drug Packaging and Labeling 
All packaging, labeling, and preparation of ALN-CC5 will be in compliance with Good 
Manufacturing Practice (GMP) specifications, as described in The Rules Governing Medicinal 
Products in the European Union, Volume 4, Annex 13, Investigational Medicinal Products, and 
any other or local applicable regulations. 
Study drug labels will include all appropriate local labeling requirements on the vial and external 
packaging.  Sample labels will be submitted to health authorities according to local country 
submission requirements. 
ALN-CC5 (solution for SC injection) is packaged in 2-mL glass vials with a fill volume of no 
less than 0.55 mL to allow for complete withdrawal of a 0.5-mL of drug product at the 
pharmacy.  The container closure system consists of a Type I glass vial, a Teflon-faced 13-mm 
stopper, and a flip-off aluminum seal. 
7.3. 
Study Drug Storage 
All doses of the study drug will be stored upright and refrigerated at approximately 2 to 8°C.  
The vial should be stored in the carton until ready for use in the storage area of the clinical study 
site pharmacy, in a secure, temperature-controlled, locked environment with restricted access.  
Any deviation from the recommended storage conditions should be reported to Sponsor and/or 
the CRO and use of the study drug halted until authorization for its continued use has been 
provided by Sponsor or designee. 
No special procedures for the safe handling of ALN-CC5 are required. 
The Sponsor will be permitted, upon request, to audit the supplies, storage, dispensing 
procedures, and records. 

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7.4. 
Study Drug Preparation 
The study drug may be dispensed only by the pharmacist.  Each clinical study site will be 
responsible for assembly and labeling of injection syringe(s) according to procedures detailed in 
the Pharmacy Manual.  The pharmacist will prepare the study drug using an aseptic technique.  
The amount (in mg) of study drug to be administered will be determined based on the assigned 
dose level for the cohort.  On study drug dosing days, the pharmacist or designee will withdraw 
the required amount of study drug into one or more syringes to be administered to the 
subject/patient on that day.  The procedure for preparing study drug and the volume to be loaded 
into each syringe will be provided in the Pharmacy Manual/Part C Pharmacy Manual. 
7.5. 
Study Drug Administration 
Subjects/patients will be administered study drug by SC injection(s) by qualified clinical study 
site staff under the supervision of the Investigator or designee and the injection site may be 
marked and mapped for later observation.  The preferred site of injection is the abdomen and for 
administration of multiple injections, the injection site should be rotated.  Optional additional 
sites are the upper arms and thighs.  If a local reaction around the injection site occurs, 
photographs may be obtained.   
In Part C, ALN-CC5 may be administered at home between visits to the clinical study center by 
a home healthcare provider trained in the administration of ALN-CC5. 
Detailed instructions for dose administration will be included in the Drug Administration 
Manual. 
7.5.1. 
Injection Site Examinations 
Further details, including guidance on AE recording in relation to ISRs, will be described in the 
Study Manual (see Section 10.4.2.1). 
7.6. 
Study Drug Accountability 
The Investigator or designee will maintain accurate records of receipt and the condition of all 
study drugs, including dates of receipt.  In addition, accurate records will be kept by the 
pharmacist of when and how much study drug is dispensed and used by each subject/patient in 
the study.  Any reason for departure from the protocol dispensing regimen must also be recorded.  
Drug accountability records and inventory will be available for verification by the Sponsor, or 
designee.  At the completion of the study, there will be a final reconciliation of all study drugs.   
Study drug must not be used for any purpose other than the present study.  Study drug, which has 
been dispensed to a subject and returned unused must not be re-dispensed to a different subject. 
Further instructions about study drug accountability will be detailed in the Pharmacy Manual. 
7.7. 
Study Drug Handling and Disposal 
Remaining study drug (all used, partially used, and unused vials) will be returned to the Sponsor 
or its agent or destroyed at the clinical study site according to applicable regulations and only 
after receipt of written authorization from the Sponsor. 

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8. 
PHARMACOKINETIC ASSESSMENTS 
Blood and urine samples will be collected for assessment of ALN-CC5 PK parameters and 
possible metabolite analysis.  The PK parameters include, but are not limited to, maximum 
(peak) plasma drug concentration (C
max), time to reach maximum plasma concentration (t
max), 
area under the plasma concentration versus time curve (AUC), and apparent terminal elimination 
half-life (t
½). 
8.1. 
Blood Sample Collection 
Blood samples will be collected for assessment of ALN-CC5 PK parameters and possible 
metabolite analysis at the time points in the Schedule of Assessments.  A detailed scheduled of 
time points for the collection of blood samples for PK analysis are in Table 10, Table 11, 
Table 12, Table 13, and Table 14 in the appendices (Section 18). 
8.2. 
Urine Sample Collection 
Urine samples for determination of ALN-CC5 concentration will be obtained from the total urine 
sample collected at the time points in the Schedule of Assessments.  A detailed scheduled of time 
points for the collection of urine samples for PK analysis are in Table 10, Table 11, Table 12, 
Table 13, and Table 14 in the appendices (Section 18).  Urine samples for will be retained on 
behalf of the Sponsor for a maximum of 7 years following the last subject’s/patient’s last visit in 
the study. 
8.3. 
Sample Analysis 
Plasma and urine samples for determination of ALN-CC5 concentration will be analyzed by a 
GLP-validated liquid chromatography-mass spectroscopy method.  Details regarding the 
collection, processing, shipping, and storage of the samples will be provided in a Laboratory 
Manual. 

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9. 
PHARMACODYNAMIC AND EXPLORATORY ASSESSMENTS 
9.1. 
Pharmacodynamic Blood Sample Collection 
Blood samples for PD analysis will be collected at the time points in the Schedule of 
Assessments.   
The PD analysis will include assessment of the impact of ALN-CC5 administration on plasma 
levels of C5 protein levels (assessed by ELISA and/or mass spectrometry-based methods) and 
serum complement activity (assessed by CAP ELISA and CCP ELISA assays). 
Samples will be analyzed at central laboratories.  Details regarding the collection, processing, 
shipping, and storage of the samples will be provided in a Laboratory Manual. 
9.2. 
Exploratory 
  
 
 
 
. 
Exploratory assessments in Parts A, B, and C of the study include inhibition of hemolysis 
(assessed by sensitized sheep RBC and 
  Samples for these analyses will 
be aliquoted from the blood sample collected for complement activity. 
For Part C, exploratory assessments in patients with PNH also include, but are not limited to, 
LDH levels, 
 
 and eculizumab levels (patients on stable doses 
of eculizumab only).  
 
 
 
 
  
Details regarding the collection, processing, storage, and shipping of samples will be in the 
Laboratory Manual. 
9.3. 
Exploratory 
 
 
  Further details regarding these 
assessments will be included in the Study Manual/Procedures. 
9.3.1. 
 
 
 
 
. 

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9.3.2. 
 
 
 
 
 
 
 
 
9.3.3. 
  
 
 
 
 
 
 
9.3.4. 
 
 
 
 
 
 
 
 

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10. 
ASSESSMENT OF SAFETY 
10.1. 
Safety Parameters 
10.1.1. Demographics and Medical History 
Subject/patient demographic data (age, gender, race, and ethnicity) will be obtained during 
screening.   
A complete medical history will be obtained at screening and will include past and present 
conditions of the following:  general, head and neck, eyes, ears, nose and throat, 
chest/respiratory, heart/cardiovascular, gastrointestinal/liver, gynecological/urogenital, 
musculoskeletal/extremities, dermatological/skin, neurological/psychiatric, endocrine/metabolic, 
hematologic/lymphatic, allergies/drug sensitivities, past surgeries, substance abuse, or any other 
disease or disorder.  The subject’s/patient’s medical history will be verified by either a personal 
physician or medical practitioner, as appropriate.  For Part C only, 
 
 will be captured as part of complete medical history. 
After the Screening visit, the medical history for each subject/patient will be updated with any 
changes during the interval since the last recording and before the first dose of the study drug.  
Any changes in medical history will be evaluated against the inclusion and exclusion criteria to 
determine the subject’s/patient’s continued eligibility for the study before the first dose. 
10.1.2. Vital Signs 
Vital signs (oral body temperature, blood pressure, heart rate, and respiration rate) will be 
measured at the time points in the Schedule of Assessments.  Vital signs will be measured in the 
supine position after the subject has rested comfortably for at least 10 minutes. 
10.1.3. Weight, Height, and Body Mass Index 
Height will be measured in centimeters and weight in kilograms.  Measurements should be 
obtained with the subject/patient wearing light clothing and without shoes using calibrated scales 
for all measurements.  BMI will be calculated from the height and weight measured at time 
points in the Schedule of Assessments. 
10.1.4. Physical Examination 
Physical examinations will be performed at the time points in the Schedule of Assessments.   
A full physical examination includes an assessment of the following:  general appearance, skin, 
eyes, ears, nose, throat, thyroid/neck, lymph nodes, abdomen, chest/respiratory, 
heart/cardiovascular, gastrointestinal/liver, dermatological/skin, neurological/psychiatric, and 
musculoskeletal system/extremities. 
A directed physical examination includes an assessment of the following:  chest/respiratory, 
heart/cardiovascular, dermatological/skin, gastrointestinal/liver, musculoskeletal/extremities, and 
abdomen.  

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10.1.5. Electrocardiogram 
Triplicate 12-lead ECGs will be recorded at the time points in the Schedule of Assessments.  
ECGs will be stored electronically on the relevant information system for the clinical study site.  
Only ECGs recorded electronically will be valid for any purpose other than safety assessment.  
ECG printouts may be filed in the eCRF for the subject/patient for medical safety reviews.  
Each ECG recorder will be set up to the required technical specifications and containing the 
information required to identify the records.  Each ECG recording will be clearly identified 
(subject/patient identification number, visit date, and the actual times of ECG recordings).  
Triplicate 12-lead ECG recordings will be measured in the supine position after the 
subject/patient has rested comfortably for at least 10 minutes.  Subjects/patients will avoid 
postural changes during the ECG recordings and clinical study site staff will ensure that 
subjects/patients remain awake during the ECG recording.  
All recorded ECGs will be reviewed by the Investigator, or designee, and the review documented 
in the eCRF.  Bazett-corrected QT interval (QTcB) will be automatically calculated by the 
clinical study site equipment and available on the ECG printout.  Fridericia-corrected QT interval 
will only be assessed at the clinical study site if QTcB is prolonged.  If a subject/patient shows 
an abnormal ECG, additional safety recordings (including 5- or 12-lead Holter ECG equipment) 
may be obtained and the abnormality followed to resolution, if required. 
Details regarding ECG assessments using clinical study site-specific equipment will be in the 
Study Manual/Procedures.   
10.1.6. Maximum Blood Volume 
The maximum total blood volume that will be collected from subjects and patients participating 
in this study will be documented in the Study Manual/Procedures.  Maximum total blood volume 
according to study part is as follows: 
 Part A:  up to 800 mL over the extended course of the study 
 Part B:  up to 900 mL over the course of the study 
 Part C:  up to 900 mL over the course of  the study 
10.1.7. Laboratory Assessments 
10.1.7.1. Biochemistry, Hematology, Coagulation, and 
 
Blood samples for determination of hematology, biochemistry, and coagulation parameters will 
be obtained at the time points in the Schedule of Assessments.  Analyses will be performed at a 
local laboratory, using routine methods, except where noted.  Details regarding the processing, 
shipping, and analysis of samples will be provided in the Laboratory Manual. 
Additional and repeat testing may be performed at the discretion of the Investigator.  In the event 
of an unexplained clinically relevant abnormal laboratory test occurring after study drug 
administration, the test should be repeated and followed up at the discretion of the Investigator 
until it has returned to the normal range and/or a diagnosis is made to adequately explain the 
abnormality. 

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Biochemistry Parameters 
 Aspartate aminotransferase (AST) 
 Urea (BUN) 
 Alanine aminotransferase (ALT) 
 Creatinine 
 Alkaline phosphatase (ALP) 
 Potassium 
 Gamma glutamyl transferase (GGT) 
 Chloride 
 Uric acid 
 Glucose 
 Bilirubin (TBIL; total and direct) 
 Inorganic phosphate 
 Cholesterol  
 Calcium 
 Triglycerides 
 Total protein 
 Sodium 
 Albumin 
 Creatine phosphokinase 
 Carbon dioxide 
 Lactate dehydrogenase (LDH) 
 C-reactive protein (CRP) 
 
Hematology Parameters 
 Hemoglobin 
 Mean corpuscular volume (MCV) 
 Hematocrit 
 Mean corpuscular hemoglobin 
concentration (MCHC) 
 Red blood cell count (erythrocytes and 
reticulocytes) 
 White blood cell count 
 Mean cell hemoglobin (MCH) 
 Differential blood count (absolute and 
%:  neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils) 
 Platelets 
 PNH (type III) cells (Part C only) 
 
Coagulation Parameters 
 Prothrombin time (PT) 
 International normalized ratio (INR) 
 Activated partial thromboplastin 
(aPTT) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 
 
 
 
 
 
 
 
  
10.1.7.2. Urinalysis 
Urine samples for determination of urinalysis parameters will be obtained at the time points in 
the Schedule of Assessments.  
Urinalysisa 
 Ketones 
 Leukocytes 
 Bilirubin 
 Urine microscopy 
 Urobilinogen 
 pH 
 Nitrite 
 Glucose 
 Specific gravity 
 Red blood cells 
 Protein 
 
a  Visual inspection for appearance and color will occur; urine microscopy will be performed if clinically indicated. 
10.1.7.3. 
 
 
 
 
Details regarding the processing, shipping, and analysis of the samples will be provided in the 
Laboratory Manual. 
10.1.7.4. Viral Serology 
Serology will be performed at the time points in the Schedule of Assessments.  During screening, 
subjects and patients will be tested for HIV-I and II antibody, HBsAg, and anti-HCV.  Results of 
the assessments will not be entered into the study database.  If a subject/patient is confirmed 
positive for any of these tests, the subject/patient will be referred for further examination, 
counseling, or treatment and is not eligible for the study. 
10.1.7.5. Drugs of Abuse and Alcohol Screening (Part A and Part B only) 
Urine will be tested for drugs of abuse (DOA) at the clinical study site at the time points in the 
Schedule of Assessments.  If a subject fails the DOA screening, they will be excluded from the 
study.  A repeat drug screen may only be performed when methodological reasons are believed 
to have led to a false positive.  Borderline positive results, unless covered by the preceding 
condition, are to be considered as positive and the subject will be excluded from the study.  If 
subjects are found to be positive due to medication (eg, flu or cold remedies) they may undergo a 
repeat drug screen if they continue to meet study requirements. 

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An alcohol test (urine and/or breathalyzer) will be performed according to local clinical study 
site policy at the time points in the Schedule of Assessments.  If a subject tests positive then they 
will be excluded from the study.  Details will be provided in the Study Manual/Procedures. 
Drugs of Abuse (Urine) 
 Amphetamines 
 Opiates 
 Barbiturates 
 Cocaine 
 Benzodiazepines 
 Methadone 
 Cannabinoids 
 
10.1.7.6. Pregnancy Screening 
Serum β-HCG test will be performed at the time points in the Schedule of Assessments.  Any 
woman with a positive pregnancy test before study entry will be excluded from the study.  Any 
woman with a positive pregnancy test during the study will be discontinued from study drug, but 
will continue to be followed for safety. 
10.1.7.7. Follicle-Stimulating Hormone Assessment 
The postmenopausal status of women will be confirmed by a follicle-stimulating hormone test at 
the time points in the Schedule of Assessments.  
10.1.8. Study-specific Vaccinations 
Meningococcal group ACWY conjugate vaccine and meningococcal group B vaccine will be 
administered in accordance with the manufacturer’s instructions.  Further details will be included 
in the Study Manual/Procedures. 
10.1.8.1. Vaccination Specifications for Part A and Part B 
Subjects will be immunized against Neisseria meningitides according to the following 
specifications before receiving the first dose of study drug: 
 Subjects who were not previously vaccinated will be vaccinated with meningococcal 
group ACWY conjugate vaccine and meningococcal group B vaccine.  Vaccinations 
should be administered within the 90 day screening period according to the following 
plan (Note:  Vaccination day is not the same as Study Day): 
 Vaccination day 1:  administer meningococcal group ACWY conjugate and 
meningococcal group B vaccine 
 Vaccination day 28:  measure ACWY titer and administer meningococcal 
group B vaccine booster 
 Vaccination day 56:  assessment of ACWY titer result; if positive, vaccination 
program is complete; if negative, consider repeat measurement of ACWY titer 
 Subjects who were previously vaccinated must have confirmed seroconversion to 
ACWY (laboratory documentation less than 12 months old is considered valid) 
before administration of the first dose of study drug.  If the last meningococcal 

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group B injection was administered more than 12 months before the Day -1 study 
visit, then a booster injection of this vaccine must be administered before 
administration of the first dose of study drug. 
 Titer measurements will be used to exclude subjects without an immune response to 
ACWY.  
10.1.8.2. Vaccination Specifications for Part C 
Patients will be immunized against Neisseria meningitides according to the following 
specifications: 
 Treatment-naïve patients with PNH who have previously received meningococcal 
vaccinations (meningococcal group ACWY conjugate vaccine and meningococcal 
group B vaccine) can start study assessments after confirming eligibility.   
 To reduce the potential for vaccine-induced breakthrough hemolytic events, patients 
with PNH, who have not been previously vaccinated, will receive ALN-CC5 and 
antibiotic prophylaxis with ciprofloxacin (according to standard practice at the 
clinical study site).  Following completion of treatment with ciprofloxacin, and within 
a maximum of 14 days after administration of the first dose of ALN-CC5, patients 
will be vaccinated with meningococcal group ACWY conjugate vaccine and 
meningococcal group B vaccine (according to standard practice at the clinical study 
site).  Subsequent prophylaxis with an appropriate antibiotic of the penicillin class 
can be administered at the Investigator’s discretion. 
 Patients with PNH who are on stable eculizumab therapy who have previously 
received both meningococcal vaccinations (meningococcal group ACWY conjugate 
vaccine and meningococcal group B vaccine) can start study assessments after 
confirming eligibility.  Patients who have not had both vaccinations can receive the 
remaining vaccination before starting treatment with ALN-CC5. 
10.1.9. Prophylactic Antibiotic Administration and Compliance Check  
Ciprofloxacin will be administered in accordance with the manufacturer’s instructions.  
Antibiotic compliance checks will be performed at the time points in the Schedule of 
Assessments.   
Subjects participating in Part A and Part B will be treated with prophylactic ciprofloxacin 
(according to standard practice at the clinical study sites) from start of dosing with study drug 
(ALN-CC5 or placebo) until serum complement activity, as assessed by CAP ELISA, returns to 
within the normal reference range.  If an individual subject’s complement functional activity as 
measured by CAP ELISA is within the reference range, prophylactic antibiotics will be stopped 
after unblinding and that subject will have completed the study.  If an individual subject who 
received ALN-CC5 has a CAP ELISA result that has not returned to within the reference range 
after unblinding, then prophylactic antibiotics will continue and the subject will be required to 
attend follow-up visits until the CAP ELISA result returns to within the reference range or until 
the SRC makes a decision on a case-by-case basis to discontinue follow-up and prophylactic 
antibiotics, whichever is sooner (see Section 3.5.3). 

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Patients in Part C will receive antibiotics at the discretion of the investigator. 
Details of antibiotic compliance methodology will be described in the Study Operations Manual. 
10.2. 
Adverse and Serious Adverse Events 
10.2.1. Definition of Adverse Events 
10.2.1.1. Adverse Event 
An AE is any untoward medical occurrence in a subject, or clinical investigational patient, 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. 
Therefore, an AE can be any unfavorable and unintended sign (eg, an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product. 
10.2.1.2. Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose of study drug: 
 Results in death; 
 Is life-threatening (an event which places the subject/patient at immediate risk of death 
from the event as it occurred.  It does not include an event that had it occurred in a more 
severe form might have caused death); 
 Requires inpatient hospitalization or prolongation of existing hospitalization; 
 Results in persistent or significant disability/incapacity; 
 Is a congenital anomaly or birth defect; 
 An important medical event that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the subject/patient or may require 
intervention to prevent one of the other outcomes listed above.  Examples of such events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias, convulsions, or the development of drug dependency or abuse. 
10.2.1.3. Suspected Unexpected Serious Adverse Reactions 
A suspected unexpected serious adverse reaction (SUSAR) is any SAE where a causal 
relationship with the study drug is at least a reasonable possibility, but is not listed in the IB 
reference safety information.  
10.2.1.4. Other Adverse Events 
AEs of clinical interest, other than SAEs and those AEs leading to discontinuation of the 
subject/patient from the study, will be classified as other adverse events (OAEs).  OAEs may be 
identified during the evaluation of safety data. 

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10.3. 
Eliciting Adverse Event Information 
The subject/patient should be asked about medically relevant changes in his/her health since the 
last visit.  The subject/patient should also be asked if he/she has been hospitalized, had any 
accidents, used any new medications, or changed concomitant medication routines (both 
prescription and OTC). 
In addition to subject/patient observations, AEs will be documented from any clinically relevant 
laboratory findings, vital signs, physical examination findings, 12-lead ECG changes, or other 
documents, that are relevant to subject/patient safety. 
10.4. 
Adverse Event Reporting 
The Investigator is responsible for reporting all AEs that are observed or reported after 
administration of the first dose of study drug through the last postdose follow-up visit regardless 
of their relationship to study drug or clinical significance. 
All AEs must be followed to satisfactory resolution or until the AE is deemed by the Investigator 
to be chronic or the patient to be stable.   
SAEs will be followed until resolved or until the SAE is considered by the Investigator to be 
chronic or the subject/patient to be stable, whichever occurs first. 
Any medical condition that is present when a subject/patient is screened and does not deteriorate 
is captured as medical history and should not be reported as an AE; however, if it does 
deteriorate at any time during the study, it may meet the definition of an AE and should be 
reported. 
All AEs must be reported on the appropriate eCRF page and recorded in the source records at the 
clinical study unit.  The description of the AE will include the onset time and date, duration, 
severity, seriousness, relationship to study drug, action obtained, and outcome (including time 
and date of resolution, if applicable).  AEs resulting from concurrent illnesses, concomitant 
medications, or progression of disease states must also be reported. 
10.4.1. Assessment of Causality 
Causal relationship assessment to drug treatment is required for purposes of reporting AEs.  To 
promote consistency, the following guidelines should be taken into consideration along with 
good clinical and scientific judgment when determining the relationship of study medication to 
an AE: 
Definitely Related: A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to the medication administration, and which 
cannot be explained by concurrent disease or other drugs or chemicals.  
The response to withdrawal of the drug should be clinically plausible. 
Possibly Related: A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to the medication administration, but which 
could also be explained by concurrent disease, or other drugs or 
chemicals.  Information on the drug withdrawal may be lacking or 
unclear. 

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Unlikely Related: A clinical event, including laboratory test abnormality, with little or no 
temporal relationship to medication administration, and which other 
drugs, chemicals, or underlying disease provide plausible explanations.   
Not Related: 
A clinical event, including laboratory test abnormality, that has no 
temporal relationship to the medication or has more likely alternative 
etiology.   
10.4.2. Assessment of Toxicity 
Standard toxicity grading according to the CTCAE (Version 4.0) will be used to grade AEs.  
Local laboratory normal values are to be applied.  Abnormal laboratory and other tests should 
always be repeated before grading in order to ensure consistency and to exclude technical errors.  
Diurnal variations in laboratory parameters and other measurements as well as baseline status 
and conditions (eg, Gilbert’s syndrome) should be taken into account when assessing whether 
abnormalities constitute a study drug-related AE and when grading, if applicable. 
The CTCAE criteria and their interpretation are consistent with the standard severity grading for 
AEs during clinical trials:  Grade I, Grade II, and Grade III AEs may constitute an SAE and/or 
SUSAR.  Grades IV and V constitute an SAE and/or SUSAR.  
The grading of the CTCAE related to off-target organ toxicities and potentially expected AEs is 
considered suitable for ALN-CC5, the study design, and the study populations in conjunction 
with the protocol suspension/stopping rules and no further qualifications are required.   
Refer to CTCAE (Version 4.0) for unique clinical descriptions of severity (Grades 1 through 5) 
for each AE based on this general guideline: 
Grade I: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade II: 
Moderate; minimal, local or non-invasive intervention indicated; limiting 
age appropriate instrumental ADL
a 
Grade III: 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL
b 
Grade IV: 
Life-threatening consequences; urgent intervention indicated 
Grade V: 
Death related to AE 
Abbreviations:  ADL = Activities of Daily Living; AE = adverse event. 
a Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
b 
Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
10.4.2.1. Injection Site Signs or Symptoms 
Individual signs or symptoms (eg, erythema, swelling, etc.) at the injection site reported by a 
subject/patient within 4 hours following dose administration will be recorded as an AE.  After 
4 hours postdose, injection site signs or symptoms will be evaluated according to the CTCAE 
criteria of Injection Site Reaction (general disorders and administration site conditions).  If, after 
4 hours postdose, the ISR CTCAE criteria are met, the event is recorded as an ISR; if the criteria 

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are not met, individual sign(s) or symptom(s) will be recorded as AE(s) under the appropriate 
System Organ Class (SOC; Medical Dictionary for Regulatory Activities [MedDRA]). 
10.5. 
Serious Adverse Event Reporting 
An assessment of the seriousness of each AE will be made by the Investigator.  Any AE and 
laboratory abnormality that meets the seriousness criteria (Section 10.2.1.2) must be reported to 
the Sponsor within 24 hours from the time that clinical study site personnel first learn of the 
event, using the SAE Report Form provided.  All SAEs must be reported regardless of the 
relationship to study drug.  The SAE must also be recorded on the standard eCRF pages.   
The initial report should include at a minimum the following information: 
 Subject/patient study number 
 Brief description and date of onset of the event 
 Event term being reported and criterion for seriousness 
 Preliminary assignment of causality to study drug 
Routine AE reporting will be via electronic data capture.  SAE reporting will be via the paper 
SAE Report Form provided in the Study Manual/Procedures.   
The Investigator will complete the SAE Report Form and fax the form via to Covance 
Pharmacovigilance and Drug Safety Services (PV and DSS) immediately (within 24 hours) of 
becoming aware of an SAE. 
SAE Reporting Contact Information 
PV and DSS fax: 
 
 PV and DSS telephone:
a 
 
a 
Where possible, SAE information should be faxed to Covance PV and DSS before initiating telephone contact. 
If follow-up is required, new information should be provided to the Sponsor as soon as it 
becomes available using the SAE Report Form.  Copies of discharge summaries, consultant 
reports, autopsy reports, and any other relevant documents may also be requested.   
Appropriate remedial measures should be performed by the Investigator or Sub-investigator 
using his/her best medical judgment to treat the SAE.  These measures and the subject/patient’s 
response to these measures should be recorded.  All SAEs, regardless of relationship to study 
drug, will be followed by the Investigator until satisfactory resolution or the Investigator or 
Sub-investigator deems the SAE to be chronic or stable.  Clinical, laboratory, and diagnostic 
measures should be employed by the Investigator or Sub-investigator as needed to adequately 
determine the etiology of the event.   
10.6. 
Suspected Unexpected Serious Adverse Reactions Reporting 
Covance Drug Safety Services Europe, Maidenhead, UK, is responsible for coordinating the 
reporting of SUSARs in accordance with the European Directive 2001/20/EC to the applicable 
REC.   

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A fatal or life-threatening SUSAR must be reported to the applicable Regulatory Authority and 
the relevant REC by the Sponsor, or delegate, within 7 days after the Sponsor first becomes 
aware of the event.  If the initial report is incomplete, a complete report must be submitted within 
8 days of sending the first response. 
A SUSAR which is not fatal or life-threatening must be reported to the applicable Regulatory 
Authority and the REC within 15 days after the Sponsor first becomes aware of the event. 
The Investigator may be informed by the Sponsor or its representatives of SAEs from other 
Investigators or clinical studies that may have relevance to this clinical trial.  These SAEs should 
also be reported promptly to the REC that approved this study. 
10.6.1. Pregnancy Reporting 
A subject/patient who becomes pregnant during this study must be instructed to stop all study 
drug administration and will continue to be followed for safety.  The Investigator or 
Sub-investigator must report a subject/patient or partner pregnancy to the Sponsor or its agency 
within 24 hours of being notified of the pregnancy.  Details of the pregnancy will be reported on 
a Pregnancy Report Form.  The subject/patient/partner shall receive any necessary counseling 
regarding the risks of continuing the pregnancy and the possible effects on the fetus.  Safety 
monitoring of the subject/patient/partner will continue until the conclusion of the pregnancy, and 
the outcome of the pregnancy will be reported to the Sponsor. 
If, in the opinion of the Investigator, knowledge of the study drug assignment is required to 
monitor the pregnancy for safety, then unblinding procedures detailed in Section 6.6.1 will be 
followed.

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11. 
STATISTICS 
11.1. 
Sample Size and Randomization 
This is a randomized Phase 1/2 study to assess the safety and tolerability of ALN-CC5 in SAD 
and MAD in healthy adult subjects and will also assess the safety and tolerability of ALN-CC5 
in patients with PNH.  The SAD and MAD portions (Part A and Part B) will be conducted as a 
double-blinded, placebo-controlled study and the multiple-dose portion in patients with PNH 
(Part C) will enroll in an open-label fashion.  The sample size was not determined based on 
power calculations.  Up to 76 participants (60 subjects and 16 patients) are expected be enrolled 
in the study (including optional cohorts).   
11.2. 
Analysis Sets 
The populations (analysis sets) are defined as follows and will be identified separately for 
subjects in Part A and Part B, and for patients in Part C: 
Safety Analysis Set: 
All subjects/patients who receive at least a single 
dose of study drug will be included in the safety 
analyses. 
PK Analysis Set: 
All subjects/patients who receive at least a single 
dose of study drug, and who have at least one 
postdose blood sample for PK parameters, and who 
have evaluable PK data will be included in the PK 
analyses. 
PD Analysis Set: 
All subjects/patients who receive at least a single 
dose of study drug and who have at least one 
postdose blood sample for the determination of 
plasma ALN-CC5 will be included in the PD 
analyses. 
11.3. 
Statistical Methodology 
A SAP will be written after finalizing the protocol and before database lock.  The specifications 
in this document will detail the implementation of all the planned statistical analyses in 
accordance with the principal features stated in the protocol.   
Statistical analyses will be primarily descriptive; no formal hypothesis testing will be conducted.  
Analyses will be performed using SAS® for Windows (Version 9.2 or higher).  Data from Part A, 
Part B, and Part C will be analyzed separately.  Summary tables for Part A and Part B will 
include results by cohort for each dose level of ALN-CC5 and placebo, where the placebo 
subjects will be combined across dose cohorts.  Descriptive statistics will be presented for 
continuous variables, and frequencies and percentages will be presented for categorical and 
ordinal variables.  Percentages will be based on the number of nonmissing values in a dose 
group.  All study data will be presented in by-subject/patient data listings. 

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In Part C, data will be analyzed by cohort for patients on the same dose and dose regimen.  
Additionally, analysis may be based on patients who are either naïve to eculizumab treatment or 
on stable doses of eculizumab (as assessed by the Investigator). 
11.3.1. Baseline Evaluations 
Demographics will be summarized for subjects/patients in the safety analysis set, by dose group 
and overall.  If the PK and PD analysis sets are a different set of subjects/patients compared to 
those included in the safety analysis set, then demographic information will be summarized 
separately for those analysis sets.  Descriptive statistics will be provided for age, height, weight, 
and BMI at screening.  Frequencies and percentages will be tabulated for gender, race, and 
ethnicity. Demographic information for patients in Part C may include additional disease-specific 
information at baseline. 
11.3.2. Safety Data Analysis 
11.3.2.1. Safety Parameters 
Safety assessments will include clinical laboratory parameters (hematology, biochemistry, 
coagulation, and urinalysis), vital signs (oral body temperature, blood pressure, heart rate, and 
respiration rate), physical examinations, 12-lead ECGs, and AE and concomitant medication 
monitoring.   
11.3.2.2. Adverse Events 
AEs will be summarized by the MedDRA SOC and Preferred Term.  Separate tabulations will be 
produced for treatment-emergent adverse events (TEAEs), TEAEs by maximum severity, 
treatment-related AEs, SAEs, and discontinuation of study drug due to AEs.  By-subject and 
by-patient listings will be provided for deaths, SAEs, and AEs leading to discontinuation of 
study drug. 
11.3.2.3. Clinical Laboratory Safety Parameters, Vital Signs, Physical Examinations, and 
12-lead Electrocardiograms 
For each continuous laboratory safety parameter (including, but not limited to, hematology, 
biochemistry, coagulation, and urinalysis) results will be categorized as low, normal, or high 
based on the laboratory normal ranges.  Shifts from baseline laboratory grade to the maximum 
laboratory grades will be examined for key safety parameters.  All out-of-range and clinically 
significant laboratory results will be identified in data listings.  Descriptive statistics will also be 
provided as actual value and change from baseline over time. 
Descriptive statistics for vital signs, and ECG interval data will be presented by actual values and 
changes over time from baseline.  Details of any abnormalities will be included in the data 
listings. 

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11.3.3. Pharmacokinetic Analysis 
11.3.3.1. Pharmacokinetic Parameters 
Blood and urine samples will be collected for assessment of PK parameters and possible 
metabolite analysis.  The PK parameters will be derived from the relevant plasma concentration 
data of ALN-CC5 by noncompartmental analysis.  To assess the single-dose and multiple-dose 
PK and the overall exposure to ALN-CC5, the PK parameters that will be derived include, but 
are not limited to, C
max, t
½, t
max, and AUC.  
For final analysis, actual sampling times, when feasible, will be used for all calculations of the 
PK parameters.  If there is any doubt in the actual time a sample was obtained, then the 
scheduled time will be used.  
11.3.3.2. Analysis 
The PK parameters will be calculated and listed for each subject/patient and each cohort, along 
with summary statistics including arithmetic and geometric means; standard deviations; 
minimum, maximum, and median values; and coefficients of variation.   
The PK data will also be displayed graphically, as appropriate.  Exploratory analyses on the PK 
data and their relationship to PD and safety evaluations may be investigated. 
11.3.4. Pharmacodynamic Analysis 
The PD parameters will be summarized using descriptive statistics for actual results and 
relative-to-baseline.  For PD parameters, baseline levels will be defined in the SAP.  Part A, 
Part B, and Part C will be analyzed separately.  The PD evaluations will include the effect of 
ALN-CC5 on plasma C5 protein and on serum complement activity.  Additional PD parameters 
are included in the exploratory analysis section. 
11.3.5. Exploratory Analysis 
Exploratory analyses will assess the effect of ALN-CC5 on inhibition of hemolysis and the effect 
of ALN-CC5 on the induction 
 in subjects and patients. 
The remainder of the exploratory analyses are in patients with PNH and include, but are not 
limited to, effect of ALN-CC5on LDH levels, 
 
 
 
 
  
  
11.4. 
Interim Analysis 
There is no formal interim analysis planned for this study. 

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11.5. 
Handling of Missing and Incomplete Data 
Unrecorded values will be treated as missing.  The appropriateness of the method(s) described 
for handling missing data may be reassessed and documented in the SAP at the data review 
before database lock.  Depending on the extent of missing values, further investigation may be 
made into the sensitivity of the analysis results to the method(s) specified. 

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12. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
12.1. 
Quality Assurance and Quality Control 
The Investigator(s) will permit trial-related monitoring, audits, and review by the REC, 
providing direct access to source data/documents.  The study may be subject to audit by the 
Sponsor or its representatives, or external agencies.  If such an audit occurs, the Investigator 
must agree to allow access to the required subject/patient records.  In the event of an audit, the 
Investigator agrees to allow the Sponsor, representatives from the Sponsor, or regulatory 
agencies access to all study records. 
12.2. 
Monitoring 
All aspects of the study will be carefully monitored by the sponsor, or designee, for compliance 
with applicable government regulations with respect to GCP and current standard operating 
procedures.  
The monitoring of this study will be performed by the Sponsor’s Monitor(s) or a designee in 
accordance with the principles of GCP as laid out by the International Conference on 
Harmonisation (ICH) in the “Good Clinical Practice: Consolidated Guideline”. 
The clinical monitor, as a representative of the Sponsor, has an obligation to follow the study 
closely.  In doing so, the monitor will visit the Investigator and site periodically as well as 
maintain frequent telephone and letter contact.  The monitor will maintain current personal 
knowledge of the study through observation, review of study records and source documentation, 
and discussion of the conduct of the study with the Investigator and staff. 

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13. 
STUDY REPORTING REQUIREMENTS 
The Sponsor will immediately notify the Investigator of important safety data (eg, toxicology; 
absorption, distribution, metabolism, excretion; teratology) that becomes available during the 
course of this study. 
The Investigator will submit reports of SAEs as outlined in this protocol.  In addition, the 
Investigator agrees to submit progress reports to his/her REC per local reporting requirements, or 
at least annually and at the conclusion of the study.  The reports will be made available to the 
Sponsor or designee. 
All deviations from the protocol (including those deemed necessary to protect subject safety) 
should be reported to the Medical Monitor and the Sponsor within 24 hours of knowledge of the 
event. 
Any communications from regulatory agencies in regard to inspections, other studies that impact 
this protocol, or the qualifications of study personnel should be promptly reported to the 
Sponsor. 

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14. 
ETHICS 
14.1. 
Informed Consent 
The informed consent is a process by which a subject/patient voluntarily confirms his/her 
willingness to participate in a clinical trial.  It is the responsibility of the Investigator or delegate 
to obtain a written informed consent from each subject/patient participating in the trial, after 
explanation of the aims, methods, benefits, and potential hazards of the trial and in accordance 
with GCP requirement (CPMP/ICH/135/95) and Directive 2001/20/EC.   
The Subject/Patient Information Sheet and ICF given to the subject/patient should be kept clear, 
relevant, and understandable, including those measures taken to safeguard subject privacy and 
the protection of personal data. 
The Investigator should provide the subject/patient with sufficient time to decide whether or not 
to participate in the trial.  The subject/patient should be also provided with a contact point where 
he/she may obtain further information. 
If more than the ICF constitutes the materials to be used in the consenting process, the 
Subject/Patient Information Sheet, ICF, and/or form for the protection of personal data should be 
translated to the local language and adapted to local requirements (eg, in respect to data 
protection).  Only the approved version of the ICF can be used in the center. 
The signatures of the ICF and the Protection of Personal Data Form must be obtained before any 
trial-specific procedures are performed on the subject/patient.  The Investigator must keep 1 form 
personally signed and dated by the subject/patient on file and a copy of it must be delivered to 
the subject/patient.  The informed consent must be documented in the source records.  The 
subject/patient should be informed if new information becomes available that might be relevant 
to the subject’s/patient’s willingness to continue participation in the study. 
14.2. 
Research Ethics Committee Approval 
It is the responsibility of the Investigator to submit this protocol, the ICF (approved by Sponsor), 
all relevant supporting information, and study-specific advertisements to the REC for review.  
Before the study onset, the protocol, any protocol amendments, ICFs, advertisements to be used 
for subject recruitment, and any other written information regarding this study to be provided to 
a subject/patient or subject’s/patient’s legal guardian must be approved by the REC. 
Before implementing changes in the study, the Sponsor and the REC must also approve any 
revised ICFs and substantial amendments to the protocol. 
National regulations and ICH require that approval be obtained from an REC before participation 
of subjects/patients in research studies. 
The Investigator will make all attempts to ensure that the REC is constituted and operates in 
accordance with ICH GCP and any local regulations. 
14.3. 
Confidentiality 
The Investigator agrees to maintain the confidentiality of the study at all times.  By signing the 
final protocol, each Investigator agrees to keep all information and results concerning the study 

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and the investigational product confidential for as long as the data remain unpublished.  This 
confidentiality obligation applies to all personnel involved at the investigational site. 
The Investigator must ensure that subject anonymity will be maintained.  On documents 
submitted to the Sponsor, subjects should not be identified by their names, but by the assigned 
subject number and initials.  If subject names are included on copies of documents, the names 
(except for initials) will be obliterated and the assigned subject number added to the document 
before submission to the Sponsor.  Documents not for submission to the Sponsor (eg, signed 
ICFs) should be maintained by the Investigator in strict confidence. 
Following GCP principles, a subject number will be used to identify the subject in their study 
records.  Laboratory samples and samples in storage will be labeled with only the subject 
number; the identity of the subject will only be known by the clinical study site.  An independent 
numbering code and the label will not contain any other personal identification information.  The 
numbering code associated with these labels will be held by the study CRO and the Sponsor, 
thereby allowing no unwarranted access to the information.  When reporting results for interim 
safety assessment and at the end of the study, the code will be shared per standard operating 
procedures with the responsible member of the Biostatistical and Data Management Departments 
of the CRO.  The numbering code will also be held for samples in storage until marketing 
approval in the countries where this study was conducted, or until notified that storage is no 
longer required. 

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15. 
DATA HANDLING AND RECORD KEEPING 
15.1. 
Inspection of Records 
The Sponsor will be allowed to conduct clinical trial site visits to the investigation facilities for 
the purpose of monitoring any aspect of the study.  The Investigator agrees to allow the monitor 
to inspect the drug storage area, study drug stocks, drug accountability records, subject charts 
and study source documents, and other records relative to study conduct. 
15.2. 
Retention of Records 
Essential study documents should be retained for the period of time required by applicable local 
law.  The essential documents include the signed and dated final protocol, signed and dated 
amendments(s), if applicable, signed and dated Curriculum Vitae of the Investigators, copies of 
the completed eCRFs, signed ICFs, REC approval and all related correspondence, financial 
agreements, regulatory approval, drug accountability, study correspondence, and subject/patient 
identification codes.  Records will not be destroyed without informing the Sponsor in writing and 
giving the Sponsor the opportunity to store the records for a longer period of time at the expense 
of the Sponsor. 
See Section 14.3 for confidentiality requirements. 

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16. 
PUBLICATION POLICY 
It is intended that after completion of the study, the data are to be submitted for publication in a 
scientific journal and/or for reporting at a scientific meeting.  A copy of any proposed manuscript 
must be provided and confirmed received at the Sponsor at least 30 days before its submission, 
and according to any additional publication details in the Investigator Agreement. 

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17.
LIST OF REFERENCES
1. 
Hill, Q.A. (2006). The incidence and prevalence of Paroxysmal Nocturnal Hemoglobinuria
(PNH) and survival of patients in Yorkshire. Blood, 108a: p. 294A.
2. Schrezenmeier, H. (2014). Baseline characteristics and disease burden in patients in the
International Paroxysmal Nocturnal Hemoglobinuria Registry. Haematologica, 99(5): p.
922-9.
3.
Lee, J.W. (2013). Clinical signs and symptoms associated with increased risk for
thrombosis in patients with paroxysmal nocturnal hemoglobinuria from a Korean Registry.
Int J Hematol, 97(6): p. 749-57.
4. 
Muus, P. (2010). Evaluation of Paroxysmal Nocturnal Hemoglobinuria Disease Burden:
The Patient
's Perspective. A Report From the International PNH Registry. Blood. 116.
5. de Latour, R.P. (2008). Paroxysmal nocturnal hemoglobinuria: natural history of disease
subcategories. Blood, 112(8): p. 3099-106.
6. 
Hillmen, P. (2004). Effect of eculizumab on hemolysis and transfusion requirements in
patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med, 350(6): p. 552-9.
7. Parker, C. (2005). Diagnosis and management of paroxysmal nocturnal hemoglobinuria.
Blood, 106(12): p. 3699-709.
8. 
Brodsky, R.A. (2010). Stem cell transplantation for paroxysmal nocturnal hemoglobinuria.
Haematologica, 95(6): p. 855-6.
9. 
Hillmen, P. (2006). The complement inhibitor eculizumab in paroxysmal nocturnal
hemoglobinuria. N Engl J Med, 355(12): p. 1233-43.
10. Brodsky, R.A. (2008). Multicenter phase 3 study of the complement inhibitor eculizumab
for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood, 111(4): p.
1840-7.
11. Hillmen, P. (2007). Effect of the complement inhibitor eculizumab on thromboembolism in
patients with paroxysmal nocturnal hemoglobinuria. Blood, 110(12): p. 4123-8.
12.
DeZern, A.E. (2013). Predictors of hemoglobin response to eculizumab therapy in
paroxysmal nocturnal hemoglobinuria. Eur J Haematol, 90(1): p. 16-24.
13. Parker, C.J. (2011). Management of paroxysmal nocturnal hemoglobinuria in the era of
complement inhibitory therapy. Hematology Am Soc Hematol Educ Program, 2011. p. 21-
9.
14. Kelly, R. (2008). Modification of the Eculizumab Dose to Successfully Manage 
Intravascular Breakthrough Hemolysis in Patients with Paroxysmal Nocturnal 
Hemoglobinuria 50th ASH Annual Meeting and Exhibition, 2008. Poster 
3441(https://ash.confex.com/ash/2008/webprogram/Paper11166.html).
15. Elbashir, S.M. (2001). Lendeckel, and T. Tuschl. RNA interference is mediated by 21- and
22-nucleotide RNAs. Genes Dev, 15: p. 188-200.

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16.Soutschek, J. (2004). Therapeutic silencing of an endogenous gene by systemic
administration of modified siRNAs. Nature, 432: p. 173-8.
17.Zimmermann, T.S. (2006). RNAi-mediated gene silencing in non-human primates. Nature,
441: p. 111-4.
18.Ashwell, G. (1974). The role of surface carbohydrates in the hepatic recognition and
transport of circulating glycoproteins. Adv Enzymol Relat Areas Mol Biol, 41: p. 99-128.
19.Seelen, M.A. (2005). Functional analysis of the classical, alternative, and MBL pathways of
the complement system: standardization and validation of a simple ELISA. J Immunol
Methods, 296: p. 187-98.
20.Ross, S.C. (1984). Complement deficiency states and infection: epidemiology, pathogenesis
and consequences of neisserial and other infections in an immune deficiency. Medicine,
63(5): p. 243-73.
21.Linder, J.A. (2005). Fluoroquinolone prescribing in the United States: 1995 to 2002. Am J
Med, 118: p. 259-68.
22.Soliris Eculizumab Assessment Report. CHMP variation assessment report
EMA/785583/2011.
23.Emergency treatment of anaphylactic reactions - Guidelines for healthcare providers. 
Annotated with links to NICE guidance July 2012, Review Date: 2013
http://www.resus.org.uk/pages/reaction.pdf
24.Jorgensen, J.H. (2005). Susceptibility of Neisseria meningitidis to 16 antimicrobial agents
and characterization of resistance mechanisms affecting some agents. J Clin Microbiol, 43:
p.3162-71.
25. Wu, H.M. (2009). Emergence of ciprofloxacin-resistant Neisseria meningitidis in North
America. N Engl J Med, 360: p. 886-92.
26.Corso, A. (2005). Emergence of Neisseria meningitidis with decreased susceptibility to
ciprofloxacin in Argentina. J Antimicrob Chemother, 55: p. 596-7.
27.

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18. 
APPENDICES 
Appendix 1:  Pharmacokinetic Assessment Time Points 
The following tables contain detailed PK schedules for the collection of blood and urine samples 
for PK analysis for the SAD (Part A), MAD (Part B), and MD (Part C) phases of the study. 
Table 10: 
Pharmacokinetic Time Points for Single-ascending Dose Cohorts 
(Part A) 
Protocol Time 
(hh:mm) 
PK Blood 
Urine PK 
Pooled Urine 
Predose (-60 minutes) 
X 
X 
 
00:00 (dose) 
 
 
X 
00:00-06:00 
00:30 (±2 mins) 
X 
 
01:00 (±5 mins) 
X 
 
02:00 (±15 mins) 
X 
 
04:00 (±15 mins) 
X 
 
06:00 (±15 mins) 
X 
X 
X 
06:00-12:00 
08:00 (±15 mins) 
X 
 
12:00 (±30 mins) 
X 
X 
X 
12:00-24:00 
24:00 (±120 mins) 
X 
X 
48:00 (±120 mins) 
X 
X 
 
 
 

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Table 11: 
Pharmacokinetic Time Points for Multiple-ascending Dose Cohorts 
(Part B)  Weekly Dosing 
Study Day 
Protocol Time 
(hh:mm) 
PK Blood Urine PK 
Pooled Urine 
Day 0 and Day 28 Predose (-60 minutes) 
X 
X 
 
 
00:00 (dose) 
 
 
X 
00:00-06:00 
 
00:30 (±2 mins) 
X 
 
 
01:00 (±5 mins) 
X 
 
 
02:00 (±15 mins) 
X 
 
 
04:00 (±15 mins) 
X 
 
 
06:00 (±15 mins) 
X 
X 
X 
06:00-12:00 
 
08:00 (±15 mins) 
X 
 
 
12:00 (±30 mins) 
X 
X 
X 
12:00-24:00 
Day 1 and Day 29 
24:00 (±120 mins) 
X 
X 
Day 2 and Day 30 
48:00 (±180 mins) 
X 
X 
 
 
Table 12: 
Pharmacokinetic Time Points for the Multiple-ascending Dose Phase 
(Part B)  Other Dosing Schedules 
Study Day 
Protocol Time 
(hh:mm) 
PK Blood Urine PK Pooled Urine 
Day 0 and Day 84 Predose (-60 minutes) 
X 
X 
 
 
00:00 (dose) 
 
 
X 
00:00-06:00 
 
00:30 (±2 mins) 
X 
 
 
01:00 (±5 mins) 
X 
 
 
02:00 (±15 mins) 
X 
 
 
04:00 (±15 mins) 
X 
 
 
06:00 (±15 mins) 
X 
X 
X 
06:00-12:00 
 
08:00 (±15 mins) 
X 
 
 
12:00 (±30 mins) 
X 
X 
X 
12:00-24:00 
Day 1 and Day 85 
24:00 (±120 mins) 
X 
X 
Day 2 and Day 86 
48:00 (±180 mins) 
X 
X 
 
 
 
 

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Table 13: 
Pharmacokinetic Time Points for the Multiple Dose Phase (Part C)  
13 Weekly Doses (Cohort 1) 
Study Day 
Protocol Time 
(hh:mm) 
PK Blood 
Urine PK 
Pooled Urine 
Day 0 and 
Day 84 
Predose (-60 minutes) 
X 
X 
 
 
00:00 (dose) 
 
 
X 
00:00-06:00 
 
00:30 (±2 mins) 
X 
 
 
01:00 (±5 mins) 
X 
 
 
02:00 (±15 mins) 
X 
 
 
04:00 (±15 mins) 
X 
 
 
06:00 (±15 mins) 
X 
X 
X 
06:00-12:00 
 
08:00 (±15 mins) 
X 
 
 
12:00 (±30 mins) 
X 
X 
X 
12:00-24:00 
Day 1 and 
Day 85 
24:00 (±120 mins) 
X 
X 
 
Table 14: 
Pharmacokinetic Time Points for the Multiple Dose Phase (Part C)  
5 Weekly Doses Followed by Once Every 2 Weeks Dosing or 
Followed by Monthly Dosing (Cohort 2 and Cohort 3) 
Study Day 
Protocol Time 
(hh:mm) 
PK Blood 
Urine PK 
Pooled Urine 
Day 0 
Predose (-60 
minutes) 
X 
X 
 
 
00:00 (dose) 
 
 
X 
00:00-06:00 
 
00:30 (±2 mins) 
X 
 
 
01:00 (±5 mins) 
X 
 
 
02:00 (±15 mins) 
X 
 
 
04:00 (±15 mins) 
X 
 
 
06:00 (±15 mins) 
X 
X 
X 
06:00-12:00 
 
08:00 (±15 mins) 
X 
 
 
12:00 (±30 mins) 
X 
X 
X 
12:00-24:00 
Day 1 
24:00 (±120 mins) 
X 
X 
 
 
 

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Appendix 2:  Schedules of Assessments for Alternative Dosing Regimens for 
Part B 
The following tables contain additional Schedules of Assessments for alternative dosing 
regimens which may be investigated in Part B of the study. 
 

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h. 12-lead ECGs will be measured in the supine position after the subject has rested comfortably for 10 minutes.  On Day 0, the ECG should be performed predose (-60 
minutes); and ±4 hours postdose .  After Day 0, the ECG should be performed predose (-60 minutes); and up to 12 hours postdose on days when study drug is 
administered. 
i. See Section 10.1.7.4 for viral serology parameters. 
j. Biochemistry, hematology, coagulation, and urinalysis parameters to be measured are described in Section 10.1.7. 
k. Collect blood samples for biochemistry and hematology only. 
l. SC injection of study drug per the Study Drug Administration Manual. 
m. Details regarding time points for collection of blood and urine samples for full PK analysis are outlined in Table 11  in the appendix (Section 18). 
n. Collect blood samples for PK analysis predose (-60 minutes); and 60±30 minutes postdose only.  Collect urine samples for PK analysis predose (-60 minutes) only. 
o. C5 levels will be measured by ELISA and/or mass spectrophotometry in a central laboratory. 
p. Serum complement activity includes:  CAP ELISA and CCP ELISA. 
q. 
 
  
 
r. See Section 10.4.2.1 for handling of ISRs. 
 
 

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e. Subjects will be treated with prophylactic ciprofloxacin from the first dose of study drug until serum complement activity returns to within the normal reference range as 
assessed by CAP ELISA or until the SRC makes a decision on a case-by-case basis to discontinue follow-up and antibiotic prophylaxis, whichever is sooner (see Section 
10.1.9 and Section 3.5.3). 
f. See Section 10.1.4 for assessments to be performed during a full and directed medical examination. 
g. Vital signs include blood pressure, heart rate, oral body temperature, and respiratory rate.  Vital signs will be measured in the supine position after the subject has rested 
comfortably for 10 minutes.  On Day 0, vital signs should be collected predose (-60 minutes); and 30±5 minutes and 4 hours (±15 minutes) postdose.  After Day 0, vital 
signs should be collected predose (-60 minutes); and up to 12 hours postdose on days when study drug is administered. 
h. 12-lead ECGs will be measured in the supine position after the subject has rested comfortably for 10 minutes.  On Day 0, the ECG should be performed predose (-60 
minutes); and ±4 hours postdose.  After Day 0, the ECG should be performed predose (-60 minutes); and up to 12 hours postdose on days when study drug is 
administered. 
i. See Section 10.1.7.4 for viral serology parameters. 
j. Biochemistry, hematology, coagulation, and urinalysis parameters to be measured are described in Section 10.1.7. 
k. Collect blood samples for biochemistry and hematology only. 
l. SC injection of study drug per the Study Drug Administration Manual. 
m. Details regarding time points for collection of blood and urine samples for full PK analysis are outlined in Table 11 in the appendix (Section 18). 
n. Collect blood samples for PK analysis predose (-60 minutes) and 60±30 minutes postdose only.  Collect urine samples PK analysis predose (-60 minutes) only. 
o. C5 levels will be measured by ELISA and/or mass spectrophotometry in a central laboratory. 
p. Serum complement activity includes:  CAP ELISA and CCP ELISA. 
q. 
 
  
. 
r. See Section 10.4.2.1 for handling of ISRs. 
 
 

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g. Vital signs include blood pressure, heart rate, oral body temperature, and respiratory rate.  Vital signs will be measured in the supine position after the subject has rested 
comfortably for 10 minutes.  On Day 0, vital signs should be collected predose (-60 minutes); and 30±5 minutes and 4 hours (±15 minutes) postdose.  After Day 0, vital 
signs should be collected predose (-60 minutes); and up to 12 hours postdose on days when study drug is administered. 
h. 12-lead ECGs will be measured in the supine position after the subject has rested comfortably for 10 minutes.  On Day 0, the ECG should be performed predose (-60 
minutes); and ±4 hours postdose .  After Day 0, the ECG should be performed predose (-60 minutes); and up to 12 hours postdose on days when study drug is 
administered. 
i. See Section 10.1.7.4 for viral serology parameters. 
j. Biochemistry, hematology, coagulation, and urinalysis parameters to be measured are described in Section 10.1.7. 
k. Collect blood samples for biochemistry and hematology only. 
l. SC injection of study drug per the Study Drug Administration Manual. 
m. Details regarding time points for collection of blood and urine samples for full PK analysis are outlined in Table 11 in the appendix (Section 18). 
n. Collect blood samples for PK analysis predose (-60 minutes) and 60±30 minutes postdose only.  Collect urine samples PK analysis predose (-60 minutes) only. 
o. C5 levels will be measured by ELISA and/or mass spectrophotometry in a central laboratory. 
p. Serum complement activity includes:  CAP ELISA and CCP ELISA. 
q. 
 
  
 
r. See Section 10.4.2.1 for handling of ISRs. 
 
 

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g. Vital signs include blood pressure, heart rate, oral body temperature, and respiratory rate.  Vital signs will be measured in the supine position after the subject has
rested comfortably for 10 minutes.  On Day 0, vital signs should be collected predose (-60 minutes); and 30±5 minutes and 4 hours (±15 minutes) postdose.  After
Day 0, vital signs should be collected predose (-60 minutes); and up to 12 hours postdose on days when study drug is administered.
h. 12-lead ECGs will be measured in the supine position after the subject has rested comfortably for 10 minutes.  On Day 0, the ECG should be performed predose (-
60 minutes); and ±4 hours postdose .  After Day 0, the ECG should be performed predose (-60 minutes); and up to 12 hours postdose on days when study drug is
administered.
i. See Section 10.1.7.4 for viral serology parameters.
j. Biochemistry, hematology, coagulation, and urinalysis parameters to be measured are described in Section 10.1.7.
k. Collect blood samples for biochemistry and hematology only.
l. SC injection of study drug per the Study Drug Administration Manual.
m. Details regarding time points for collection of blood and urine samples for full PK analysis are outlined in Table 11 in the appendix (Section 18).
n. Collect blood samples for PK analysis predose (-60 minutes) and 60±30 minutes postdose only.  Collect urine samples PK analysis predose (-60 minutes) only.
o. C5 levels will be measured by ELISA and/or mass spectrophotometry in a central laboratory.
p. Serum complement activity includes:  CAP ELISA and CCP ELISA.
q.
.
r. See Section 10.4.2.1 for handling of ISRs.

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g. Vital signs include blood pressure, heart rate, oral body temperature, and respiratory rate.  Vital signs will be measured in the supine position after the subject has rested 
comfortably for 10 minutes.  On Day 0, vital signs should be collected predose (-60 minutes); and 30±5 minutes and 4 hours (±15 minutes) postdose.  After Day 0, vital 
signs should be collected predose (-60 minutes); and up to 12 hours postdose on days when study drug is administered. 
h. 12-lead ECGs will be measured in the supine position after the subject has rested comfortably for 10 minutes.  On Day 0, the ECG should be performed predose (-60 
minutes); and ±4 hours postdose.  After Day 0, the ECG should be performed predose (-60 minutes); and up to 12 hours postdose on days when study drug is 
administered. 
i. See Section 10.1.7.4 for viral serology parameters. 
j. Biochemistry, hematology, coagulation, and urinalysis parameters to be measured are described in Section 10.1.7. 
k. Collect blood samples for biochemistry and hematology only. 
l. SC injection of study drug per the Study Drug Administration Manual. 
m. Details regarding time points for collection of blood and urine samples for full PK analysis are outlined in Table 11 in the appendix (Section 18). 
n. Collect blood samples for PK analysis predose (-60 minutes) and 60±30 minutes postdose only.  Collect urine samples PK analysis predose -60 minutes) only. 
o. C5 levels will be measured by ELISA and/or mass spectrophotometry in a central laboratory. 
p. Serum complement activity includes:  CAP ELISA and CCP ELISA. 
q. 
 
  
 
r. See Section 10.4.2.1 for handling of ISRs. 

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Appendix 3:  Schedules of Assessments for Alternative Dosing Regimens for 
Part C 
The following tables contain additional Schedules of Assessments for alternative dosing 
regimens which may be investigated in Part C of the study.

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o. Serum complement activity includes:  CAP ELISA and CCP ELISA. 
p. Exploratory
 are described in Section 9.3 . 
q. See Section 10.4.2.1 for handling of ISRs. 
r. Collect blood samples for biochemistry and hematology only. 
 
 

ALN-CC5 
     Clinical Study Protocol ALN-CC5-001 
Amendment 4_16 August 2016 
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g. 12-lead ECGs will be measured in the supine position after the subject has rested comfortably for 10 minutes.  On Day 0, the ECG should be performed predose (-60 
minutes); and ±4 hours postdose.  After Day 0, the ECG should be performed predose (-60 minutes); and up to 12 hours postdose on days when study drug is 
administered. 
h. See Section 10.1.7.4 for viral serology parameters. 
i. Biochemistry, hematology, coagulation, and urinalysis parameters to be measured are described in Section 10.1.7. 
j. For patients receiving treatment with eculizumab, a blood sample for the measurement of eculizumab levels will be collected before and 60±30 minutes after each 
treatment with eculizumab.  Single weekly samples will be taken on the weeks between eculizumab treatments on the days that ALN-CC5 is administered.  If eculizumab 
treatment is stopped, weekly samples will be taken, thereafter. 
k. SC injection of study drug per the Study Drug Administration Manual.  Patients on stable doses of eculizumab will continue receiving treatment concomitantly with 
ALN-CC5; patients will receive their last dose of eculizumab when at least 2 consecutive measurements of C5 levels demonstrate a degree of suppression consistent with 
complement inhibition.  Patients who are naïve to eculizumab treatment may begin ALN-CC5 administration.  ALN-CC5 may be administered at home between visits to 
the clinical study center by a home healthcare provider trained in the administration of ALN-CC5. 
l. Details regarding time points for collection of blood and urine samples for full PK analysis are outlined in Table 14 in the appendix (Section 18). 
m. Collect a blood and urine sample for PK analysis at any time during the visit. 
n. C5 levels will be measured by ELISA and/or mass spectrophotometry in a central laboratory. 
o. Serum complement activity includes:  CAP ELISA and CCP ELISA. 
p. Exploratory
 are described in Section 9.3. 
q. See Section 10.4.2.1 for handling of ISRs. 
r. Collect blood samples for biochemistry and hematology only. 
 
 

ALN-CC5 
     Clinical Study Protocol ALN-CC5-001 
Amendment 4_16 August 2016 
Alnylam Pharmaceuticals                                                                          Confidential                                                                                                                     130 
j. For patients receiving treatment with eculizumab, a blood sample for the measurement of eculizumab levels will be collected before and 60±30 minutes after each 
treatment with eculizumab.  Single samples will be collected on the weeks between eculizumab treatments on the days that ALN-CC5 is administered.  If eculizumab 
treatment is stopped, samples will be collected, thereafter, according to the dosing regimen administered. 
k. SC injection of study drug per the Study Drug Administration Manual.  Patients on stable doses of eculizumab will continue receiving treatment concomitantly with 
ALN-CC5; patients will receive their last dose of eculizumab when at least 2 consecutive measurements of C5 levels demonstrate a degree of suppression consistent with 
complement inhibition.  Patients who are naïve to eculizumab treatment may begin ALN-CC5 administration. 
Patients will return to the study center on days when study drug is administered.  Assessments will be performed according to the dosing regimen administered.  
ALN-CC5 may be administered at home between visits to the clinical study center by a home healthcare provider trained in the administration of ALN-CC5. 
l. Collect a blood and urine sample for PK analysis at any time during the visit. 
m. C5 levels will be measured by ELISA and/or mass spectrophotometry in a central laboratory. 
n. Serum complement activity includes:  CAP ELISA and CCP ELISA. 
o. Exploratory
 are described in Section 9.3. 
p. See Section 10.4.2.1 
for handling of ISRs.