Conditions: Paroxysmal Nocturnal Hemoglobinuria
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 15
Healthy volunteers: no

Brief summary:
Long term management of patients with complement related diseases including Paroxysmal Nocturnal Haemoglobinuria and Atypical Haemolytic Uraemic Syndrome

Detailed description:
Patients with diseases requiring complement inhibition who have previously taken part in Akari clinical trials and who wish to continue to receive rVA576 (Coversin) after their active participation in the parent trial has completed and patients treated under compassionate use or named patient arrangements who wish to continue on rVA576 (Coversin) therapy

Arms:
arm 1: The study population will consist of patients who have completed participation in clinical trials under other Akari protocols and who wish to continue to receive rVA576 (Coversin) for up to 4 years.

Interventions: intervention 1: rVA576
Intervention descriptions: intervention 1: The study population will consist of patients who have completed participation in clinical trials under other Akari protocols and who wish to continue to receive rVA576 (Coversin).

Protocol document:
Prot_000.pdf: 
 
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Akari Protocol AK581 V3.0   
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© Akari Therapeutics PLC 2016 
    
 
 
 
 
 
 
 
CONSERVE: rVA576 (Coversin) Long Term Safety and Efficacy Surveillance Study 
 
 
PROTOCOL NUMBER:  
AK581 
 
DATE:  
 
 
11 January 2019 
 
VERSION NUMBER: 
3.0 
 
SPONSOR:   
            Akari Therapeutics Plc 
 
EudraCT number                    2016-004129-18 
 
This protocol is the property of Akari Therapeutics, Plc. It is provided subject to the 
recipient’s agreement to maintain it in confidence, and is intended solely for the 
guidance of this clinical investigation. This protocol may only be disclosed to those 
associated with the clinical investigation who have a need to know and who have 
agreed in advance to maintain it in confidence. It may not be disclosed with any third 
party or used other than for its intended purpose unless approved in advance and in 
writing by Akari Therapeutics Plc. 
 
 
 
 
 


 
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© Akari Therapeutics PLC 2016 
  
SPONSOR ADDRESS:                                   Akari Therapeutics Plc. 
 
 
  
 
 
 
 
AUTHORISED SIGNATORIES: 
 
 
 
 
 
 
 
 
 
 
SPONSOR’S MEDICAL EXPERT:  
 
 
 
 
 Akari Therapeutics Plc.  
 
  
 
 
 
 
 
 
 
24 HOUR MEDICAL CONTACT:                
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                         
                                                                        
 
 
 
 
  
 
CENTRAL LAB 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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List of Abbreviations 
Abbreviation 
Definition/Term 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
aHUS 
Atypical Haemolytic Uraemic Syndrome 
AD 
Ablating Dose  
CH50 U q/mL 
Classical haemolytic 50% lysis Units Equivalent/mL 
CRO 
Contract Research Organisation 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-Linked Immunosorbent Assay 
EORTC 
European Organisation for Research and Treatment of Cancer  
ESRD 
End Stage Renal Disease 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GvHD 
Graft versus host disease 
HED 
Human Equivalent Dose 
ICF 
Informed Consent Form 
ICH 
International Committee on Harmonisation 
IMP 
Investigational Medical Product 
IRB 
Institutional Review Board (or equivalent, e.g. Ethics Committee) 
ITT 
Intention to Treat 
LDH 
lactate dehydrogenase 
LEC 
Local Ethics Committee 
MAC 
Membrane Attack Complex 
MG 
Myasthenia gravis 
MW 
Molecular Weight 
NHP 
Non-human Primate 
NOAEL 
No Observable Adverse Event Level 
OmCI 
Ornithodoros moubata Complement Inhibitor 
PBS 
Phosphate-buffered Saline 
PEX 
Plasma Exchange 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PNH 
Paroxysmal Nocturnal Haemoglobinuria 
PP 
Per Protocol 
QA 
Quality Assurance 
QC 
Quality Control 
QoL 
Quality of Life 
s.c. 
Subcutaneous 
SAE 
Serious Adverse Event 


 
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Abbreviation 
Definition/Term 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedures 
STEC 
Shiga toxin-producing Escherichia coli 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TCA 
Terminal Complement Activation 
TMA 
Thrombotic microangiopathy 
TTP 
Thrombotic Thrombocytopaenic Purpura 
ULN 
Upper limit of normal 
WFI 
Water for Injection 
 
 




 
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Contents 
List of Abbreviations ................................................................................................................. 3 
Protocol Signature Page ............................................................................................................. 5 
1. 
Introduction ...................................................................................................................... 13 
 
PNH ........................................................................................................................... 13 
 
aHUS ......................................................................................................................... 14 
2. 
Prior Experience with the Investigational Product .......................................................... 14 
 
Investigational Product .............................................................................................. 14 
 
Summary of non-clinical and clinical studies relevant to the clinical trial ............... 16 
 
Non-clinical ....................................................................................................... 18 
 
Clinical .............................................................................................................. 19 
 
Previous experience in patients ................................................................................. 21 
 
Summary of known and potential risks and benefits to human subjects .................. 23 
 
Description of and justification of route of administration, dosage regimen and 
treatment period(s) ............................................................................................................... 29 
3. 
Trial Purpose, Objectives and Endpoints ......................................................................... 32 
 
Trial purpose & Objectives ....................................................................................... 32 
 
Endpoints ................................................................................................................... 33 
 
Safety & Efficacy Endpoints: ............................................................................ 33 
Additional Endpoints: ................................................................................................... 35 
4. 
Trial population ................................................................................................................ 35 
 
Inclusion criteria ........................................................................................................ 35 
 
Exclusion criteria....................................................................................................... 36 
 
Meningitis.................................................................................................................. 36 
 
Meningitis prophylaxis .................................................................................... 36 
 
Active Meningococcal Infection ...................................................................... 37 
 
Concomitant Therapy ................................................................................................ 37 
 
Prohibited Medications ............................................................................................. 37 
 
Contraception ............................................................................................................ 37 
 
Exposure of partners during the study .......................................................... 38 
 
Sperm Donation ............................................................................................... 38 
 
Egg Donation .................................................................................................... 39 
 
Breast Feeding .................................................................................................. 39 
5. 
Trial Design and Procedures ............................................................................................ 39 
 
Trial Design: .............................................................................................................. 39 


 
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Dose Changes: ........................................................................................................... 39 
5.3 Duration of trial.............................................................................................................. 40 
5.4 Trial procedures ............................................................................................................. 40 
5.4.1  
Screening ........................................................................................................... 40 
5.4.2 
 Dosing period(s) .............................................................................................. 41 
5.4.3  
Exiting the trial ................................................................................................ 41 
5.4.4  
End of Study/Follow-up ................................................................................... 41 
5.5 
Measurements conducted on blood draws ................................................................ 51 
5.5.1 
CH50 assay ....................................................................................................... 51 
5.5.2 
Antibodies (ADA) ............................................................................................. 51 
5.5.3 
LTB4.................................................................................................................. 51 
5.5.4 
LDH Isoenzymes .............................................................................................. 51 
5.5.5 
Total C5 Levels ................................................................................................. 51 
5.5.6 
Fluorescein-labelled proaerolysin FLAER / Flow Cytometry ..................... 51 
5.5.8 
Pharmacokinetics (PK) and Pharmacodynamics (PD) (aHUS only) .......... 52 
5.6 
Efficacy Assessments ................................................................................................ 52 
5.7 
Safety Assessments ................................................................................................... 52 
5.9 
Definition of an inadequate response ........................................................................ 56 
5.10 Missed doses ............................................................................................................. 56 
5.11 Rescue Therapy (aHUS only) ................................................................................... 57 
5.11.1 Plasma Transfer (aHUS only) ......................................................................... 58 
5.11.2 Dialysis / Haemofiltration................................................................................ 58 
5.12 Quality of life questionnaires (EORTC QLQ C30 , EQ-5D-5L & FACIT-F) .......... 59 
6 
Stopping Rules and Discontinuation Procedures ............................................................. 59 
6.1 
Termination or suspension of the study .................................................................... 59 
6.2 
Withdrawal criteria .................................................................................................... 60 
6.3 
Accountability procedures......................................................................................... 61 
6.4 
Compliance................................................................................................................ 61 
6.5 
Interruption of Treatment .......................................................................................... 62 
7 
Safety Reporting .............................................................................................................. 62 
7.1 
Safety Definitions ...................................................................................................... 62 
7.1.1 
Adverse Event .................................................................................................... 62 
7.1.2 
Adverse Drug Reaction ...................................................................................... 62 
7.1.3 
Unexpected Adverse Reaction ........................................................................... 63 
7.1.4 
Serious Adverse Event (SAE) or Serious Adverse Reaction ............................. 63 


 
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7.1.5 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ............................ 63 
7.2 
Procedures for Recording of Adverse Events ........................................................... 64 
7.2.1 
General ............................................................................................................... 64 
7.2.2 
Pre-existing Conditions ...................................................................................... 65 
7.2.3 
Overdose ............................................................................................................ 65 
7.2.4 
Pregnancy ........................................................................................................... 66 
7.2.5 
Reporting of Adverse Events ............................................................................. 66 
7.3 
Reporting Procedures for Serious Adverse Events ................................................... 67 
7.4 
Expedited Safety Reporting ...................................................................................... 67 
7.5 
Development Safety Update Reports ........................................................................ 68 
8 
Data Handling and Source Documents ............................................................................ 68 
9 
Statistics ........................................................................................................................... 69 
9.1 
Statistical methods..................................................................................................... 69 
9.2 
Number of patients .................................................................................................... 71 
9.3 
Interim analyses......................................................................................................... 71 
9.4 
Assessment of pharmacokinetics and complement activity ...................................... 71 
9.5 
Significance level ...................................................................................................... 71 
9.6 
Missing, unused or spurious data .............................................................................. 71 
9.7 
Deviation from the statistical analysis plan............................................................... 71 
9.8 
Patients to be included in the statistical analysis....................................................... 71 
10 Quality Control and Assurance ........................................................................................ 72 
11 Ethical Conduct of the Study ........................................................................................... 72 
11.1 Ethical considerations and EC approval.................................................................... 72 
12 Financing, Indemnity and Insurance ................................................................................ 72 
13 Publication Policy ............................................................................................................ 73 
14 Study Record Retention ................................................................................................... 73 
14.1 Clinical study report (CSR) ....................................................................................... 74 
14.2 Handling and retention of blood and pathological samples ...................................... 74 
15 References ........................................................................................................................ 75 
16 Appendices ....................................................................................................................... 77 
 


 
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Protocol Title: 
 
CONSERVE: rVA576 (Coversin) Long Term Safety and Efficacy 
Surveillance Study 
Protocol Number: 
 
AK581  
Sponsor: 
 
Akari Therapeutics Plc 
 
 
 
Investigational Product(s): 
 
rVA576 (Coversin) powder for solution for subcutaneous injection, 
18mg/vial 
Phase of Development: 
 
III 
Indication: 
Long term management of patients with 
diseases including PNH and aHUS 
Study Center(s): 
 
Multi-centre  
Objectives: 
Primary Objective:  
To determine the safety profile of long-term rVA576 (Coversin) treatment. 
 
 
 
Study Design: 
Open-label, non-comparative 
 
Planned Number of Subjects: 
Approximately 50 patients 
 
Subject Population: 
 
Patients with diseases requiring complement inhibition who have previously 
taken part in Akari clinical trials and who wish to continue to receive 
rVA576 (Coversin) after their active participation in the previous trial has 
completed  and patients treated under compassionate use or named patient 
arrangements who wish to continue on rVA576 (Coversin) therapy. 
 
Criteria for Inclusion: 
Inclusion Criteria: 
 
1) Patients 18 years and above treated with rVA576 (Coversin) under 
other Akari clinical trial protocols and wish to remain on rVA576 
(Coversin) at the conclusion of that trial. 
2) In the opinion of the treating responsible clinician patient is 
receiving clinical benefit from continued treatment with study 
drug.  
3) Evidence of sustained complement inhibition by CH50 assay. 
4) Women of childbearing potential (WOCBP) must agree to use 
effective contraception consistently throughout the study and have 
a negative pregnancy test at screening.Women are considered post-
menopausal and not of childbearing potential if they have had 12 
months of amenorrhea and considered sterile if they have had 
surgical bilateral oophorectomy (with or without hysterectomy) or 
tubal ligation at least six weeks previously. 
5) Males with a childbearing potential partner must agree to use 
effective contraception consistently OR have had a vasectomy. 
6) Weight >50kg.  
 


 
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7) Received appropriate prophylaxis against Neisseria meningitidis 
infection, by both immunisation and continuous or intermittent 
antibiotics. 
8) Patient is willing to give voluntary written informed consent.  
9) The patient is willing in the process of preparation and self-
administration of the study drug. 
 
 Criteria for Exclusion: 
Exclusion Criteria: 
 
1. Patient experienced any safety event in the previous study protocol, 
which puts the patient at unacceptable risk in the current protocol 
in the clinical judgement of the investigator and sponsor.  
2. 
Patient is unwilling to complete the Quality of Life instruments and 
diary cards. 
3. Active meningococcal infection (section 4.3.2 for additional 
information).  
4. Any other reason for which, in the opinion of the Investigator, it 
would not be in the interests of the patient to remain on rVA576 
(Coversin). 
5. If female, the subject is pregnant or lactating or intending to 
become pregnant before, during, or within 90 days after last dose; 
or intending to donate ova during such period. 
6. If male, the subject intends to donate sperm during this study or 
for 90 days after last dose. 
7. Failure to satisfy the Investigator of fitness to participate for any 
other reason or any condition which, in the opinion of the 
investigator, could increase the subject's risk from participating in 
the study or confound the outcome of the study. 
8. Use of prohibited medication (e.g. Eculizumab (Soliris®), 
Chemotherapeutic agents, any other drug acting directly on the 
complement system). 
9. The subject has a history of drug abuse (defined as any illicit drug 
use) or a history of alcohol abuse within one year prior to 
screening. 
10. Participation in other clinical trials with investigational product. 
  
Concurrent control 
None 
 
Treatment Regimen: 
 
Test Product, Dose and Mode of Administration:  
 
rVA576 (Coversin) 18 mg/vial powder for solution for injection. When the 
contents of one vial are reconstituted with 0.6 mL Water for Injection 
(WFI) and drawn up according to the instruction manual the resulting 
solution consists of rVA576 (Coversin) 30mg/mL in an extractable volume 
of greater than or equal to 0.5mL phosphate-buffered saline (PBS), pH 7.2. 
The product is administered subcutaneously.  
 
It is expected that all patients being treated under this protocol will have 
been on a stable dose of rVA576 (Coversin) prior to entering the study and 
will remain on that dose initially. Should a change in dose or dose 


 
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frequency become desirable, the responsible investigator will have 
discretion to alter the treatment regime in consultation with the Sponsor’s 
medical representative. During any such changes careful monitoring of 
complement inhibition is mandatory and this should include regular 
assessment of haematological/biochemical parameters (e.g. serum LDH) 
and CH50 as well as the patient’s clinical status. 
 
In the event of an increase of dose or dose frequency, an ablating dose  (AD) 
may be given to ensure complete complement inhibition before the new dose 
is started. It is assumed that a reduction of dose or dose frequency would 
only be considered if the patient’s prior complement control was adequate 
and so no AD need be given before commencing the new dose.  
 
The ablating dose (AD) consists of 2 doses; an initial dose of 60mg followed 
12 hours later by 1 dose of 30mg. A suggested regimen to be followed in the 
event of an inadequate response to rVA576 (Coversin) treatment is given 
below: 
 
 PNH patients 
 
Ablating Doses (if required) 
Dose 
Interval 
60mg 
Single dose 
30mg 
1  x 12 hourly dose 
Inadequate Response 
Existing 
Switch to 
Dose 
Interval 
Dose 
Interval 
15mg 
12 hourly 
22.5mg 
12 hourly 
22.5mg 
12 hourly 
45mg 
24 hourly 
30mg 
24 hourly 
45mg 
24 hourly 
45mg 
24 hourly 
22.5mg 
12 hourly 
 
aHUS patients  
 
Ablating Doses (if required) 
Dose 
Interval 
60mg 
Single dose 
30mg 
1 x 12 hourly dose 
Inadequate Response 


 
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Existing 
Switch to 
Dose 
Interval 
Dose 
Interval 
30mg 
12 hourly 
After assessment decision will be 
made in collaboration with the 
Sponsor and PI. 
45mg  
24 hourly 
30mg 
12 hourly 
 
 
 
 
 Duration of Treatment: 
 Up to 4 years 
 
Patients for whom rVA576 (Coversin)  was found to be effective in this 
clinical trial and who wish to continue on the drug following conclusion of 
this trial, will continue to receive rVA576 (Coversin), subject to approval of 
the applicable governmental agency, until rVA576 (Coversin) receives 
marketing approval or another treatment of benefit becomes available.  If 
Akari encounters any issues with the availability of the drug, it will allocate 
available drug to such patients in a manner which is fair and consistent with 
ethical requirements. 
 


 
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1. Introduction 
rVA576 (Coversin) is a small protein complement C5 inhibitor which prevents the 
cleavage of C5 by C5 convertase into C5a and C5b and thereby inhibits generation of 
the membrane attack complex, C5b-9 (MAC). It is effective in inhibiting terminal 
complement activity irrespective of the activating pathway. 
 
 
 
 
 
 
 
 
 
  
 PNH 
PNH is an acquired genetic haemolytic anaemia, in which failure to synthesise GPI-
anchored proteins prevents affected blood cells from attaching the complement 
regulatory proteins CD55 and CD59 to their surface, making them vulnerable to attack 
by normal background complement activity. The resulting intravascular haemolysis of 
affected red blood cells (RBC) causes free haemoglobin to be released into the 
bloodstream. Some lysis of RBC may also be extravascular caused by complement 
deposition on cell surfaces and subsequent phagocytosis via the reticulo-endothelial 
system, in particular Kupfer cells and splenic phagocytes [Brodsky et al, 2014]. In the 
bloodstream, free haemoglobin causes depletion of nitric oxide with resultant smooth 
muscle spasm causing or contributing to symptoms such as dysphagia, erectile 
dysfunction, abdominal pain and, possibly, pulmonary hypertension. 
PNH is characterised by red blood cell haemolysis, large vessel thrombosis particularly 
affecting the hepatic, visceral, cerebral and dermal veins and impaired haematopoiesis. 
The relationship between aplastic anaemia and PNH is not fully understood, however 
there is a greater incidence of PNH in patients with a history of aplastic anaemia, 
possibly because PNH clones have a higher rate of proliferation in this condition than 
normal stem cells. Treatment of aplastic anaemia with immunosuppressants is known 
to increase PNH clone size but whether the cells so produced are more or less 
susceptible to haemolysis than other PNH cells remains controversial. PNH patients 
with bone marrow aplasia are more likely to require blood transfusion because of the 
impaired production of normal red cells. 
Treatment of PNH is by bone marrow allograft or, where available, by terminal 
complement blockade with the only approved complement C5 inhibitor, the 
monoclonal antibody eculizumab. Untreated, patients with PNH have a reduced life 
expectancy, principally because of major thrombotic events. Side effects of repeated 
blood transfusion, such as iron accumulation, also contribute to the morbidity of the 
disease. 
 














 
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T
 
 
 
 
 
 
 
 Description of and justification of route of administration, dosage regimen 
and treatment period(s) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 




 
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3. Trial Purpose, Objectives and Endpoints 
 Trial purpose & Objectives 
The objective of the trial is to provide a database of information regarding long-term 
administration of rVA576 (Coversin) to show that it remains safe for long periods and is 


 
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acceptable to patients and show that the effect observed in the previous clinical trial is 
maintained. It also provides the opportunity to adjust an individual patient’s dose or dose 
frequency should it be considered desirable. All patients enrolled into the CONSERVE 
study will have transitioned from a parent clinical trial. 
 
The specific objectives of the study are: 
• To observe the long term safety and efficacy of rVA576 (Coversin) in a period 
exceeding the 6 months of treatment.  
• To assess the long term patient acceptability of rVA576 (Coversin) using the 
EORTC QLQ-C30 (for some PNH only),  EQ-5D-5L & FACIT-F (both PNH 
& aHUS)  instruments and the Sponsor non validated questionnaire. 
• To observe the changes, if any, in the production of anti-drug antibodies (ADA) 
and whether such antibodies are, or become, neutralising 
 
 Endpoints 
 Safety & Efficacy Endpoints:  
Primary:   
• Long term safety of rVA576 (Coversin) therapy as assessed by AEs, serious 
adverse events (SAEs), vital signs, results of standard laboratory tests (clinical 
chemistry, haematology and urinalysis), and results of electrocardiograms (ECGs). 
 
PNH Secondary:  
1. Proportion of subjects with thrombotic and haemolytic event-free status   
during each 3 month time period since the start of the study. 
2. Time to thrombotic or haemolytic event since the start of the  study.  
3. Proportion of subjects who require PRBC transfusion during each 3-month 
period since the start of the study and over the entire period of the study, 
with analysis of i) subjects who were transfusion-dependent when they 
started receiving rVA576 (Coversin), ii) subjects who were transfusion-
independent when they started receiving rVA576 (Coversin), and iii) all 
subjects, and further stratification of these proportions by a) patients who 
were complement inhibitor-naïve prior to treatment with rVA576 
(Coversin), and b) patients who received treatment with another 
complement inhibitor before switching to rVA576 (Coversin).   
4. Time to first transfusion since joining the study.  
5. Proportion of subjects with no adverse change in overall scores of Quality 
of Life using the EORTC QLQ-C30, the EQ-5D-5L and FACIT-F 
instruments at each 3-month time period since the start of the study. 
6. Proportion of subjects with serum Lactate Dehydrogenase (LDH) <1.8, >1.8 
to 2.4, >2.4 to 3, and >3 times the upper limit of normal (ULN) at each 3-
month time period since the start of the study.  


 
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7. Proportion of subjects with median serum Lactate Dehydrogenase (LDH) 
<1.8, >1.8 to 2.4, >2.4 to 3, and >3 times the upper limit of normal 
(ULN) over the entire duration of the study. 
8. Proportion of transfusion-independent subjects at each 3-month time point, 
with haemoglobin (g/L) above the baseline haemoglobin value they had at 
the start of the trial from which they entered CONSERVE. With baseline 
for CAPSTONE (AK580) defined as the haemoglobin value at which they 
received their qualifying transfusion (the set point) or for COBALT 
(AK579) and CONSENT (AK578) the haemoglobin value at which patients 
entered those trials.  With separate analysis of subjects who were i) 
transfusion-independent prior to receiving rVA576 (Coversin) and remain 
transfusion-independent and ii) transfusion-dependent prior to receiving 
rVA576 (Coversin). 
9. Proportion of transfusion-independent subjects over the entire duration of 
the study with mean haemoglobin (g/L) above the baseline haemoglobin 
value they had at the start of the trial from which they entered CONSERVE. 
With baseline haemoglobin defined as for the previous secondary endpoint 
(#8).  With separate analysis of subjects who were i) transfusion-
independent prior to receiving rVA576 (Coversin) and remain transfusion-
independent and ii) transfusion-dependent prior to receiving rVA576 
(Coversin). 
10. Proportion of patients experiencing Major Adverse Vascular Events 
(MAVE) over the entire period of the study. 
11. Time to first Major Adverse Vascular Event (MAVE) for each subject since 
joining the study. 
12. Number of Major Adverse Vascular Events (MAVE) over the entire period 
of the study. 
 
aHUS Secondary:  
1. Proportion of subjects with Normal Platelet count [defined as Platelet count 
≥ 150 x109/L] at each 3-month time point since the start of the study and 
over the entire period of the study. 
2. Proportion of subjects entering study with complete TMA response who 
continue to exhibit complete TMA response with preserved renal function, 
defined as hematologic normalization (platelet count ≥150 X 109/L and 
LDH ≤ ULN) and preservation of kidney function (<25% increase in SCr 
from baseline of previous study), during each 3-month time period since the 
start of this study. 
3. Proportion of subjects with complete TMA response with improved renal 
function defined as normalization of haematological parameters 
(normalisation of platelet count and LDH≤ULN) and ≥ 25% decrease in SCr 
from baseline of previous study during each 3-month time period since the 
start of the study. 
4. Proportion of subjects who exhibit haematological normalisation (platelet 
count ≥150 X 109/L and LDH ≤ ULN) during each 3-month time period 
since the start of this study. 


 
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5. Proportion of subjects with improvement in renal function defined as a 
decrease in SCr over three consecutive measurements from baseline of 
previous study without the need for dialysis even if not within the normal 
range.  
6. Proportion of subjects who are TMA event-free during each 3-month time 
period since the start of the study. 
7. Platelet mean count change at each 3-month time period since the start of 
the study. 
8. Quality of Life measures from baseline at 3 monthly intervals up to the end 
of study in FACIT-F instrument and the EQ-5D-5L instrument.  
 
Additional Endpoints: 
• 
PK and PD parameters during treatment. 
 
4. Trial population 
The study population will consist of patients who have completed participation in clinical 
trials under other Akari protocols and who wish to continue to receive rVA576 (Coversin). 
Patients may be male or non-pregnant females using adequate methods of contraception if 
of childbearing potential. All patients will enter the trial on the same dose and dose 
frequency as they were receiving at the end of the previous trial.  
 Inclusion criteria  
 
1) Patients 18 years and above treated with rVA576 (Coversin) under other Akari clinical 
trial protocols and wish to remain on rVA576 (Coversin) at the conclusion of that trial. 
2) In the opinion of the treating responsible clinician patient is receiving clinical benefit 
from continued treatment with study drug.  
3) Evidence of sustained complement inhibition by CH50 assay. 
4) Women of childbearing potential (WOCBP) must agree to use effective contraception 
consistently throughout the study and have a negative pregnancy test at screening. 
Women are considered post-menopausal and not of childbearing potential if they have 
had 12 months of amenorrhea and considered sterile if they have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks 
previously. 
5) Males with a childbearing potential partner must agree to use effective contraception 
consistently OR have had a vasectomy. 
6) Weight ≥50kg.  
7) Received appropriate prophylaxis against Neisseria meningitidis infection, by both 
immunisation and continuous or intermittent antibiotics. 
8) The patient is willing to give voluntary written informed consent.  
9) The patient is willing in the process of preparation and self-administration of the 
study drug. 
  


 
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 Exclusion criteria  
1. Patient experienced any safety event in the previous study protocol, which puts the 
patient at unacceptable risk in current protocol as judged by the investigator and 
sponsor.  
2. Patient is unwilling to complete the Quality of Life instruments and diary card. 
3. Active meningococcal infection  (section 4.3.2 for additional information). 
4. Any other reason for which, in the opinion of the Investigator, it would not be in the 
interests of the patient to remain on rVA576 (Coversin). 
5. If female, the subject is pregnant or lactating or intending to become pregnant before, 
during, or within 90 days after last dose; or intending to donate ova during such time 
period. 
6. If male, the subject intends to donate sperm during this study or for 90 days after last 
dose. 
7. Failure to satisfy the Investigator of fitness to participate for any other reason or any 
other condition which, in the opinion of the investigator, could increase the subject's 
risk from participating in the study or confound the outcome of the study. 
8. Use of prohibited medication (e.g. Eculizumab (Soliris®), Chemotherapeutic agents, 
any other drug acting directly on the complement system). 
9. The subject has a history of drug abuse (defined as any illicit drug use) or a history of 
alcohol abuse within one year prior to screening. 
10. Participation in other clinical trials with investigational product. 
 
 Meningitis  
 Meningitis prophylaxis 
It is known that the products of C5 complement activation are important in protection 
against infection by gram negative bacteria especially Neisseria sp. [Ram et al, 2010]. 
This is believed to be the only known hazard of blocking this stage of the complement 
cascade and subjects taking part in previous trials of complement C5 inhibitors were 
found to be at greater risk of Neisseria infection, particularly meningococcal infection 
[Dymtrijuk et al, 2008].  
Prophylaxis against Neisseria Meningitis. will be mandatory  in this study and may 
consist of either or both active immunisation against meningitis A, C, W and Y (and B 
in countries where the Bexsero® vaccine is approved) and prophylactic antibiotics. The 
exact nature of meningococcal prophylaxis during complement inhibitor therapy will 
be according to local practice/guidelines  and will be recorded in the eCRFs.  
The patient would have been vaccinated for prophylaxis against meningitis during the 
previous study and similar vaccination is not required to be repeated at the beginning 
of this study.The patient’s history of meningococcal vaccines will be transferred from 
the previous study they participated in. 
In this study the anti-meningococcal measures employed in individual cases will be at 
the discretion of the Investigators and in accordance with local practice.  In limited 
duration toxicological studies, with both eculizumab and rVA576 (Coversin), no 
adverse events or findings attributable to C5 blockade have been reported but 


 
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Investigators are advised to be alert for possible infectious events even in subjects who 
have received meningococcal immunisation.  
 Active Meningococcal Infection 
The patient with active meningococcal or other significant infection at screening will 
undergo risk benefit assessment by the investigator and sponsor for continuing to 
receive AK581 study treatment. On risk-benefit assessment, if the treatment with 
rVA576 (Coversin did not continue, the eligibility for enrolment in AK581 study will 
be evaluated after treatment of infection. 
 
 
 Concomitant Therapy 
At screening, the PI will ask the patient about any medication that is currently ongoing. 
During the course of the study, patients should be reminded to record any concomitant 
medications in their patient diaries and the PI should discuss medications at each visit. 
All concomitant medications, including herbal and vitamin supplements, must be 
recorded in the diary card/patient medical records and captured in electronic case report 
form (eCRF). 
 Prohibited Medications 
The following medications are not permitted whilst the patient is taking part in this 
study. The PI should discuss at each visit with the patient. 
• Eculizumab (Soliris®) 
• Chemotherapeutic agents 
• Any other drug acting directly on the complement system 
 
 
 Contraception 
There are no specific, identified risks to mother or foetus from rVA576 (Coversin) 
therapy. A segment 1 reproductive toxicology study has been undertaken in mice 
(YUU0001) to assess the effects of 0, 0.5, 5 and 10 mg/kg/day rVA576 (Coversin) on 
the fertility and early embryonic development of the mouse when administered for at 
least 14 days before and during pairing, and then to Day 6 of gestation in females and 
until the day before necropsy for males. The study reported no deaths or clinical signs 
considered to be associated with the doses of rVA576 (Coversin) test; the causes of 
death for 1 male and 1 female found dead during the study were considered to be 
unrelated to test item administration. There was no effect of rVA576 (Coversin) on 
body weight, food intake, mating activity, fertility and pregnancy or uterine 
implantation. There were no findings at necropsy considered to be related to rVA576 
(Coversin) and group mean ovary and testes weights for animals given the test item 
were similar to Controls. Segment 2 and 3 reproductive toxicology studies will be 
undertaken prior to seeking market approval. Until the results from reproductive 
toxicology studies are completed, patients being treated with rVA576 (Coversin) should 
be advised to use the following precautions against sexual exposure and pregnancy. 


 
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Patients who are or become sexually active during the course of the study must use, 
with their partner, approved methods of highly effective contraception from the time of 
signing the Informed Consent Form (ICF) until 90 days after the last dose of rVA576 
(Coversin).  
Women of childbearing potential (WOCBP) are considered those women who have 
menarche and until becoming post-menopausal unless permanently sterilised. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy, and 
bilateral oophorectomy.  A postmenopausal state is defined as no menses for 12 months 
without an alternative cause. 
Two or more of the following methods are acceptable and must include one barrier 
method: 
• Surgical sterilisation (i.e. bilateral tubal removal, bilateral overay removal, 
hysterectomy for female partners; vasectomy for males) 
• Placement of an intrauterine device or intrauterine system 
• Hormonal contraception associated with the inhibition of ovulation 
(implantable, patch, oral) 
• Barrier methods (for male patients, this must be a condom; for female patients, 
either their partner’s use of a condom or the patient’s use of an occlusive cap 
[diaphragm 
or 
cervical/vault 
caps] 
with 
spermicidal 
foam/gel/film/cream/suppository). Barrier methods must be used in conjunction 
with another method.  
Alternatively, true abstinence is acceptable when consistent with the patient’s preferred 
and usual lifestyle. If a patient is usually not sexually active but becomes active during 
the course of study, they and their partner should use two of the contraceptive methods 
listed above. Any female patient who becomes pregnant during the course of the trial 
will be withdrawn from the trial unless she consents to a termination of the pregnancy. 
Male patients who have been sterilised are required to use one barrier method of 
contraception (condom). 
 Exposure of partners during the study 
There is a risk of drug exposure through ejaculate (which also applies to vasectomised 
males) which might be harmful to the sexual partners, including pregnant partners, of 
male patients. Barrier contraception should be used throughout the study and for 90 
days after the last day of IMP administration.  
Fathering a child through samples before IMP exposure is acceptable. Similarly, a 
surrogacy through frozen eggs collected before IMP exposure is acceptable i.e. prior to 
previous study participation.   
 Sperm Donation 
Male patients should not donate sperm for the duration of the study and for at 
least 90 days after the last day of IMP administration.  
 


 
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 Egg Donation 
Female patients should not donate eggs whilst on the study and for at least 90 
days after the last day of IMP administration.  
 Breast Feeding 
Female patients must agree not to breastfeed whilst on the trial and for at least 
90 days after the last day of IMP administration. 
 
5. Trial Design and Procedures 
 Trial Design:  
The trial is an open-label, non-comparative study in approximately 50 patients, 18 years 
and above with either PNH or aHUS who have participated in another rVA576 (Coversin) 
and who wish to remain on the study.  
 Dose Changes:  
If the Investigator considers that a change in dose or dose frequency is necessary, it is 
suggested that the schedule shown in Table 7 is followed. Please note that Ablating Doses 
may only be needed if the change is to a higher dose or dose frequency. A change to an 
increased dose is mandated by an inadequate response (see definition below) but may also 
occur at the discretion of the Investigator in consultation with the Sponsor. 
Table 7: Dose Decision Table: Suggested schedule for changing dose/dose interval in 
case of inadequate response  
PNH patients  
 
Ablating Doses (if required) 
Dose 
Interval 
60mg 
Single dose 
30mg 
1  x 12 hourly dose 
Inadequate Response 
Existing 
Switch to 
Dose 
Interval 
Dose 
Interval 
15mg 
12 hourly 
22.5mg 
12 hourly 
22.5mg 
12 hourly 
45mg 
24 hourly 
30mg 
24 hourly 
45mg 
24 hourly 
45mg 
24 hourly 
22.5mg 
12 hourly 
 


 
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aHUS patients 
Note: aHUS pts from the parent study will rollover to AK581 with the dosing regimen (taken) on the last dosing 
day of the parent study  
 
Ablating Doses (if required) 
Dose 
Interval 
60mg 
Single dose 
30mg 
1 x 12 hourly dose 
Inadequate Response 
Existing 
Switch to 
Dose 
Interval 
Dose 
Interval 
30mg 
12 hourly 
After assessment decision will be 
made in collaboration with the 
Sponsor and PI. 
45mg  
24 hourly 
30mg 
12 hourly 
 
   5.3 Duration of trial 
Up to 4 years 
 
Patients for whom rVA576 (Coversin) was found to be effective in this clinical trial 
and who wish to continue on the drug following conclusion of the trial, will continue 
to receive rVA576 (Coversin), subject to approval of the applicable governmental 
agency, until rVA576 (Coversin) receives marketing approval. If Akari encounters 
any issues with the availability of the drug, it will allocate available drug to such 
patients in a manner which is fair and consistent with ethical requirements. 
5.4 Trial procedures 
5.4.1  Screening 
Patients considered unsuitable for inclusion in this trial should be identified by 
their Investigator before the end of their participation in the preceding trial (i.e. 
should the investigator feel participation in the long term safety study is not in  
the patient’s benefit or if the patient declines to participate in AK581) allowing 
adequate time for any alternative therapy to be implemented. The Investigators 
should discuss the suitability of patients to enter AK581 with the Sponsor at 
least four weeks before the likely time of entry in order that documentation, 
including ICF, can be put in place and continuity of drug supply can be ensured.                         
Ideally the patient will be entered on the long term safety trial on the last day of 
dosing of the parent trial on condition that they have provided consent. 


 
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5.4.2 
Dosing period(s) 
 Patients will be dispensed drug at suitable timepoints during the trial 
5.4.3  Exiting the trial 
Patients may choose to leave the trial at any time or may be withdrawn by the 
Investigator in case of lack of efficacy, adverse reactions to rVA576 (Coversin), 
lack of compliance or for any other reason which, in the opinion of the 
Investigator, makes their continued participation no longer in their best 
interests. 
Patients will also leave this trial, or an extended access trial if one is required, 
once rVA576 (Coversin) is fully approved and reimbursed for their indication 
in their country and once continuity of supply has been ensured. 
5.4.4  End of Study/Follow-up 
All patients will have a follow up clinic visit at 1 Month + 7 days  and  all 
women of child bearing potential (WOCBP) will have a follow up visit at Month 
3 +7 days from last dose. 
.


 
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Table 8: Schedule of Events for PNH Patients 
 
EVENT (PNH) 
Entry 
i1 
Months 
(±7 days) 
2 
Months 
(±7 days) 
3 
Months 
(±7 days) 
6 
Months 
(±7 days) 
9 
Months 
(±7 days) 
12 
Months 
(±7 days) 
15 
Months 
(±7 days) 
18 
Months 
(±7 days) 
21 
Months 
(±7 days) 
24 
Months 
(±7 days) 
Medical History. Eligibility & Informed Consent & 
demographics 
 
 
 
 
 
 
 
 
 
 
 
iiiPhysical Examination if not done within 7 days of 
entry 
 
 
 
 
 
 
 
 
 
 
 
ivVital Signs (including weight) at every visit 
  vii 
 
 
 
 
 
 
 
 
 
 
xiECG 
 vii 
 
 
 
 
 
 
 
 
 
 
Urinalysis (including pregnancy testing)viii 
 vii 
 
 
 
 
 
 
 
 
 
 
iiHaematology & Chemistry including LDH, FBC 
and creatinine (local or central labs)  
 vii 
 
 
 
 
 
 
 
 
 
 
iiCH50, unbound rVA576 (Coversin) blood level 
(PK) & LTB4 (Central lab)  
vii 
 
 
 
 
 
 
 
 
 
 
ADA  (Central lab) 
vii 
 
 
 
 
 
 
 
 
 
 
ixAdditional blood draws for further indepth 
analysis                                      (Total LDH and 
LDH Isoenzymes)  (Central lab) 
vii 
 
 
 
 
 
 
 
 
 
 
Total C5 level (Central lab) 
vii 
 
 
 
 
 
 
 
 
 
 
FLAER and/or Flow Cytometry (local or central)   
vii 
 
 
 
 
 
 
 
 
 
 
 


 
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© Akari Therapeutics PLC 2016 
 
 
Table 8: Schedule of Events for PNH Patients (Continued) 
 
EVENT (PNH) 
Entry 
i1 
Months 
(±7 days) 
2 
Months 
(±7 days) 
3 
Months 
(±7 days) 
6 
Months 
(±7 days) 
9 
Months 
(±7 days) 
12 
Months 
(±7 days) 
15 
Months 
(±7 days) 
18 
Months 
(±7 days) 
21 
Months 
(±7 days) 
24 
Months 
(±7 days) 
vEORTC-QLQ-C30, EQ-5D-5L & FACIT-F 
questionnaires (if not done within 7 days of entry) 
& Sponsor non-validated questionnaire 
 
 
 
 
 
 
 
 
 
 
 
viDrug Accountability 
 
 
 
 
 
 
 
 
 
 
 
AE and Concomitant Medication reporting 
 
 
 
 
 
 
 
 
 
 
 
MAVE Assesment  
 
 
 
 
 
 
 
 
 
 
 


 
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Table 8: Schedule of Events for PNH Patients (Continued) 
 
EVENT (PNH) 
27 
Months (±7 
days) 
30 
Month
s (±7 
days) 
 
33 
Months 
(±7 days) 
 
36 Months 
(±7 days) 
 
39 
Month
s (±7 
days) 
42 
Months 
(±7 days) 
 
45 
Months (±7 
days) 
 
48 Months (±7 
days) 
End of study 
Visit 
xFollow up visit after   1 
month (±7 days)                  
(inc 3 month follow up visit for 
females) 
Early 
Termination 
iiiPhysical Examination 
 
 
 
 
 
 
 
 
 
 
ivVital Signs (including weight)  at every visit 
 
 
 
 
 
 
 
 
 
 
xiECG 
 
 
 
 
 
 
 
 
 
 
Urinalysis (including pregnancy testing)viii 
 
 
 
 
 
 
 
 
 
 
iiHaematology & Chemistry including LDH, FBC 
and creatinine (local labs) 
 
 
 
 
 
 
 
 
 
 
iiCH50, unbound rVA576 (Coversin) blood level 
(PK)  & LTB4 (Central lab)     
 
 
 
 
 
 
 
 
 
 
ADA (Central lab)  
 
 
 
 
 
 
 
 
 
 
ixAdditional blood draws for further indepth 
analysis (Total LDH and LDH Isoenzymes)  
 
 
 
 
 
 
 
 
 
 
Total C5 level   
 
 
 
 
 
 
 
 
 
 
FLAER and/or Flow Cytometry (local or central)    
 
 
 
 
 
 
 
 
 
vEORTC-QLQ-C30, EQ-5D-5L & FACIT-F 
questionnaires & Sponsor non-validated questionnaire  
 
 
 
 
 
 
 
 
 
 
viDrug Accountability  
 
 
 
 
 
 
 
 
 
 


 
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Table 8 Notes (for PNH patients):  
i. 
Investigator visits may take place more frequently if needed or desired (unscheduled visits/testing where needed), but the schedule shown is the minimum 
permitted  
ii. 
All blood draws will be taken pre-dose. If not possible, a note to that effect must be made in the medical records and captured in the eCRFs 
iii. 
Physical Examination - Inclusive of vein assessment and injection site inspection 
iv. 
Vital Signs – Diastolic and Systolic blood pressure &pulse rate  
v. 
Patients must complete the Quality of Life (QOL) Instruments and sponsor non-validated questionnaire at every clinic visit   
vi. 
Drug accountability will be performed at each visit.  Patients are requested to bring in empty vials only and inform the site of unused vials remaining in 
their fridge. 
vii. 
Test to be conducted at entry  if not done within 14 days of entry visit. 
viii. 
Pregnancy tests for women of childbearing potential must be done monthly. The current protocol design requires a pregnancy test at each hospital visit 
and then every 3 months after Month 3 (Months 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48 & ET). In addition Home Pregnancy tests 
must be repeated every month during the use of rVA576 (Coversin) and up to 90 days after the last dose of rVA576 (Coversin) by the patient. 
ix. 
Total LDH and LDH isoenzymes via a central laboratory maybe required as per the schedule to monitor patient safety (unscheduled visit/test is also 
permitted) 
x. 
All patients will have a follow up clinic visit at 1 Month + 7 days in addition all women of childbearing potential (WCBP) will have a follow up visit at 
Month 3 +7 days from last dose whereby urine pregnancy test will be conducted on site. 
xi. 
Routine ECG to be performed at entry and then annually during the study. (Limb lead or 12 lead ECG machines are acceptable) 
FLAER/Flow Cytometry: Local lab or via Central Lab  (if not available locally).  A 7 day window is permitted for each visit.  
 Table 8: Schedule of Events for PNH Patients (Continued) 
 
EVENT (PNH) 
27 
Months (±7 
days) 
30 
Month
s (±7 
days) 
 
33 
Months 
(±7 days) 
 
36 Months 
(±7 days) 
 
39 
Month
s (±7 
days) 
42 
Months 
(±7 days) 
 
45 
Months (±7 
days) 
 
48 Months (±7 
days) 
End of study 
Visit 
xFollow up visit after   1 
month (±7 days)                  
(inc 3 month follow up visit for 
females) 
Early 
Termination 
AE and Concomitant Medication reporting 
 
 
 
 
 
 
 
 
 
 
MAVE Assessment 
 
 
 
 
 
 
 
 
 
 


 
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Table 9: Schedule of Events for aHUS patients 
EVENT (aHUS) 
Entry 
i1 
Months 
(±7 days) 
2 
Months 
(±7 days) 
3 
Months 
(±7 days) 
6 
Months 
(±7 days) 
9 
Months 
(±7 days) 
12 
Months 
(±7 days) 
15 
Months 
(±7 days) 
18 
Months 
(±7 days) 
21 
Months 
(±7 days) 
24 
Months 
(±7 days) 
Medical 
History. 
Eligibility, 
Informed 
Consent & demographics 
 
 
 
 
 
 
 
 
 
 
 
iiiPhysical Examination if 
not done within 7 days of 
entry 
 
 
 
 
 
 
 
 
 
 
 
ivVital 
Signs 
(including 
weight)  at every visit 
 vii 
 
 
 
 
 
 
 
 
 
 
xECG 
  vii 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
(including 
pregnancy testing)viii 
  vii 
 
 
 
 
 
 
 
 
 
 
iiCH50, unbound rVA576 
(Coversin) blood level (PK) 
& LTB4 (Central Lab)   
vii 
 
 
 
 
 
 
 
 
 
 
ADA  (Central Lab) 
vii 
 
 
 
 
 
 
 
 
 
 
iiHaematology 
& 
Chemistry including LDH, 
FBC and creatinine (local 
or Central labs)  
 
  vii 
 
 
 
 
 
 
 
 
 
 
Total 
C5 
level 
&   
C3 (aHUS only)  
vii 
 
 
 
 
 
 
 
 
 
 


 
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Table 9: Schedule of Events for aHUS patients (Continued) 
EVENT (aHUS) 
Entry 
i1 
Months 
(±7 days) 
2 
Months 
(±7 days) 
3 
Months 
(±7 days) 
6 
Months 
(±7 days) 
9 
Months 
(±7 days) 
12 
Months 
(±7 days) 
15 
Months 
(±7 days) 
18 
Months 
:(±7 days) 
21 
Months 
:(±7 days) 
24 
Months 
(±7 days) 
Thrombotic Markers  (D-
dimer, Prothrombin f1/f2) 
vii 
 
 
 
 
 
 
 
 
 
 
Pro-inflammatory Markers 
(platelet E and P-selectin, 
CRP (high-sensitivity) 
vii 
 
 
 
 
 
 
 
 
 
 
Haemolytic 
Markers 
(Haptoglobin,  Schistocyte 
count) 
vii 
 
 
 
 
 
 
 
 
 
 
Dialysis Assessment & Plasma 
Transfer record 
 
 
 
 
 
 
 
 
 
 
 
vEQ-5D-5L and FACIT -F  
questionnaires (if not done 
within 7 days of entry) & 
Sponsor 
non-validated 
questionnaire 
 
 
 
 
 
 
 
 
 
 
 
viDrug Accountability 
 
 
 
 
 
 
 
 
 
 
 
AE 
and 
Concomitant 
Medication reporting 
 
 
 
 
 
 
 
 
 
 
 


 
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Table 9: Schedule of Events for aHUS patients (Continued) 
EVENT (aHUS) 
27 
Months 
(±7 
days) 
30 
Months 
(±7 
days) 
 
33 
Months 
(±7 days) 
 
36 Months 
((±7 days) 
 
39 
Months (±7 
days) 
42 
Months (±7 
days) 
 
45 
Months (±7 
days) 
 
48 Months 
(±7 days) 
End of 
study Visit 
 ixFollow up 
visit after   1 
month (±7 
days)   
(inc 3 month 
follow up visit for 
females) 
Early  
Termination 
iiiPhysical Examination if not done 
within 7 days of entry 
 
 
 
 
 
 
 
 
 
 
ivVital Signs (including weight)  at 
every visit 
 
 
 
 
 
 
 
 
 
 
xECG 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
(including 
pregnancy 
testing)viiii 
 
 
 
 
 
 
 
 
 
 
iiCH50, 
unbound 
rVA576 
(Coversin) blood level (PK) & 
LTB4 (Central Lab)  
 
 
 
 
 
 
 
 
 
 
ADA (Central Lab)  
 
 
 
 
 
 
 
 
 
 
iiHaematology 
& 
Chemistry 
including 
LDH, 
FBC 
and 
creatinine (local labs)  
 
 
 
 
 
 
 
 
 
 
Total C5 level &   C3 (aHUS only)   
 
 
 
 
 
 
 
 
 
 
Thrombotic 
Markers 
(D-dimer, 
Prothrombin f1/f2) 
 
 
 
 
 
 
 
 
 
 
 


 
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Table 9: Schedule of Events for aHUS patients (Continued) 
EVENT (aHUS) 
27 
Months 
(±7 
days) 
30 
Months 
(±7 
days) 
 
33 
Months 
(±7 days) 
 
36 Months 
((±7 days) 
 
39 
Months (±7 
days) 
42 
Months (±7 
days) 
 
45 
Months (±7 
days) 
 
48 Months 
((±7 days) 
End of 
study Visit 
 ixFollow up 
visit after   1 
month (±7 
days)   
(inc 3 month 
follow up visit for 
females) 
Early  
Termination 
Pro-inflammatory 
Markers 
(platelet E and P-selectin, CRP 
(high-sensitivity) 
 
 
 
 
 
 
 
 
 
 
Haemolytic 
Markers 
(Haptoglobin,  Schistocyte count) 
 
 
 
 
 
 
 
 
 
 
Dialysis 
Assessment 
& 
Plasma 
Transfer record 
 
 
 
 
 
 
 
 
 
 
vEQ-5D-5L 
and 
FACIT 
-F  
questionnaires & Sponsor non-
validated questionnaire 
 
 
 
 
 
 
 
 
 
 
viDrug Accountability 
 
 
 
 
 
 
 
 
 
 
AE and Concomitant Medication 
reporting 
 
 
 
 
 
 
 
 
 
 


 
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Table 9 Notes (for aHUS patients):  
i. 
Investigator visits may take place more frequently if needed or desired (unscheduled visits/testing where needed), but the schedule shown is the minimum 
permitted  
ii. 
All blood draws will be taken pre-dose. If not possible, a note to that effect must be made in the the medical records and captured in the eCRFs 
iii. 
Physical Examination – Inclusive of vein assessment and injection site inspection 
iv. 
Vital Signs – Diastolic and Systolic blood pressure & pulse rate  
v. 
Patients must complete the Quality of Life (QOL) Instruments and sponsor non-validated questionnaire at every clinic visit   
vi. 
Drug accountability will be performed at each visit.  Patients are requested to bring in empty vials only and inform the site of unused vials remaining in 
their fridge. 
vii. 
Test to be conducted at entry if not done within 14 days of entry visit 
viii. 
Pregnancy tests for women of childbearing potential must be done monthly. The current protocol design requires a pregnancy test at each hospital visit 
every  month, and then every 3 months after Month 3 (Months 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42 45, 48 & ET). In addition Home 
Pregnancy tests must be repeated every month during the use of rVA576 (Coversin) and up to 90 days after the last dose of rVA576 (Coversin) by the 
patient.  
ix. 
All patients will have a follow up clinic visit at 1 Month + 7 days in addition all women of childbearing potential (WCBP) will have a follow up visit  at 
Month 3 +7 days from last dose whereby urine pregnancy test will be conducted on site 
x. 
Routine ECG to be performed at entry and then annually during the study. (Limb lead or 12 lead ECG machines are acceptable)  
A 7 day window is permitted for each visit.  
 


 
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5.5 Measurements conducted on blood draws 
5.5.1 CH50 assay 
It appears that in PNH and aHUS, close to 100% inhibition of CH50 activity is necessary for 
clinical control of the disease. Serum CH50 assay is currently the most sensitive and quickest 
means of detecting inadequate control during anti-complement therapy as other indicators, such 
as LDH lag 24 - 48 hours behind the change in CH50. In practice, the Quidel ELISA assay, 
which is used to measure complement activity in units of CH50 U Eq/mL has a lower limit of 
quantification (LLOQ) of 10 CH50 U Eq/mL with individual normal baseline values ranging 
from 58-156 CH50 U Eq/mL. Thus the assay is insensitive to differences in CH50 when there 
is <10 CH50 U Eq/mL residual complement activity. Therefore, for practical purposes, the 
Central Laboratory (which will conduct all CH50 assays during the trial) considers values less 
than 10 CH50 U Eq/mL as completely inhibited. In previous trials (AK577, AK578 and 
AK579) with rVA576 (Coversin) the LLOQ of the CH50 was 8 CH50 EU/mL. The LLOQ has 
increased because the assay is now being performed using an automated system for the ELISA. 
CH50 samples will be collected as per Schedule of Events.  
5.5.2 Antibodies (ADA) 
Serum will be analysed for ADA formation to rVA576 (Coversin), as per schedule of events 
and stored and shipped frozen for analysis. 
5.5.3 LTB4 
Plasma (EDTA-treated) will be collected as per Schedule of Events and stored and shipped 
frozen for analysis. 
5.5.4 LDH Isoenzymes  
The assay determines the absolute LDH value and the proportions of LDH Isoenzymes 1 to 5. 
The serum sample should be stored and shipped to The Doctors Laboratory  (TDL) at ambient 
temperature immediately. Do not store samples at 2-8°C. Do not use frozen or haemolysed 
samples.  
5.5.5 Total C5 Levels  
C5 is the complement protein bound by rVA576 (Coversin). C5 concentration in blood will 
be measured by ELISA to understand how and if individual subject levels of C5 vary through 
time. Serum samples used should be stored and shipped frozen prior to analysis. 
5.5.6 Fluorescein-labelled proaerolysin FLAER / Flow Cytometry  
FLAER accurately determines the number and proportion of white blood cells that lack GPI-
anchor and therefore lack the complement regulatory proteins CD55 and CD59. 
The whole blood EDTA sample is analysed from an ambient temperature sample. Flow 
cytometry using anti-CD55 and anti-CD59 antibodies identifies the number and proportion of 
red blood cells deficient in these GPI-linked proteins. Absence of CD55 and CD59 are 


 
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diagnostic for PNH. Clone size (proportion of cells affected) can change through time and with 
C5 inhibition. 
5.5.7 Central Laboratory Testing (if not done within 14 days of entry) 
 
LTB4 
Anti-Drug Antibody (ADA) 
CH50 
rVA576 Level (PK) 
C5 
LDH Isoenzyme 
C3 (aHUS only) 
 
 
If any site is unable to use the standard laboratory kits provided by the Central Laboratory, the 
site needs to inform the Sponsor immediately (providing justification) as it may have an impact 
on the analysis of samples and ultimately the study results. 
 
5.5.8 Pharmacokinetics (PK) and Pharmacodynamics (PD) (aHUS only) 
Blood samples for PK and PD will be collected as detailed in the schedule of events. Samples 
for PK and PD will be taken 5 – 60 minutes before IMP administration. The date and exact 
time of collection must be recorded. 
 
The sample for PK/PD (CH50) analysis may be taken prior and/or after plasma exchange 
and/or dialysis. As the CH50 results are unlikely to be available for some days, the Investigator 
should be guided by the history, clinical signs or Platelet count and LDH as to whether it is 
necessary to administer additional Ablating Doses. Clinical signs of intravascular haemolysis 
following resumption of dosing mandates re-initiation of the Ablating dose schedule. The CRO 
and the Sponsor should be informed as soon as possible. 
 
5.6 Efficacy Assessments 
Measures of clinical efficacy will be assessed by the Investigator. The Sponsor (or designee) 
will review all eCRFs regulary for all patients in the study.  
Details of safety and efficacy endpoints are detailed in section 3.2.1 
5.7 Safety Assessments 
5.7.1 Medical History and Present Conditions 
 
A complete medical history will include an evaluation  of the previous medical history from 
the previous rVA576 (Coversin) trial which will be transferred to the current database. 
 
As all patients enrolled into the CONSERVE study will have transitioned from a parent clinical 
trial, a full new medical history and examination is not considered necessary unless there has 
been a lag time in entry into the long term study  The investigator responsible for the patient’s 
treatment will decide if there have been significant changes in the patient’s condition since 
being in the previous study to warrant an additional examination and new entries to the medical 
history page. If there has been development of a new medical condition (with diagnosis) in the 
previous study this will be considered as part of the patient’s  medical history for this study. 
 
Plasma Transfer/Dialysis History is also required for aHUS patients. 


 
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Relevant data held in databases from previous rVA576 (Coversin) trials will be transferred to 
the current database in pdf format. 
 
5.7.2 Physical Examination (if not done within 7 days of entry) 
 
• General appearance 
• Dermatological / skin 
• Haematologic / lymphatic 
• Heart / cardiovascular 
• Respiratory 
• Vein and injection site inspection 
 
5.7.3 Vital Signs & Weight  
 
Blood pressure and pulse rate will be measured in the supine position after the patient 
has rested comfortably. Body weight  will be recorded, if not done within 14 days of 
entry. Measurements will be recorded in the patient’s eCRF.   
 
5.7.4 Cardiac Safety  
 
Routine ECG should be performed at entry and then annually during the study. The ECG 
traces (using Limb lead or 12 lead ECG depending on what is available at site) will be 
reviewed, signed, and dated by a physician and he/she will record on the trace whether 
whether the ECG is normal or abnormal and if deemed abnormal, whether the abnormality 
is clinically significant (CS) or not clinically significant (NCS). 
 
5.7.5 Clinical Laboratory Safety Tests (if not done within 14 days of entry) 
 
All samples will be collected in accordance with acceptable laboratory procedures at 
the time points specified  in the Schedule of Events Table 8 &Table 9. Additional and 
repeat testing may be performed at the discretion of the Investigator.  All clinical 
laboratory safety tests will be performed locally by each clinical unit unless this is not 
possible in a participating country.    
 
Baseline haematology, chemistry and urinalysis will be performed at entry unless these 
investigations have taken place within 14 days of screening. 
5.7.6 Major Adverse Vascular Event (MAVE) Assessment 
 
The MAVE will be used to collect information on large and small vessel thrombosis as 
well as micro thrombosis and will be recorded always pre-dose at each clinic visit. 
 
5.7.7 Pregnancy Test 
 
Pregnancy tests for women of childbearing potential (WOCBP) must be done monthly. 
The current protocol design requires a urine pregnancy test at entry and at each clinic 
visit. In addition, home pregnancy tests must be repeated every month during the use 
of rVA576 (Coversin) and up to 90 days after the last dose of rVA576 (Coversin) by 
the patient. 


 
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5.7.8 Additional Investigational & Safety Testing 
 
Additional, non-genetic testing may be conducted on retained samples if deemed 
appropriate by the Investigator or should additional research suggest further 
investigation is required to improve disease evaluation and drug response. Consent for 
additional, currently undetermined, exploratory analysis will be in place prior to further 
analysis. The patient may refuse additional testing on their retained samples at any point 
and this will not influence their participation in the study.   
Additional and repeat blood draws considered necessary for safety and well-being of 
the patient may be performed at the discretion of the Investigator.  
Further to the above, the Sponsor and Investigator may request additional blood 
samples, (not listed in the Schedule of Events), to be taken during the course of the 
study to support further non-genetic testing, should there be insufficient blood 
remaining in the retained sample. A maximum study blood draw volume of 800mL per 
patient will not be exceeded inclusive of additional testing. 
 
Additional, currently undetermined, exploratory analysis is likely to be done for C3, 
C3a, C5a and sC5b9.  
 
Haematology Parameters 
 
White blood cell count 
Neutrophils absolute  
Red blood cell count 
Lymphocytes absolute 
Haemoglobin 
Monocytes absolute 
Mean Cell Haemoglobin (MCH) 
 
Mean Cell Haemoglobin Concentration 
(MCHC) 
Haematocrit 
Eosinophils absolute 
Erythrocyte sedimentation rate (ESR) 
Basophils absolute 
Platelets 
Mean Cell Volume (MCV) 
Reticulocytes 
 
 
Chemistry Parameters 
 
Lactate dehydrogenase & LDH 
isoenzymes 
Glucose (Random) 
Sodium 
Alkaline phosphatase 
Potassium 
Alanine Aminotransferase (ALT) 
Bicarbonate 
Aminotransferase (AST) 
Urea 
Creatine Kinase (CK) 
Creatinine 
Total Bilirubin 
Chloride 
Bilirubin (Direct) (only if Total is 
elevated) 
Albumin 
Phosphate (Inorganic) 
Calcium 
Protein (Total) 
Gamma Glutamyl Transpeptidase (GGT) 
 
 


 
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Urinalysis Parameters 
 
Leukocytes 
Ketones 
Protein  
Nitrates 
Bilirubin 
Blood 
Glucose 
hCG (female WOCBP patient) 
pH 
Specific gravity 
At Discretion of PI Based on Urinalysis 
Results 
Microbiology  
Urine Microscopy 
Pregnancy testing 
Urobilinogen 
 
 
 
5.8 Data that can be carried over from previous study to current AK581 study: 
 
If done within 7 days of entry:  
o Physical exam & QOL 
 
If done within 14 days of entry:   
o CH50 + complement factors and activation markers, rVA567 level (PK), 
LTB4, Haematology, Chemistry, Urinalysis. 
If ECG, vital signs, Pregnancy testing and MAVE are done on the same day as the end of study 
visit for the previous study as the entry day for the long term safety study, then these procedures 
do not need to be repeated again. 
 
Note: laboratory results can only be used if they are from the same reference laboratory 
in both studies. 
 
 
aHUS Parameters 
 
If done within 14 days of entry: 
 
o Thrombotic Markers (D-dimer, prothombin f1/f2) 
o Pro-inflammatory Markers (platelet E and P-selectin, CRP (high-sensitivity)   
o Haemolytic Markers (Haptoglobin) 
o Schistocyte count 
o Dialysis Assessment & Plasma Transfer record   
 
 
 
 
 
 
 
 
 
 
 
 


 
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5.9     Definition of an inadequate response 
 
If patients show evidence of persistent loss of disease control (on clinical or 
haematological or biochemical or CH50 parameter), the Investigator may increase the 
dose or the dose frequency in line with the table in section 5.10 if they are not already 
on the maximum permitted dose. This should only be done in consultation with the 
Sponsor’s Medical Director and after other possible causes such as poor compliance 
have been eliminated. The subject may require additional investigations (including 
blood tests) to evaluate loss of disease control and dose adjustment. 
 
5.10 Missed doses 
For PNH patients: 
For a missed dose of more than >24 hours, the sample for PD (CH50) analysis should 
be taken if possible just prior to the next morning dose of rVA576 (Coversin). As the 
CH50 results will not be available for some days the Investigator should be guided by 
the history, clinical signs or platelet count and LDH. In some cases, the PI may feel 
that an ablating dose is not required and the patient should resume their usual dosing 
schedule as soon as possible.  In PNH, clinical signs of intravascular haemolysis 
following resumption of dosing mandates re-initiation of the AD schedule. The CRO 
and the Sponsor should be informed as soon as possible.  
 
Dose 
Interval 
Missed Dose <4hr 
Missed Dose <24hrs 
Missed 
dose 
by 
day(s)>24hrs 
15mg 
12 hourly 
 
 
 
 
Dose to be taken 
as soon as patient 
realizes 
Take 15mg dose immediately 
and 15mg dose at usual time  
 
Take 
ablating 
dose 
60mg/30mg. then take 
dose 
as 
per 
usual 
routine 
22.5mg 
12 hourly 
Take 22.5mg dose immediately 
and 22.5 mg dose at usual time  
30mg 
12 hourly 
Take 30mg dose immediately 
and 30mg dose at usual time  
30mg 
24 hourly 
Take 45mg dose immediately 
and 45mg dose at usual time  
45mg 
24 hourly 
Take 45mg dose immediately 
and 45mg dose at usual time  
 
For aHUS patients: 
In the event of one missed dose (defined as a dose not taken within a one-hour time 
window either side of the specified time) the following procedure should be adopted by the 
patient: 


 
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• 
Take the appropriate dose as per the day of the protocol as soon as possible and then 
resume the usual dosing schedule at the specified times 
In the event of more than one missed dose the CRO and the Investigator’s clinic should 
be informed as soon as possible and the following procedure should be adopted: 
• 
Take 60 mg Coversin followed by 30 mg 12 hours later and then resume the usual 
dosing schedule (i.e. between 07:00 and 11:00 hrs daily) at the first time point after the 
ablation doses. 
The Investigator’s clinical staff should arrange for a Central laboratory blood draw for 
PK/PD to be taken 3 days + 1 day after first becoming aware of the missed doses in this 
situation.  
The sample for PD (CH50) analysis should be taken just prior to dosing with rVA576 
(Coversin). 
As the CH50 results are unlikely to be available for some days the Investigator should be 
guided by the history, clinical signs or platelet count and LDH as to whether it is necessary 
to administer additional Ablating Doses. 
If 3 or more consecutive doses have been missed the patient’s ability or willingness to 
comply with the protocol should be discussed and consideration should be given as to 
whether that subject should continue in the study.  
5.11 Rescue Therapy (aHUS only) 
Plasma Transfer or Dialysis/Hemofiltration will be considered Rescue Therapy.  
 
If Rescue Therapy is known to be required on a day during treatment, then the Rescue Therapy 
should be completed before any rVA576 (Coversin) is given to the subject on that day, if 
possible. 
 
The following rules should be used when the Investigator administers Rescue Therapy to the 
subject:  
 
Administer 60 mg rVA576 (Coversin) within 60 minutes after the end of each Rescue therapy.  
 
• If ≤ 6hrs to the next scheduled dose:15mg of rVA576 (Coversin) at the next scheduled 
dose, then resume to dose subject was prior Rescue Therapy.  
• If > 6hrs to next scheduled dose: 30 mg of rVA576 (Coversin) at the next scheduled 
dose, then resume to dose subject was prior Rescue Therapy.  


 
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Examples: 
Dose/time 
Rescue Therapy (RT) and ablation 
dose 
Next Dose/Time 
Next 
Dose/Time 
30 mg /9am 
 
RT ends at 4pm then 60 mg of rVA576 
(Coversin) (within 1hr after end of PT) 
≤6hrs till the next scheduled dose 
15mg/9pm 
 
30mg/9am  
45mg /8am  RT ends at 12pm then 60 mg of 
rVA576 (Coversin) (within 1hr after 
end of PT) 
>6hrs till the next scheduled dose 
Evening dose 8pm 
30 mg of rVA576 
(Coversin) 
45mg/8am 
 
It is the responsibility of the PI to ensure that details regarding the medication, therapy, or 
procedure are recorded in full in the patient’s source/chart and CRF. 
 
Additional PK/PD samples may be required in case of Rescue Therapy.  
 
5.11.1 Plasma Transfer (aHUS only) 
The need for Plasma Transfer during the clinical trial should be guided by:  
 
a) A new decrease in platelet counts > 25% below the previous / baseline 
Platelet Count value and to a level less than 100 x 109/L; or  
b) A new decrease in platelet count below 40 x 109/L; or  
c) An emergent and new neurological, renal or another clinical event as 
prospectively defined for each patient.  
d) In the judgement of the Principal Investigator administering Plasma 
Transfer is required for the best interests of the subject. 
 
If one of these conditions applies, then the Investigator may, at his or her discretion, precribe 
Plasma Transfer treatment based on the clinical assessment of the subject. The investigator 
should inform the CRA if Plasma Transfer  is required during the clinical trial.  
 
If Plasma Transfer treatment is required, the following details need to be recorded in the subject 
medical records for each event:  
Start and end date; Total number of sessions; Fresh Frozen Plasma volume used for each 
session (ml/kg/session); and Adverse reactions. 
 
5.11.2 Dialysis / Haemofiltration 
Subjects will not be generally permitted to receive new Dialysis unless there is compelling 
medical need, for example due to: 
 
a) Hypervolaemia unresponsive to diuretics  
b) Refractory electrolyte imbalance, or  


 
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c) New-onset uraemic encephalopathy, and after discussion with the Sponsor that 
details regarding the medication, therapy, or procedure are recorded in full in 
the patient’s source/chart and CRF. 
d) It is deemed necessary by the PI in the best interests of the subject 
 
If dialysis treatment is administered, the following details need to be recorded in the subject 
medical records for each event: Start and end date; Serum creatinine value at the start and end 
of dialysis; Total number of sessions; Type of dialysis membrane used; Type of generator 
used; Type of dialysis; Adverse reactions 
 
5.12 Quality of life questionnaires (EORTC QLQ C30 , EQ-5D-5L & FACIT-F) 
The subject will complete the EORTC QLQ C30 (for some PNH patients only), EQ-5D-5L 
and FACIT-F (both PNH & aHUS) questionnaires and Sponsor non validated questionnaire 
at each clinic visit. The data will be transcribed to the eCRF and subsequently analysed.  
EORTC  is a questionnaire designed to assess (some of) the different aspects that define the 
QoL of (a specific group of) patients  
FACIT-F (functional assessment of chronic illness therapy - fatigue) is a 13-item fatigue 
scale, which uses a symptom specific measure.  
The EQ-5D questionnaire is made up of two components; health state description and 
evaluation. In the description section, health status is measured in terms of five dimensions 
(5D); mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Mobility 
dimension asks about the person's walking ability. Self-care dimension asks about the ability 
to wash or dress by oneself, and usual activities dimension measures performance in "work, 
study, housework, family or leisure activities". In pain/discomfort dimension, it asks how 
much pain or discomfort they have, and in anxiety/depression dimension, it asks how anxious 
or depressed they are. The respondents self-rate their level of severity for each dimension 
using a five-level (EQ-5D-5L) scale. In the evaluation part section, the respondents evaluate 
their overall health status using the visual analogue scale (EQ-VAS). 
The Questionnaire on self-injection will be completed by the patient (this is a non-validated 
questionnaire). 
 
6 Stopping Rules and Discontinuation Procedures 
6.1 Termination or suspension of the study 
The Sponsor may prematurely terminate or suspend the study at any time for the 
following reasons: 
• Safety concerns e.g. occurrence of many serious ADRs 
• Achieving the purpose of the study is considered impossible (e.g. inadequate 
recruitment of subjects) 
If the study is prematurely terminated or suspended, the Sponsor should promptly 
inform the Investigators. The Investigator or designee should promptly inform the 


 
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participating subjects and change the study medication to other appropriate 
therapy(ies).  
The Investigator may prematurely terminate or suspend the study at their medical 
institution with the agreement of the Sponsor. This may be done at any time during the 
study if they consider that ensuring patient safety during the study is difficult due to 
safety concerns (e.g., occurrence of many SAEs). 
The Sponsor may prematurely terminate or suspend the study at a particular medical 
institution at any time during the course of the study, if major violations/deviations of 
the protocol or other procedures has not been improved or ICH GCP has not been 
followed. 
If the study is prematurely terminated or suspended, the Sponsor should promptly 
inform the Investigators. The Investigator or  designee, should promptly inform the, 
participating subjects and change the study medication to another appropriate 
therap(ies) and inform the corresponding Ethics Committees. All supplies should be 
returned. 
Whichever party terminates the study will provide a written statement as to the reason 
for the termination. 
The Sponsor (or CRO) will notify Regulatory Authorities as appropriate of premature 
terminations. The Investigator or their designee should promptly inform the 
corresponding Ethics Committee (EC).  
 
6.2 Withdrawal criteria  
In accordance with applicable regulations, a patient has the right to withdraw from the 
study at any time and for any reason, without prejudice to their future medical care by 
the physician or at the Institution. Should a patient withdraw from the study, then the 
patient will not undergo any further study-specific procedures or receive any treatment 
mandated by the protocol. 
If a subject fails to attend scheduled trial assessments, the Investigator must determine 
the reasons and the circumstances as completely and accurately as possible. 
In the event of the premature withdrawal of a patient from the trial, the end of trial visit 
should be carried out as completely as possible. Minimally, a safety assessment should 
be performed.  
In the case of withdrawal due to the occurrence of unacceptable toxicity, the patient 
will be requested to remain under the supervision of the Investigator until the toxicity 
has resolved or is no longer considered to be clinically significant by the Investigator. 
If an Adverse Event classified as severe results in patient withdrawal from the study, 
the subject will be followed until the AE (or SAE) resolves or stabilises, and any 
interventions required to resolve or stabilise the event will be recorded in the eCRF. 


 
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All withdrawals must be documented in the eCRF. A patient may be withdrawn in any 
of the following circumstances.  
• Withdrawal of consent (mandatory withdrawal) 
• Intake of non-permitted concomitant medication (may be discussed with the 
Sponsor and dependent on the nature of the medication) 
• Patient is non-compliant with more than three consecutive missed doses and 
two missed clinic visits, in the opinion of the Investigator (discretionary 
withdrawal) 
• If discontinuation is considered necessary by the Investigator and/or Sponsor 
(mandatory withdrawal) 
• Request of Regulatory Agency (mandatory withdrawal) 
• Patient develops an illness that would compromise his participation in the study 
(may be discussed with sponsor) 
• Patient is not achieving complete inhibition at the maximum assigned dose 
(inadequate response to rVA576 (Coversin) treatment) 
• Pregnancy, unless the patient wishes to consent to a termination. 
 
6.3 Accountability procedures 
In accordance with GCP, the clinical unit will account for all study medication. The 
clinical unit are responsible for study medication accountability, reconciliation, and 
record maintenance.  
Drug accountability records will be maintained during the study as follows:  
• Amount of study medication received from the Sponsor 
• Amount distributed to each patient and returned by them 
• Amount of unused drug returned to the Sponsor or destroyed at Sponsor's 
request.  
In addition, in the event of necessary disposal of opened but wasted medication, the 
disposal should be documented appropriately (i.e. witnessed) in accordance with 
applicable local regulations, and GCP procedures.  
Patients are required to return used and expired vials to the clinical unit and report to 
the site the number of unused vials remaining in their fridge. Storage bags will be 
provided to each patient. For all unused study medication, the patient should adhere to 
the storage instructions until the study medication is returned to the clinical unit. 
If for any reason a site cannot dispose of used vials at site due to local policy, then they 
need to inform the Sponsor immediately.  
6.4 Compliance 
Reasonable levels of compliance are assumed as a condition of entry (prior enrolment 
in and completion of a rVA576 (Coversin) clinical trial). As a measure of compliance, 
all empty rVA576 (Coversin) vials will be returned to the clinical unit and diary cards 


 
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will be reviewed by research staff. At the end of the study, all unused vials will be 
returned to the Sponsor or representative or destroyed at site. 
In addition to the above measures, clinic staff may call the patient’s home or set up an 
automated text message reminder according to the subjects dosing schedule.  
 
Example text as follows: “A gentle reminder - please administer your medicine this 
morning/evening and record the time, dose and location of injection in the Patient 
Dosing Diary.  
 
6.5 Interruption of Treatment 
If treatment is interrupted, either for reasons outside the patient’s or the investigator’s 
control or because it is considered to be in the patient’s best interest  it may be resumed 
at the discretion of the investigator and Sponsor. Any interruption of >24 hours will 
require an ablating regimen of 60mg followed by 30mg 12 hours later before resuming 
normal dosing, this should be discussed with the Sponsor. In the event of an interruption 
of treatment of >28 days, the investigator should discuss with the Sponsor the 
advisability of resuming treatment. 
 
7 Safety Reporting 
All AEs occurring from the signing of the voluntary Informed Consent Form (ICF) to 
the end of the trial visit will be recorded. All adverse events, whether or not considered 
to be related to the study drug, will be monitored and reported at all stages of the study.  
Adverse events occurring between clinic visits will be reported by the patient or 
recorded at the next clinic visit and entered on the adverse event form of the case report 
forms. All adverse events must be fully recorded in the patient notes throughout the 
entire study period and will be transcribed into the subject’s eCRF. 
 
7.1  
Safety Definitions 
7.1.1 Adverse Event 
Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of the study 
medication, whether or not considered related to the study medication. 
 
7.1.2 Adverse Drug Reaction 
All untoward and unintended responses to an investigational medicinal product (IMP) related 
to any dose administered.  
 
All cases judged by either the reporting medically qualified professional or the Sponsor as 
having a reasonable suspected causal relationship to the study medication qualify as adverse 
drug reactions.   


 
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7.1.3 Unexpected Adverse Reaction 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g. Investigator’s Brochure for an unauthorized investigational 
medicinal product or summary of product characteristics for an authorized product). 
 
7.1.4 Serious Adverse Event (SAE) or Serious Adverse Reaction 
Any untoward medical occurrence or effect that at any dose results in: 
• Results in death, 
• Is life-threatening,  
• Requires inpatient hospitalization or prolongation of existing hospitalization, (Note: 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfils any other serious criteria, the event is serious. Hospitalization 
for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered to be an AE. [NB This means that admission (i.e. inpatient, out patient, <24 
hours, > 24hour) for blood transfusion does not constitute an SAE as it is for treatment 
of a pre-existing condition]. 
• Results in persistent or significant disability/incapacity,  (Note: The term disability 
means a substantial disruption of a person’s ability to conduct normal life functions.  This 
definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, or accidental 
trauma (e.g. sprained ankle) that may interfere or prevent everyday life functions but do 
not constitute a substantial disruption).  
• Is a congenital anomaly/birth defect. 
 
NOTE: Other events that may not result in death, are not life threatening, or do not require 
hospitalization, may be considered a serious adverse event when, based upon appropriate 
medical judgment, the event may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of such events include, but 
are not limited to, severe early onset reaction such as anaphylaxis, vasovagal episodes, 
episodes of hypotonia, hyperreactivity or hyperventilation, convulsions, etc. 
 
All SAEs will be reported to the Sponsor (or designee) within 24 hours of occurrence. The 
Sponsor (or their designee) will be responsible for reporting the AE to the appropriate 
regulatory authorities and the ECs within the legally specified period. It is important to 
distinguish between SAEs and severe AEs. Severity is a measure of intensity whereas 
seriousness is defined by the criteria above. An AE of severe intensity need not necessarily be 
considered serious. For example, a migraine headache that incapacitates a patient for many 
hours may be considered a severe AE, whereas a stroke that results in a limited degree of 
disability may be considered mild, but should be reported as an SAE. 
 
7.1.5 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A serious adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g. Investigator’s Brochure for an unapproved investigational product or 
Summary of Product Characteristics for an approved product). 


 
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7.2 Procedures for Recording of Adverse Events 
7.2.1 General 
All adverse events occurring during the Study (from the timepoint of signing of the Informed 
Consent Form (ICF) until completion of patient`s study participation or premature withdrawal) 
observed by the Investigator or reported by the patient, whether or not attributed to the IMP, 
shall be recorded in patient`s medical records and on the eCRF. 
   
The following information shall be recorded:  
 
• description,  
• date of onset and end date,  
• severity,  
• assessment of relatedness to the IMP,  
• seriousness, 
• measures taken for management of the AE, 
• outcome of the event.   
 
Follow-up information should be provided as necessary.  
 
AEs considered as being related to the IMP as judged by a medically qualified Investigator, or 
the Sponsor, must be followed until their resolution or when patient`s status is considered as 
stable. All related AEs that result in a patient’s withdrawal from the Study or are present at the 
end of the Study, should be re-evaluated and if needed followed until a satisfactory resolution 
occurs. 
 
It will be left to the Investigator’s clinical judgment whether or not an AE is of sufficient 
severity to require termination of IMP administration. A patient may also voluntarily withdraw 
from IMP administration due to AEs perceived as intolerable.  If either of these occurs, the 
patient will be given appropriate care under medical supervision until symptoms cease or the 
condition becomes stable. 
 
The severity of reported events shall be assessed on the following scale:  
  
• 1 = mild 
• 2 = moderate 
• 3 = severe  
• 4 = life threatening 
• 5 = death 
 
The causal relationship of AEs to the IMP must be assessed by the Investigator, or by a 
medically qualified designee, in accordance with the following criteria: 
 
 
 
 
 
 
 








 
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• 15 calendar days for SUSARs involving hospitalization or prolongation of 
hospitalization or persistent or significant disability/incapacity or congenital 
anomaly/birth defect or any other significant clinical/laboratory event of major concern 
in the opinion of the Investigator. 
 
Day zero (clock start) for expedited reporting purposes is the date of initial information or of 
the relevant follow-up information received in any form (in writing or verbally) by any 
personnel of the Sponsor or contracted parties including the CRO and the PVP. 
 
All SUSARs will be reported to the respective competent authorities, ECs (IRBs) and 
Investigators within specified timelines in accordance with corresponding national legislation.  
 
 
7.5 Development Safety Update Reports 
Development Safety Update Reports will be prepared by Akari Therapeutics Plc (or designee), 
on an annual basis and distributed to all competent authorities and to relevant ECs in 
accordance with the corresponding national regulations.  
 
8 Data Handling and Source Documents 
Patient data will be collected on eCRFs and will be substantiated by source documents at 
the clinical site. The eCRFs will be completed according to guidelines provided by the CRO 
and their SOPs. Source documentation supporting the eCRF data should indicate the 
patient’s participation in the study and should document the dates and details of all study 
procedures, AEs and patient status. 
The Investigator must maintain source documents, such as laboratory reports, complete 
medical history, ECG read outs and physical examination reports. All source documents 
should be accessible for verification by the site monitor, auditor, the EC, or for inspections 
by the regulatory authorities. In addition, the site will allow the Sponsor and assigned CRO 
direct access to all source documents and will permit trial-related auditing of clinical, 
pharmacy and laboratory facilities. 
Direct access to these documents must be guaranteed by the Investigator or their designee, 
or the study coordinator, who must provide support at all times for these activities. 
The nature and location of all sources of original data required to complete the eCRF will 
be identified by the CRO and the site staff.  
Parent trial data used to assess patient safety and eligibility for enrollment will be entered 
into the AK581 database. Where applicable, assessment data collected at the subject’s 
parent trial end of study visit will be captured. Coversin dosing history, parent trial ECG 
and LDH results, and plasma (blood) transfusion/dialysis history will be available in the 
AK581 subject casebooks. 
The Study Monitor will perform 100% source data verification to ensure adequate quality 
control and assurance of patient data. An explanation of missing data must be given. 


 
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All data entered into the eCRF will be saved directly into the study database. This data will 
be validated both manually and programmatically. Clarification of data will be requested 
from the study site as requested. The database will be quality assured and will be available 
for statistical analysis according to the SAP. 
Patient data will be reviewed for major protocol deviations by the Study Monitor during 
site visits and the entire team will review the database at timed intervals prior to the 
database lock. 
9 Statistics 
9.1 Statistical methods 
A Statistical Analysis Plan (SAP)  is in place. There will be no formal statistical 
inferences. All the study data will be analysed descriptively. Standard summary 
statistics will be produced for observed values, and changes from entry (where 
applicable) at the relevant post-entry timepoint.  
For continuous variables, these statistics will include the number of patients with 
available data, mean, standard deviation, median, minimum, maximum. For 
categorical variables, these statistics will consist of patient counts and associated 
percentages. Unless otherwise specified, missing data will not be included in the 
denominator for percentage calculation. Time to event data will be summarised using 
graphs and summary statistics from the Kaplan-Meier method. 
Listings will also be used to display data at the individual patient’s level. 
Data will be reported at each 3-month time point since the start of the study (where 
applicable) and over the entire period of the study (where applicable). 
Results will be reported for all patients and then separately for PNH and aHUS patients. 
- 
The incidence of AEs, and serious adverse events (SAEs) will be summarised over 
time for all patients. 
 
- 
Vital signs, results of standard laboratory tests (clinical chemistry, haematology 
and urinalysis), and results of limb lead or 12 lead electrocardiograms (ECGs) will 
be summarised over time for all patients. 
 
- 
The proportion of subjects with no adverse change in overall scores of Quality of 
Life using the EORTC QLQ-C30 (some PNH patients only), the EQ-5D-5L and 
FACIT-F instruments will be summarised over-time. 
For PNH patients, additional summaries will include : 
- The proportion of subjects with thrombotic and haemolytic event-free status  
- The time to thrombotic or haemolytic event since entry. 
- The time to first transfusion since entry.  
- The proportion of subjects with serum Lactate Dehydrogenase (LDH) <1.8, >1.8 to 
2.4, >2.4 to 3, and >3 times the upper limit of normal (ULN).  


 
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- The proportion of subjects with median serum Lactate Dehydrogenase (LDH) <1.8, 
>1.8 to 2.4, >2.4 to 3, and >3 times the upper limit of normal (ULN). 
- The proportion of subjects who require PRBC transfusion.  
- The proportion of transfusion independent subjects, with haemoglobin (g/L) above 
the baseline haemoglobin value they had at the start of the parent trial.  
- The proportion of transfusion-independent subjects over the entire duration of the 
study with mean haemoglobin (g/L) above the baseline haemoglobin value they had at 
the start of the parent trial. 
- The incidence, number and time to first Major Adverse Vascular Event (MAVE) for 
each PNH subject will be summarised. 
Results may also be reported separately for i) subjects who were transfusion-dependent 
when they started receiving rVA576 (Coversin), and ii) subjects who were transfusion-
independent when they started receiving rVA576 (Coversin), and further stratification 
of these proportions by a) patients who were complement inhibitor naïve prior to 
treatment with rVA576 (Coversin), and b) patients who received treatment with 
another complement inhibitor before switching to rVA576 (Coversin) and where 
applicable i) transfusion-independent prior to receiving rVA576 (Coversin) and remain 
transfusion-independent and ii) transfusion-dependent prior to receiving rVA576. 
For aHUS patients, additional summaries will include: 
- The proportion of subjects with Normal Platelet count [defined as Platelet count ≥ 
150 x1 09/L]  
- The proportion of subjects entering the study with complete TMA response who 
continue to exhibit complete TMA response with preserved renal function, defined as 
haematologic normalization (platelet count ≥150 X 109/L and LDH ≤ ULN) and 
preservation of kidney function (<25% increase in SCr from baseline of the parent 
trial). 
- The proportion of subjects with complete TMA response with improved renal 
function defined as normalization of haematological parameters (normalisation of 
platelet count and LDH≤ULN) and ≥ 25% decrease in SCr from baseline of the parent 
trial. 
- The proportion of subjects who exhibit haematological normalisation (platelet count 
≥150 X 109/L and LDH ≤ ULN). 
The proportion of subjects with improvement in renal function defined as a decrease 
in SCr over three consecutive measurements from baseline of the parent trial without 
the need for dialysis even if not within the normal range.  
- The proportion of subjects who are TMA event-free. 
- Platelet mean count change over-time. 
Other endpoints will be described as indicated above depending on whether its  
outcome measure is a continuous or categorical variable. 


 
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9.2 Number of patients 
This is an open-label study to evaluate the safety experience of long term rVA576 
(Coversin) treatment in approximately 50 patients.  
9.3 Interim analyses 
The Sponsor reserves the right to review accruing safety and efficacy data from the 
study as a management aid to assist in the design of future studies. 
9.4 Assessment of pharmacokinetics and complement activity  
Blood (5mL) samples for CH50 assays and rVA576 (Coversin) levels will be collected 
according to the schedule presented in Table 8 & Table 9. Serum samples will be 
taken to measure complement activity, rVA576 (Coversin) levels and anti-drug 
antibodies. Blood-EDTA and blood-citrate will be used for other measures. Safety 
blood samples will take precedence over all other procedures. 
PK parameters will be described over-time using summary statistics and lines and 
mean plots as appropriate. 
PD parameters will be described over-time using summary statistics and graphical 
displays such as waterfall plots and lines plots as appropriate. 
9.5 Significance level 
All analyses will be descriptive. 
9.6 Missing, unused or spurious data 
Missing data that cannot be retrieved from source records or other repositories will be 
recorded as such in the eCRFs and will not be entered into the statistical analysis. 
Spurious data will be examined by the Sponsor’s monitor, medical or statistical 
advisors and a decision made as to how it should be handled. If there is an obvious 
transcription or data entry error, such as a misplaced decimal point in a biochemical 
parameter, this will be discussed with the CRO or the laboratory and, if all parties 
agree, it will be corrected and endorsed by both the PI and the Sponsor.  
Unused data (e.g. superfluous blood pressure recordings or haematological results in 
addition to those required by the protocol) will remain part of the source 
documentation and only be incorporated into the trial documents and analysis if there 
is reason for them to be (e.g. an unexpected fall in blood pressure that might constitute 
an AE). 
9.7 Deviation from the statistical analysis plan 
It is not envisaged that there should be any deviations from the SAP. Any unexpected 
deviations will be included in any interim reports and the Final Study Report. 
9.8 Patients to be included in the statistical analysis 
The primary analysis will be intention to treat (ITT) and all patients entered and who 
sign informed consent will be included.   


 
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All patients will be included in the safety analysis, whether completing the trial 
according to the protocol or not. Analyses of efficacy at various time points (6 months 
12 months, 2, 3, 4 and 5 years) will be made for all patients reaching those points. 
‘End of study’ will be defined as the point at which the last patient has exited the study 
and has been seen at the 3 month end of study follow-up visit. 
The final analysis will be performed using data collected up to the end of the study.  
This data will be presented in a Final Study Report. 
The Database will be locked when the last patient last follow-up visit occurs.  
10  Quality Control and Assurance 
The hospitals / departments taking part in the trial are responsible for maintaining their 
own SOPs and QA / QC procedures. The Sponsor or their delegate will also implement 
and maintain quality control and quality assurance procedures with written standard 
operating procedures (SOPs) to ensure that the study is conducted and data are 
generated, documented and reported in compliance with the Protocol, ICH GCP and all 
applicable regulatory requirements. The Sponsor or delegate will be responsible for 
monitoring the trial and carrying out 100% source data verification. The Sponsor will 
be responsible for overseeing clinical trial activities. 
The study will be in accordance with the provisions of the Declaration of Helsinki and 
all revisions thereof, in accordance with ICH GCP and as required by applicable 
regulatory requirements. 
Any necessary training for the study will be provided to Investigators and study 
personnel by the Sponsor or their designee prior to study initiation. 
 
11  Ethical Conduct of the Study 
11.1 Ethical considerations and EC approval 
The study will be conducted in accordance with all appropriate regulatory requirements 
and under an approved protocol. The study will be conducted in accordance with 
current ICH GCP, all applicable patient privacy requirements and the ethical principles 
outlined in the Declaration of Helsinki. 
12 Financing, Indemnity and Insurance 
The Sponsor will have a commercial contract in place with the CRO and the 
hospitals/universities will be responsible for any payments to patients for payment of 
travel and other expenses reimbursable by the Sponsor on delivery of receipts. 
The Sponsor has a clinical trials insurance policy in place. A copy of the 
policy/certificate of insurance will be supplied separately. Provision is made for (1) The 
indemnity or compensation in the event of injury or death attributable to the clinical 
trial and (2) Insurance or indemnity to cover the liability of the Investigator or Sponsor. 


 
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Akari Therapeutics Plc will indemnify the Investigators from all or any claims arising 
out of this study except for their negligence or malpractice and providing that the study 
is conducted according to the standards established by the protocol. 
In the event that it can be demonstrated that a patient suffers any significant 
deterioration in health or well-being or any harmful susceptibility or toxicity, as a direct 
result of their participation in this study, then Akari Therapeutics Plc will agree to abide 
by the current Association of the British Pharmaceutical Industry (ABPI) Guidelines 
with regard to compensation payable to the patient residing in the UK. The amount of 
compensation will be calculated by reference to the level of damages commonly 
awarded according to local law for similar injuries occurring in patients residing outside 
the UK. 
13  Publication Policy 
The key design elements of this protocol will be posted in a publicly accessible 
database. 
The CRO has no independent publication rights.  
Akari Therapeutics Plc actively encourages publication of clinical trial data in reputable 
peer reviewed journals. Authorship will be discussed and agreed in advance. If the 
Investigator drafts a publication, he/she agrees to send it to Akari Therapeutics for 
review and comment before its submission to the journal.  In cases where Akari 
Therapeutics Plc considers that the proposed publication contains information which 
should be protected as valuable confidential information or is out of compliance with 
applicable laws and regulations, Akari Therapeutics Plc reserves the right to delay 
submission to the journal, until the required deletion or amendment of the confidential 
information from the proposed publication has been performed. 
 
14  Study Record Retention 
The Investigators shall ensure that the documents contained in the Investigator Site File 
are retained for 15  years after the conclusion of the trial. The Sponsor shall ensure that 
the documents contained in the Trial Master File are retained for 25 years after the 
conclusion of the trial. The Sponsor and Investigators will ensure that during this period 
the files are complete, legible and readily available to the licensing authority on request. 
All data derived from the study will remain the property of Akari Therapeutics Plc. 
All correspondence (e.g. with the Sponsor, or designee, Ethics Committee) relating to 
this study should be kept in the appropriate files. Records of patient’s source 
documents, eCRF’s, IMP inventory pertaining to the study must be kept on file. 
If the Investigator moves, withdraws from the study or retires, the responsibility for 
maintaining the records may be transferred to another person who will accept 
responsibility. Notice of transfer must be made to and agreed by the Sponsor. 
 


 
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14.1 Clinical study report (CSR) 
The results of this clinical study must be summarised by the Sponsor (or designee) and 
a final audited report must be retained on file. This report will include discussions on 
the study objectives, methodology, findings and conclusions. The Principal 
Investigator(s) will be asked to review and comment on the draft report and the Chief 
Investigator will be required to sign the final version. All Investigators will be provided 
with a final copy of the Clinical study report. The report must be archived with all other 
study documents. An interim CSR may also be required to support authorisation 
applications. 
14.2 Handling and retention of blood and pathological samples 
Samples should be handled according to the instructions provided in the Laboratory 
Manual. The duration of retention of blood and pathological samples will be in 
accordance with details provided in the patient information leaflet and agreed to by 
signing the ICF.  
 
 
 


 
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15  References 
Brodsky, R, A. Bone Marrow Failure, Paroxysmal nocturnal hemoglobinuria. Blood, 30 
October 2014, volume 124, number 18 
 
Thomson N, Ulrickson M. Maintenance eculizumab dose adjustment in the treatment of 
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Agostini, C., L. Trentin, M. Facco, and G. Semenzato. New aspects of hypersensitivity 
pneumonitis. Current opinion in pulmonary medicine 2004; 10:378-382. 
 
de Vries, B., J. Kohl, W. K. Leclercq, T. G. Wolfs, A. A. van Bijnen, P. Heeringa, and W. 
A. Buurman. Complement factor C5a mediates renal ischemia-reperfusion injury 
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Dmytrijuk, A., K. Robie-Suh, M. H. Cohen, D. Rieves, K. Weiss, and R. Pazdur. FDA 
report: Eculizumab (Soliris®) for the treatment of patients with paroxysmal nocturnal 
hemoglobinuria. The oncologist 2008; 13:993-1000. 
 
Francischetti, I. M., A. Sa-Nunes, B. J. Mans, I. M. Santos, and J. M. Ribeiro. The role of 
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Fredslund, F., N. S. Laursen, P. Roversi, L. Jenner, C. L. Oliveira, J. S. Pedersen, M. A. 
Nunn, S. M. Lea, R. Discipio, L. Sottrup-Jensen, and G. R. Andersen. Structure of and 
influence of a tick complement inhibitor on human complement component 5. Nature 
immunology 2008; 9:753-760. 
 
Godau, J., T. Heller, H. Hawlisch, M. Trappe, E. Howells, J. Best, J. Zwirner, J. S. 
Verbeek, P. M. Hogarth, C. Gerard, N. Van Rooijen, A. Klos, J. E. Gessner, and J. Kohl. 
C5a initiates the inflammatory cascade in immune complex peritonitis. J Immunol 2004; 
173:3437-3445 
Greinacher A and Warkentin TE. The direct thrombin inhibitor hirudin. Thromb Haemost 
2008; 99: 819-829. 
 
Hepburn, N. J., A. S. Williams, M. A. Nunn, J. C. Chamberlain-Banoub, J. Hamer, B. P. 
Morgan, and C. L. Harris. In vivo characterization and therapeutic efficacy of a C5-specific 
inhibitor from the soft tick Ornithodoros moubata. J Biol Chem 2007; 82:8292-8299. 
 
Lang, B., and A.. Autoimmune disorders of the neuromuscular junction. Current opinion in 
pharmacology 2009; 9:336-340. 
 
Mollnes, T. E., and M. Kirschfink. Strategies of therapeutic complement inhibition. Mol 
Immunol 2006; 43:107-121. 
 
Nozaki, M., B. J. Raisler, E. Sakurai, J. V. Sarma, S. R. Barnum, J. D. Lambris, Y. Chen, K. 
Zhang, B. K. Ambati, J. Z. Baffi, and J. Ambati. Drusen complement components C3a and 
C5a promote choroidal neovascularization. Proceedings of the Nat Acad Sci 2006;103:2328-
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Nunn, M. A., A. Sharma, G. C. Paesen, S. Adamson, O. Lissina, A. C. Willis, and P. A. 
Nuttall. Complement inhibitor of C5 activation from the soft tick Ornithodoros moubata. J 
Immunol 2005; 174:2084-2091. 
 
Ram S, Lewis LA, Rice PA.  Infections of people with complement deficiencies and patients 
who have undergone splenectomy. Clin Microbiol Rev. 2010; 23(4):740 -780 
 
Roversi, P., Ryffel, B., Togbe, D., et al. Bifunctional Lipocalin Ameliorates Murine Immune 
Complex-induced Acute Lung Injury. J. Biol Chem 2013; 288:18789-18802. 
 
Sarma, V. J., M. Huber-Lang, and P. A. Ward. Complement in lung disease. Autoimmunity 
2006; 39:387-394. 
 
Sissons, J. G., J. Liebowitch, N. Amos, and D. K. Peters. Metabolism of  the fifth 
component of complement, and its relation to metabolism of the third component, in 
patients with complement activation. J Clin Invest 1977; 59:704-715.24. 
Tuzun, E., J. Li, S. S. Saini, H. Yang, and P. Christadoss. Targeting classical complement 
pathway to treat complement mediated autoimmune diseases. Advances in experimental 
medicine and biology 2008; 632:265-272. 
 
Ward, P. A., N. C. Riedemann, R. F. Guo, M. Huber-Lang, J. V. Sarma, and F. S. Zetoune. 
Anti-complement strategies in experimental sepsis. Scand J Infect Dis 2003; 35:601-603. 
 
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Structural basis for therapeutic inhibition of complement C5. Nat Struct Mol Biol 2016; 
23(5): 378-386. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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16  Appendices 
Appendix 1:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SAP_001.pdf: 
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN 
CONSERVE:  
rVA576 (Coversin) Long Term Safety and Efficacy Surveillance Study 
Drug Name: 
Coversin, nomacopan, OmCI, rVA576, rEV576 
Study Number: 
AK581 
EudraCT Number: 
2016-004129-18 
Name of Sponsor: 
Akari Therapeutics Plc 
Address: 
Protocol Version (Date): 
Protocol Version 3.0 (11 Januray 2019) 
SAP Version: 
Final V 1.0 
SAP Date: 
3 April 2020 
AK581 CSR Section 16
Akari Therapeutics Plc
30th April 2021
Section 16 Page 735 of 3564
NCT03829449


 
SAP SIGNATURE PAGE 
 
STUDY TITLE: CONSERVE: Coversin Long Term Safety and Efficacy  
                                                     Surveillance Study 
 
We, the undersigned, have reviewed and approve this statistical analysis plan. 
 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AK581 CSR Section 16
Akari Therapeutics Plc
30th April 2021
Section 16 Page 736 of 3564


TABLE OF CONTENTS 
 
1 
INTRODUCTION .......................................................................................... 6 
2 
STUDY OBJECTIVES AND STUDY DESIGN ........................................... 6 
2.1 
Study Objectives ............................................................................................. 6 
2.2 
Study Design ................................................................................................... 6 
2.3 
Study Data ...................................................................................................... 7 
2.4 
Study Endpoints .............................................................................................. 8 
2.4.1 
Primary Endpoint ..................................................................................... 8 
2.4.2 
Secondary Endpoints ............................................................................... 8 
2.5 
Additional Endpoints: ..................................................................................... 9 
3 
EFFICACY AND SAFETY VARIABLES .................................................. 10 
3.1 
Baseline (study entry) and Parent trial Baseline ........................................... 10 
3.2 
Entry ............................................................................................................. 10 
3.2.1 
Medical History ..................................................................................... 10 
3.2.2 
Demographics ........................................................................................ 10 
3.2.3 
Eligibility ................................................................................................ 11 
3.2.4 
Transfusions and Complement inhibitor history .................................... 11 
3.3 
Efficacy Measurements and Variables ......................................................... 11 
3.3.1 
Blood transfusions ................................................................................. 11 
3.3.2 
Serum Lactate dehydrogenase (LDH).................................................... 11 
3.3.3 
CH50 Levels ........................................................................................... 11 
3.3.4 
EORTC QLQ-C30 .................................................................................. 12 
3.3.5 
EQ-5D-5L .............................................................................................. 13 
3.3.6 
FACIT-F ................................................................................................. 14 
3.3.7 
Self-Injection Questionnaire .................................................................. 14 
3.4 
Safety Measurements and Variables ............................................................. 14 
3.4.1 
Major Adverse Vascular Event (MAVE) Assessment ............................. 14 
3.4.2 
Thrombotic and Haemolytic Events ....................................................... 15 
3.4.3 
Adverse Events (AEs) ............................................................................. 15 
3.4.4 
Safety Clinical Laboratory Measurements ............................................ 16 
3.4.5 
Vital Signs .............................................................................................. 18 
3.4.6 
Weight .................................................................................................... 18 
3.4.7 
Electrocardiogram ................................................................................. 18 
3.4.8 
Anti-drug Antibodies (ADA) .................................................................. 19 
3.4.9 
Physical Examination ............................................................................ 19 
3.4.10 Pharmacokinetic Coversin Levels .......................................................... 19 
3.4.11 Fluorescein-labelled proaerolysin FLAER / Flow Cytometry ............... 19 
3.5 
Compliance and Exposure ............................................................................ 20 
3.6 
Concomitant Medications ............................................................................. 20 
3.7 
Presentation................................................................................................... 20 
4 
STATISTICAL METHODS PLANNED ..................................................... 21 
4.1 
Changes from Protocol ................................................................................. 21 
4.2 
Analysis Sets ................................................................................................. 21 
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30th April 2021
Section 16 Page 737 of 3564


4.2.1 
Screened Set ........................................................................................... 21 
4.2.2 
Full Analysis Set .................................................................................... 21 
4.3 
Review of Data and SAP Finalisation .......................................................... 21 
4.4 
Statistical Methods, definitions .................................................................... 22 
4.5 
General Data Handling Rules ....................................................................... 22 
4.6 
Patient Disposition ........................................................................................ 22 
4.7 
Demographics and Baseline Characteristics ................................................. 22 
4.8 
Medical History ............................................................................................ 22 
4.9 
Study Drug Exposure and Compliance......................................................... 22 
4.10 
Concomitant Medications ............................................................................. 23 
4.11 
Analysis of Efficacy ..................................................................................... 23 
4.11.1 Blood Transfusions ................................................................................ 23 
4.11.2 LDH ........................................................................................................ 23 
4.11.3 Transfusion-independence and Haemoglobin ....................................... 23 
4.11.4 CH50 ...................................................................................................... 24 
4.11.5 EORTC QLQ-C30 .................................................................................. 24 
4.11.6 EQ-5D-5L .............................................................................................. 24 
4.11.7 FACIT-F ................................................................................................. 24 
4.12 
Analysis of Safety ......................................................................................... 24 
4.12.1 Adverse Events ....................................................................................... 24 
4.12.2 Clinical Laboratory Assessments ........................................................... 25 
4.12.3 Vital Signs .............................................................................................. 25 
4.12.4 Electrocardiogram ................................................................................. 25 
4.12.5 Thrombotic and Haemolytic Events ....................................................... 25 
4.12.6 Major Adverse Vascular Event (MAVE) ................................................ 26 
4.13 
Interim Analysis............................................................................................ 26 
4.14 
Data Safety Monitoring Board (DSMB)....................................................... 26 
5 
SAMPLE SIZE DETERMINATION ........................................................... 26 
6 
PROGRAMMING SPECIFICATIONS ....................................................... 26 
7 
APPENDIX 1................................................................................................ 27 
7.1 
Tables ............................................................................................................ 27 
7.2 
Listings ......................................................................................................... 29 
7.3 
Figures .......................................................................................................... 30 
 
 
AK581 CSR Section 16
Akari Therapeutics Plc
30th April 2021
Section 16 Page 738 of 3564


 
LIST OF ABBREVIATIONS 
 
ADA 
Anti-drug Antibodies 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BP 
Blood Pressure 
CH50 
Classical haemolytic 50% lysis 
CH50 U Eq/ml 
Classical haemolytic 50% lysis units equivalent / ml 
CI 
CSR 
Confidence Interval 
Clinical Study Report 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EORTC 
European Organisation for Research and Treatment of Cancer  
EQ-5D-5L 
EuroQol 5 dimensional 5 level 
ET 
Early termination 
FAS 
FLAER 
Full Analysis Set 
Fluorescein-labelled proaerolysin 
Hb 
Haemoglobin 
ICF 
Informed consent form 
LDH 
Lactate dehydrogenase 
LLN 
LLOQ 
Lower limit of normal 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
Pharmacokinetics 
PNH 
Paroxysmal Nocturnal Haemoglobinuria 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
SDTM 
Standard deviation 
Study Data Tabulation Model 
TE 
Treatment-emergent 
ULN 
ULOQ 
Upper limit of normal 
Upper limit of quantification 
 
AK581 CSR Section 16
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30th April 2021
Section 16 Page 739 of 3564


1 
Introduction 
This document provides a description of the statistical methods and procedures to be 
implemented for the analysis and reporting of data from the Akari Therapeutics study with 
protocol number AK581.  Any deviations from this statistical analysis plan (SAP) after 
database lock will be clearly documented in the final clinical study report (CSR). 
This SAP is based on the Clinical Study Protocol Version 3.0, dated 11 January 2019. A 
previous version had been developed between June and December 2017 but was not 
finalised or approved. Therefore this document is considered version 1.0. 
This SAP only describes the analyses that will be performed for PNH patients given  
that the aHUS trial has been terminated due to inability to recruit. Therefore as no 
aHUS patients will enter AK581, all references to objectives and analyses related to 
aHUS patients have been removed from this SAP.   
2 
Study Objectives and Study Design 
 
The objective of the trial is to provide a database of information regarding long-term 
administration of rVA576 (Coversin) to show that it remains safe for long periods and is 
acceptable to patients and show that the effect observed in the previous clinical trial is 
maintained. It also provides the opportunity to adjust an individual patient’s dose or dose 
frequency should it be considered desirable. All patients enrolled into the CONSERVE 
study will have transitioned from a parent clinical trial. 
 
 
 
 
 
 
2.1 
Study Objectives 
The specific objectives of the study are: 
 
• 
To observe the long term safety and efficacy of rVA576 (Coversin)  
• 
To assess the long term patient acceptability of rVA576 (Coversin) using the 
EORTC QLQ-C30 (for some PNH only),  EQ-5D-5L & FACIT-F instruments and 
the Sponsor non validated questionnaire. 
• 
To observe the changes, if any, in the production of anti-drug antibodies (ADA) 
and whether such antibodies are, or become, neutralising. 
2.2 
Study Design 
The trial is an open-label, non-comparative study in up to approximately 50 patients, 18 
years and above with either PNH or aHUS who have participated in another rVA576 
(Coversin) and who wish to remain on the study. 
 
The study population will consist of patients with diseases requiring complement 
inhibition who have previously taken part in Akari clinical trials and who wish to 
AK581 CSR Section 16
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30th April 2021
Section 16 Page 740 of 3564


continue to receive rVA576 (Coversin) after their active participation in the previous trial 
has completed  and patients treated under compassionate use or named patient 
arrangements who wish to continue on rVA576 (Coversin) therapy. 
 
The study visit schedule and procedures intended to be performed at each visit are displayed 
in the study protocol Tables 8 and 9. 
2.3 
Study Data 
All patients enrolled into the CONSERVE study will have transitioned from a parent 
clinical trial and all will have been previously treated with rVA576. 
Parent trial data used to assess patient safety and eligibility for enrollment will be entered 
into the AK581 database. Where applicable, assessment data collected at the subject’s 
parent trial end of study visit will be captured. Coversin dosing history, parent trial ECG 
and LDH results, and plasma (blood) transfusion/dialysis history will be available in the 
AK581 subject casebooks. 
Where applicable and where possible, parent trial locked databases will be used and 
pooled with the AK581 database: 
- 
Raw data from AK578 CONSENT   
- 
Study Data Tabulation Model (SDTM) and/or Analysis Data Model (ADaM) 
datasets from AK579 COBALT 
- 
SDTM and/or ADaM datasets from AK580 CAPSTONE 
 
See section 3.1, for the definitions of baseline (study entry) and parent trial baseline. 
AK581 CSR Section 16
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30th April 2021
Section 16 Page 741 of 3564


2.4 
Study Endpoints 
2.4.1 Primary Endpoint 
Long term safety of rVA576 (Coversin) therapy as assessed by AEs, serious adverse events 
(SAEs), vital signs, results of standard laboratory tests (clinical chemistry, haematology 
and urinalysis), and results of electrocardiograms (ECGs). 
2.4.2 Secondary Endpoints  
 
1. 
Proportion of subjects with thrombotic and haemolytic event-free status   during 
each 3 month time period since the start of the study. 
2. 
Time to thrombotic or haemolytic event since the start of the  study.  
3. 
Proportion of subjects who require PRBC transfusion during each 3-month period 
since the start of the study and over the entire period of the study, with analysis of i) subjects 
who were transfusion-dependent when they started receiving rVA576 (Coversin), ii) 
subjects who were transfusion-independent when they started receiving rVA576 
(Coversin), and iii) all subjects, and further stratification of these proportions by a) patients 
who were complement inhibitor-naïve prior to treatment with rVA576 (Coversin), and b) 
patients who received treatment with another complement inhibitor before switching to 
rVA576 (Coversin).   
4. 
Time to first transfusion since joining the study.  
5. 
Proportion of subjects with no adverse change in overall scores of Quality of Life 
using the EORTC QLQ-C30, the EQ-5D-5L and FACIT-F instruments at each 3-month 
time period since the start of the study. 
6. 
Proportion of subjects with serum Lactate Dehydrogenase (LDH) <1.8, >1.8 to 2.4, 
>2.4 to 3, and >3 times the upper limit of normal (ULN) at each 3-month time period since 
the start of the study.  
7. 
Proportion of subjects with median serum Lactate Dehydrogenase (LDH) <1.8, 
>1.8 to 2.4, >2.4 to 3, and >3 times the upper limit of normal (ULN) over the entire duration 
of the study. 
8. 
Proportion of transfusion-independent subjects at each 3-month time point, with 
haemoglobin (g/L) above the baseline haemoglobin value they had at the start of the trial 
from which they entered CONSERVE. With baseline for CAPSTONE (AK580) defined as 
the haemoglobin value at which they received their qualifying transfusion (the set point) or 
for COBALT (AK579) and CONSENT (AK578) the haemoglobin value at which patients 
entered those trials.  With separate analysis of subjects who were i) transfusion-independent 
prior to receiving rVA576 (Coversin) and remain transfusion-independent and ii) 
transfusion-dependent prior to receiving rVA576 (Coversin). 
9. 
Proportion of transfusion-independent subjects over the entire duration of the study 
with mean haemoglobin (g/L) above the baseline haemoglobin value they had at the start 
of the trial from which they entered CONSERVE. With baseline haemoglobin defined as 
for the previous secondary endpoint (#8).  With separate analysis of subjects who were i) 
transfusion-independent prior to receiving rVA576 (Coversin) and remain transfusion-
independent and ii) transfusion-dependent prior to receiving rVA576 (Coversin). 
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10. 
Proportion of patients experiencing Major Adverse Vascular Events (MAVE) over 
the entire period of the study. 
11. 
Time to first Major Adverse Vascular Event (MAVE) for each subject since joining 
the study. 
12. 
Number of Major Adverse Vascular Events (MAVE) over the entire period of the 
study. 
 
2.5 
Additional Endpoints: 
PK and PD parameters during treatment, to include terminal complement activity measured 
by CH50 ELISA, unbound nomacopan concentration measured by ELISA and total C5 
concentration measured by ELISA. 
 
 
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30th April 2021
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3 
Efficacy and Safety Variables 
3.1 
Baseline (study entry) and Parent trial Baseline 
In order to describe changes over time, and compare values to the pre-Coversin dosing 
value (historical baseline), some parameters (LDH, CH50, quality of life scores, 
haemoglobin) may have both parent trial baseline values and CONSERVE baseline values 
used in analyses. To avoid any confusion the term “baseline” will always refer to 
CONSERVE baseline, while ‘Parent trial baseline’ will be used otherwise. 
Baseline will therefore be defined as the last measurement prior to CONSERVE study 
entry. 
Parent trial baseline will be defined as : 
- 
Baseline for CAPSTONE (AK580) defined as the value at which they received 
their qualifying transfusion (the set point)  
- 
Baseline for COBALT (AK579) or CONSENT (AK578) the value at which 
patients entered those trials.   
3.2 
Entry  
Written informed consent will be obtained before any study procedures are performed.  The 
following procedures will be performed exclusively at the Entry visit.  
 
3.2.1 Medical History 
A complete medical history will include an evaluation  of the previous medical history from 
the previous rVA576 (Coversin) trial which will be transferred to the current database. 
 
As all patients enrolled into the CONSERVE study will have transitioned from a parent 
clinical trial, a full new medical history and examination is not considered necessary unless 
there has been a lag time in entry into the long term study  The investigator responsible for 
the patient’s treatment will decide if there have been significant changes in the patient’s 
condition since being in the previous study to warrant an additional examination and new 
entries to the medical history page. If there has been development of a new medical 
condition (with diagnosis) in the previous study this will be considered as part of the 
patient’s  medical history for this study. 
 
All medical history data will be coded using the MedDRA dictionary version available at 
the time of the analysis. 
 
3.2.2 Demographics 
Demographic information (date/year of birth, age, sex, ethnicity, race and blood group) will 
be collected at study entry. 
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3.2.3 Eligibility 
Evaluation of the study inclusion/exclusion criteria (see study AK581 trial Protocol 
sections 4.1 and 4.2) will be assessed at Entry. 
3.2.4 Transfusions and Complement inhibitor history 
Patients will be classified in subgroups as follows: 
i) 
Patients who were transfusion-dependent when they started receiving rVA576 
(Coversin),  
ii) 
Patients who were transfusion-independent when they started receiving 
rVA576 (Coversin),   
 
and further groupings will be performed as follows:  
a)  
Patients who were complement inhibitor-naïve prior to treatment  
 
with rVA576 (Coversin), 
b)  
Patients who received treatment with another complement inhibitor before 
of the switching to rVA576 (Coversin).   
3.3 
Efficacy Measurements and Variables 
3.3.1 Blood transfusions 
Details of blood transfusions administered during the study will be captured at all visits. 
Infusion type (PRBC or platelet), date, volume, reason and whether the transfusion was 
used as a method of PNH treatment will be recorded. 
Patients who were transfusion-independent when they started receiving rVA576 (Coversin) 
and remain transfusion-independent will be identified. 
3.3.2 Serum Lactate dehydrogenase (LDH) 
Lactate dehydrogenase (LDH) values will be obtained  as per the schedule of events.  
Changes and percent changes from the Parent trial baseline to each assessment of this study 
will be derived. 
To permit the comparison of LDH values from different local laboratories, the ratio of the 
recorded LDH value to the local laboratory upper limit of normal (ULN) will be derived.  
Values below the ULN will provide a ratio of less than one; values above the ULN will 
provide a ratio of greater than one. 
Indicators will be derived for each patient at every visit, to identify whether the LDH value 
≤1.8, >1.8 to 2.4, >2.4 to 3, and >3 times the ULN.The median serum LDH will also be 
derived for each patient. 
3.3.3 CH50 Levels 
Blood samples for CH50 will be collected as per the schedule of events and analysed in the 
Central Laboratory. The Central Laboratory considers values less than 10 CH50 U Eq/mL 
as completely inhibited. In previous trials (AK577, AK578 and AK579) with rVA576 
(Coversin) the lower limit of quantification (LLOQ) of the CH50 was 8 CH50 EU/mL. The 
LLOQ has increased because the assay is now being performed using an automated system 
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for the ELISA. Results recorded as below the LLOQ will be imputed using half of the lower 
limit of quantification that applies to the sample for the purpose of calculating change from 
baseline, or percentage change from baseline, for summaries and figures. 
The absolute change and percentage change from the parent trial Baseline to each 
subsequent assessment will be derived. 
3.3.4 EORTC QLQ-C30 
Patients are to complete the EORTC QLQ-C30 as per the schedule of events. 
QLQ-C30 comprises 30 questions on daily quality of life, with each question having a 
response score on a scale of 1-4 or 1-7.  QLQ-C30 incorporates a global health status, five 
functional scales (physical, role, cognitive, emotional and social), three symptom scales 
(fatigue, nausea/vomiting, pain), and six single items (dyspnoea, insomnia, appetite loss, 
constipation, diarrhoea, financial difficulties).  Each scale and single item is derived and 
scaled to fall in the range 0 to 100, where a high score represents higher response.  Table  
lists the scores to be derived and the items used in their derivation. 
Table 1: QLQ-C30 Scales 
Derived Scale 
Scale 
Items 
#Items 
Range 
Global health status 
QL 
29, 30 
2 
6 
Functional scale – Physical Functioning 
PF 
1, 2, 3, 4, 5 
5 
3 
Functional scale – Role Functioning 
RF 
6, 7 
2 
3 
Functional scale – Emotional Functioning 
EF 
21, 22, 23, 24 
4 
3 
Functional scale – Cognitive Functioning 
CF 
20, 25 
2 
3 
Functional scale – Social Functioning 
SF 
26, 27 
2 
3 
Symptom scale – Fatigue 
FA 
10, 12, 18 
3 
3 
Symptom scale – Nausea and Vomiting 
NV 
14, 15 
2 
3 
Symptom scale – Pain 
PA 
9, 19 
2 
3 
Symptom item – Dyspnoea 
DY 
8 
1 
3 
Symptom item – Insomnia 
SL 
11 
1 
3 
Symptom item – Appetite Loss 
AP 
13 
1 
3 
Symptom item – Constipation 
CO 
16 
1 
3 
Symptom item – Diarrhoea 
DI 
17 
1 
3 
Symptom item – Financial Difficulties 
FI 
28 
1 
3 
 
The following algorithm will be used in deriving the functional and symptom scale scores: 
1. Derive the raw score (RS) for each functional and symptom score by deriving the 
average of the contributing items (I). 
RS = (I1 + I2 +…+In)/n 
 
2. Derive the standardised score (Score) for each functional and symptom score by 
mapping the raw score to the range from 0 to 100, where a higher score represents 
a better level of function or a worse level of symptoms. 
For Function scales: 
Score = {1 – (RS-1)/range} x 100 
 
For Symptom scales and Global health status: 
Score = {(RS-1/range} x 100 
 
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3. For derived scales that include two or more items, a derived value will be 
calculated if at least half of the items are non-missing.  If more than half of the 
items are missing then the scale will be set to missing. 
 
For each of the standardised function scales, symptom scales, global health status scale and 
standardised single item scales the Baseline for each patient is parent trial baseline.  The 
absolute change from the parent trial Baseline to each subsequent assessment will be 
derived for each of the standardised scales and standardised single item scores. 
Changes in the global health status will be identified as adverse if the score has decreasd 
(negative absolute change from the parent trial Baseline) in a 3-month time period. 
Patients with no adverse change at each 3-month time period since the start of the study 
will be identified. 
3.3.5 EQ-5D-5L 
Patients were to complete the EQ-5D-5L as per the schedule of events . 
EQ-5D-5L comprises 5 questions (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression), each with five levels plus the EQ Visual Analogue scale.  The patient 
response to each of the 5 questions will be mapped to the score indicated in Table 2.  The 
five mapped responses, also known as the 5L profile, will then be used to obtain a 
normalised score for each patient assessment by obtaining the country-specific normalised 
value from the Crosswalk Index Value Calculator. 
Table 2: EQ-5D-5L Response Scores 
Question 
Response 
Score 
Q1: 
Mobility 
I have no problems in walking  
1 
I have slight problems in walking  
2 
I have moderate problems in walking  
3 
I have severe problems in walking  
4 
I am unable to walk  
5 
Q2: 
Self-Care 
I have no problems washing or dressing myself 
1 
I have slight problems washing or dressing myself 
2 
I have moderate problems washing or dressing myself 
3 
I have severe problems washing or dressing myself 
4 
I am unable to wash or dress myself 
5 
Q3: 
Usual Activities 
I have no problems doing my usual activities 
1 
I have slight problems doing my usual activities 
2 
I have moderate problems doing my usual activities 
3 
I have severe problems doing my usual activities 
4 
I am unable to do my usual activities 
5 
Q4: 
Pain/Discomfort 
I have no pain or discomfort 
1 
I have slight pain or discomfort 
2 
I have moderate pain or discomfort 
3 
I have severe pain or discomfort 
4 
I have extreme pain or discomfort 
5 
Q5: 
Anxiety/Depression 
I am not anxious or depressed 
1 
I am slightly anxious or depressed 
2 
I am moderately anxious or depressed 
3 
I am severely anxious or depressed 
4 
I am extremely anxious or depressed 
5 
 
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The absolute change from the Parent trial baseline to each subsequent assessment will be 
derived. 
Changes in the normalised score will be identified as adverse if the score has decreasd 
(negative absolute change from the parent trial Baseline) in a 3-month time period. 
Patients with no adverse change at each 3-month time period since the start of the study 
will be identified. 
3.3.6 FACIT-F 
The FACIT-F (functional assessment of chronic illness therapy - fatigue) version 4 
comprises 41 items measuring an individual’s level of fatigue during their usual daily 
activities. The level of fatigue is measured on 5 subscales (Physical Well-Being subscale, 
Social/Family Well-Being subscale, Emotional Well-Being subscale, Functional Well-
Being subscale and additional concerns). 
Where applicable, item variables will be reverse coded for the purpose of generating the 
scale scores as per the FACIT-F scoring guidelines. For each patient, at each visit, the 
FACT-G Total Score, FACIT-F Total Score and  FACIT-F Trial Outcome Index will be 
calculated. For guidelines on handling missing data and scoring options, the administration 
and scoring guidelines in the manual or on-line at www.facit.org will be used. 
Changes in the FACIT-F Total score will be identified as adverse if the score has decreased 
(negative absolute change from Baseline) in a 3-month time period. 
Patients with no adverse change at each 3-month time period since the start of the study 
will be identified. 
Where possible, the change from the Parent Baseline may also be described. Parent trials 
AK580, AK585 and AK578 used version 4 of the FACIT questionnaire, while AK579 did 
not collect this data. 
3.3.7 Self-Injection Questionnaire 
Patients will complete a non-validated questionnaire at every visit to determine whether 
self-injection by patients is well-accepted and the support provided sufficient.  Each 
question was to be answered using one of the available categorical scores.   
No derivations will be performed on this data. This data will only be listed. 
3.4 
Safety Measurements and Variables 
3.4.1 Major Adverse Vascular Event (MAVE) Assessment 
The MAVE will be used to collect information on large and small vessel thrombosis as well 
as micro thrombosis and will be recorded always pre-dose at each clinic visit. 
MAVE will be recorded as part of the AEs and the following details will be reported: 
• MAVE location: 
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o Limbs 
o Lungs 
o Brain 
o Heart 
o Kidneys 
o Intestines 
o Liver 
o Other 
• Method of diagnosis: 
o MRI 
o Ultrasound 
o Angiogram 
o Other 
3.4.2 Thrombotic and Haemolytic Events 
Thrombotic and Haemolytic Events will include, but are not limited to, the following: 
haemolytic anaemia, thrombocytopenia, red blood cell hemolysis indicated by dark urine, 
Budd-Chiara syndrome, any other thrombotic or hemolytic event deemed to be associated 
with PNH. 
A haemolytic event will be defined as a rise in LDH or other biochemical evidence of 
haemolysis (eg increasing serum bilirubin or liver enzymes) accompanied by an increase 
in symptoms (eg myalgia, erectile dysfunction, fatigue) and/or frank haemoglobinuria. 
Increased symptoms without objective haematological or biochemical evidence of 
haemolysis will not be counted as haemolytic events. 
 
In addition, the following signs and symptoms may be reviewed and classified as 
Thrombotic/Haemolytic events if appropriate: 
• Acute kidney failure 
• Hypertension  
• Myocardial infarction 
• Stroke 
• Lung complications (e.g. Pulmonary embolism) 
• Pancreatitis 
• Liver necrosis 
• Encephalopathy (brain dysfunction 
• Seizure 
• Coma 
• Premature death (secondary to neurologic, cardiac, kidney, and gastrointestinal 
organ dysfunction) 
 
3.4.3 Adverse Events (AEs) 
All AEs, which occurred at any time after signing the informed consent form (ICF), will be 
recorded in the electronic Case Report Form (eCRF).  The following details will be reported 
for each adverse event: 
 
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• Start and stop dates 
 
• Severity, using CTCAE  grading 1 to 5 
 
• Relationship to study treatment: 
o Unrelated 
o Possibly Related 
o Related 
 
• Serious: 
o Yes 
o No 
 
• Action taken with study treatment: 
o Dose increased 
o Dose not changed 
o Dose reduced 
o Drug interrupted 
o Drug withdrawn 
o Not applicable 
o Unknown 
o Other 
 
 
• Outcome 
o Fatal 
o Not recovered/not resolved 
o Recovered/resolved 
o Recovered/resolved with sequelae 
o Recovering/resolving 
o Unknown 
 
Other action taken, whether the AE caused discontinuation, details of death, hospitalisation, 
last dose before the event and other information reated to the AE will be collected and listed. 
Treatment emergent adverse events are defined as any AE with a recorded start date/time 
on or after the date/time of start of study medication.  All patients enrolled into the 
CONSERVE study will have transitioned from a parent clinical trial and all will have been 
previously treated with rVA576, therefore all AEs recorded under protocol AK581 will be 
considered treatment-emergent. 
3.4.4 Safety Clinical Laboratory Measurements 
A blood and urine sample will be collected for clinical laboratory measurements 
(haematology, biochemistry and urinalysis) as per the schedule of events. The following 
laboratory parameters for haematology, chemistry and urinalysis will be evaluated at each 
clinical site’s local laboratory: 
Haematology 
• Haemoglobin [g/L] 
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• Haematocrit [%] 
• Mean cell haemoglobin [pg] 
• Mean cell haemoglobin concentration [g/L] 
• Mean cell volume [fL] 
• Red blood cell count [10^12/L] 
• Erythrocyte sedimentation rate [mm/h] 
• Platelets [10^9/L] 
• White blood cell count [10^9/L] 
• Neutrophils absolute [10^9/L] 
• Lymphocytes absolute [10^9/L] 
• Monocytes absolute [10^9/L] 
• Eosinophils absolute [10^9/L] 
• Basophils absolute [10^9/L] 
• Reticulocytes [10^9/L] 
Chemistry 
• Lactate dehydrogenase [U/L] 
• Sodium [mmol/L] 
• Potassium [mmol/L] 
• Bicarbonate [mmol/L] 
• Urea [mmol/L] 
• Creatinine [µmol/L] 
• Chloride [mmol/L] 
• Albumin [g/L] 
• Calcium [mmol/L] 
• Gamma-glutamyl transpeptidase [U/L] 
• Glucose (random) [mmol/L] 
• Alkaline phosphatase [U/L] 
• Alanine aminotransferase [U/L] 
• Aspartate aminotransferase [U/L] 
• Creatine kinase [U/L] 
• Total Bilirubin [µmol/L] 
• Bilirubin (Direct) (only if Total is elevated) [µmol/L] 
• Phosphate (Inorganic) [mmol/L] 
• Protein (Total) [g/L] 
For each of the haematology and chemistry parameters, values from the locally reported 
laboratory will be converted to the standardised units shown in parenthesis during statistical 
programming of the SDTM datasets. 
Urinalysis 
• Leukocytes 
• Protein 
• Bilirubin 
• Glucose 
• pH 
• Ketones 
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• Nitrates 
• Blood 
• hCG (female patients) 
• Specific gravity 
At the discretion of the Investigator: 
• Microbiology 
• Urine microscopy 
• Pregnancy testing 
• Urobilinogen 
 
Central Laboratory Testing 
The following parameters may also be evaluated at the Central Laboratory but are not 
mandatory: 
• LTB4 
• Total LDH and LDH Isoenzyme 
• Total bound and unbound C5 
 
Out-of-range laboratory data will be flagged as low or high according to gender and 
laboratory specific normal ranges. 
The absolute change from Baseline to each subsequent assessment will be derived for each 
of the continuous laboratory parameters. 
Haemoglobin 
For Haemoglobin, the Parent trial baseline will be used. Patients with an haemoglobin 
above the baseline haemoglobin value they had in the parent trial will be flagged. 
The mean haemoglobin value post study entry will be calculated for each patient.  
3.4.5 Vital Signs 
Blood pressure and pulse rate will be measured in the supine position after the patient has 
rested comfortably as per the schedule of events.  
The change from Baseline to each subsequent assessment will be derived for each vital 
signs parameter. 
3.4.6 Weight  
Patient’s weight will be recorded as per the schedule of events.   
Changes from Baseline to each post baseline assessment will derived. 
3.4.7 Electrocardiogram 
Routine ECG will be performed at entry and then annually during the study. The following 
ECG parameters will be recorded in the eCRF: 
• 
Heart rate (beats/min) 
• 
PR interval (msec) 
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• 
QRS duration (msec) 
• 
QT interval (msec) 
• 
QTc interval (msec) 
• 
RR interval (msec) 
• 
Overall interpretation 
 
Interpretation of the ECG will be performed by the investigator and reported as normal,  
abnormal, inderterminate, and if deemed abnormal, whether the abnormality is clinically 
significant or not clinically significant.   
Changes in each ECG parameter from Baseline or any additional unscheduled ECGs, will 
be derived. 
3.4.8 Anti-drug Antibodies (ADA) 
Serum samples will be analysed for ADA formation to rVA576 (Coversin) as per the 
schedule of events. ADA analyses may be performed at a later stage and results reported 
separately from the main CSR.   
3.4.9 Physical Examination 
A physical examination, covering the following aspects, will be performed as per the 
schedule of events: 
• General appearance 
• Dermatological/skin 
• Haematologic/lymphatic 
• Heart/cardiovascular 
• Respiratory 
• Vein and injection site inspection 
No derivations will be performed on this data. This data will only be listed. 
3.4.10 Pharmacokinetic Coversin Levels 
A blood sample for unbound rVA576 Coversin levels will be collected as per the schedule 
of events. 
Unbound nomacopan, total C5 and serum LTB4 levels will be summarised overtime and 
spaghetti plot of concentrations through time will be produced. 
Additional exploratory figures may be produced in order to investigate threshold levels that 
should be exceeded to ensure >90% inhibition of terminal complement activity. Additional 
PK analyses may be performed at a later stage and results reported separately from the main 
CSR.    
3.4.11 Fluorescein-labelled proaerolysin FLAER / Flow Cytometry  
A blood sample will be collected for flow cytometry measurements at study entry, Month 
3, 15, 24, 33 and 48. The following parameters will be evaluated at each clinical site’s local 
laboratory: 
• Red blood cells and neutrophils: % cells negative for CD55, CD59, and both CD55 
and CD59 and/or 
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• Granulocytes:  % cells negative for CD24, CD16, CD24 and FLAER, CD16 and 
FLAER and/or 
• Granulocytes, monocytes: % cells negative for FLAER and/or Monocytes: % cells 
negative for CD14, and both CD14 and FLAER 
 
No derivations will be performed on this data. This data will only be listed. 
 
3.5 
Compliance and Exposure 
Exposure will be derived as the number of days between the first and last dose of study 
medication in this study. 
Study medication compliance will be derived as the proportion of doses that the patient 
received during the exposure period.  
The overall patient compliance (%) will be derived as: 
= 1 - (Total number of missed doses / Total number of planned doses ) 
 
This derived compliance will be categorised: 
• <95% 
• 95% to <99% 
• 99% to 100% 
• >100% 
3.6 
Concomitant Medications 
All medications recorded on the Concomitant Medications eCRF will be considered as used 
during the treatment period (i.e., concomitant).  
All concomitant medication will be coded with Anatomical Therapeutic Chemical (ATC) 
class and preferred term. 
3.7 
Presentation 
Statistical analyses will be performed using SAS® (Version 9.3 or later).  All available data 
will be presented in patient data listings, which will be sorted by site number, patient 
identifier and where appropriate, visit and/or visit date. 
Descriptive statistics (n, mean, standard deviation, median, first quartile, third quartile, 
minimum, and maximum) will be used to summarise the continuous efficacy and safety 
data.  Discrete measures will be summarised using count and percentage.  Unless otherwise 
stated, descriptive statistics showing the mean or median will be displayed to one decimal 
place more than the original data; the standard deviation will be displayed to two decimal 
places more than the original data; minimum and maximum will be displayed to the same 
number of decimal places as the original data. 
Any significance tests or confidence intervals will be exploratory. 
Unless otherwise stated, all data will be listed. 
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4 
Statistical Methods Planned 
4.1 
Changes from Protocol 
• ADA analyses may be performed at a later stage and results will be reported 
separately from the main CSR. 
• The LDH categories referenced in the protocol were < 1.8, >1.8 to 2.4, >2.4 to 3, 
and >3 times the upper limit of normal (ULN), given that these do not cover LDH 
equal to 1.8ULN, the following categories will be used serum LDH ≤ 1.8, >1.8 to 
2.4, >2.4 to 3, and >3 ULN 
4.2 
Analysis Sets 
4.2.1 Screened Set  
The Screened Set will include all patients screened for participation in the study.  
4.2.2 Full Analysis Set  
The primary analysis will be intention to treat and all patients who entered and signed 
informed consent will be included. The Full Analysis Set (FAS) will therefore include all 
enrolled patients.  
All patients will be included in the safety analysis, whether completing the trial according 
to the protocol or not. Analyses of efficacy at various time points (6 months 12 months, 2, 
3, 4 and 5 years) will be made for all patients reaching those points. The FAS will be the 
population used for assessing safety and efficacy and will be used for all outputs with the 
exception of patient disposition summary and data listings. 
4.3 
Review of Data and SAP Finalisation 
Patient data will be reviewed for major protocol deviations by the Study Monitor during 
site visits and the entire team will review the database at timed intervals prior to the 
database lock. 
Missing data that cannot be retrieved from source records or other repositories will be 
recorded as such in the eCRFs and will not be entered into the statistical analysis. Spurious 
data will be examined by the Sponsor’s monitor, medical or statistical advisors and a 
decision made as to how it should be handled. If there is an obvious transcription or data 
entry error, such as a misplaced decimal point in a biochemical parameter, this will be 
discussed with the CRO or the laboratory and, if all parties agree, it will be corrected and 
endorsed by both the PI and the Sponsor.  
Unused data (e.g. superfluous blood pressure recordings or haematological results in 
addition to those required by the protocol) will remain part of the source documentation 
and only be incorporated into the trial documents and analysis if there is reason for them to 
be (e.g. an unexpected fall in blood pressure that might constitute an AE). 
The final analysis will be performed using data collected up to the end of the study. This 
data will be presented in the CSR. 
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4.4 
Statistical Methods, definitions 
4.5 
General Data Handling Rules 
Values from the locally reported laboratory will be converted to the standardised units at 
the SDTM level. 
Laboratory values recorded as below the LLOQ or above the upper limit of quantification 
(ULOQ) will be handled as follows: results recorded as below will be imputed using half 
of the LLOQ for the purpose of calculating change from baseline, or percentage change 
from baseline, for summaries and figures. Measurements recorded as above the ULOQ will 
be imputed using the quantification limit. The raw data will be displayed in the listings. 
The data may be log transformed, this will be guided by the degree of skewness and 
variability in the data within and between subjects across time. 
4.6 
Patient Disposition 
Patient disposition will be provided for all screened patients, showing the number and 
percentage of patients who received study drug, completed the study visit schedule or 
withdrew early.  For patients who withdraw from the study, the primary reason for the 
withdrawal will also be summarized.   
The total number of patients who were screened and the number who failed screening will 
be tabulated.  Screen failures and screen failure reasons will be listed in a data listing. 
The number of patients Screened and the number and percentage of patients included in the 
FAS will be presented. 
4.7 
Demographics and Baseline Characteristics 
Demographic characteristics will be summarized.  
4.8 
Medical History 
Medical history findings at study entry will be summarized. 
4.9 
Study Drug Exposure and Compliance 
Exposure to study medication, defined as the number of days between first and last dose 
(see section 3.5), will be summarized using descriptive statistics.  In addition, a table will 
be provided to display the number and percentage of patients with exposure in the following 
categories: 
• 1-182 days 
• 183-365 days 
• 366-730 days 
• 731-1095 days 
Study medication percentage compliance will be summarised using descriptive statistics.  
The count and percentage of patients with overall compliance will also be tabulated: 
• <95% 
• 95% to <99% 
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• 99% to 100% 
• >100% 
4.10 Concomitant Medications 
The numbers and percentages of patients taking concomitant medications will be 
summarised by ATC and preferred term. 
4.11 Analysis of Efficacy 
All presentations and analyses of efficacy data will be conducted on the FAS.  All efficacy 
data will be listed.  
4.11.1 Blood Transfusions 
The proportion of subjects who require PRBC transfusion during each 3-month period since 
the start of the study and over the entire period of the study will be summarised. This 
summary will also be produced by subgroup of patients based on their transfusions and 
complement inhibitor history as defined in section 3.2.4.  
The number of RBC or platelet transfusions  per patient during the study will be 
summarised using descriptive statistics.  Patients with no recorded transfusions will be 
included with an imputed count of zero. 
The time (days) to first transfusion for each patient will be summarized using Kaplan-Meier 
methodology. Kaplan-Meier estimates of the proportion of patients receiving at least one 
transfusion during the study will be displayed with 95% two-sided confidence limits. The 
median, 95% Confidence Interval of the median, 25th and 75th percentiles of the time to 
first transfusion will be produced. 
4.11.2 LDH  
The derived LDH ratio of reported:ULN values over time will be presented as a (spaghetti) 
line plot for all patients. Observed values and change from baseline will be summarised. 
Boxplots over time will also be presented to provide an indication of how the mean and 
median LDH ratio changes over the course of the study. 
The number and percentage of patients with serum LDH ≤ 1.8, >1.8 to 2.4, >2.4 to 3, and 
>3 times the upper limit of normal (ULN) at each 3-month time period since the start of the 
study will be summarised 
The number and percentage of patients with median serum LDH ≤ 1.8, >1.8 to 2.4, >2.4 to 
3, and >3 times the upper limit of normal (ULN) over the entire duration of the study will 
also be summarised. 
4.11.3 Transfusion-independence and Haemoglobin  
The proportion of transfusion-independent subjects with haemoglobin (g/L) above the 
baseline haemoglobin value as defined in section 3.3.4 will be summarised at each 3-month 
time point. 
The proportion of transfusion-independent subjects over the entire duration of the study 
with mean haemoglobin (g/L) above the baseline haemoglobin value as defined in section 
3.3.4 will be summarised.   
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These summaries will be repeated separately for patients : 
i) 
transfusion-independent prior to receiving rVA576 (Coversin) and remain 
transfusion-independent  
ii) 
transfusion-dependent prior to receiving rVA576 (Coversin). 
 
4.11.4 CH50 
Observed values, change from baseline, and ratio to baseline expressed as a percentage 
(also called % activity) in CH50 will be summarised at each applicable study visit. 
4.11.5 EORTC QLQ-C30  
Observed values and change from baseline of the standardised function scales, symptom 
scales, global health status scale and standardised single item scales will be summarised at 
each applicable study visit.  
The proportion of patients with no adverse change in the global health status scale will be 
summarised for each 3-month time period since the start of the study. 
4.11.6 EQ-5D-5L  
Observed values and change from baseline of the EQ-5D-5L Crosswalk normalised score 
will be summarised at each applicable study visit. 
The proportion of patients with no adverse change in the normalised score will be 
summarised for each 3-month time period since the start of the study. 
4.11.7 FACIT-F 
Observed values and change from baseline of the FACT-G Total Score, FACIT-F Total 
Score and  FACIT-F Trial Outcome Index will be summarised at each applicable study 
visit. 
The proportion of patients with no adverse change in the FACIT-F Total Score will be 
summarised for each 3-month time period since the start of the study. 
4.12 Analysis of Safety 
All presentations and analyses of safety data will be conducted on the FAS.  All safety data 
will be listed.  
4.12.1 Adverse Events 
A summary overview of adverse events will be provided, which presents the number and 
percentage of patients from the FAS satisfying each of the following categories: 
• Any AEs 
• Serious AEs (SAEs) 
• Drug-related AEs 
• SAEs leading to death 
• AEs leading to discontinuation 
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The number and percentage of patients with AEs, and number of AEs will be summarised 
by MedDRA System Organ Class, High Level Term, and Preferred Term.  In this summary, 
any patient reporting multiple episodes of the same AE (i.e. same preferred term), will be 
counted once. The incidence of SAE will also be summarised. The listings will contain all 
data available. 
The number and percentage of patients with AEs will be summarised by reported severity 
within each preferred term within system organ class.  In this summary, any patients 
reporting multiple episodes of the same AE (i.e. same preferred term), will be counted once 
against the most severely reported category. 
A list of patients reporting any SAEs and a list of patients reporting any AEs that led to an 
interruption or withdrawal of the study medication will be provided. 
4.12.2 Clinical Laboratory Assessments 
Observed values and change from baseline will be summarised at each applicable study 
visit for the parameters listed in Section 3.3.4. Counts and percentages of patients in each 
category will be used to summarise categorical urinalysis parameters for the baseline visit 
and each post-baseline assessment.   
Counts and percentages of patients with haematology and chemistry observations that are 
below (<LLN) or above (>ULN) the limit of normal at any post baseline visit will be 
summarised. Patients with haematology or chemistry observations that are below (<LLN) 
or above (>ULN) the limit of normal at any post baseline visit will be listed, as well as 
patients with markedly abnormal values. 
4.12.3 Vital Signs 
Observed values and change from baseline of Vitals signs measurements will be 
summarised at each applicable study visit.  
Subjects with markedly abnormal values for vital signs will be listed. 
4.12.4 Electrocardiogram 
The number and percentage of patients who have an ECG post-baseline Overall 
interpretation that falls within each category (‘Normal’; ‘Abnormal, Not Clinically 
Significant’; ‘Abnormal, Clinically Significant’) will be tabulated. 
Observed values and change from baseline of ECG measurements will be summarised at 
each applicable study visit.  
4.12.5 Thrombotic and Haemolytic Events 
The number and percentage of patients 
i) 
without a thrombotic event,  
ii) 
without a haemolytic event, 
iii) 
without either a thrombotic or haemolytic event,  
 
will be summarized at each visit. The time (days) to first event for each patient will be 
summarized using Kaplan-Meier methodology. Kaplan-Meier estimates of the proportion 
of patients achieving each event during the study will be displayed with 95% two-sided 
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confidence limits. The median, 95% Confidence Interval of the median, 25th and 75th 
percentiles of the time to achieving event will be produced. 
4.12.6 Major Adverse Vascular Event (MAVE)  
The number and percentage of patients with MAVEs, and number of MAVEs will be 
summarised by MedDRA System Organ Class, High Level Term, and Preferred Term.  In 
this summary, any patient reporting multiple episodes of the same MAVE (i.e. same 
preferred term), will be counted once. The listings will contain all data available. 
The time (days) to first MAVE for each patient will be summarized using Kaplan-Meier 
methodology. Kaplan-Meier estimates of the proportion of patients experiencing MAVE 
events during the study will be displayed with 95% two-sided confidence limits. The 
median, 95% Confidence Interval of the median, 25th and 75th percentiles of the time to 
experiencing event will be produced. 
4.13 Interim Analysis 
The Sponsor reserves the right to review accruing safety and efficacy data from the study 
as a management aid to assist in the design of future studies. 
4.14 Data Safety Monitoring Board (DSMB) 
Not applicable 
5 
Sample Size Determination 
This is an open-label study to evaluate the safety experience of long term rVA576 
(Coversin) treatment in up to approximately 50 patients.  
6 
Programming Specifications 
The programming specification, including the mock-up analysis tables, figures, and data 
listings, as well as the derived database specification, will be prepared in a stand-alone 
documents. 
 
 
AK581 CSR Section 16
Akari Therapeutics Plc
30th April 2021
Section 16 Page 760 of 3564


7 
APPENDIX 1 
 
7.1 
Tables  
 
Table 14.1.1 
Patient Disposition – Screened Set 
Table 14.1.2 
Demographics and Baseline Characteristics – Full Analysis Set 
Table 14.1.3 
Medical History –Full Analysis Set 
Table 14.1.4 
Concomitant Medication by ATC and preferred term – Full Analysis 
Set 
Table 14.1.5 
Transfusions and Complement Inhibitor history Subgroup – Full 
Analysis Set 
 
Table 14.2.1.1 
Incidence of PRBC transfusions by timeperiod and overall – Full 
Analysis Set 
Table 14.2.1.1 
Incidence of PRBC transfusions by timeperiod and overall by 
Subgroups – Full Analysis Set 
Table 14.2.1.2 
Time to first PRBC transfusion – Full Analysis Set 
Table 14.2.1.3 
Number of transfusions – Full Analysis Set 
Table 14.2.1.4 
Summary of Transfusion-independence – Full Analysis Set 
 
Table 14.2.2.1 
EORTC QLQ-C30 by visit: observed values and change from baseline 
– Full Analysis Set 
Table 14.2.2.1 
Summary of EORTC QLQ-C30 adverse changes at each 3 month period 
– Full Analysis Set 
Table 14.2.2.2 
EQ-5D-5L by visit: observed values and change from baseline – Full 
Analysis Set 
Table 14.2.2.2 
Summary of EQ-5D-5L adverse changes at each 3 month period – Full 
Analysis Set 
Table 14.2.1.3 
FACIT-F by visit: observed values and change from baseline – Full 
Analysis Set 
Table 14.2.1.3 
Summary of FACIT-F adverse changes at each 3 month period – Full 
Analysis Set 
 
Table 14.2.2.1 
Serum LDH by visit: observed values and change from baseline – Full 
Analysis Set 
Table 14.2.2.2 
Summary of Serum LDH levels at each 3-month time period – Full 
Analysis Set 
Table 14.2.2.3 
Summary of median Serum LDH levels – Full Analysis Set 
 
Table 14.2.3.1 
Summary of Transfusion-independence and Haemoglobin at each 3-
month time period – Full Analysis Set 
Table 14.2.3.2 
Summary of Transfusion-independence and Haemoglobin at each 
month time period by Subgroups – Full Analysis Set 
Table 14.2.3.3 
Summary of Transfusion-independence and mean Haemoglobin – Full 
Analysis Set 
Table 14.2.3.4 
Summary of Transfusion-independence and mean Haemoglobin by 
Subgroups – Full Analysis Set 
 
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Akari Therapeutics Plc
30th April 2021
Section 16 Page 761 of 3564


Table 14.3.1.1 
Summary overview of AEs – Full Analysis Set 
Table 14.3.1.2 
AEs – Full Analysis Set 
Table 14.3.1.3 
AEs by maximum severity – Full Analysis Set 
Table 14.3.1.4 
Serious AEs– Full Analysis Set 
 
Table 14.3.2.1 
Haematology parameters by visit: observerd values and change from 
baseline – Full Analysis Set 
Table 14.3.2.2 
Chemistry parameters by visit: observerd values and change from 
baseline – Full Analysis Set 
Table 14.3.2.3 
Urinalysis parameters by visit: observerd values and change from 
baseline – Full Analysis Set 
Table 14.3.2.4 
Categorical Urinalysis parameters by visit: observerd values– Full 
Analysis Set 
Table 14.3.3 
Vital signs by visit: observerd values and change from baseline – Full 
Analysis Set 
Table 14.3.4.1 
Electrocardiogram by visit: observerd values and change from baseline 
– Full Analysis Set 
Table 14.3.4.2 
Electrocardiogram by visit: overall interpretation – Full Analysis Set 
 
Table 14.3.5.1 
Thrombotic Events – Full Analysis Set 
Table 14.3.5.2 
Haemolytic Events – Full Analysis Set 
Table 14.3.5.3 
Time to first Thrombotic Events – Full Analysis Set 
Table 14.3.5.4 
Time to first Haemolytic Events – Full Analysis Set 
Table 14.3.5.5 
Time to first Thrombotic or Haemolytic Events – Full Analysis Set 
Table 14.3.6.1 
Major Adverse Vascular Events – Full Analysis Set 
Table 14.3.6.2 
Time to first MAVE – Full Analysis Set 
 
Table 14.3.7 
Study drug exposure and compliance – Full Analysis Set 
 
Table 14.4.1.1 
CH50 by visit: observed value and change from baseline – Full Analysis 
Set 
Table 14.4.1.2 
CH50 by visit: observed value and percentage activity – Full Analysis 
Set 
 
Table 14.4.2.1  
Unbound nomacopan, total C5 and serum LTB4 levels – Full Analysis 
Set 
 
 
AK581 CSR Section 16
Akari Therapeutics Plc
30th April 2021
Section 16 Page 762 of 3564


 
7.2 
Listings 
Listing 16.2.1.1 
Patient Disposition 
Listing 16.2.1.2 
Screen failures and screen failure reasons 
Listing 16.2.1.3 
Visit dates  
Listing 16.2.2 
Protocol deviations 
Listing 16.2.3 
Exclusion from the analysis populations  
 
Listing 16.2.4.1 
Demographic Data 
Listing 16.2.4.2 
Eligibility Criteria 
Listing 16.2.4.3 
Medical History  
Listing 16.2.4.4 
Childbearing potential 
Listing 16.2.4.5 
Serum Pregnancy Test 
Listing 16.2.4.6 
Concomitant Medication  
 
Listing 16.2.5.1 
Exposure and Compliance 
Listing 16.2.5.2 
Drug Accountability 
 
Listing 16.2.6.1 
Transfusions 
Listing 16.2.6.2 
EORTC QLQ-C30 legend 
Listing 16.2.6.3 
EORTC QLQ-C30  
Listing 16.2.6.4 
EQ-5D-5L legend 
Listing 16.2.6.5 
EQ-5D-5L  
Listing 16.2.6.6 
FACIT-F legend 
Listing 16.2.6.7 
FACIT-F 
Listing 16.2.6.8 
Self-Injection Questionnaire  
 
Listing 16.2.7.1 
Adverse events 
Listing 16.2.7.2 
Serious adverse events 
Listing 16.2.7.3  
Adverse events leading to discontinuation or leading to death 
 
Listing 16.2.8.1.1 Haematology 
Listing 16.2.8.1.2 Haematology – out of normal range and markedly abnormal values 
Listing 16.2.8.2.1 Chemistry 
Listing 16.2.8.2.2 Chemistry – out of normal range and markedly abnormal values 
Listing 16.2.8.3.1 Urinalysis 
Listing 16.2.8.3.2 Urinalysis – out of normal range and markedly abnormal values 
 
Listing 16.2.9.1 
Vital Signs 
Listing 16.2.9.2 
Electrocardiogram 
 
Listing 16.2.10.1 Thrombotic and Haemolytic Events  
Listing 16.2.10.2 Major Adverse Vascular Events  
 
Listing 16.2.10.1 CH50  
Listing 16.2.10.2 ADA sampling 
Listing 16.2.10.3 PK sampling 
Listing 16.2.10.4 Fluorescein-labelled proaerolysin FLAER / Flow Cytometry 
AK581 CSR Section 16
Akari Therapeutics Plc
30th April 2021
Section 16 Page 763 of 3564


Listing 16.2.10.5 Physical Examinations abnormalities 
Listing 16.2.10.6 Neisseria Meningitidis Immunisation History 
 
 
7.3 
Figures  
 
Figure 14.2.1 Line plot of derived LDH ratio over time  
Figure 14.2.2  Boxplots of LDH ratio over time 
 
Figure 14.4.1 Line plot of Unbound nomacopan over time 
Figure 14.4.2 Line plot of total C5 over time 
Figure 14.4.3 Line plot of serum LTB4 over time 
AK581 CSR Section 16
Akari Therapeutics Plc
30th April 2021
Section 16 Page 764 of 3564