A Phase I, Double-blind, Parallel, Randomised and Placebo-controlled Trial Investigating the Safety and Immunogenicity of a Chlamydia Vaccine, CTH522, in Healthy Adults
Phase: PHASE1
Conditions: Trachoma
Sponsor: Statens Serum Institut

CONFIDENTIAL 
Page 1 of 70 
14 December 2020 
Final 5.1  
CTH522 
Protocol CHLM-02 
PROTOCOL 
Title: A phase I, double-blind, parallel, randomised and placebo-controlled trial investigating the 
safety and immunogenicity of a chlamydia vaccine, CTH522, in healthy adults  
SSI trial Code: CHLM-02 
EudraCT No.: 2019-001090-88 
ClinicalTrial.gov No.: NCT03926728 
Trial phase: I 
Version: Final 5.1 
Date: 14 December 2020 
Clinical trial manager: 
Vaccine Development Department 
Statens Serum Institut 
Denmark 
Confidentiality:  
This document contains confidential information. The contents may not be used, divulged or 
published without prior written consent of Statens Serum Institut. This information cannot be 
used for any other purpose than the conduct and evaluation of the clinical investigation by the 
investigator(s), regulatory authorities and members of the ethics committee. 

 
 
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Page 2 of 70 
 
14 December 2020 
  
 
Final 5.1  
CTH522 
 
Protocol CHLM-02 
 
1 
Synopsis 
Title 
A phase I, double-blind, parallel, randomised and placebo-controlled trial investigating the 
safety and immunogenicity of a chlamydia vaccine, CTH522, in healthy adults 
Trial code 
CHLM-02 
EudraCT 
2019-001090-88 
ClincialTrial.gov 
NCT03926728 
Trial phase 
Phase I 
Trial period 
Q3 2019–Q4 2020 
Principal 
investigator(s) 
, MD, NIHR Imperial Clinical Research Facility, Hammersmith Hospital, 
Imperial College Healthcare NHS Trust, London 
Investigational 
site(s) 
NIHR Imperial Clinical Research Facility 
Hammersmith Hospital, Imperial College Healthcare NHS Trust, Du Cane Road, London W12 
0HS 
Primary objective • 
To evaluate the safety of CTH522-CAF01 administered IM in different doses 
• 
To evaluate the safety of non-adjuvanted CTH522 administered TO or ID simultaneously 
with CTH522-CAF01 IM 
• 
To evaluate the safety of CTH522-CAF09b administered IM 
Secondary 
objective(s) 
• 
To evaluate the serum IgG antibody responses obtained after IM administration of CTH522-
CAF01 in different doses  
• 
To evaluate the serum IgG antibody responses obtained after TO or ID administration of 
non-adjuvanted CTH522 simultaneously with CTH522-CAF01 IM  
• 
To evaluate the serum IgG antibody responses obtained after IM administration of CTH522-
CAF09b 
• 
To evaluate the serum IgG antibody response obtained after TO administered on Day 140  
Exploratory 
objective(s) 
• 
To evaluate the systemic and mucosal immunogenicity after vaccination with CTH522 with 
or without different adjuvants and administration routes  
Primary endpoint • 
Solicited local injection site reactions after ID and/or IM administration of the vaccines: 
erythema, pruritus, pain, tenderness, swelling, and warmth 
• 
Solicited local reactions after TO administration of the vaccine: watering eyes, swelling of 
eyelid, eye redness, and eye discomfort 
• 
Solicited systemic reactions after IM and/or ID administration of the vaccines: oral 
temperature > 38.3°C, chills, myalgia and rash  
• 
Any other adverse events (AEs) 
Secondary 
endpoints  
• 
Seroconversion for anti-CTH522 IgG at any time points after vaccination of CTH522  
 
Exploratory 
endpoints 
• 
Systemic and ocular antibodies 
o 
Cell-mediated immune response measured by Elispot and/or flow cytometry 
o 
Antibody responses measured by T- and B-cell Elispot 
o 
Serum neutralising antibodies against serovars D-G 
• 
Isolation and characterisation of CTH522–antigen-specific memory B-cells in the systemic 
compartments (dependent on the elicited specific memory T- and B-cell numbers) 

 
 
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14 December 2020 
  
 
Final 5.1  
CTH522 
 
Protocol CHLM-02 
 
Trial design 
This is a phase I, double-blind, parallel, randomised, and placebo-controlled trial of the 
chlamydia vaccine, CTH522, in healthy adults. It is planned to randomly assign 66 subjects into 
six cohorts. Cohorts A–D investigate CTH522-CAF01 administered IM in two doses (85 µg and 
15 µg). Cohort E investigates CTH522-CAF09b administered IM in one dose (85 µg). Cohort F 
is the placebo group (see figure below). All subjects in the active groups (cohort A-E) will 
receive three IM injections of the adjuvanted CTH522 and some (cohort B and C) will received 
the non-adjuvanted CTH522 via the TO or ID route (given at the same time as the 2nd and 3rd IM 
vaccinations). All active groups will receive TO administration as a boost at Day 140 of either 
the non-adjuvanted CTH522 (12 µg in each eye) or placebo.  
The enrolled subjects will complete 12 trial visits (Vs): 
• 
V1 (Day -90 to -1): eligibility is assessed and informed consent is obtained; medical 
history, vital signs (including BMI) are taken; physical and eye examinations are 
performed: concomitant medications (CM) and AEs are recorded; blood samples for 
screening of hepatitis B and C, HIV, syphilis and safety biochemistry/haematology are 
drawn; urine is collected for pregnancy test and PCR for C. Trachoma and gonorrhoea 
infections  
• 
V2 (Day 0): eligibility is assessed; eye and symptom-direct physical examination are 
performed and vital signs are taken; AEs and CMs are reviewed and recorded; urine is 
collected for pregnancy test; randomisation; blood and ocular samples for safety and 
immunogenicity determination before vaccination; 1st IM vaccination; subjects observed for 
any immediate AE for 60 minutes after the vaccination; diary card is issued 
• 
V3 (Day 14): diary card reviewed; AEs and CM recorded; vital signs are taken and 
symptom-directed physical examination is performed; blood samples for safety and 
immunogenicity are drawn  
• 
V4 (Day 28): AEs and CM recorded; vital signs are taken; eye and symptom-directed 
physical examinations are performed; blood samples for safety and immunogenicity 
determination taken before vaccination; urine for pregnancy and ocular samples are taken; 
2nd IM vaccinations together with ID or TO vaccination; subjects observed for any 
immediate AE for 60 minutes after the vaccination; diary card is issued  
• 
V5 (Day 42): diary card reviewed; AEs and CM are recorded; vital signs and ocular 
samples are taken; eye and symptom-directed physical examination are performed; blood 
samples for safety and immunogenicity are drawn 
• 
V6 (Day 56): AEs and CM are recorded; eye and symptom-directed physical examination 
are performed; blood samples for immunogenicity determination are drawn; ocular sample 
is taken 
• 
V7 (Day 112): AEs and CM are recorded; vital signs are taken; eye and symptom-directed 
physical examinations are performed; blood samples for safety and immunogenicity 
determination are drawn before vaccination; urine for pregnancy and ocular samples are 
taken; 3rd IM vaccinations together with ID or TO vaccination; subjects are observed for 
any immediate AE for 60 minutes after the vaccination; diary card is issued  
• 
V8 (Day 126): diary card is reviewed; AEs and CM are recorded; vital signs are taken, eye 
and symptom-directed physical examination are performed; blood samples for safety and 
immunogenicity determination are drawn; ocular sample is taken 
• 
V9 (Day 140): AEs and CM are recorded; vital signs are taken; eye and symptom-directed 
physical examinations are performed; blood samples for safety and immunogenicity 
determination are drawn before vaccination; urine for pregnancy and ocular sample are 
take; final vaccination with a TO CTH522 (or placebo) boost; subjects are observed for any 
immediate AE for 60 minutes after the vaccination; diary card is issued 
• 
V10 (Day 143): diary card is reviewed; AEs and CM are recorded; vital signs are taken; eye 
and symptom-directed physical examination are performed; blood samples for 
immunogenicity assessment are drawn and ocular sample is taken 

 
 
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14 December 2020 
  
 
Final 5.1  
CTH522 
 
Protocol CHLM-02 
 
• 
V11 (Day 154): diary card is reviewed, AEs and CM are recorded; vital signs are taken; eye 
and symptom-directed physical examinations are performed; blood samples for safety and 
immunogenicity determination are drawn and ocular sample is taken 
• 
V12 (Day 238): end-of-trial visit; AEs and CM are reviewed and recorded; vital signs are 
taken; eye, physical examinations are performed; urine is collected for pregnancy and PCR 
for C. Trachoma and gonorrhoea infection test; blood samples for safety and 
immunogenicity determination are drawn and ocular sample is taken 
 
Trial population 
and planned 
sample size 
The trial plans to screen approximately 110 subjects with the aim to randomise and enrol 66 
subjects. The enrolled subjects will be healthy male and female volunteers aged 18–45 years.    
Inclusion and 
exclusion criteria 
Inclusion criteria:  
• 
IC1: Healthy males and females between 18–45 years old on the day of the first vaccination 
• 
IC2: Has been properly informed about the trial and signed the consent form 
• 
IC3: Is willing and likely to comply with trial procedures 
• 
IC4: Is prepared to grant authorised persons access to his/her trial-related medical record 
• 
IC5: Is willing to use acceptable contraceptive measures during the trial (two weeks before 
and two weeks after the trial). Heterosexually active female capable of becoming pregnant 
must agree to use hormonal contraception, intrauterine device, intrauterine hormone-
releasing system, or to complete abstinence from at least two weeks before the first 
vaccination until at least two weeks after the last. Complete abstinence (defined as 
refraining from heterosexual intercourse) must be in line with the preferred and usual 
lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-
ovulation methods), withdrawal and progestogen-only oral hormonal contraception where 
inhibition of ovulation is not the primary mode of action are not acceptable methods of 
contraception 
Exclusion criteria: 
General 
• 
EX1: Is positive for C. trachomatis via urine PCR or has a known history of C. trachomatis 
• 
EX2: Is positive for gonorrhoea via urine PCR test, or HIV, hepatitis B/C, syphilis via blood 
tests 

STATENS 
SERUM 
INSTITUT 
CONFIDENTIAL 
14 December 2020 
Final 5.1 
Page 5 of70 
CTH522 
Protocol CHLM-02 
Investigational 
medicinal 
produets 
Dosages and 
route of 
administrntion 
•
EX3: Has a significant active disease such as cru·diac, liver, immunological, neurological,
psychiati·ic or clinically significant abn01mality of haematological or biochemical
parameters
•
EX4: Has BMI c:": 35 kg/m2 
•
EX5: Is cruTently pa1ticipating in another clinical triaI with an investigational or non­
investigational dmg or device, or was treated with ru1 investigational dmg within 28 days
before the first vaccination
•
EX6: Has received, or plans to receive, any immunisation within 14 days of the start ofthe
ti·ial or dlll'ing the ti·ial immunisations
•
EX7: Is cru1·ently receiving ti·eatment v.rith systemic immunosuppressive agents. Topical
steroids are allowed uniess applied to the IM or ID injection site
•
EX8: Has a condition which in the opinion of the investigator is not suitable for
pruticipation in the trial
•
EX9: Is known or confinned to have allergy to any ofthe vaccine constituents
•
EXl 0: Is unable to refrain from use of contact lenses. Contact lenses should be avoided two
days before TO administration and for seven days later (longer if ru1y ongoing local eye AE)
•
EXl 1: Has any evident ocular disease upon eye exrun (prior to first vaccination) or any
medical liistory of oculru· disease that, in the opinion ofthe investigator, may impact the
subject's pa1ticipation in the ti·ial
Female-specific 
•
EX12: Is pregnant (positive pregnru1cy test) or breastfeeding or not willing to use
contraception dlll'ing the tl'ial
•
EXl 3: Has confu-med his tory of pelvic inflammatory disease or significant gynaecologicaI
diseases
The dosages for the investigational medicinal produets (IMPs) are presented in the table below. 
Saline 0.9% NaCl solution for placebo are to be administered IM, TO and ID. The non­
adjuvanted CTH522 to be given TO is ready to be used. The CTH522-CAF0 1 and CTH522-
CAF09b (both to be given IM) and CTH522 to be given ID will be reconstituted at the site. 
IMP (l'Outes) 
CTH522 
Per dose volume 
CTH522-CAF0 1 (IM) 
85 µg 
0.5 ml 
15 µg 
0.5 ml 
CTH522-CAF09b1 (IM) 
85 µg 
0.5 ml 
CTH522 (TO) 
24 Ptg1 
0.04 ml 
CTH522 (ID) 
24 µg 
0.1 ml 
1subiects receive 12 112 in each eve.
The preferred location for IM and ID ad1ninist1·ations is into (IM) or into the skin overlying (ID) 
the non-dominant deltoid muscle. Each IM admitiistration will consist of 85 Ĉtg CTH522-
CAF01, 15 Ptg CTH522-CAF01 or 85 Ptg CTH522-CAF09b in a volume of0.5 ml per injection. 
Each ID administration will consist of24 µg CTH522 in a volume of0.l ml per injection. The 
IM and ID injections must be admi1iistered within five 1ninutes of each other and approximately 
2 cm aprut from each other. As long as the two injections are adini1iistered v.ritliin five minutes, it 
does not matter which one (IM or ID) is given first. The 1M injection will be perfonned with a 
1-2 ml polypropylene syringe via a 23-25-gauge needle. The ID injection will be with a 1 ml
syringe via a microneedle device. The TO admi1iistration in both eyes will consist of 24 µg
CTH522 (non-adjuvanted) in a volume of0.04 ml; thus, each eye is ad1ninistered 12 Ptg of
CTH522 TO in a 0.02 1nI drop. The eye di·ops should be given five niinutes apart, with the right
side first to follow by the lefl side. The TO ad1ninistrations will be perfonned using a Gilson
MICROMAN positive displacement pipette.

 
 
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CTH522 
 
Protocol CHLM-02 
 
Statistical 
methods 
No sample size calculations have been made. The sample size is considered adequate for review 
of the safety profile of the described interventions for a phase I trial. 
The basis for safety analysis is the safety analysis set (SAF), which consists of all subjects 
randomised and exposed to the IMPs. Full analysis set (FAS) will include subjects with observed 
data for all randomised subjects. A per-protocol analysis set (PP) will include subjects who 
completed the trial without deviations judged to influence the primary endpoints. The primary 
analysis will be carried out for SAF and FAS and PP. 
Categorical data will be summarised descriptively by treatment, using the number and 
percentages of subjects. Continuous data will be presented using the number of subjects, mean, 
standard deviation, median, minimum and maximum. Both the absolute values and the change 
from baseline will be presented. 
Primary efficacy data will be presented descriptively over time using box-plots over time. If the 
nature of data allow, a formal statistical test will be performed using time to event analysis. 
AE=adverse event; CM=concomitant medication; FAS=full analysis set; ID=intradermal; IM=intramuscular; 
IMP=investigational medicinal product; PP=per-protocol analysis set; SAF=safety analysis set; TO=topical ocular; 
V=visit 
 
 

 
 
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14 December 2020 
  
 
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CTH522 
 
Protocol CHLM-02 
 
2 
Table of Contents 
1 
Synopsis ..................................................................................................................................... 2 
2 
Table of Contents ...................................................................................................................... 7 
3 
List of Abbreviations and Definitions ................................................................................... 10 
4 
Signature page......................................................................................................................... 13 
5 
Relevant addresses .................................................................................................................. 14 
6 
Introduction ............................................................................................................................ 15 
7 
Trial objectives ........................................................................................................................ 17 
7.1 
Primary objectives ....................................................................................................................17 
7.2 
Secondary objectives ................................................................................................................17 
7.3 
Exploratory objectives ..............................................................................................................17 
7.4 
Primary endpoint .......................................................................................................................17 
7.5 
Secondary endpoint ...................................................................................................................17 
7.6 
Exploratory endpoints ...............................................................................................................18 
8 
Investigational plan ................................................................................................................ 19 
8.1 
Overall trial design ....................................................................................................................19 
8.2 
Trial procedures ........................................................................................................................23 
8.3 
Trial population and planned number of subjects .....................................................................24 
8.3.1 
Inclusion criteria ........................................................................................................24 
8.3.2 
Exclusion criteria .......................................................................................................25 
8.4 
Randomisation procedure .........................................................................................................26 
8.5 
Blinding and unblinding ...........................................................................................................26 
8.6 
Immunogenicity assessments ....................................................................................................27 
8.7 
Safety assessments ....................................................................................................................29 
8.8 
Predetermined reasons for discontinuation ...............................................................................29 
8.9 
Contraindications ......................................................................................................................30 
8.9.1 
Temporary contraindications .....................................................................................30 
8.9.2 
Permanent contraindications .....................................................................................30 
8.10 
Collection and handling of samples ..........................................................................................30 
8.11 
Laboratory assays......................................................................................................................30 
8.12 
Planned schedule of trial ...........................................................................................................31 
9 
Investigational medicinal products ....................................................................................... 32 
9.1 
Composition of trial products ...................................................................................................32 
9.2 
Dose and administration of trial products .................................................................................32 

 
 
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CTH522 
 
Protocol CHLM-02 
 
9.2.1 
Dosage and route .......................................................................................................32 
9.2.2 
Treatment administered .............................................................................................33 
9.3 
Packaging and labelling of trial products ..................................................................................34 
9.4 
Storage and shelf-life information for trial products ................................................................34 
9.5 
Transport procedures for trial products .....................................................................................35 
9.6 
Treatment compliance procedures ............................................................................................35 
9.7 
Drug accountability procedures ................................................................................................35 
9.8 
Precautions and overdosing ......................................................................................................35 
9.9 
Concomitant medications ..........................................................................................................36 
10 
Adverse events......................................................................................................................... 37 
10.1 
Standard recording and assessment of adverse events ..............................................................38 
10.1.1 
Collection and recording of AEs ...............................................................................38 
10.1.2 
Assessments ...............................................................................................................38 
10.2 
Expedited reporting of adverse event........................................................................................40 
11 
Data management and statistical analysis ............................................................................ 40 
11.1 
General considerations ..............................................................................................................40 
11.2 
Data management......................................................................................................................40 
11.3 
Database release meeting and database lock .............................................................................41 
11.4 
Statistical methods ....................................................................................................................41 
11.4.1 
Subject disposition.....................................................................................................42 
11.4.2 
Demographics and baseline characteristics ...............................................................42 
11.4.3 
Exposure and treatment compliance ..........................................................................42 
11.4.4 
Safety analysis ...........................................................................................................42 
11.4.5 
Immunogenicity analysis ...........................................................................................43 
11.4.6 
Exploratory immunogenicity analysis .......................................................................43 
11.4.7 
Interim analysis .........................................................................................................43 
11.4.8 
Sample size determinations .......................................................................................43 
12 
Ethical aspects ......................................................................................................................... 44 
12.1 
Risks and benefits .....................................................................................................................44 
12.2 
Biobanking ................................................................................................................................45 
13 
Good clinical practice considerations ................................................................................... 46 
13.1 
Declaration of Helsinki and good clinical practice ...................................................................46 
13.2 
Participant information and informed consent ..........................................................................46 
13.3 
Ethics committee and HRA submission and approval ..............................................................47 

 
 
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CTH522 
 
Protocol CHLM-02 
 
13.4 
Competent authority submission and approval .........................................................................47 
13.5 
Local investigator site approval ................................................................................................47 
13.6 
Personal data protection ............................................................................................................47 
13.7 
Investigator’s responsibility and delegation of trial-related duties ...........................................48 
13.8 
Trial oversight and monitoring .................................................................................................48 
13.9 
Audit and inspection .................................................................................................................49 
13.10 
Source data and essential documents and retention times ........................................................49 
14 
Agreement and financial settlement ..................................................................................... 50 
15 
Insurance and indemnity statement ...................................................................................... 50 
16 
Confidentiality and disclosure ............................................................................................... 51 
17 
Modifications to the protocol ................................................................................................. 52 
18 
References ................................................................................................................................ 53 
19 
Appendices .............................................................................................................................. 55 
19.1 
Appendix 1: FDA guidelines ....................................................................................................55 
19.2 
Appendix 2: Insurance certificate .............................................................................................70 
 
 
 

 
 
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14 December 2020 
  
 
Final 5.1  
CTH522 
 
Protocol CHLM-02 
 
3 
List of Abbreviations and Definitions 
AE 
Adverse event 
Al(OH)3 
Aluminium hydroxide used in CHLM-01 trial as an adjuvant 
combined to CTH522 
ALT 
Alanine aminotransferase 
BMI 
Body mass index 
C. trachomatis 
Bacterium Chlamydia trachomatis can cause trachoma, contagious 
inflammatory disease of the eye  
CA 
Competent authority 
CAF01 
Adjuvant promotes both strong neutralising antibody titres and 
Th1 responses. Combined with CTH522, CAF01 is used in the 
CHLM-02 trial  
CAF09b 
Adjuvant that, when formulated with other vaccines, resulted in a 
high frequency of antigen-specific CD8+ T-cells (29). Combined 
with CTH522, CAF09b is used in the CHLM-02 trial 
CI 
Confidence Intervals 
CIOMS form 
Serious adverse event is reported via the Council for International 
Organisations of Medical Sciences form and sent to the authority 
CM 
Concomitant medication 
CRA 
Clinical Research Associate 
CRO 
Contract research organisation 
CTH522 
Non-adjuvanted chlamydia antigen 
CTH522-CAF01 
Chlamydia antigen combined with adjuvant CAF01, an on-site 
reconstituted IMP used in CHLM-02 
CTH522-CAF09b 
Chlamydia antigen combined with adjuvant CAF09b, an on-site 
reconstituted IMP used in CHLM-02 
CTR 
Clinical trial report 
DDA 
Dimethyldioctadecylammonium bromide 
EC 
Ethics committee 
eCRF 
Electronic Case Record Form  
EDC 
Electronic data capture (system used for electronic recording in the 
eCRF) 
ELISA 
Enzyme-linked immunosorbent assay 
Elispot 
Enzyme-linked immunospot assay 
EX 
Exclusion criteria 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FSFV 
First subject’s first visit 
GCP 
Good clinical practice according to ICH GCP E6 
GMP 
Good manufacturing practice 

 
 
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14 December 2020 
  
 
Final 5.1  
CTH522 
 
Protocol CHLM-02 
 
HIV 
Human immunodeficiency virus 
HRA 
Health Research Authority 
IB 
Investigator’s brochure 
IC 
Inclusion criteria 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICHT  
Imperial College Healthcare NHS Trust (investigator site) 
ICL 
Imperial College London 
ICS  
Intracellular cytokine staining 
ID 
IF 
Intradermal 
Investigator’s file 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IM 
Intramuscular 
IMP 
Investigational medicinal product. The non-adjuvanted CTH522 to 
be given TO is ready to be used IMP. The CTH522-CAF01 and 
CTH522-CAF09b (both to be given IM) and CTH522 (to be given 
ID) are reconstituted at the site    
LSLV 
Last subject’s last visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
MMG 
Monomycoloyl glycerol analogue 
MOMP 
Major outer membrane molecule 
NIHR 
 
National Institute for Health Research 
PBMC  
Peripheral blood mononuclear cell(s) 
PCR 
Polymerase chain reaction 
PI 
Principal investigator 
Poly I:C  
Polyinosinic:polycytidylic acid 
PP 
Per-protocol set 
PT 
MedDRA preferred term 
RBC 
Red blood cells 
SAE 
Serious adverse event 
SAF 
Safety Analysis Set 
SAP 
Statistical analysis plan 
SSI 
Statens Serum Institut 
SUSAR 
Suspected unexpected serious adverse reaction 
TDB 
Trehalose dibehenate 
TMF 
TO 
Trial master file 
Topical ocular 

 
 
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CTH522 
 
Protocol CHLM-02 
 
V1, V2, V3, … 
Trial Visit 1, Visit 2, Visit 3, … 
VD4  
Variable domains 
WBC 
White blood cell  
WHO 
World Health Organisation 
WHO-DDE 
World Health Organisation Drug Dictionary Enhance 
 
 

m
STATENS 
SERUM 
INSTITUT 
C1'.H522 
4 
Signature page 
Principal investigator, Imperial 
College Healthcare NHS Trust: 
Non-clinical investigator, 
Imperial College London: 
Trial stat i sti cian 
Sponsor's representative, SSI: 
Trial manager, SSI: 
CONFIOENTIAL 
14 December 2020 
Final 5.1 
date & signature 
----14.. 12 2020 
date & signature 
date & signature 
date & signature 
date & signature 
Page 13 of70 
?rOloc<ll CHI Ms02 
l6-Dec-20 
l4-DEC-2020 

STATENS 
SERUM 
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CONFIDENTIAL 
14 December 2020 
Final 5.1 
Page 14 of70 
CTH522 
Protocol CHLM-02 
5 
Relevant addresses 
Relevant trial staff and personnel from clinical research organisations (CROs) are listed in Tab le 1. 
Contact information on the serious adverse event (SAE) repo1iing is listed in Table 2. 
Table 1: Relevant trial staffand personnel 
Clinical trial manager: 
-
Pharmacovigilance manager: 
ert: 
Sponsor's representative.: 
NIHR Imperial Clinical Research Facility, 
Hammersmith Hospital, Imperial College 
Healthcare NHS Trnst, 
Du Cane Road, London 
Wl2 OHS, United Kin dom 
Wright-Fleming Wing, St. Ma1y's Hospital 
Campus, Imperial College London, No1folk 
Place, London W2 lPG, United Kin°dom 
Statens Sernm Institut 
Vaccine Development Department 
5 Artillerivej 
DK-2300 Co enhaoen S 
Statens Sernm Institut 
Vaccine Development Department 
5 Artillerivej 
DK-2300 Co enha0en S 
Statens Sernm Institut 
Infectious Disease Immunology 
5 Artillerivej 
DK-2300 Co enhaoen S 
Statens Senun Institut 
Vaccine Development Department 
5 Artillerivej 
Phone: 
Email 
Phone: 
Email: 
Phone: 
Email: 
Phone: 
Email: 
Phone: 
Mobile: 
Email: 
1------------- DK-2300 Co enhaoen S 
Trial statistician: 
Phone: 
-
Email: 
Pharmacovigilance specialist: 
Table 2: Serious adverse event and medical emergenc.y reporting contact information 
SAE repo1ts from investigational 
site to SSI and CRO: 
Emergency phone numbers for 
subjects: 
SAE rep01t via t:rial database. An email notification is sent to 
and SSI 
(Monday-Friday 0900-1700) 
( outside nonnal working hours) 

 
 
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CTH522 
 
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6 
Introduction 
Trachoma is a contagious inflammatory disease of the eye following infection by a 
bacterium Chlamydia trachomatis (C. trachomatis). Although the disease is preventable, the 
infection caused blindness in 1.9 million people worldwide according to WHO fact sheet from 2019 
[1]. Classical control measures such as diagnosis, screening programs, and treatment have been 
intensified in recent years, but the number of C. trachomatis infections is still increasing. As these 
infections are not effectively controlled, an effective vaccine is required [2, 3].  
The TracVac Consortium consisting of Imperial College London (ICL) in the UK, Statens Serum 
Institut (SSI) in Denmark, London School of Hygiene & Tropical Medicine in the UK and The 
French Alternative Energies and Atomic Energy Commission (CEA) in France plan to conduct this 
phase I trial with a vaccine (CTH522) against trachoma following successful pre-clinical studies.  
Statens Serum Institut has developed the novel recombinant vaccine antigen (CTH522, 53.9 kDa). It 
is a recombinant version of the major outer membrane molecule (MOMP) from C. trachomatis, 
which is designed to induce broadly neutralising antibodies. CTH522 is highly immunogenic and 
contains conserved T-cell epitopes, frequently recognized by C. trachomatis infected patients, 
combined with B-cell epitopes spanning the protective VD4 region in MOMP from the four most 
frequent human C. trachomatis serovars [4, 5]. 
CTH522 protects against genital C. trachomatis infection in the mouse model and is highly 
immunogenic in mice, rabbits, guinea pigs and minipigs [4]. There was no evidence of a broader 
toxic effect of the adjuvanted CTH522-CAF01 and CTH522-Al(OH)3 when administered 
intramuscularly (IM) and boosted intranasally with non-adjuvanted CTH522 to Gottingen minipigs 
in a good laboratory practice-compliant repeat dose study [6]. 
CTH522 was also evaluated in the EpiOcular In vitro test provided by MatTek. The MatTek 
EpiOcular™ model is a commercially available 3D model of the human corneal epithelium, derived 
from normal human epidermal keratinocytes. The cells have been cultured in vitro to form a multi-
layered structure which closely resembles the corneal epithelium of the human eye. The 
EpiOcular™  In Vitro test categorised CTH522 600 Test Item as “no category”, which were  
considered as non-irritant if the tissue viability after exposure is >60%. Hence CTH522 is 
concluded to be non-irritant to the eye [7].  
Following the EpiOcular In vitro test, a study investigating safety and immunogenicity of CTH522 
with or without the adjuvant CAF01 or CAF09b administered IM or in combination of topical 
ocular (TO) and intradermal (ID) was conducted in 36 cynomolgus macaques. The study found no 
major clinical observation after vaccination and concluded that the adjuvants were safe for the 
tested animals. Therefore, this study supports the suitability of CTH522-CAF01 and CTH522-
CAF09b as safe, immunogenic, and potentially effective vaccines to induce immunity in C. 
trachomatis uninfected individuals [8].  

 
 
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A first-in-man clinical trial with 35 volunteers using CTH522 took place at Imperial College 
Healthcare NHS Trust, London during 2016–2017 (CHLM-01, EudraCT 2015-004330-10). The 
volunteers received three IM (CTH522 adjuvanted with CAF01 or Al(OH)3) administrations at Day 
0, 28, and 112, followed by two intranasal (non-adjuvanted) at Day 126 and 140. Based on the 
safety results of this phase I trial, the tested antigen CTH522 is considered safe when adjuvanted 
with Al(OH)3 or CAF01. All actively vaccinated subjects achieved seroconversion (both 2- and 4-
fold) whereas none of the subjects in the placebo group did; hence the CTH522 showed to be 
immunogenic when combined with either Al(OH)3 or CAF01 adjuvants. Furthermore, after the third 
vaccination and onwards, CAF01 enhanced the CTH522-specific IgG response statistically 
significantly more than Al(OH)3 in the trial population [9].  
In the present CHLM-02 trial, the CTH522 antigen will be administered non-adjuvanted or 
adjuvanted with CAF01 or CAF09b. The CAF01 adjuvant promotes both strong neutralising 
antibody titres and Th1 responses in mice, pigs and non-human primates [4, 10, 11]. Furthermore, 
CAF01 has proven safe and immunogenic in other clinical trials such as with the tuberculosis 
vaccine Ag85B-ESAT-6:H1[12], first-in-human chlamydia vaccine CTH522 [9] and malaria 
vaccine (GLURP-MSP3) [13].   
The CAF09b is a novel adjuvant that, when formulated with other vaccines, resulted in a high 
frequency of antigen-specific CD8+ T-cells in animal study [14].  CAF09b is a cationic liposomal 
adjuvant consisting of the cationic lipid dimethyldioctadecylammonium bromide (DDA) and a 
monomycoloyl glycerol analogue (MMG) with the TLR3 agonist polyinosinic:polycytidylic acid 
(poly I:C)) electrostatically adsorbed to the surface of the liposomes. Based on animal toxicity 
studies, CAF09b is expected to be safe and tolerable in humans as well. Currently, two investigator-
initiated trials (ClinicalTrial.gov NCT03412786 and NCT03715985) with CAF09b-adjuvanted 
vaccines are being conducted in cancer patients in Denmark. As of 02 May 2019, 18 subjects have 
been enrolled between the two trials where 30 IM and 25 intraperitoneal vaccinations with a 
CAF09b-containing vaccine have been administered; no SAEs have been reported. 
On the basis of the results of these clinical and non-clinical studies described above, it is considered 
safe to start a clinical phase I trial with CTH522-CAF01 and CTH522-CAF09b as well as non-
adjuvanted CTH522 in healthy adult volunteers. The vaccines in the CHLM-02 trial will be given 
IM, ID and TO. The main purpose of including TO and ID administrations in addition to the IM is 
to test if these vaccination routes demonstrate a higher ability to facilitate an ocular immune 
response than the IM vaccinations alone. A boost of CTH522 given TO at Day 140 seeks to 
investigate if a TO only boost will increase the ocular immune response.  
 
 

 
 
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7 
Trial objectives 
7.1 
Primary objectives 
• To evaluate the safety of CTH522-CAF01 administered IM in different doses 
• To evaluate the safety of non-adjuvanted CTH522 administered TO or ID simultaneously 
with CTH522-CAF01 IM 
• To evaluate the safety of CTH522-CAF09b administered IM 
7.2 
Secondary objectives 
• To evaluate the serum IgG antibody responses obtained after IM administration of CTH522-
CAF01 in different doses  
• To evaluate the serum IgG antibody responses obtained after TO or ID administration of 
non-adjuvanted CTH522 simultaneously with CTH522-CAF01 IM  
• To evaluate the serum IgG antibody responses obtained after IM administration of CTH522-
CAF09b 
• To evaluate the serum IgG antibody response obtained after TO administration if non-
adjuvanted CTH522 on Day 140  
7.3 
Exploratory objectives 
• To evaluate the systemic and mucosal immunogenicity after vaccination with CTH522 with 
different adjuvants and administration routes 
7.4 
Primary endpoint  
• Solicited local injection site reactions after ID and/or IM administration of the vaccines: 
erythema, pruritus, pain, tenderness, swelling, and warmth 
• Solicited local reactions after TO administration of the vaccine: watering eyes, swelling of 
eyelid, eye redness, and eye discomfort 
• Solicited systemic reactions after IM and/or ID administration of the vaccines: oral 
temperature > 38.3°C, chills, myalgia and rash  
• Any other adverse events (AEs) 
7.5 
Secondary endpoint 
• Seroconversion for anti-CTH522 IgG at any time points after vaccinations   

 
 
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7.6 
Exploratory endpoints 
• Systemic and ocular antibodies 
o Cell-mediated immune response measured by Elispot and/or flow cytometry 
o Antibody responses measured by T- and B-cell Elispot 
o Serum neutralising antibodies against serovars D-G 
• Isolation and characterisation of CTH522–antigen-specific memory B-cells in the systemic 
compartments (dependent on the elicited specific memory T- and B-cell numbers) 

 
 
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8 
Investigational plan 
8.1 
Overall trial design 
The present trial is a phase I, double-blind, parallel, randomised, and placebo-controlled trial of the 
chlamydia vaccine, CTH522, in healthy adults. The trial will be conducted at Imperial College 
Healthcare NHS Trust (ICHT), London, in the UK.  
It is planned to randomly assign 66 subjects into six cohorts. Cohorts A-D investigate CTH522-
CAF01 administered IM in two doses (85 µg and 15 µg). Cohort E investigates CTH522-CAF09b 
administered IM in one dose (85 µg). Cohort F is the placebo group (Figure 1). The enrolled 
subjects will complete 12 trial visits (Vs) (Table 3). 
All subjects in the active groups (cohort A-E) will receive three IM injections of the adjuvanted 
CTH522 and some (cohort B and C) will received the non-adjuvanted CTH522 via the TO or ID 
route (given at the same time as the 2nd and 3rd IM vaccinations). All active groups will receive TO 
administration as a boost at Day 140 of either the non-adjuvanted CTH522 (12 µg in each eye) or 
placebo.  
• Cohort A will receive three IM vaccination of 85µg CTH522-CAF01. This cohort is divided 
into two groups: A1 will receive ID placebo at Day 28 + Day 112, and TO placebo at Day 
140, while A2 will receive TO placebo at Day 28 + Day 112, and non-adjuvanted TO 
CTH522 boost at Day 140.  
• Cohort B will receive three IM vaccinations of 85 µg CTH522-CAF01. This cohort is 
divided into two groups: B1 will receive TO vaccination of the non-adjuvanted CTH522 at 
Day 28 and 112 and TO placebo at Day 140, while B2 will receive the same for Day 28 and 
112, but non-adjuvanted TO CTH522 boost at Day 140. The two additional TO doses of 
CTH522 (12 µg in each eye) are administered in each eye. The rationale for this schedule is 
to investigate the impact of simultaneous TO administration of the antigen on the 
immunogenicity results.  
• Cohort C will receive three IM vaccinations of 85 µg CTH522-CAF01. This cohort is 
divided into two groups: C1 will receive ID vaccination of the non-adjuvanted 24 µg 
CTH522 at Day 28 and 112 and TO placebo at Day 140, while C2 will receive the same for 
Day 28 and 112, but TO 12 µg CTH522 boost in each eye at Day 140. The rationale for this 
schedule is to investigate the impact of simultaneous ID administration of the antigen on the 
immunogenicity results. 
• Cohort D will receive three IM vaccinations of 15 µg CTH522-CAF01. The rationale for the 
A and D cohorts is to investigate the impact of the two IM CTH522 doses on the 
immunogenicity results. 

 
 
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• Cohort E will receive three IM vaccinations of 85 µg CTH522-CAF09b.  The rationale for 
the A and E cohorts is to investigate the impact of the adjuvant on the immunogenicity 
results. 
• Cohort F will receive only placebo in form of 0.9% NaCl (IM, ID and TO).  

 
 
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Figure 1: Trial diagram 

CTH522 
STATENS 
SERUM 
INSTITUT 
Table 3: Trial flow chart 
T rial visit (V) 
Trial day 
Windows (days) 
Infonned consent 
Med. hist+demographics 
In-/exclusion criteria 
Blood for hep B and C, 
HIV, syphilis 
PCR for C. Trachoma and 
eonon-hoea infection1 
Urinary pregnancy test 
Physical examination 
Eye exam including 
retina* 
Eye exam""" 
Record weight/height 
Vita! signs2 
Conc-omitant medication 
Randomisation 
Vaccination and route 
Issue diary card 
Review diaiy card 
Symptom-directed PE 
Record adverse events 
Safety lab3 
Semm IgG ELISA 6 
Semm IgA ELISA+ai1ti-
CTH522 IgG subtypes + 
neutralising ab6 
Oculai· anti-CTH522 IgG 
+ IgA ELISA (strio)
T- and B-cell Elispot
frozen PBMCs7 
ICS flow frozen PBMCs7 
Transcriptional analysis 
frozen PBMCs8 
End-of-trial 
1 
2 
-
0 
-90 to
0 
-1
X 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
1 
IM 
X 
X 
X 
X 
x• 
xs 
X 
X 
X 
X 
X 
X 
CONFIDENTIAL 
14 December 2020 
Final 5.1 
3 
4 
14 
28 
5 
42 
V2+ 
V2+ 
V4+ 
12-16
26-30
12-16
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
2 
IM 
ID 
TO 
X 
X 
X 
X 
X 
X 
X 
X 
X 
xs 
xs 
xs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6 
7 
56 
112 
V4+ 
V4+ 
26-30
77-91
X 
X 
X 
X 
X 
X 
3 
IM 
ID 
TO 
X 
X 
X 
X 
X 
xs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ID=intradennal; IM=intramuscular; PE=physical examination; TO=topical ocular; V=visit 
Page 22 of70 
Protocol CHLM-02 
8 
9 
10 
11 
12 
126 
140 
143 
154 
238 
V7+ 
V7+ 
V9+ 
V9+ 
V9+ 
12-16 
26-30
2-4
12-16
91-105
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
4 
TO 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
xs 
xs 
xs 
xs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*A biomicroscopy (e.g. via slit lamp examination), examining all ai·eas of the eye including the retina which can be perfonned by a specialist
at an eye clinic. If this procedtu·e cannot be perfonned at Vl, it is acceptable at V2 as long as it is peifonned prior to the fo-st vaccination.
**Eye examination not involving fondoscopy or any other examination modality that necessitates tmacceptable prolonged closeness betv,een
examiner and participant or where the examination cannot be pe1formed using standard personal protective equipment for examiner and
participant.
1single urine PCR tests for C. Trachoma and gonorrhoea; 2biood pressure, hea1t rate and oral temperattu·e; taken pre-vaccination whCll
scheduled at vaccination visits (V2, V4, V7 ai1d V9); 3Safety lab: renal urea and electrolytes (sodituu, potassituu, chloride, m·ea, and
creatinine); liver fonction tests (alanine aminotransferase, alkaline phosphatase, total bilimbin, total protein, albumin); foll blood cotu1t
(WBC, lymphocytes, monocytes, eosinophils, neutrophils, basophils, RBC, HGB, 'HCT, and platelets): 4total blood for safety:

 
 
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approximately 13 ml; 5total blood for safety: approximately 8 ml; 6amount of blood: approximately 1 x 10 ml; 7amount of blood in heparin 
tubes: 5 x 6 ml; 8amount of blood in heparin tubes: 2 x 6 ml 
8.2 
Trial procedures 
At V1 (Day -90 to -1), the volunteers’ eligibility is assessed according to the pre-specified 
inclusion/exclusion criteria and the informed consent is obtained. The medical history, vital signs 
(including BMI) are taken, physical and eye examinations are performed. Refer to Table 3 for eye 
examination method required at V1. Concomitant medications (CM) and AEs are recorded. Blood 
samples for screening of hepatitis B and C, HIV, syphilis and safety biochemistry/haematology are 
drawn. Urine is collected for pregnancy test and PCR for C. Trachoma and gonorrhoea infections.  
At V2 (Day 0), the inclusion/exclusion criteria are assessed again. Eye and symptom-direct physical 
examination are performed and vital signs are taken. Refer to Table 3 for eye examination method 
required at V2. Any AEs and CMs are reviewed and recorded. Urine is collected for pregnancy test. The 
volunteers are randomised according to the randomisation scheme via the eCRF. Before the 1st IM 
vaccination, blood samples for safety and immunogenicity determination (please refer to type of tests in 
Table 4) are drawn and ocular samples are taken. The volunteers (hereafter subjects) receive the 1st IM 
vaccination. The subjects are observed for any immediate AE for 60 minutes after the vaccination. The 
diary card is issued with instructions before discharge from the site.  
At V3 (Day 14), the diary card is collected and reviewed. Adverse events and CM are reviewed and 
recorded. Vital signs are taken and symptom-directed physical examination is performed as necessary. 
Blood samples for safety and immunogenicity (please refer to type of tests in Table 4) are drawn.  
At V4 (Day 28), the AEs and CM are reviewed and recorded. Vital signs are taken. Eye and symptom-
directed physical examinations are performed. Refer to Table 3 for eye examination method required at 
V4. Before the vaccinations, blood samples for safety and immunogenicity determination (please refer to 
type of tests in Table 4) are drawn, and urine for pregnancy and ocular samples are taken. The subjects 
receive the 2nd IM vaccinations together with ID or TO vaccination as specified in the Figure 1. In the 
event that the first TO vaccinations are planned for several subjects on the same day, there should be a 
minimum of two hours between the TO dosing for each subject. The two hour lagging between the TO 
doses should be performed for the first five subjects receiving TO doses and can be discontinued after the 
first these five subjects if there are no safety concerns. The subjects are observed for any immediate AE 
for 60 minutes after the vaccination. The diary card is issued with instructions before discharge from the 
site.  
At V5 (Day 42), the diary card is collected and reviewed, AEs and CM are reviewed and recorded. Vital 
signs and ocular samples are taken. Eye and symptom-directed physical examination are performed. Refer 
to Table 3 for eye examination method required at V5. Blood samples for safety and immunogenicity 
(please refer to type of tests in Table 4) are drawn.  
At V6 (Day 56), the AEs and CM are recorded. Eye and symptom-directed physical examination are 
performed. Refer to Table 3 for eye examination method required at V6. Blood samples for 
immunogenicity determination are drawn (please refer to type of tests in Table 4). Ocular sample is taken. 

 
 
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14 December 2020 
  
 
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At V7 (Day 112), the AEs and CM are recorded. Vital signs are taken. Eye and symptom-directed 
physical examinations are performed. Refer to Table 3 for eye examination method required at V7. 
Before the vaccinations, blood samples for safety and immunogenicity determination (please refer to type 
of tests in Table 4) are drawn, and urine for pregnancy and ocular samples are taken. The subjects receive 
the 3rd IM vaccinations together with ID or TO vaccination as specified in the Figure 1. The subjects are 
observed for any immediate AE for 60 minutes after the vaccination. The diary card is issued with 
instructions before discharge from the site.  
At V8 (Day 126), the diary card is collected and reviewed. The AEs and CM are recorded. Vital signs are 
taken, eye and symptom-directed physical examination are performed. Refer to Table 3 for eye 
examination method required at V8. Blood samples for safety and immunogenicity determination (please 
refer to type of tests in Table 4) are drawn. Ocular sample is taken. 
At V9 (Day 140), the AEs and CM are recorded. Vital signs are taken. Eye and symptom-directed 
physical examinations are performed. Refer to Table 3 for eye examination method required at V9. 
Before the vaccinations, blood samples for safety and immunogenicity determination (please refer to type 
of tests in Table 4) are drawn, urine for pregnancy and ocular sample are taken. The subjects receive the 
final vaccination with a TO CTH522 (or placebo) boost as specified in the Figure 1. The subjects are 
observed for any immediate AE for 60 minutes after the vaccination. The diary card is issued with 
instructions before discharge from the site.  
At V10 (Day 143), the diary card is reviewed. The AEs and CM are recorded. Vital signs are taken. Eye  
and symptom-directed physical examination are performed. Refer to Table 3 for eye examination method 
required at V10. Ocular sample is taken. 
At V11 (Day 154), the diary card is collected and reviewed, AEs and CM are recorded. Vital signs are 
taken. Eye and symptom-directed physical examinations are performed. Refer to Table 3 for eye 
examination method required at V11. Blood samples for safety and immunogenicity determination 
(please refer to type of tests in Table 4) are drawn and ocular sample is taken. 
V12 (Day 238) is the end-of-trial visit. The AEs and CM are reviewed and recorded. Vital signs are taken. 
Eye and physical examinations (including symptom-directed) are performed. Refer to Table 3 for eye 
examination method required at V12. Urine is collected for pregnancy and PCR for C. Trachoma and 
gonorrhoea infection test. Blood samples for safety and immunogenicity determination (please refer to 
type of tests in Table 4) are drawn and ocular sample is taken. 
8.3 
Trial population and planned number of subjects 
The trial plans to screen approximately 110 subjects with the aim to randomise 66 subjects. The enrolled 
subjects will be healthy males and females aged 18–45 years.    
8.3.1 
Inclusion criteria 
• IC1: Healthy males and females between 18–45 years old on the day of the first vaccination 

 
 
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14 December 2020 
  
 
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• IC2: Has been properly informed about the trial and signed the consent form 
• IC3: Is willing and likely to comply with trial procedures 
• IC4: Is prepared to grant authorised persons access to his/her trial-related medical record 
• IC5: Is willing to use acceptable contraceptive measures during the trial (two weeks before and 
two weeks after the trial). Heterosexually active female capable of becoming pregnant must agree 
to use hormonal contraception, intrauterine device, intrauterine hormone-releasing system, or to 
complete abstinence from at least two weeks before the first vaccination until at least two weeks 
after the last. Complete abstinence (defined as refraining from heterosexual intercourse) must be 
in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal and progestogen-only oral 
hormonal contraception where inhibition of ovulation is not the primary mode of action are not 
acceptable methods of contraception 
8.3.2 
Exclusion criteria 
General 
• EX1: Is positive for C. trachomatis via urine PCR or has a known history of C. trachomatis 
• EX2: Is positive for gonorrhoea via urine PCR test, or HIV, hepatitis B/C, syphilis via blood tests 
• EX3: Has a significant active disease such as cardiac, liver, immunological, neurological, 
psychiatric or clinically significant abnormality of haematological or biochemical parameters  
• EX4: Has BMI ≥ 35 kg/m2   
• EX5: Is currently participating in another clinical trial with an investigational or non-
investigational drug or device, or was treated with an investigational drug within 28 days before 
the first vaccination 
• EX6: Has received, or plans to receive, any immunisation within 14 days of the start of the trial or 
during the trial immunisations 
• EX7: Is currently receiving treatment with systemic immunosuppressive agents. Topical steroids 
are allowed unless applied to the IM or ID injection site 
• EX8: Has a condition which in the opinion of the investigator is not suitable for participation in 
the trial 
• EX9: Is known or confirmed to have allergy to any of the vaccine constituents 

 
 
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14 December 2020 
  
 
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• EX10: Is unable to refrain from use of contact lenses. Contact lenses should be avoided two days 
before TO administration and for seven days later (longer if any ongoing local eye AE) 
• EX11: Has any evident ocular disease upon eye examination (prior to first vaccination) or any 
medical history of ocular disease that, in the opinion of the investigator, may impact the subject’s 
participation in the trial 
Female-specific 
• EX12: Is pregnant (positive pregnancy test) or breastfeeding or not willing to use contraception 
during the trial 
• EX13: Has confirmed history of pelvic inflammatory disease or significant gynaecological 
diseases 
8.4 
Randomisation procedure 
The randomisation will be performed via the eCRF system at the site. Randomisation data is kept strictly 
confidential, accessible only to authorised persons, until the time of unblinding. Only when the trial has 
been completed or for expedited purpose, and the database has been locked, the codes will be broken and 
made available for data analysis. 
8.5 
Blinding and unblinding 
Blinding will be obtained by shielding the subjects from seeing the preparation of the trial drug and by 
having unblinded trial personnel not involved in any trial assessments (immunogenicity or safety) 
responsible for preparing and administering the trial drug. This unblinded staff will prepare and 
administer trial drug, and be the only ones doing IMP accountability. 
During vaccination, the blinded staff will be shielded from seeing trial drug or any procedures related 
hereto. This blinded staff will observe the subject and monitor any AEs during or after vaccination. 
All used material will be removed by the unblinded staff without revealing the identity of the fluid. The 
IMP accountability will be monitored by an unblinded clinical research associate (CRA). 
The PI and delegates at the site will have access via the IBM Clinical Development trial database to 
unblind individual subjects and obtain information on trial drug administered in case of a medical 
emergency. The investigator should only unblind the treatment allocation to a subject during the clinical 
trial if it is relevant to the safety of the subject. The identity of the IMP would be revealed by the PI or 
designee for that subject only.  
It may be necessary for the CRO to unblind a subject’s treatment for expedited reporting to the 
Competent Authorities (CA) and/or Research Ethic Committee (EC). In these situations, the CRO will 
keep the unblinding from the PI, site staff, subject, and SSI personnel involved in monitoring, data 
analysis and interpretation. In cases of suspected unexpected adverse reactions (SUSAR), the unblinding 
will be known to the safety manager at SSI.   

 
 
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Unblinding of a subject is performed in the IBM Clinical Development trial database and is only possible 
for persons who have obtained rights to perform unblinding. The date of unblinding, reason and the 
person performing the unblinding are saved via an audit trail. 
A screen-dump of the unblinding page including the information of the unblinded subject, the reason for 
unblinding, date and person performing the unblinding, is made and printed. This print is filed in an 
envelope with the subject’s allocation number and sealed with a label and kept in a secure at the site. 
The IBM Clinical Development system has an up-time of more than 99%, so system-down is a small risk. 
In case of system-down, a designated person at 
, who is not otherwise involved in any trial-
related work, can be contacted to obtain information of the trial drug allocated to any specific subject.  
Subjects with unblinded treatment allocation will not be withdrawn and will not be replaced.  
8.6 
Immunogenicity assessments 
The immunogenicity objective, anti-CTH522 IgG, will be determined using ELISA at SSI.  
The immunogenicity will further be analysed using a panel of exploratory assays performed at SSI and 
ICL as outlined in Table 4. The serum IgA ELISA + anti-CTH522 IgG subtypes + neutralising antibody 
test for the mucosal immune response, whereas the ocular anti-CTH522 IgG + IgA ELISA test the 
immune response in the eye. The T- and B-cell Elispot and ICS flow using frozen PBMCs assess the cell-
mediated immunity. The transcriptional analysis consists of taking PBMCs and re-stimulating in vitro 
with CTH522. The aim is to identify gene transcription profiles associated with Th17 T-cells, Th1, and 
Th2 in the different active vaccine groups. 

CTH522 
STATENS 
SERUM 
INSTITUT 
CONFIDENTIAL 
14 December 2020 
Final 5.1 
Table 4: Safety and immunogenicity assessments 
Analysed 
Medium, amount 
Laboratory tests 
at: 
and unit 
Safety 
Safety lab 
ICHT 
Blood 
1 X 13 (8) ml 
Immw1ogenicity 
Senun lgG ELISA 1 
SSI 
Blood 
1 X 10 ml 
Semm IgA ELISA+ anti-
Blood 
CTH522 lgG subtypes + 
SSI 
1 X 10 ml 
neutralising antibodies2 
T- and B-cell Elispot
T-cell: SSI
Blood in heparin tube 
frozen PBMCs2 
B-cell: ICL
5 x6ml 
ICS flow frozen PBMCs2 
ICL 
Blood in heparin tube 
5 x 6ml 
Transcriptional analysis 
SSI 
Blood in heparin tube 
frozen PBMCs2 
2x6ml 
Total blood collection 
For immunogenicity 
For safety 
Visit 
1 
2 
3 
Day 
-
0 
14 
13 
8 
8 
10 
10 
10 
10 
30 
30 
30 
30 
12 
92 
80 
13 
8 
8 
Page 28 of70 
Protocol CHLM-02 
4 
5 
6 
7 
8 
9 
10 
11 
12 
28 
42 
56 
112 
126 
140 
143 
154 
238 
8 
8 
8 
8 
8 
8 
8 
10 
10 
10 
10 
10 
IO 
10 
10 
10 
10 
10 
10 
10 
10 
10 
10 
30 
30 
30 
30 
30 
30 
30 
30 
30 
30 
30 
30 
30 
30 
30 
12 
12 
80 
80 
80 
50 
92 
80 
92 
80 
8 
8 
8 
8 
8 
8 
8 
ICHT=lmpenal College Healthcare NHS Tmst; ICL=Impenal College London; ICS=intrncellular cytokine staining; PBMC=peripheral blood monornuclear cell; SSI=Statens 
Semm Institut 
1for secondary endpoints 
2for explorato1y endpoints 

 
 
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8.7 
Safety assessments 
The trial staff must record all AEs, non-serious and serious, expected and unexpected in the relevant 
form of the eCRF. This starts from the time after the subject has signed the informed consent form 
(ICF) at V1 until the end-of-trial at V12. 
The source of AEs covers, for example, the subject’s response to questions about his/her health (a 
standard non-leading question), information from diary card, symptoms spontaneously reported by 
a subject, results from pre-defined laboratory testing and examinations where the findings are 
assessed by the investigator to be clinically significant changes or abnormalities, and other 
information relating to the subject’s health becoming known to the investigator (for example 
hospitalisation). 
The subjects will remain at the site for 60 minutes after each vaccination so that any immediate AEs 
observed may be recorded. It is also documented if no immediate AEs occurred. Trial staff will 
ensure that the subjects have a diary card, ruler to measure and thermometer to enable them to 
record AEs while away from the clinical site. 
From the day of vaccination until seven days later, solicited AEs and unsolicited AEs will be 
recorded through the use of diary cards. Between Day 7–14, the subject will be asked to fill in 
details in the diary only if they experience an AE or if any medications were taken.  
8.8 
Predetermined reasons for discontinuation 
The trial may be terminated at any time if participation in the trial is no longer considered safe by 
the PI, the sponsor or the regulatory authorities. 
A subject is free to discontinue from the trial at any time without giving a reason. The investigator 
may at any time withdraw a subject if his/her participation is no longer considered safe or relevant. 
The date and reason (if given) for discontinuation must be recorded in the eCRF. In the case of 
pregnancy and/or anaphylactic reactions, the subject must be withdrawn. In case of an identified 
pregnancy, the pregnancy form(s) is to be used. If a subject for any reason leaves or is withdrawn 
from the trial or has a significant protocol deviation, he/she will not be replaced if the subject has 
received at least one trial vaccination.   
Because the healthy subjects gain no benefit from participation in the trial, dosing in the trial must 
be stopped if:  
• there is one or more subjects with SAEs considered to be related to the IMP  
• there are two or more subjects with a severe AE considered to be at least possibly related to 
the IMP (based on the judgement of the investigator) 
• there are two or more subjects with clinically significant AEs considered to be at least 
possibly related to the IMP (based on the judgement of the investigator) and which are 

 
 
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deemed to have impacted to a significant degree on the safety or physical or mental integrity 
of the affected subject(s), or which have resulted in permanent discontinuation of dosing in 
the affected subject(s) 
8.9 
Contraindications 
8.9.1 
Temporary contraindications 
The below conditions (events) are considered temporary contraindications to the trial products and 
are assessed before each vaccination is administered.  
• Oral temperature > 38.3°C measured immediately before each vaccination 
• Acute illness as judged by the investigator 
• Antipyretics used on the day of vaccination 
• Systemic treatment with immunosuppressive agents  
• Ongoing conjunctivitis or similar on the day of TO administration 
If the subject is experiencing one of the above conditions, the vaccination must be postponed until 
he/she has recovered. On the rescheduled visit, the subject should be checked for the above 
temporary contraindications. If the subject is found to be eligible, the vaccine can be administered 
while maintaining the planned intervals. 
8.9.2 
Permanent contraindications 
If the subject experienced the following events or received the following medication, he/she must 
be withdrawn from the trial: 
• acute anaphylactic reaction after administration of any of the trial vaccines 
• ocular disease  
8.10 
Collection and handling of samples 
Detailed information on the collection and handling of blood, ocular strips and frozen PBMC will 
be described in Laboratory Manuals. During the trial, approximately 85 ml of blood will be 
collected for laboratory screening and safety tests, and approximately 800 ml of blood will be 
collected for immunogenicity assessments (Table 4)  
8.11 
Laboratory assays 
Testing for C. trachomatis infection, gonorrhoea, syphilis, HIV, hepatitis B and C will be done at 
the laboratory facility at Charing Cross Hospital, which is part of ICHT. 
 

 
 
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Laboratory safety tests will be analysed at the lab facility at Hammersmith Hospital, which is also 
part of ICHT. Peripheral blood will be collected and analysed for the following biochemistry and 
haematology parameters at the timepoints specified in Table 3:  
• Renal urea and electrolytes profile (sodium, potassium, chloride, urea, creatinine) 
• Liver function tests (ALT, alkaline phosphatase, total bilirubin, total protein, albumin) 
• Full blood count: WBC, lymphocytes, monocytes, eosinophils, neutrophils, basophils, RBC, 
haemoglobin, haematocrit, and platelets) 
FDA guidelines on toxicity grading scale for subjects enrolled in vaccine trials will be used by the 
investigator for grading the intensity of AEs including lab-related AEs (Appendix 1). 
A pregnancy test will be performed on-site by analysis of a urine sample for human chorionic 
gonadotrophin collected from female subjects at screening, the day of the vaccination and the final 
visit. Testing will be done at the NIHR Imperial Clinical Research Facility.  
Serum IgG samples will be analysed at SSI. Other exploratory immunogenicity analysis will be 
analysed as specified in Table 4. Samples for PBMC isolation will be shipped on the day of 
collection from the investigator site to ICL, for processing and storage. The serum IgG samples will 
be processed and stored at the investigator site until the last sample has been collected. All samples 
intended to be analysed at SSI will be shipped after the last subject’s last visit (LSLV) but no later 
than two weeks after date of LSLV. The samples must be shipped on dry ice with storage conditions 
monitored during the transport to SSI by use of a temperature logger. Documentation of the 
dispatch of samples from the investigational site and the receipt of the samples at SSI should be in 
accordance with the relevant SSI procedures for dispatch and receipt of samples. It is the 
responsibility of the site to pack the samples according to the above and arrange the transport from 
the site to SSI. 
8.12 
Planned schedule of trial 
The schedule below is subject to change. The date of the first subject’s first visit (FSFV) is defined 
as the date the first subject has had his/her first trial visit.  The end of the trial is defined as LSLV, 
and the EC and MHRA will be notified within 90 days of the date of LSLV. 
• Planned submission of clinical trial application to MHRA and EC:  Q2 2019 
• Planned FSFV: Q3 2019 
• Planned LSLV: Q4 2020 
• Database lock: Q1 2021 
• Planned final integrated clinical trial report (CTR):   Q1 2021 

CTH522 
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9 
lnvestigational medicinal produets 
9.1 
Composition of trial produets 
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Tue drng produets CTH522 and adjuvant CAF0l were manufactured and filled at 
 in 
 and the adjuvant CAF09b was manufactured and filled at 
 for 
SSI. Tue drng produets and adjuvants are labelled at SSI according to good manufacturing practices 
(GMP). Saline (0.9% NaCl) for injection will be used as placebo, and water for injection will be 
used to reconstitute CTH522 for ID injection. Saline and water for injection will be ward stock, 
sourced comrnercially by the investigator site, in individual single-use ampoules. 
Tue non-adjuvanted CTH522 to be given TO is ready to be used. The CTH522-CAF01 and 
CTH522-CAF09b (both to be given IM) and CTH522 to be given ID will be reconstituted at the 
site. The composition of the IMPs is described in Table 5. 
Table 5: Composition of IMPs 
IMP (routes) 
CTH522 
Per dose volume 
CTH522-CAF01 (IM) 
85 7lg 
15 µ.g 
CTH522-CAF09b1 (IM) 
85 7tg 
CTH522 (TO) 
24 71g1 
CTH522 (ID) 
24 µ.g 
1subjects receive 12 8tg in each eye. 
9.2 
Dose and administration of trial produets 
9.2.1 
Dosage and route 
0.5 ml 
0.5 ml 
0.5 ml 
0.04 ml 
0.1 ml 
Pre-clinical data from mice showed that there was a direct conelation between antigen dose and 
antibody titres, i.e. increasing the dose ten times (5-50 ¤tg) lead to significant higher antibody titres 
and lowering the antigen dose (25-0.2 µg) lead to a drop in the antibody response. The lowest 
amount of CTH522 antigen needed to elicit a protective immune response in humans is unknown 
(please see Investigator's Brochure (IB) for more details). A literature review of recently published 
vaccine trials involving IM imrnunisation of recombinant proteins shows that well-tolerated doses 
range from 5-160 µg [14-19], and generally increasing the dose from 5-30 ¤tg to 80-100 µg will 
increase the antibody titres [18, 19]. However, a fmiher increase in dose does not seem to affect the 
antibody titre [15, 18]. Therefore, 85 ¥Lg CTH522 antigen with adjuvant Al(OH)3 or CAF0l were 
tested in a non-clinical study in minipigs using IM and intranasal administrations. No treatment­
related adverse clinical signs were recorded, and no evidence of systernic toxicity was found [9]. 
When comparing non-adjuvanted CTH522 with adjuvanted CTH522-Al(OH)3 or CTH522-CAF01, 
a significantly higher level of anti-CTH522 IgG antibodies was measured by ELISA. Therefore, SSI 
evaluated a CTH522 antigen dose of 85 ¦Lg for IM inununisation in the first-in-human trial using IM 
and intranasal administration [9]. For the IM immunisations in the CHLM-01 trial, a classical 
prirne-boost vaccination regime was adopted: a priming (two vaccinations fom weeks apart) 

 
 
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followed by a boosting vaccination after 12 weeks. The CHLM-01 trial was designed to generate 
high titre primary antibody response following priming and allow enough time for the antibody 
affinity maturation process before boosting [20]. The results of that trial showed that a dose of 85 
µg for IM immunisation was highly immunogenic when used in a classic prime-boost vaccination 
schedule [9].  
For the CTH522 dose to be administered TO, a formulation containing 600 µg/ml CTH522 was 
found acceptable. Regarding the TO dose volume, a dose of 0.02 ml was deemed acceptable to 
avoid to significant spill-off from the topical ocular administration of a drop of CHT522. In 
combination, this consequently leads to a TO dose of 12 µg (given as 0.02 ml drop). In this trial, 
one drop is administered to each eye per vaccination, hence the total TO dose is 24 µg. 
In the trial, it will be investigated if the TO or ID vaccination with CTH522 given concomitantly 
with CTH522-CAF01 IM will lead to increased immune responses. The TO dose of CTH522 is 24 
µg, therefore the ID dose of CTH522 is also 24 µg, given as 100 µl ID.  
The CAF01 adjuvant human dose was based on the results from the ACAF01-01 trial, a CAF01 
dose-escalation trial completed in the Netherlands. The results of the ACAF01-01 trial concluded 
that a 625 µg/125 µg of DDA/TDB in CAF01 is the optimal human dose [12]. Also, this dose was 
found efficient when combined with CTH522 in the first-in-human clinical trial (CHLM-01) [9].  
The CAF09b adjuvant is, like CAF01, a liposomic adjuvant formed by DDA and incorporating the 
MMG glycolipid into the liposome membrane for both stability and immunostimulatory reasons. 
The human dose level of CAF09b was therefore set based on the CAF01 dose levels of DDA and 
glycolid (TDB in CAF01 vs MMG in CAF09b), being 625 µg/125 µg of DDA/MMG in CAF09b. 
In addition to the DDA and MMG, the CAF09b contains the TLR3 agonist poly I:C, 
electrostatically bound to the liposome surface.   
The poly I:C level had in pre-clinical studies (as the adjuvant CAF09) being at the same dose level 
as MMG. From a formulation and stability perspective, however, a lower dose of poly I:C relative 
to DDA/MMG was found optimal, resulting in 31 µg poly I:C combined with 625 µg/125 µg 
DDA/MMG to give CAF09b. This CAF09b 625/125/31 µg DDA/MMG/poly I:C was tested and 
found safe and acceptable in a repeated dose toxicological study in rabbits (as part of a toxicology 
study for a cancer vaccine) as well as the two ongoing clinical trials.  
9.2.2 
Treatment administered 
The randomised subjects will be vaccinated with the IMPs (non-adjuvanted CTH522) and 
reconstituted IMPs (adjuvanted CTH522) accordingly to the schedule and route specified in Figure 
1. On-site reconstitution of the adjuvanted IMPs is performed by mixing the CTH522 with CAF01 
or CAF09b. Specific instruction of the on-site reconstitution can be found in the Vaccine 
Management Manual, which is prepared by SSI. 

 
 
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The preferred location for IM and ID administrations is into (IM) or into the skin overlying (ID) the 
non-dominant deltoid muscle. Each IM administration will consist of 85 µg CTH522-CAF01, 15 µg 
CTH522-CAF01 or 85 µg CTH522-CAF09b in a volume of 0.5 ml per injection. Each ID 
administration will consist of 24 µg CTH522 in a volume of 0.1 ml per injection. The IM and ID 
injections must be administered within five minutes of each other and approximately 2 cm apart 
from each other. As long as the two injections are administered within five minutes, it does not 
matter which one (IM or ID) is given first. The IM injection will be performed with a 1–2 ml 
polypropylene syringe via a 23–25-gauge needle. The ID injection will be with a 1 ml syringe via a 
microneedle device.  
The TO administration in both eyes will consist of 24 µg CTH522 (non-adjuvanted) in a volume of 
0.04 ml; thus, each eye is administered 12 µg of CTH522 TO in a 0.02 ml drop. The eye drops 
should be given five minutes apart, with the right side first to follow by the left side. The TO 
administrations will be performed using a Gilson MICROMAN positive displacement pipette, 
which will be provided by ICL.  
Each colour coded vial and cardboard box of IMPs is labelled with the content of the vial as 
described in the Vaccine Management Manual. The identity of the injected trial vaccine will be 
known to the clinical site staff administering the trial vaccine and by the unblinded trial monitor. 
However, the identity of the trial vaccine administered will remain unknown to the subject during 
the trial.  
The IMPs should only be administered by authorised staff as indicated in the investigational site 
signature and delegation form.  
9.3 
Packaging and labelling of trial products 
The IMPs and adjuvants (excipients) are filled into vials (inner packaging) and are packed in 
cardboard boxes (outer packaging) according to GMP. The labels for inner- and outer packaging 
will be produced and printed at SSI according to the ‘EU Guidelines to Good Manufacturing 
Practice Medicinal Products for Human and Veterinary Use Annex 13, Investigational Medicinal 
Products’ [21]. Placebos are the commercially available saline solution.  
9.4 
Storage and shelf-life information for trial products 
The IMPs and adjuvants must be stored according to the protocol in a safe and locked place at the 
site under the responsibility of the site PI and/or at central storage under the responsibility of a 
pharmacist. The expiry dates of the drug products and excipients are indicated on the labels of the 
cardboard boxes. They should not be used after the indicated dates. The final reconstitution of the 
IMPs and the storage conditions are described Vaccine Management Manual. 
The freezers and refrigerators used to store IMPs and adjuvants must be equipped with 
thermometers, and the temperature must be controlled on a daily basis and documented in the 
storage condition logs under the responsibility of the PI/pharmacist. Relevant clinical site staff will 

 
 
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monitor the storage conditions of IMPs and adjuvants during the trial. In case of deviations in 
storage conditions identified by either the site investigator or monitor, SSI must be contacted to 
decide if they can be used in the trial or must be replaced. 
9.5 
Transport procedures for trial products 
The drug products and adjuvants will be released by a qualified person, and subsequently 
transported to the clinical site when the clinical trial has been approved by the CA and by the 
relevant EC. The transport of the drug products and adjuvants will be arranged according to 
standard operating procedures at SSI. Temperature loggers will be used for monitoring the storage 
conditions during the transport. Procedures will be in place for documenting the dispatch of IMPs 
and adjuvants from SSI and the receipt at the site. During the trial, the monitor will check that the 
dispatch/receipt documentation in the investigator’s file (IF) is adequate and correct. 
9.6 
Treatment compliance procedures 
As this clinical trial is investigating vaccines that are administered by the staff at the site, the issue 
of subject treatment compliance will be addressed by evaluating the vaccine administration data 
recorded by the staff in trial-related documents/logs. During the trial, the monitor will check that 
vaccine administration data is recorded correctly. 
9.7 
Drug accountability procedures 
It is the site’s responsibility that all unused and used IMPs and adjuvants are accounted for during 
the trial and documented in the relevant trial documents/logs. Any unused IMPs and adjuvants are 
to be destructed after completion of the trial and after the approval by SSI. During the trial, the 
monitor will check that drug accountability is maintained. Empty vials and vaccine cardboard boxes 
are kept at the site until the close-out monitoring visit.  
9.8 
Precautions and overdosing 
Anaphylactic reactions are very rare but a potential risk when administering vaccines. Therefore 
anaphylactic kit must be kept available for immediate use in the room where the injections are 
given. Medical staff trained in resuscitation must be in the clinic for the vaccination and 60 minutes 
after that.  
Vasovagal syncope (i.e. fainting) can occur before, during and after injection and blood sampling. 
The site should minimise the occurrence of this reaction by allowing the subject to lie down or 
recline during the administration of vaccine and blood draws.  
After administration of the vaccine, the subject must stay at the NIHR Imperial Clinical Research 
Facility (i.e. clinical site) for 60 minutes so that the staff can observe for any immediate AEs. 
Before the subject leaves the site, any AEs are reviewed and recorded in the source documents by 
delegated staff. 

 
 
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9.9 
Concomitant medications 
Non-trial vaccines received within 14 days before or after trial vaccination should be avoided. If a 
non-trial vaccine is to be administered, consider the following: 
• Subjects should be advised (but not required) to increase the spacing between trial and 
COVID-19 vaccines to at least 28 days 
 
• Non-trial vaccines should preferably be not injected into the same arm as the trial vaccine. 
  
Systemic immunosuppressive agents, such as a corticosteroid, may not be administered during the 
trial. Dermal steroids are allowed but not if applied to the IM or ID injection sites.  
Antipyretics/analgesics may not be taken within 24 hours before the day of vaccination. If taken, 
the vaccination should be postponed. Furthermore, during the first 72 hours after the vaccination, 
antipyretics/analgesics should be avoided. If taken, the details of the medication should be recorded 
in the diary card and in the CM pages of the eCRF. 
Other medications (except for vitamins and minerals) are recorded in diary cards and subsequently 
transferred to the eCRF by relevant trial staff at the site.  
 
 

 
 
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10 
Adverse events 
The following definitions are in accordance with the EU Guidance (CT-3) (2011/C 172/01) and 
European Clinical Trial Directive 2001/20/EC of 4 April 2001 [22]. 
• An AE is any untoward medical occurrence in a subject administered a medicinal product 
and which does not necessarily have a causal relationship with the administered trial 
product. An AE can, therefore, be any unfavourable and unintended sign (including an 
abnormal laboratory finding, for example), symptom or disease temporally associated with 
the use of a medical product, whether or not considered related to the medicinal product. 
The definition also covers medication errors and uses outside what is foreseen in the 
protocol. 
• An adverse drug reaction is an AE where a causal relationship to the trial product is at 
least a reasonable possibility, i.e. a causal relationship cannot be ruled out.  
• An unexpected adverse reaction is a reaction that is by nature or severity of which is not 
consistent with the IB. 
• An unsolicited AE is an event that will be sought from each vaccination, through non-
leading AE questioning such as ‘how have you been feeling’, and through symptom-directed 
physical examination. Unscheduled laboratory testing and other investigations may be 
performed as required to investigate the AE. 
• An SAE or serious adverse reaction is any untoward medical occurrence that at any dose: 
o results in death 
o is life-threatening. The term ‘life-threatening’ refers to an event where the subject was at 
risk of death at the time of the event, it does not refer to an event which hypothetically 
could have caused death, had it been more severe 
o requires inpatient hospitalisation or prolongation of existing hospitalisation 
o results in persistent or significant disability/incapacity 
o is a congenital anomaly or birth defect 
o is an important medical event. The term refers to a medically important event that does 
not meet any of the SAE criteria but may require medical or surgical consultation or 
intervention to prevent one of the other serious outcomes listed above 
• A SUSAR is a suspected unexpected serious adverse reaction according to the definitions given 
above. 

 
 
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10.1 
Standard recording and assessment of adverse events 
10.1.1 
Collection and recording of AEs 
The source of AEs covers, for example, the subject’s response to questions about his/her health (a 
standard non-leading question), information from diary card, symptoms spontaneously reported by 
a subject, investigations and examinations where the findings are assessed by investigator to be 
clinically significant changes or abnormalities, other information relating to the subject’s health 
becoming known to the investigator (for example hospitalisation). 
Safety data are collected according to the timeframe specified in the flow chart (Table 3). The 
solicited AEs listed below will be collected via the diary cards:  
• Solicited local injection site reactions after ID and/or IM administration of the vaccines: 
erythema, pruritus, pain, tenderness, swelling, and warmth 
• Solicited ocular reactions after TO administration of the vaccine: watering eyes, swelling of 
eyelid, eye redness, and eye discomfort 
• Solicited systemic reactions after IM and/or ID administration of the vaccines: oral 
temperature > 38.3°C, chills, myalgia and rash  
• Any other AEs 
The investigator or delegated staff must record all AEs, non-serious and serious, expected and 
unexpected in the relevant form of the eCRF.  
The date of onset is the date when the first sign(s) or symptoms were first noted. If the AE is an 
abnormal clinically significant laboratory test or outcome of an examination the onset date is the 
date the sample was taken or the examination was performed. 
If an AE or SAE is still ongoing or the outcome is unknown at the end of the trial (at the subject's 
last visit), it must be followed up by the investigator/delegate until it has been resolved or stabilised. 
All SAEs must be recorded on the Serious Adverse Event form in the eCRF. If the investigator has 
unblinded the trial drug allocation of the subject, the screen-dump from the unblinding is forwarded 
together with the completed Serious Adverse Event (SAE) form to SSI (please see Section 5 for 
contact information).  
10.1.2 
Assessments 
The investigator/delegate must assess the characteristics of the event(s) according to the below 
criteria: 
• Seriousness. For the assessment of the seriousness of the adverse event, please see 
definition under Section 10. 

 
 
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• Causality. The causal relationship between an AE and the trial product must be assessed by 
the investigator using the terms listed below. A ‘suspected adverse reaction’ is defined as an 
AE which has been assessed as possibly, probably or certainly related to the product 
administered (i.e. which has a reasonable suspected causal relationship to the product 
administered): 
o Not related: An AE that is definitely NOT related to the product administered 
o Related: An AE that is either: 
 possibly related with a reasonable time relationship to product administration, 
but which can also be explained by concurrent disease, other drugs or other 
cause,  
 probably related with a reasonable time relationship to product administration, 
and which is unlikely to be attributed to concurrent disease, other drugs or other 
cause, or 
 certainly related with the AE occurring in a plausible time relationship to product 
administration and which cannot be explained by concurrent disease, other drugs 
or other cause. 
• Expectedness. Expectedness is assessed according to the Reference Safety Information 
section in the newest version of the IB. No expected AEs are listed in the Reference 
Safety Information. Hence, all related SAEs in this trial should be reported as SUSARs. 
• Intensity. The intensity of an AE must be assessed by the investigator using the FDA 
guidance in Appendix 1 [21]. Where a specific AE is not listed in the guidance, its 
intensity must be assessed by the investigator using the following terms: 
o Mild (Grade 1): No interference with daily activity  
o Moderate (Grade 2): Some interference with daily activity not requiring medical 
intervention 
o Severe (Grade 3): Prevents daily activity and requires medical intervention 
o Potentially life-threatening (Grade 4): Emergency visit or hospitalisation 
• Outcome. The outcome of an AE must be assessed by the investigator using the 
following terms: 
o Recovered/resolved 
o Recovered/resolved with sequelae 

 
 
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o Recovering/resolving 
o Not recovered/not resolved 
o Fatal 
o Unknown 
10.2 
Expedited reporting of adverse event 
If an SAE occurs, immediate reporting is required by completing the Serious Adverse Event form, 
in the eCRF. The site PI must submit the completed SAE form via the eCRF at the latest within 24 
hours of first knowledge. Once entered into the eCRF, the sponsor and delegated 
pharmacovigilance will be notified by email.  
All SUSARs should be sent on an expedited basis by the CRO to the MHRA and the Research 
Ethics Committee according to the timelines listed below. The blinded SUSAR reports will be 
archived in the Trial Master File (TMF) at SSI and in the investigator´s file. 
• For fatal or life-threatening SUSAR reports, notification as soon as possible, but no later 
than seven calendar days after first knowledge of the event and final reporting after an 
additional eight calendar days. 
• For other SUSARs reporting, as soon as possible, but no later than 15 calendar days after 
first knowledge of the event.  
A Development Safety Update Report should be prepared in accordance with ICH Guideline E2F 
on Development Safety Update Report at yearly intervals and submitted to the MHRA. The 
Development International Birth Date is 13-Mar-2016. 
11 
Data management and statistical analysis 
11.1 
General considerations 
Data management and statistical analysis will be performed by 
 on behalf of SSI.  
11.2 
Data management 
CHLM-02 is run as a Electronic Data Capture (EDC) trial, i.e. relevant data are entered by the site 
directly into the clinical database. Electronically transferred data will be handled and managed by 
 as well as the database and application.  
The eCRF is designed to capture required information in compliance with GCP standards. The 
eCRF system is hosted by IBM eClinical, an EDC software and services company that is EU-US 
Privacy Shield certified. 

 
 
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All data, except for immunogenicity data, will be collected using an eCRF compliant with 21 CFR 
Part 11 regulation. Safety laboratory data will be collected via the local laboratories and transferred 
to the eCRF by the trial staff at the site.  
Data management will be performed in accordance with applicable standards and data cleaning 
procedures. Only authorised access to the eCRF will be possible using an encrypted username and 
password. Roles in the system are given according to functions. All tasks performed in the eCRF 
are logged in an audit trail.  
The eCRF will contain validation checks according to the Trial Validation Plan to maintain an 
ongoing quality check of data entered. All data validation will be performed as part of the system. 
The investigator will approve the data using an electronic signature and thereby confirm the 
accuracy of the data recorded. 
Medical History and AEs will be coded using the pre-defined version of the Medical Dictionary for 
Regulatory Activities (MedDRA) concerning system organ class, high-level group term, high-level 
term, preferred term and lowest level term. Concomitant medication will be coded using the 
WHOCC-ATC/DDD, an Anatomical Therapeutic Chemical classification system and the Defined 
Daily Dose drug dictionary. Coding of AE and CM shall be entered into the trial database. 
Further details about trial setup and closure will be documented in the Data Handling Protocol 
prepared by 
. 
11.3 
Database release meeting and database lock 
Before releasing the database for statistical analyses and trial reporting, the data manager will 
ensure that all quality control procedures in connection with data capture, cleaning and 
reconciliation of data have been finalised and documented. Protocol deviations will also be 
discussed at this meeting. The data manager is responsible for setting up a database release meeting 
with relevant trial team members. This meeting shall be held before the unblinding of the trial. 
11.4 
Statistical methods 
The trial statistician prepares the SAS program/randomisation details description for the unblinded 
statistician/programmer. The unblinded statistician/programmer imports the randomisation list to 
the eCRF so that the site can automatically randomise the subjects via the eCRF and receive the 
allocated randomisation number and treatment. 
The baseline is defined as the last assessment with available data before the first administration of 
trial medication.  
The basis for safety analysis is the safety analysis set (SAF). The SAF consist of all subjects 
randomised and exposed to the IMPs, including subjects who are withdrawn after exposure to the 
IMP. The analysis of primary endpoints and all safety endpoints will be based on the SAF. Full 

 
 
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analysis set (FAS) will include subjects with observed data for all randomised subjects. A per-
protocol analysis set (PP) will include subjects who completed the trial without deviations judged to 
influence the primary endpoints. The analysis sets will be defined at the data release meeting, which 
will take place prior to unblinding of the trial. The primary analysis will be carried out for SAF and 
FAS and PP. 
Categorical data will be summarised descriptively by treatment, using the number and percentages 
of subjects. Continuous data will be presented using the number of subjects, mean, standard 
deviation, median, minimum and maximum. Both the absolute values and the change from baseline 
will be presented. 
Primary efficacy data will be presented descriptively over time using box-plots over time. If the 
nature of data allow, a formal statistical test will be performed using time to event analysis. 
11.4.1 
Subject disposition 
The disposition of subjects regarding inclusion in the SAF, FAS and PP and their trial completion 
status will be tabulated by treatment based on all randomised subjects and will also be presented in 
a listing. A separate listing of discontinued subjects will be included. 
Protocol deviations will be summarised by treatment group for all randomised subjects. 
11.4.2 
Demographics and baseline characteristics 
The three treatment groups (Cohort A-C) will be compared descriptively concerning a disposition, 
demography, baseline characteristics (age and race), medical history and CM, using both the SAF 
and the FAS. However, if the difference between SAF and FAS is two subjects or less, then only 
the SAF will be used. Similar comparison of the other cohorts. 
11.4.3 
Exposure and treatment compliance 
It is planned that 91% of the subjects will randomise to receive the 85 µg CTH522-CAF01, 15 µg 
CTH522-CAF01, or 85 µg CTH522-CAF09b in addition to the successive administration of the 
non-adjuvanted CTH522 or the placebo. The other 9% of the randomised subjects will receive only 
the placebo consisting of 0.9% NaCl. Treatment compliance is documented as a drug accountability 
log.  
11.4.4 
Safety analysis 
The binary primary endpoints are: 
• Solicited injection site reactions after IM and ID administration with the following PTs: 
injection site erythema, injection site pruritus, injection site pain, injection site swelling and  
injection site warmth 
• Solicited ocular reactions after TO administration with the following PTs: lacrimation 
increased, swelling of eyelid, ocular hyperaemia and ocular discomfort 

 
 
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• Solicited systemic reactions after vaccination with the following PTs: body temperature 
increased, chills, myalgia and rash 
The frequencies of the binary endpoints will be presented with the corresponding 95% CI. 
These endpoints will be analysed by pairwise comparison of active treatment groups versus placebo 
in 2 x 2 tables (presenting number and percentage of subjects experiencing the criteria) using 
Fishers exact test. Also, active treatment groups will be compared similarly. 
Adverse drug reaction will be presented descriptively by treatment group (number of subjects, 
percentage of subjects experiencing the event and number of events), in tables of system organ class 
and PTs in summary tables presenting each group in separate columns. 
Vital signs are presented descriptively by treatment group and visit. Both absolute values and 
changes from baseline are presented both in tables and in box-plots by visit. 
11.4.5 
Immunogenicity analysis 
Percentage of subjects achieving seroconversion for anti-CTH522 IgG antibody at any time points 
after vaccination(s) will be descriptively presented. The criteria for seroconversion will be specified 
in the SAP by 
 Imperial and SSI. The SAP will be finalised before the unblinded review. 
11.4.6 
Exploratory immunogenicity analysis 
Exploratory immunogenicity analyses will be performed separately from the primary and secondary 
analyses. Hence, the results from the exploratory analyses will not be included in the trial’s CTR.  
11.4.7 
Interim analysis 
No interim analysis is planned. 
11.4.8 
Sample size determinations 
No sample size calculations have been made. The sample size is considered adequate for review of 
the safety profile of the described interventions for a phase I trial. 
 
 

 
 
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12 
Ethical aspects 
The background of the CHLM-02 trial is to investigate the safety and immunogenicity of the 
chlamydia vaccine. SSI (sponsor) and ICL will, as part of the TracVac Consortium, conduct this 
trial and ICHT will host and act as the investigator site. The trial is partly funded by Horizon 2020. 
The grant covers expenses to materials, the staff at SSI and the investigator’s site and the CROs 
managing data management, statistics and pharmacovigilance on behalf of SSI. Work items 
outsourced from SSI to ICL, investigator’s site and the CROs are covered by signed agreements and 
Task Orders. 
The trial will be conducted in accordance with the latest version of the Declaration of Helsinki [23] 
and ICH GCP. An application to conduct the trial will be submitted to MHRA and the EC for 
approval. 
The subjects will receive verbal and written information about the purpose of trial and its nature, 
including details of any potential risks. 
The total amount of blood required from each volunteer throughout the trial period of nine months 
will be approximately 900 ml as compared to 470 ml normally drawn from blood donors as a single 
donation; in the UK, men are allowed to donate every 12 weeks and every 16 weeks for women. 
Blood samples will be coded before the blood samples are sent for laboratory analyses. Only the 
investigator and his medical collaborators will have access to information that may link laboratory 
results with personal identification. 
All non-clinical information supports the suitability of CTH522-CAF01 as a safe, immunogenic, 
and possibly effective vaccine to induce immunity in C. trachomatis uninfected individuals. The 
safety and reactogenicity of the CTH522 vaccines are expected to be comparable to the safety 
observed in a previous phase I clinical trial with CTH522 adjuvanted with CAF01 and Al(OH)3 
(CHLM-01) [9]. 
Based on animal toxicity studies [8] and the two ongoing clinical trials (ClinicalTrial.gov 
NCT03412786 and NCT03715985), CAF09b is expected to be safe and tolerable.  
CTH522 adjuvanted with CAF09b has not been tested in humans before but based on the 
information above and the results of the non-human primates study (CTH522-CAF01, CTH522-
CAF09b) and the EpiOcular In vitro test (CTH522) it is considered safe to initiate the present trial.    
12.1 
Risks and benefits 
At present, there is only data available for CTH522 with or without the adjuvants CAF01 or 
Al(OH)3 from a completed clinical trial that included 35 adult female volunteers [9]. From this trial, 
safety data where CTH522-CAF01 have been administered IM are known. The related AEs (> one 
in ten subjects) after IM administration of CTH522-CAF01 reported were: 

 
 
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• injection site pain, injection site tenderness and injection site movement impairment after 
IM vaccination 
• sneezing, nasal congestion and rhinorrhoea after intranasal vaccination 
• systemic reactions after IM or IN vaccination were headache, fatigue, malaise and myalgia 
The most frequently reported treatment-emergent AEs were headache, oropharyngeal pain, and 
dysmenorrhoea. Please refer to the IB for more information.  
Based on general considerations, experience from clinical trials with CAF01, CAF09b and 
CTH522, the IMPs to be used in the present trial are expected to be safe. 
Anaphylactic reactions are very rare. However, appropriate medical treatment and trained staff will 
be available in case an anaphylactic reaction occurs. 
Vasovagal syncope (i.e. fainting), may occur. It will be attempted to minimise the occurrence of this 
reaction, by allowing the subjects to lie down during the administration of vaccine and blood 
drawings.  
The trial personnel performing the procedures will inform the subjects on the procedures before 
blood drawings and administration of vaccine, and it will be emphasised to the subject, that 
participation is voluntary and that he/she at any time can withdraw from the trial.  
This is a healthy volunteer trial, so there will be no direct health benefit to the individual subject. 
However, they will undergo general health and sexually transmitted infection screening. Sexually 
transmitted infection may be asymptomatic, and if diagnosed, the subjects will be counselled and 
offered referral to the confidential service provided by their local NHS genitourinary medicine 
clinic. If trial results are satisfactory, further clinical trials will be initiated and may lead to a 
marketed vaccine against trachoma and/or genital chlamydia.  
The subjects will receive payment to compensate them for their time, inconvenience, travel 
expenses, etc. They will be paid £100 per scheduled clinic visit, to a maximum of £1200, paid as a 
lump sum at the end of participation. Volunteers who attend screening but who are not enrolled will 
not receive payment. 
12.2 
Biobanking 
The storage, handling and use of the samples in the SSI Biobank are in compliance with relevant 
personal data protection laws and EC regulations. 
After the finalisation of the clinical trial, the serum samples will be stored at the research biobank at 
SSI and ICHT. The samples may be used for standardisation, quality control and future assays 
related to chlamydia vaccine research and development. The samples will only be identifiable by a 

 
 
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subject number. The subject will be informed of this procedure in the information sheet, and 
consent will be sought. 
13 
Good clinical practice considerations 
13.1 
Declaration of Helsinki and good clinical practice 
The clinical trial is planned, and will be conducted and reported in compliance with this protocol, as 
well as the latest versions of the ‘Declaration of Helsinki’ [23], the ICH E6 (R2) [24] and Directive 
2001/20/EC [25]. 
13.2 
Participant information and informed consent 
The written subject information and the informed consent form (ICF) will not be taken into use until 
approved by the EC(s) and UK Health Research Authority (HRA). 
The subjects will be recruited through the clinical site’s healthy volunteer database, posters and 
information meetings at universities and other public forums, advertisements in newspapers and 
social media. All written recruiting material will be approved in advance by the concerned EC.  
Before the first trial-related visit, the potential subject are given ample time to reflect on the trial 
information. At the first visit, the subject information and ICF are reviewed thoroughly with the 
subject. The verbal review will always be conducted by a physician or nurse, and encompasses: 
• Comprehensible presentation of background and objectives of the clinical trial 
• Presentation of the trial design (randomised)  
• Any predictable benefits, risks, adverse reactions, inconveniences, complications and 
disadvantages 
• Potential risks 
• Right to reflection 
• Right to waive information on clinical trial results 
• Description of the IMPs 
• That collection and extradition of information to/from the subject’s subject files in the 
Health Care System may occur 
• Remuneration and reimbursement of transportation expenses 
• Questions from the subject 

 
 
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The subjects will always be given the opportunity to discuss participation with a physician prior to 
first dosing. 
It is emphasised to the subject that participation is voluntary and that he/she at any time can 
withdraw from the trial. The potential subject is informed that data collected during participation in 
the trial is confidential. 
The review of the written information with the subject and the signing of the ICF take place under 
undisturbed environment. Should there be a need for further reflection before signing the consent 
form, the potential subject is offered another 24 hours to reflect. A new appointment is made for the 
signing of the ICF. Once the ICF is signed, medical examination and other trial-related activities 
can be performed. 
13.3 
Ethics committee and HRA submission and approval 
The trial will NOT be initiated until it has been approved by both EC and HRA. The PI and the 
sponsor will collaborate on the submission of the project to the EC and HRA. An electronic initial 
submission form is completed on www.myresearchproject.org.uk. The PI and the sponsor must sign 
the submission form and send to the EC together with the other required documentation. 
13.4 
Competent authority submission and approval 
A request for a clinical trial authorisation will be submitted for approval to the MHRA in the UK. 
The application will be submitted by ICL on behalf of SSI as GCP sponsor of the trial.  
13.5 
Local investigator site approval 
Screening or inclusion of subjects will only be initiated after approval by the clinical site’s local 
NHS R&D Office, which is issued only after EC, HRA and MHRA approval. 
13.6 
Personal data protection 
The subjects’ personal data will be protected in accordance with the EU General Data Protection 
Regulation and the Clinical and Directive 2001/20/EC. The PI is responsible for keeping a 
screening log of trial subjects including personal information such as full name, address and 
personal identification number. 
The trial documents containing personal information, e.g. the screening log and the signed ICFs, 
will be kept in a safe place at the investigational site at all times, and will not be transferred to the 
sponsor or any third party for 25 years.  
All other trial documents or electronic records will not contain personal information but will 
identify the trial subjects by use of a subject number. Only, through linking this subject number to 
the screening log, the PI can identify the subject. 

 
 
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At the completion of the trial, normally at the site-closure monitoring visit, the site PI must date and 
sign off the subject log(s) for completeness. 
13.7 
Investigator’s responsibility and delegation of trial-related duties 
The site PI is responsible for: 
• The conduct of the clinical trial in accordance with the protocol, current GCP guidelines, 
and other applicable national requirements and regulations 
• Documenting the receipt, storage, dispensing and accountability of drug products and 
adjuvants as appropriate 
• All data including AEs being recorded in the eCRFs and for the immediate reporting of 
SAEs to SSI and CRO as described in Section 10  
• Being available to answer or clarify any protocol related queries from the CA or ECs 
• Keeping a log of all subjects  
• Signing the Investigator Statement Form 
If the site PI delegates her responsibilities to other staff members, it has to be documented in the 
clinical site signature and delegation form. This documentation has to be completed before trial 
initiation, which is to be updated during the trial and to be signed off for correctness at the end of 
the trial. The PI is responsible for supervising any individual or party to whom she delegates trial-
related duties. 
Before trial initiation, SSI must collect current, dated and signed curriculum vitae for all 
participating investigators and other relevant trial staff including monitors and data managers. The 
signature and delegation form(s) and the dated and signed curriculum vitae must be kept in the IF. 
13.8 
Trial oversight and monitoring 
The sponsor will conduct trial oversight by employing a risk-based approach and other quality 
control measures. Trial oversight activities are described in the Trial Oversight Manual.  
Monitoring will be performed by SSI according to SSI GCP standard operating procedures and a 
trial specific monitoring plan. The purpose of the monitoring is to verify the rights and well-being 
of the trial subjects, the accuracy, completeness and correctness of the data and the conduct of the 
trial according to this protocol, GCP, applicable trial manuals and applicable regulations and laws. 
Qualifications of the monitor(s) will be kept in the TMF at the sponsor’s site. 

 
 
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A trial initiation monitoring visit will be performed at the site before enrolment of the first subject 
in the trial, and subsequent routine monitoring visits will be performed during the trial as per the 
monitoring plan. At trial completion, a close-out monitoring visit will be performed. 
13.9 
Audit and inspection 
The selected site for the present trial participated in the previous CTH522 trial, CHLM-01. Before 
the CHLM-01 trial, the site was audited by the Quality Assurance staff from SSI. No further audit 
for the current trial is planned. The audit documentation from CHLM-01 will be filed in this trial’s 
TMF.  Shall there be a need for additional audit or inspection, the site must give access to the 
auditors and inspectors to all trial-related documents, including the subject identification log(s) 
and/or personal medical records. The PI would need to inform the sponsor immediately and vice 
versa, if an inspection has been requested by an authority. 
13.10 
Source data and essential documents and retention times 
Source data is defined as all information in original records and certified copies of original records 
of clinical findings, observations or other activities in the trial necessary for the reconstruction and 
evaluation of the trial. Source data are contained in source documents (original records or certified 
copies). 
At the site, a document, which identifies all (expected) source documents and the location of these, 
will be prepared (and signed off by the PI) before the initiation of the trial. Examples of clinical site 
sources are: 
• EC and CA approval documents 
• Signed ICFs  
• Subject screening log/identification code list 
• Investigator’s or nurse’s notes/worksheets (for data not recorded or not recorded directly in 
the eCRF) 
• eCRF for data recorded directly in the eCRF 
• Completed diaries 
• Completed CIOMS reporting forms (generated by Pharmacovigilance) 
• Vaccine inventory and accountability log(s) 
• Serum sample inventory and accountability log(s) 
• Logs of monitoring of storage conditions of IMPs and serum samples 

 
 
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It is the responsibility of the PI to archive all source data (all source documents from which the 
eCRF entries are derived) in the trial subject’s medical records according to the national 
recommendation.  
Entries in the eCRF will be verified with source documentation. The review of medical records will 
be performed in a manner to ensure that subject confidentiality is maintained. 
The trial monitor from SSI will check the eCRF for accuracy and completion and perform source 
data verification according to the trial monitoring plan.  
Essential documents are those documents which individually or collectively permit evaluation of 
the conduct of the trial and the quality of the data produced. These documents serve to demonstrate 
the compliance of the investigator, sponsor (via monitoring) with the standards of GCP. 
Before initiation of the trial, an IF will be set up at the investigational site and a TMF at the 
sponsor’s site following the ICH E6 (R2) guideline. These systems will contain essential 
documents. The completeness of the IF with the GCP essential documents will be documented as 
part of the site-closure monitoring visit. The IF and the TMF shall retain the essential documents for 
the timeframe stipulated in their respective national laws.  
14 
Agreement and financial settlement 
An agreement between SSI (trial sponsor) and ICHT (investigator site) will be signed before 
inclusion of the first subject. These agreements will clearly state the rights and obligations of the 
concerned parties and are the legally binding documents between the parties. This protocol, in its 
current version, or its current version at any time in case of subsequent modifications 
(amendments), will be an appendix to the agreement between the investigator institution and the 
sponsor. The agreement must be signed by the legal representatives of the parties before the 
inclusion of the first subject in the trial. 
ICHT must grant the PI permission to conduct the trial on its premises. This permission must be 
given before the inclusion of the first subject in the trial. 
This trial is funded by a grant from the EU Framework Programme for Research and Innovation 
Horizon 2020. The results of the trial will be published according to the dissemination strategy as 
detailed in the TracVac Consortium Agreement.  
15 
Insurance and indemnity statement 
SSI carries a product liability insurance programme including cover for clinical trials. The insurance 
programme covers worldwide and is currently placed with insurer XL Insurance (Appendix 2). The 
policy covers claims arising from injury/injuries caused by trial medication used in this clinical trial 
sponsored by SSI, if the trial product has been used in accordance with the instructions given in the 

 
 
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protocol. An updated insurance certificate will be provided separately, without updating the 
protocol, if applicable. 
In the event that any recruited subject in the trial should suffer any personal injury resulting from 
participation in the clinical trial, SSI agrees to indemnify the institution where the clinical trial is 
being undertaken, and through the institution, any of its employees or agents participating in the 
trial, against liability imposed by law, but not assumed voluntarily, and arising from the use of the 
trial products, provided that: 
• SSI shall not indemnify against, nor have any obligation whatsoever as regards liability 
arising from or related to any error, omission, intentional wrongful act, or other negligence 
on the part of said institutions or persons, such as medical malpractice 
• any such institution or person seeking indemnity 
• has fully complied with the protocol for the trial  
• has promptly notified SSI of any notice of any type of claim, or the likelihood of a claim, 
relating to the trial 
• as regards any claim, makes no statement, takes no action, nor makes any commitment 
affecting SSI’s interests, without SSI’s prior written consent, and further, provides all 
reasonable and necessary assistance to SSI in the defence of any claim, allowing SSI, at its 
cost and in its discretion to take over the defence of any action and to have full control in 
handling the claim 
Before initiation of the clinical trial, SSI will present an indemnity statement to the PI signed by the 
director of Vaccine Development Department. 
16 
Confidentiality and disclosure 
All eCRF data, information and results generated by SSI, as well as information on product 
development, patented or not, including patent applications and manufacturing processes not 
previously published, are considered confidential and shall remain the sole property of SSI. 
No data from the clinical trial, unless approved by SSI in writing, may be published, presented or 
communicated, except to MHRA or EC(s), before the issue of the final CTR or before being 
published. A CTR will be prepared by SSI. The names of authors and their order of appearance in 
the publication are stated in the agreement. 

 
 
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17 
Modifications to the protocol 
The trial procedures may be modified if the signing parties agree to the modifications. If the 
modifications are substantial, MHRA, HRA, EC and ICHT R&D must be notified as required, and 
approve the modifications before implementation. All substantial modifications should be 
documented by issuing new amended versions of the protocol implementing the modifications.  

 
 
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18 
References 
[1] WHO. Trachoma key facts. 2019. p. Trachoma key facts. 
[2] Brunham RC, Rappuoli R. Chlamydia trachomatis control requires a vaccine. Vaccine. 
2013;31:1892-7. 
[3] ECDC. Facts about chlamydia. European centre for Disease Prevention and Control; 2019. 
[4] Olsen AW, Follmann F, Erneholm K, Rosenkrands I, Andersen P. Protection Against 
Chlamydia trachomatis Infection and Upper Genital Tract Pathological Changes by Vaccine-
Promoted Neutralizing Antibodies Directed to the VD4 of the Major Outer Membrane Protein. J 
Infect Dis. 2015;212:978-89. 
[5] Nunes A NP, Borrego MJ, Gomes JP. Adaptive evolution of the Chlamydia trachomatis 
dominant antigen reveals distinct evolutionary scenarios for B- and T-cell epitopes: worldwide 
survey. PLoS One. 2010;5. 
[6] Agger EM, Rosenkrands I, Hansen J, Brahimi K, Vandahl BS, Aagaard C, et al. Cationic 
liposomes formulated with synthetic mycobacterial cordfactor (CAF01): a versatile adjuvant for 
vaccines with different immunological requirements. PLoS One. 2008;3:e3116. 
[7] Laboratories CR. CTH522 600 Test Item: MatTek EpiOcular™ Eye Irritation Test (EIT) for 
assessment of the Ocular Irritation Potential of Test Items In Vitro. Charles River Laboratories; 
2018. 
[8] TracVac. Safety of new vaccines against trachoma in cynomolgus macaques. 2019. 
[9] Abraham S JH, Bang P, Cheesemana H, Dohn RB, Cole T, Kristiansen MP, Korsholm KS,et al. 
Safety and immunogenicity of chlamydia vaccine candidate CTH522 adjuvanted with CAF01 or 
Alum: a first-in-human, randomised, double-blind, placebo-controlled, phase 1 study. Lancet. 
Accepted 2019;Accepted 2019. 
[10] Lindenstrom T, Woodworth J, Dietrich J, Aagaard C, Andersen P, Agger EM. Vaccine-
induced th17 cells are maintained long-term postvaccination as a distinct and phenotypically stable 
memory subset. Infect Immun. 2012;80:3533-44. 
[11] Frenzel A, Hust M, Schirrmann T. Expression of recombinant antibodies. Front Immunol. 
2013;4:217. 
[12] van Dissel JT, Joosten SA, Hoff ST, Soonawala D, Prins C, Hokey DA, et al. A novel 
liposomal adjuvant system, CAF01, promotes long-lived Mycobacterium tuberculosis-specific T-
cell responses in human. Vaccine. 2014;32:7098-107. 
[13] Dejon-Agobe JC A-NU, Lalremruata A, Homoet A, Engelhorn J, Paterne Nouatin O, Edoa JR, 
Fernandes JF, Esen M, Mouwenda YD, Betouke Ongwe EM, Massinga-Loembe M, Hoffman SL, 
Sim BKL, Theisen M, Kremsner PG, Adegnika A, Lell B, Mordmüller B. Controlled human 
malaria infection of healthy lifelong malaria-exposed adults to assess safety, immunogenicity and 
efficacy of the asexual blood stage malaria vaccine candidate GMZ2. Clin Infect Dis. 2018. 
[14] Korsholm KS HJ, Karlsen K, Filskov J, Mikkelsen M, Lindenstrøm T, Schmidt TS, Andersen 
A, Christensen D. Induction of CD8+ T-cell responses against subunit antigens by thenovel cationic 
liposomal CAF09 adjuvant. Vaccine. 2014;32:3927–35. 
[15] Ellis RD, Wu Y, Martin LB, Shaffer D, Miura K, Aebig J, et al. Phase 1 study in malaria naive 
adults of BSAM2/Alhydrogel+CPG 7909, a blood stage vaccine against P. falciparum malaria. 
PLoS One. 2012;7:e46094. 
[16] Otsyula N AE, Bergmann-Leitner E, Koech M, et al. Results from tandem Phase 1 studies 
evaluating the safety, reactogenicity and immunogenicity of the vaccine candidate antigen 
Plasmodium falciparum FVO merozoite surface protein-1 (MSP1(42)) administered intramuscularly 
with adjuvant system AS01. Malar J. 2013;12:29. 

 
 
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[17] Wressnigg N BP, Pollabauer EM, O'Rourke M, Portsmouth D, et al. . A Novel multivalent 
OspA vaccine against Lyme borreliosis is safe and immunogenic in an adult population previously 
infected with Borrelia burgdorferi sensu lato. Clin Vaccine Immunol. 2014;21:1490-9. 
[18] El Sahly HM, Patel SM, Atmar RL, Lanford TA, Dube T, Thompson D, et al. Safety and 
immunogenicity of a recombinant nonglycosylated erythrocyte binding antigen 175 Region II 
malaria vaccine in healthy adults living in an area where malaria is not endemic. Clin Vaccine 
Immunol. 2010;17:1552-9. 
[19] Jepsen MPG, Jogdand PS, Singh SK, Esen M, Christiansen M, Issifou S, et al. The malaria 
vaccine candidate GMZ2 elicits functional antibodies in individuals from malaria endemic and non-
endemic areas. J Infect Dis. 2013;208:479-88. 
[20] CA S. Vaccine immunology. In: Plotkin, editor. Vaccines. 6 ed: Elsevier Saunders; 2013. p. 
14-32. 
[21] EudraLex. The Rules Governing Medicinal Products in the European Union. EU Guidelines to 
Good Manufacturing Practice Medicinal Products for Human and Veterinary Use Investigational 
Medicinal Products. 2010. 
[22] European Commission. Communication from the Commission-Detailed guidance on the 
collection, verification and presentation of adverse event/reaction reports arising from clinical trials 
on medicinal products for human use (‘CT-3’)  
[23] World Medical Association. WMA Declaration of Helsinki-Ethical principles for medical 
research involving human subjects. 2018. 
[24] Guideline IH. Integrated addendum to ICH E6 (R1): Guideline for good clinical practice E6 
(R2). 2016. 
[25] Communities TCotE. Directive 2001/20/EC of the European Parliament and the council of 4 
April 2001 on the approximation of the laws, regulations and administrative pro-vision of the 
Member States relating to the implementation of good clinical practice in the conduct of clinical 
trials on medicinal products for human use. 2001. 
 
 

 
 
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19 
Appendices 
19.1 
Appendix 1: FDA guidelines 
 

 
 
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CTH522 
STATENS 
SERUM 
INSTITUT 
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14 December 2020 
  
 
Final 5.1  
CTH522 
 
Protocol CHLM-02 
 

 
 
CONFIDENTIAL 
Page 68 of 70 
 
14 December 2020 
  
 
Final 5.1  
CTH522 
 
Protocol CHLM-02 
 

 
 
CONFIDENTIAL 
Page 69 of 70 
 
14 December 2020 
  
 
Final 5.1  
CTH522 
 
Protocol CHLM-02 
 

STATENS 
SERUM 
INSTITUT 
CONFIDENTIAL 
14 December 2020 
Final 5.1 
Page 70 of70 
CTH522 
Protocol CHLM-02 
19.2 
Appendix 2: Insurance certificate