Observer Blinded, Randomised Study to Investigate Safety, Tolerability and Long-term Immunogenicity of Different Dose Regimens and Formulations of MV-CHIK in Healthy Volunteers
Phase: PHASE2
Conditions: Chikungunya Virus Infection
Sponsor: Themis Bioscience GmbH

Official Protocol Title: 
NCT number: 
NCT03635086 
Document Date: 
08-Aug-2018
Observer blinded, randomised study to investigate safety,
tolerability and long-term immunogenicity of different dose
regimens and formulations of MV-CHIK in healthy volunteers

 
 
 
 
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1. 
STUDY SYNOPSIS 
Title of the 
Study 
Observer blinded, randomised study to investigate safety, tolerability and 
long-term immunogenicity of different dose regimens and formulations of 
MV-CHIK in healthy volunteers 
Study 
Centres 
Celerion, 22-24 Lisburn Road, Belfast 
Study Period Study start, FSI Jun-2018 
Study Phase 
Clinical phase II  
Objectives 
− To investigate immunogenicity and safety of different MV-CHIK dose 
regimes, 28 days after one or two vaccinations 
 
− To investigate the immunogenicity and safety of a novel liquid vaccine 
formulation 
 
− To compare immunogenicity, safety and tolerability between different 
doses and formulations of MV-CHIK during a treatment period of 56 days 
 
− To evaluate the long-term immunogenicity of MV-CHIK up to one year 
after the first vaccination 
 
− To evaluate cellular responses induced by one or two immunisations 
 
− To collect human sera for efficacy evaluation, by passive transfer of 
anti-Chikungunya antibodies to virus susceptible non-human primates 
 
Study 
Design 
Observer blinded, randomised immunogenicity and safety phase II trial in  
60 healthy volunteer female and male subjects. 
 
After completion of screening procedures, subjects will be randomised to one 
of five treatment groups (A, B, C, D or E): 
 
A: 12 subjects will receive two low dose treatments with MV-CHIK 5x104 
 
(0.5 log) TCID50 /dose on day 0 and 28 (lyophilised formulation) 
 
B: 12 subjects will receive two low dose treatments with MV-CHIK 1x105 
 
(0.5 log) TCID50 /dose on day 0 and 28 (liquid frozen formulation) 
 
C: 12 subjects will receive two low dose treatments with MV-CHIK 1x105 
 
(0.5 log) TCID50 /dose on day 0 and 28 (liquid SPS® formulation) 
 
D: 12 subjects will receive two high dose treatments with MV-CHIK 1x106 
 
(0.5 log) TCID50 /dose on day 0 and 28 (liquid frozen formulation) 
 
E: 12 subjects will receive one high dose treatment with MV-CHIK 1x106 
 
(0.5 log) TCID50 /dose on day 0 (liquid frozen formulation) and placebo 
 
on day 28 
 
After the screening visit, subjects will perform visits on study days 0, 14, 28, 
42 and 56 for immunogenicity sample collection and safety follow up and 
additionally return to site on day 182 (6 months) and 365 (12 months) for long-
term immunogenicity serum sampling. 
Serum samples for passive transfer will be collected on days 0, 28, 56, 365. 
 
 
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Number of 
Subjects 
60 healthy subjects 
Main 
Inclusion 
Criteria 
Healthy female or male volunteers, 18 - 55 years old at screening. 
Investigation
al Medicinal 
Product 
MV-CHIK, a live-attenuated recombinant measles vaccine expressing 
Chikungunya virus antigens, in concentrations of: 
 
5x104 (0.5 log) TCID50 / dose – lyophilised - low dose 
1x105 (0.5 log) TCID50 / dose – liquid frozen - low dose 
1x105 (0.5 log) TCID50 / dose – liquid SPS - low dose 
1x106 (0.5 log) TCID50 / dose – liquid frozen - high dose 
 
Presented in three different formulations: 
 
-  Lyophilised formulation: powder for suspension in water for injection 
-  Liquid frozen formulation: suspension for injection 
-  Liquid SPS® formulation: suspension in a proprietary “Stabilising and 
Protecting Solution” for injection 
 
MV-CHIK vaccine administered by intra muscular (i.m.) injection. 
Placebo 
Physiological saline solution (0.9% NaCl), administered by i.m. injection 
Duration of 
the Study 
Study duration per subject will be 12 months, comprising of 8 weeks treatment 
period Visit 1 - Visit 5 (study day 0 until day 56) and 44 weeks follow up period, 
including Visit 6 + Visit 7 (post day 56 until day 365). Study subjects are free 
to participate in other clinical studies after completion of the treatment period 
on day 56.  
The end of study will be defined as date of the last visit of the last subject. 
Criteria for 
Evaluation 
 
Primary end-point  
− 
Immunogenicity 28 days after the last MV-CHIK vaccination confirmed by 
the presence of functional antibodies as determined by the plaque 
reduction neutralisation test (PRNT50) 
 
Secondary end-points: 
− 
Rate of solicited and unsolicited adverse events during the treatment 
period up to study day 56  
− 
Serious adverse events during the treatment period until study day 56 
− 
Immunogenicity on days 0, 28 (for group A-D), 0, 56 (for group E) and on 
day 182 and 365 (for all) confirmed by the presence of functional 
antibodies as determined by the plaque reduction neutralisation test 
(PRNT50). 
− 
Measurement of anti-Chikungunya antibodies on days 0, 28, 56, 182 and 
365 determined by enzyme linked immunosorbent assay (ELISA)  
− 
Measurement of anti-Measles antibodies on days 0, 28, 56 determined by 
enzyme linked immunosorbent assay (ELISA) 
− 
Induction of Chikungunya specific immune responses on days 0, 14, 28, 
42 and 56 as determined by T-cell assay. 
− 
Safety 
laboratory 
parameters 
(haematology, 
serum 
chemistry, 
coagulation, urinalysis)  
 
 
 
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Statistical 
Methods 
 
Data Analysis: 
The immunogenicity analysis will compare the anti-Chikungunya PRNT50 
antibody geometric mean titre (GMT) 28 days after the last MV-CHIK 
vaccination in the Per Protocol (PP) analysis population between the 
treatment groups. GMTs and GMT ratios will be estimated by applying an 
analysis of variance including the factor treatment group. This will be done 
using log10 transformed data and taking the anti-log of the resulting point 
estimates for the least squares means, least squares means differences and 
the corresponding 2-sided 95% CIs.  
P-values will also be provided to compare GMTs between the treatment 
groups adjusted for multiple comparisons according to Tukey-Kramer. 
Likewise, seroconversion rates will be compared between groups.  
Seroconversion will be defined as anti-Chikungunya PRNT50 titres ≥10. 
Measles- and Chikungunya- ELISA titres will be analysed as described 
above.  
In addition, the long-term stability of anti-Chikungunya antibodies determined 
by PRNT50 and ELISA, 6 months and one year after the first immunisation, 
will be analysed compared between the five treatment groups. 
 
The analysis of safety will be performed by means of descriptive measures 
in the Safety Population. All subjects entered into the study who receive at 
least one vaccination will be included in the safety analysis. For solicited 
local, solicited systemic and unsolicited AEs, the number and percentage of 
subjects with AEs will be summarised for each treatment group, overall, by 
system organ class /preferred term, AE grade, and relatedness. Solicited 
and unsolicited AEs (local and systemic) will be analysed descriptively. 
Laboratory values and vital signs as well as changes in laboratory values from 
baseline will be analysed descriptively by time point and treatment group.  
 
Interim Analysis: 
A preliminary analysis including safety and immunogenicity data will be 
performed after all subjects completed Visit 5 (day 56) and therefore 
terminated the treatment period of the study. The purpose of this analysis is 
to provide highly valuable data for further Chikungunya vaccine development 
including the efficacy evaluation, by passive transfer. 
Results from this interim analysis will not have any impact on the study design 
or the subjects during the follow up period of the study.  
 
The final analysis will be conducted once the last subject has completed the 
study. 
 
 
 
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2. 
LIST OF ABBREVIATIONS 
Ab 
Antibody 
AE 
Adverse Event 
AESI 
Adverse Event of special interest 
ALT 
Alanine Aminotransferase (SGPT) 
aPTT 
Abbreviated Partial Thrombin Time 
AST 
Aspartate Aminotransferase (SGOT) 
CA 
Competent Authority 
CCID50 
Cell Culture Infectious Dose 50% 
CHIKV 
Chikungunya Virus 
CRO 
Clinical Research Organisation 
CV 
Curriculum Vitae 
DSMB 
Data Safety Monitoring Board 
(e)CRF 
(electronic) Case Report Form 
EC 
Ethics Committee 
ELISA 
Enzyme Linked Immunosorbent Assay 
ER 
Emergency Room 
FDA 
(United States) Food and Drug Administration 
FSI 
First Subject In 
GCP 
Good Clinical Practice 
GMO 
Genetically Modified Organism 
GMT 
Geometric Mean Titre 
HAS 
Human Serum Albumin 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HSD 
Honest Significant Difference 
IEC 
Independent Ethics Committee 
i.m. 
Intra Muscular 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat 
MAE 
Medically-attended Adverse Event 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-To-Treat 
Mo 
Month 
MV 
Measles Virus 
PBMC 
Peripheral Blood Mononuclear Cell 
PP 
Per-Protocol 
PRNT50 
Plaque Reduction Neutralisation Test 50% 
PT 
Prothrombin Time 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SPS 
Stabilising and Protecting Solutions 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TCID50 
Tissue Culture Infective Dose 50% 
WHO 
World Health Organisation 
 
 
 
 
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3. 
TABLE OF CONTENTS 
1. 
STUDY SYNOPSIS ................................................................................................... 4 
2. 
LIST OF ABBREVIATIONS ........................................................................................ 7 
4. 
BACKGROUND INFORMATION AND RATIONAL ...................................................12 
4.1 
Investigational Drug ............................................................................................. 12 
4.2 
Disease Background ............................................................................................ 12 
4.3 
Preclinical Studies ................................................................................................ 13 
4.3.1 
Preclinical Immunogenicity Studies ...............................................................13 
4.3.2 
Preclinical Toxicity Studies ............................................................................14 
4.4 
Clinical Studies .................................................................................................... 14 
4.4.1 
Phase I Study ................................................................................................15 
4.4.2 
Phase II Studies ............................................................................................18 
4.5 
Study Rationale .................................................................................................... 20 
4.6 
Benefit/Risk Assessment ..................................................................................... 21 
5. 
TRIAL OBJECTIVES AND MEASUREMENTS .........................................................22 
5.1 
Primary Objective ................................................................................................. 22 
5.2 
Secondary Objectives .......................................................................................... 22 
6. 
TRIAL DESIGN .........................................................................................................23 
6.1 
Overall Study Design ........................................................................................... 23 
6.2 
Study Endpoints ................................................................................................... 23 
6.2.1 
Primary Endpoint ...........................................................................................23 
6.2.2 
Secondary Endpoints ....................................................................................23 
6.3 
Treatment Groups ................................................................................................ 24 
6.4 
Study Flowchart ................................................................................................... 25 
6.5 
Study Procedures ................................................................................................ 26 
7. 
PARTICIPANT IDENTIFICATION .............................................................................27 
7.1 
Trial Participants .................................................................................................. 27 
7.2 
Inclusion Criteria .................................................................................................. 27 
7.3 
Exclusion Criteria ................................................................................................. 27 
8. 
TRIAL PROCEDURES .............................................................................................29 
8.1 
Informed Consent ................................................................................................ 29 
8.2 
Randomisation ..................................................................................................... 29 
8.3 
Blinding and Code-breaking ................................................................................. 29 
8.4 
Screening Procedures .......................................................................................... 30 
8.4.1 
Screening Visit, (VS, 1-28 days prior to Visit 1) .............................................30 
8.5 
Treatment Period ................................................................................................. 30 
8.5.1 
Visit 1 (day 0) ................................................................................................30 
 
 
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8.5.2 
Visit 2 (day 14 1 day) ...................................................................................31 
8.5.3 
Visit 3 (day 28 5 days) .................................................................................31 
8.5.4 
Visit 4 (day 42 5 days) .................................................................................32 
8.5.5 
Visit 5 (day 56 5 days) .................................................................................32 
8.6 
Follow up Period .................................................................................................. 33 
8.6.1 
Visit 6 (day 182 14 days) .............................................................................33 
8.6.2 
Visit 7 (day 365 14 days), termination visit ...................................................33 
8.7 
Early Termination Visit (ET) ................................................................................. 33 
8.8 
Unscheduled Visits .............................................................................................. 33 
8.9 
Discontinuation/Withdrawal of Subjects ............................................................... 34 
8.9.1 
Safety Stopping Rules ...................................................................................34 
8.9.2 
Replacement of Subjects ...............................................................................35 
8.10 
End of Study ........................................................................................................ 35 
8.11 
Handling of Samples ............................................................................................ 36 
8.11.1 
Samples for Safety Laboratory Parameters ...................................................36 
8.11.2 
Immunogenicity Samples ..............................................................................36 
8.11.3 
Serum Samples for Passive Transfer ............................................................37 
8.11.4 
Pregnancy Test – Contraception ...................................................................38 
8.11.5 
Labelling, Storage and Transport of Samples ................................................39 
9. 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) ..................................................41 
9.1 
Investigational Medicinal Product Description ...................................................... 41 
9.1.1 
MV-CHIK vaccine – test product ....................................................................41 
9.1.2 
Placebo .........................................................................................................41 
9.2 
Packaging and Labelling ...................................................................................... 42 
9.3 
Dose Regimen ..................................................................................................... 42 
9.4 
Storage and Transport Conditions........................................................................ 43 
9.5 
IMP Preparation and Distribution ......................................................................... 43 
9.6 
GMO Handling ..................................................................................................... 44 
9.7 
Route and Method of Administration of IMP ......................................................... 44 
9.8 
Treatment Compliance ......................................................................................... 44 
9.9 
Study Drug Accountability .................................................................................... 44 
9.10 
Prior and Concomitant Therapy ........................................................................... 45 
9.10.1 
Permitted Prior and Concomitant Therapy .....................................................45 
9.10.2 
Forbidden Prior and Concomitant Therapy ....................................................45 
10. 
SAFETY REPORTING ..............................................................................................46 
10.1 
Definitions ............................................................................................................ 46 
10.1.1 
Adverse Event (AE) .......................................................................................46 
 
 
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10.1.2 
Adverse Reaction (AR) ..................................................................................46 
10.1.3 
Serious Adverse Event (SAE)........................................................................46 
10.1.4 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ........................47 
10.1.5 
Causality .......................................................................................................47 
10.1.6 
Severity .........................................................................................................47 
10.1.7 
Expectedness ................................................................................................47 
10.1.8 
Outcome .......................................................................................................48 
10.2 
Recording of Adverse Events ............................................................................... 48 
10.3 
Reporting of Serious Adverse Events ................................................................... 49 
10.4 
Follow-up of Adverse Events ................................................................................ 49 
10.5 
Reporting of SUSARs .......................................................................................... 50 
10.6 
Reporting of Pregnancies ..................................................................................... 50 
10.7 
Development Safety Update Reports ................................................................... 51 
11. 
ASSESSMENT OF SAFETY .....................................................................................52 
11.1 
Safety Laboratory Parameter Assessments ......................................................... 52 
11.2 
Symptom-directed Physical Examination ............................................................. 52 
11.3 
System-based Physical Examination ................................................................... 52 
11.4 
Vital Signs and Body Temperature ....................................................................... 52 
11.5 
Post Vaccination Reactogenicity Assessments .................................................... 52 
11.6 
Local and Systemic Tolerability ............................................................................ 53 
11.7 
Subject Diary ....................................................................................................... 53 
12. 
STATISTICS .............................................................................................................55 
12.1 
Interim Analysis .................................................................................................... 55 
12.2 
Methods of Statistical Immunogenicity Analysis ................................................... 55 
12.3 
Methods of Statistical Safety Analysis .................................................................. 55 
12.4 
Determination and Justification of Sample Size.................................................... 56 
12.5 
Analysis Populations ............................................................................................ 56 
12.5.1 
Safety Population ..........................................................................................56 
12.5.2 
Modified Intent-to-Treat (mITT) Population ....................................................56 
12.5.3 
Per-Protocol (PP) Population ........................................................................56 
12.6 
Statistical Analysis Plan ....................................................................................... 57 
12.7 
Missing Data ........................................................................................................ 57 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................58 
13.1 
Periodic Monitoring .............................................................................................. 58 
13.2 
Audit and Inspection ............................................................................................ 58 
14. 
ETHICS ....................................................................................................................59 
14.1 
Ethical Conduct of the Study ................................................................................ 59 
14.2 
Independent Ethics Committees (IEC) ................................................................. 59 
 
 
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14.3 
Regulatory Authority ............................................................................................ 59 
15. 
DATA HANDLING AND RECORD KEEPING ...........................................................60 
15.1 
Source Data and Records .................................................................................... 60 
15.2 
Access to Data ..................................................................................................... 60 
15.3 
Data Collection..................................................................................................... 60 
15.4 
Electronic Case Report Forms (eCRFs) ............................................................... 61 
15.4.1 
eCRF Entries .................................................................................................61 
15.4.2 
Changes to eCRF Data .................................................................................61 
15.4.3 
eCRF Entry Validation ...................................................................................61 
15.5 
Confidentiality of Subject’s Data ........................................................................... 62 
15.6 
Record Maintenance, Archiving and Destruction .................................................. 62 
16. 
CHANGES IN THE CONDUCT OF THE STUDY ......................................................63 
16.1 
Protocol Amendments .......................................................................................... 63 
16.2 
Study Termination ................................................................................................ 63 
17. 
DEVIATIONS FROM THE PROTOCOL ....................................................................64 
17.1 
Relevant Protocol Deviations ............................................................................... 64 
17.2 
Serious Breaches ................................................................................................. 64 
17.3 
Premature Subject Withdrawal ............................................................................. 64 
18. 
FINANCE AND INSURANCE ....................................................................................65 
18.1 
Contractual and Financial Details ......................................................................... 65 
18.2 
Insurance ............................................................................................................. 65 
19. 
REPORTING AND PUBLICATION ...........................................................................65 
19.1 
Clinical Study Report............................................................................................ 65 
19.1 
Publication Policy ................................................................................................. 65 
20. 
REFERENCES .........................................................................................................66 
21. 
APPENDICES ...........................................................................................................68 
 
List of Tables: 
Table 1: Treatment Groups and Vaccination Schedule .................................................... 24 
Table 2: Study Procedures .............................................................................................. 26 
Table 3: Blood Sample Collection .................................................................................... 38 
Table 4: Dose Regimen ................................................................................................... 42 
Table 5: Grading of Local Reactions ................................................................................ 53 
Table 6: Grading of Systemic Reactions .......................................................................... 53 
 
 
 
 
 
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4. 
BACKGROUND INFORMATION AND RATIONAL 
4.1 
Investigational Drug  
The MV-CHIK vaccine includes a backbone of measles virus (Schwarz Vaccine strain), which 
has been developed at the Institute Pasteur (Combredet C. 2003). Chikungunya Virus 
structural proteins have been inserted into the MV genome (MV-CHIK) and are expressed as 
the vaccine antigens. The backbone has already been tested in previous trials of MV-HIV 
construct (Lorin C. 2004; Stebbings R. 2012; ClinicalTrials.gov Identifier: NCT01320176). A 
detailed description of the vaccine construct and mechanism of action can be found in the 
current version of the Investigators’ Brochure. 
4.2 
Disease Background 
Chikungunya virus, a mosquito-borne pathogen that causes chikungunya fever, has been 
spreading dramatically throughout tropical areas worldwide [Enserik 2008; Rezza 2007; Wang 
2008]. Recent large outbreaks have been reported in parts of Asia (mainly southeast) and Latin 
America. Due to global travel and wide distribution of suitable mosquito vector species, the risk 
for spreading to temperate regions has increased [Jain 2008] with local transmission reported 
in Europe (Italy in 2007, France in 2010 and 2014) and the continental United States (Florida 
in 2014, Texas in 2015). Puerto Rico experienced a dramatic outbreak in 2014 with over 35,000 
suspected and confirmed cases reported. Incidence has since dropped off significantly with 
only 177 confirmed cases in 2016 [PAHO website]. 
Chikungunya virus is transmitted to humans primarily by the mosquitoes Aedes aegypti 
[Tsetsarkin 2007] and Aedes albopictus, which are common in many tropical and non-tropical 
urban areas [Vazeille 2007]. Transmission of the virus occurs predominantly in an urban cycle 
whereby the mosquito spreads the disease from human to human following an epidemiological 
pattern similar to dengue [Jain 2008]. Vertical transmission of chikungunya virus has also been 
described from mothers who were viremic at the time of delivery [Gerardin 2008]. 
Most individuals present with symptomatic disease after an incubation period of 2 to 12 days 
although not all individuals infected with the virus will develop symptoms. However, individuals 
acutely infected with chikungunya virus, whether clinically apparent or asymptomatic, can 
contribute to the transmission of the disease if active vectors are present. 
Acute disease is most often characterised by the acute onset of high fever (>102°F/39°C). The 
fever typically lasts from several days up to 2 weeks. Other signs and symptoms may include 
headache, diffuse back pain, myalgias, nausea, vomiting, polyarthritis, rash, and conjunctivitis. 
After the onset of fever, the majority of infected persons develop severe, often debilitating 
polyarthralgia. Joint symptoms are usually symmetric and occur most commonly in wrists, 
elbows, fingers, knees, and ankles but also more proximal joints. The lower extremity 
arthralgias can be severely disabling resulting in a slow, broad based, halting gait that can 
persist for months. The patients may suffer from severe pain, tenderness, swelling and 
stiffness and they cannot perform normal tasks or go to work. Acute symptoms of chikungunya 
fever typically resolve within 7 to 10 days. Following the acute phase, a number of patients 
continue to experience prolonged symptoms, lasting several weeks to months, including 
fatigue, incapacitating joint pain, and tenosynovitis or oedematous polyarthritis. Chronic 
 
 
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disease is defined by symptoms that persist for more than 3 months [CDC/PAHO Chikungunya 
virus, 2011]. 
The frequency of persons reporting persistent symptoms varies substantially by study and the 
time that had elapsed between symptom onset and follow-up. Studies from South Africa note 
that 12%−18% of patients will have persistent symptoms at 18 months and up to 2 to 3 years 
later. More recent studies in India revealed that the proportion of patients with persistent 
symptoms at 9-12 months was 22% and additional 22% reported symptoms for more than one 
year (Paul BJ, 2011).  
Data from La Réunion have found that as many as 60% of patients complained of persistent 
symptoms 36 months after disease onset. In almost one half of these patients the joint pain 
had negative impact on their everyday life and on their ability to work (Schilte C, 2013).  
During 2005-2006 several European countries reported imported cases from travellers 
returning from the Indian Ocean region including France (808 imported cases). A detailed 
follow up of 47 patients that returned to Marseilles. 38 patients remained symptomatic after the 
tenth day with severe joint pain and tenosynovitis with a dramatically limited ability to ambulate 
and carry out activities in daily life (Simon F, 2007). 
4.3 
Preclinical Studies  
Immunogenicity of MV-CHIK and protective effects against infection have previously been 
demonstrated in a series of preclinical studies in mice and cynomolgous monkeys. These 
experiments are described in detail in the current version of the Investigators’ Brochure. 
4.3.1 Preclinical Immunogenicity Studies 
Preclinical evaluation of the MV-CHIK vaccine was demonstrated in the measles vaccine virus 
susceptible mouse strain CD46-IFNAR. The animals are transgenic for the human CD46 
receptor, which allows measles vaccine entry into host cells. In addition, the animals are 
deficient in the Type 1 Interferon receptor (IFNAR) to facilitate virus replication. 
Single or two vaccinations of the mice resulted in high levels of chikungunya virus neutralising 
antibodies. All immunised mice were protected from lethal challenge with chikungunya virus, 
even after a single immunisation, demonstrating a strong protective capacity in this 
experimental model. Passive transfer of immune sera to highly susceptible IFNAR mice 
conferred protection from lethal chikungunya virus challenge. Importantly, pre-existing 
immunity to measles virus did not impair the protective capacity of MV-CHIK. The vaccine also 
conferred neutralisation against homologous and heterologous circulating strains of 
chikungunya virus. The vaccine characterisation and proof of concept is described by Brandler, 
et al [Brandler 2013]. 
Immunogenicity was also demonstrated in immunocompetent animals (non-human primates). 
Cynomolgus macaques were immunised twice with MV-CHIK at 2 doses. Neutralising 
antibodies, as determined by plaque reduction neutralisation test (PRNT50), were induced by 
one or 2 immunisations. In addition, all vaccinated animals were protected against viremia and 
disease symptoms after challenge with the homologous Chikungunya virus wild type strain 
(For details please refer to the current Investigators Brochure). 
 
 
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Pr ot o c ol M V -C HI K -2 0 5  
   E u dr a C T 2 0 1 8 -0 0 0 2 1 1 -2 5  V er si o n 1. 4 , 0 8 -A u g u st -2 0 1 8  
P a g e 1 4 /6 8  
4. 3. 2  Pr e cli ni c al T o xi cit y St u di e s  
4. 4  
C li ni c al St u di e s  
M V -C HI K h a s b e e n e v al u at e d i n o n e c o m pl et e d p h a s e I st u d y  ( M V-C HI K -1 0 1 , E u dr a C T  2 0 1 3 -
0 0 1 0 8 4 -2 3 ). C urr e ntl y t h er e ar e 3  o n g oi n g cli ni c al tri al s wit h M V -C HI K.  O n e  a d diti o n al p h a s e  I 
cli ni c al tri al c o n d u ct e d  i n t h e U S A u n d er a n I N D ( N T C 0 3 0 2 8 4 4 1) a n d t w o f urt h er p h a s e II tri al s, 
c o n d u ct e d  i n E ur o p e ( M V-C HI K -2 0 2 i n A u stri a a n d G er m a n y, E u dr a C T 2 0 1 5 -0 0 4 0 3 7 -2 6/ 
N T C 0 2 8 6 1 5 8 6) a n d i n t h e U S A ( M V -C HI K -2 0 4 i n P u ert o Ri c o, N T C 0 3 1 0 1 1 1 ).  
S af et y d at a fr o m all 3 o n g oi n g st u di e s will b e s h ar e d i n r e al ti m e wit h t h e s p o n s or a n d 
c o m m u ni c at e d t o all  cli ni c al tri al sit e s i n or d er t o e n s ur e t h at a n y s af et y si g n al s t h at e m er g e 
ar e pr o m ptl y a d dr e s s e d.  
 
 
 
 
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4.4.1 Phase I Study 
MV-CHIK-101: 
A phase I study has been conducted in Austria at the Medical University, Vienna, Department 
of Clinical Pharmacology (EudraCT: 2013-001084-23):  
Observer blinded, block-randomised, active and placebo-controlled, dose escalation trial to 
evaluate the optimal dose of MV-CHIK, a new vaccine against Chikungunya virus, in regard to 
immunogenicity, safety and tolerability in healthy volunteers.  
The purpose of this first-in-man study was to evaluate the optimal dose considering 
immunogenicity, safety and tolerability of the MV-CHIK vaccine. We further analysed the 
immunogenicity, safety and tolerability of MV-CHIK during the vaccination period up to 28 days 
after the last vaccination. 
Each subject received an i.m. injection of one of the doses of MV-CHIK on day 0 and either an 
i.m. injection with MV-CHIK on day 28 and an i.m. injection with placebo control on day 90 or 
the other way around (placebo control on day 28 and MV-CHIK on day 90). 
Doses (volumes administered): 
Cohort #1: 0.05 mL; 1,5x104 (± 0,5x104) TCID50 
Cohort #2: 0.25 mL; 7,5x104 (± 2,7x104) TCID50 
Cohort #3: 1 mL; 3,0x105 (± 1,1x105) TCID50  
A control group received Priorix®, an approved Measles, Mumps, Rubella vaccine that contains 
the parental measles vaccine Schwarz strain. Sterile saline has been injected as placebo 
treatment. The phase I clinical batch was present at a ready to use liquid formulation at a single 
concentration. In contrast, the proposed phase II clinical trial IMP will be presented as 
lyophilised product.  
Out of 44 healthy male or female volunteers screened 42 subjects (98% (41/42) Caucasians, 
55% (23/42) female, mean age 30.5 ± 7.3 years) have been enrolled into the study from 
November 2013 to June 2014.  
Immunogenicity Analysis: 
The vaccine immunogenicity was determined by the presence and quantity of functional 
Chikungunya virus neutralising antibodies in the sera of vaccinated subjects. The 
neutralisation titres were determined by 50% plaque reduction neutralisation test (PRNT50) and 
total antibody levels were determined by hemagglutination inhibition assays (HIA). 
The primary end-point of the study, which was immunogenicity on day 28 after the first 
vaccination, showed that a single MV-CHIK immunisation elicits functional antibodies in all 
treatment cohorts. The medium and high dose groups induced similar levels of neutralising 
antibodies, which were significantly higher than the low dose group and the Priorix® control 
groups. A second immunisation at one or three months interval boosted the titres in all 
treatment groups clearly, figure 1). The low dose group showed relatively low titres of both 
functional and total antibody levels. A second immunisation did boost the titres clearly, 
however, this dose level is not suitable for a single shot vaccine. The medium dose group 
elicited significantly higher titres after one or two immunisations. The highest functional and 
total anti-CHIKV titres were elicited in the highest dose group. The functional antibodies were 
persistent over the study period. Very similar results were obtained by HAI. Total antibody 
levels have been induced by a single immunisation and boosted by a second dose. 
 
 
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The Measles antibody titres as measured by ELISA were boosted in all treatment groups (MV-
CHIK and Priorix®) after the first vaccination. No clear trend between the individual groups was 
visible but an increase in Measles virus dose increased the geometric mean titre (GMT). The 
measles ELISA titres that were induced after the first immunisation were close to the detection 
limit of the assay. Therefore, a not additive effect was visible after a second immunisation. 
The subjects that entered the study were not pre-selected for a specifically high or low Measles 
antibody titre. The subjects were randomly allocated to the individual treatment cohorts. To 
analyse the effect of pre-existing anti-measles immunity on the immunogenicity of the MV-
CHIK vaccine, we investigated if a baseline anti-measles titre would cause a difference 
between the PRNT50 titres on day 28 after the first immunisation of all subjects in MV-CHIK 
dose groups (independently of their dose group). This analysis showed that subjects that had 
a low, medium or high measles titre at baseline were equally prone for the immunogenicity of 
the MV-CHIK vaccine. Thus, the pre-existing immunity to the vaccine vector did not interfere 
with the vaccine immunogenicity. 
 
 
 
Figure 1: Induction of neutralising antibodies after two immunisations.  
Closed squares show the results of subjects that were boosted on Day 28 after the first immunisation. Open 
squares depict PRNT levels of subjects that were boosted on day 90 after the first immunisation. 
 
Safety Analysis: 
Vital sign checks including measurement of blood pressure, pulse rate and axillary body 
temperature as well as physical examination were performed at all visits. Additionally, the 
injection site was inspected and evaluated for local side effects by the investigator at each visit 
and before and 6 hours after each vaccination. Grading of local pain, tenderness, redness, 
swelling, itching and induration was performed according to the respective FDA guidance for 
industry and the guidance of the Brighton Collaboration. Accordingly, local side effects were 
graded as mild (grade 1), moderate (grade 2), severe (grade 3) and potentially life-threatening 
(grade 4). All participants were provided with a template that allows estimation of local 
reactions (supplementary information).  
Pain, itching and induration were graded as mild if they did not interfere with daily activity, as 
moderate if they did compromise activity or necessitated repeated use of non-narcotic pain 
reliever/anti-inflammatory and pain relieving ointment (itching and induration) and as severe if 
they prevented daily activity. Grade 4 pain/itching included the need for Emergency room (ER) 
0
28
56
120
0
28
56
120
0
28
56
120
1
10
100
1000
PRNT50Titer
Low
Medium
High
Boost
D28orD90
Boost
Boost
D28orD90
D28orD90
 
 
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visit or hospitalisation. Swelling and erythema below a diameter of 5 cm were rated as mild. 
Swelling/erythema exceeding 10 cm in diameter were considered to be severe and necrosis 
indicated grade 4 swelling/erythema (supplementary information). 
 Furthermore, participants were requested to keep a study diary in order to record all local and 
systemic symptoms and any adverse event occurring during the first two weeks after 
vaccination starting with the first entry 6 hours (±1) after vaccination. The subjects themselves 
recorded the assessments once daily at the same time each day. Completeness and accuracy 
of self-reported symptoms and side effects were verified at each visit by a study-related 
physician. Diaries were reviewed together with the particular participant at each visit and 
participants were interviewed for any adverse events. Diaries had to be signed by both the 
particular participant and the reviewing physician at the end of each vaccination period to 
confirm and ensure completeness and reliability of self-reporting. The investigator collected 
the diaries at each visit and new ones were dispensed after vaccination. 
Solicited and non-solicited adverse events (AEs) were reported separately. Solicited AEs 
included pyrexia, flu like illness, headache and injection-site- related side effects (erythema, 
swelling, induration and pain). 
In general, MV-CHIK vaccine had an acceptable tolerability profile. All adverse events 
observed were treatment emergent AEs and were recovered without any sequelae before or 
at study end. 
The most frequently solicited AEs were headache (57.1%), injection site pain (50.0%), 
influenza like illness (45.2%), vaccination site pain (40.5%), fatigue (38.1%), nausea (31.0%), 
myalgia (26.2%) and arthralgia (23.8%). The most frequently related solicited AEs were 
injection site pain (50.0%), vaccination site pain (40.5%), headache (28.6%) and fatigue 
(23.8%). 
Unsolicited AEs were AEs with none of the preferred terms of solicited AEs. 28 subjects 
(66.7%) had a total of 73 unsolicited AEs. Two subjects (4.8%) had two severe unsolicited 
AEs, five subjects (11.9%) had seven related unsolicited AEs and 19 subjects (45.2%) reported 
33 unsolicited AEs where an action was taken. Two subjects (4.8%) reported two serious 
unsolicited AEs. The most frequently unsolicited AEs were nasopharyngitis (26.2%) and 
oropharyngeal pain (11.9%). 
Special attention was directed to any occurrence of joint pain during the MV-CHIK study due 
to significant joint pathology caused by CHIKV. The subjects were asked to report any 
symptoms of joint pain in their subject diary and they were asked for any symptoms during 
each visit. Overall, 23.8% (10/42) of the subjects reported any signs of joint pain or arthralgia 
during the treatment period, 11.9% (5/42) of which were rated as related to the study treatment. 
In all 5 cases the joint pain was described as transient musculoskeletal pain, which was 
accompanied by flu like symptoms. Pain in the limbs associated with MV-CHIK injection was 
largely graded as mild (82%), was self-limiting and did not engender any withdrawals from the 
study. The rate of musculoskeletal pain decreased from 12% (n=5; 67% mild) at the first visit 
to 2% (n=1; 100% mild) at visit 5. No signs of inflammation were observed. 
Severe and serious AEs occurred only for subjects treated with MV-CHIK. All serious AEs 
reported were non-local and unsolicited. Overall, seven severe AEs occurred (in six 
participants), of which five were solicited and related to vaccination including headache, local 
erythema, local induration, local pain and pyrexia.  
 
 
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The number of overall AEs and related AEs increased with the MV-CHIK dose. In addition, 
local reactions to MV-CHIK vaccination increased dose-dependently and were deemed related 
to the high inoculation volume (1mL) together with the formulation’s salt buffer content. 
The evaluation of safety laboratory parameters (haematology, serum chemistry, urinalysis) did 
not indicate any safety issues. There were no clinically relevant abnormalities observed in 
haematology, clinical chemistry, coagulation or urinalysis laboratory parameters. 
The Clinical Study Report has been finalised in Q4/2014. The study results were published in 
Ramsauer et. al. Lancet Infect Dis 2015. 
 
MV-CHIK-203: 
This clinical phase I study (protocol 15-0038) sponsored by the Division of Microbiology and 
Infectious Diseases (DMID), National Institute of Allergy and Infectious Disease (NIAID), and 
National Institute of Health (NIH), currently conducted in Iowa (USA), intends to investigate 
safety, immunogenicity and schedule of MV-CHIK in 180 subjects age 18-45. This study is 
comparing 2 doses of MV-CHIK (5×104 and 5×105 TCID50) given at three different intervals (1 
month, 3 months and 6 months). Each of these six cohorts will contain 30 consented subjects 
of which 25 will receive MV-CHIK and 5 will receive saline placebo. This study is currently 
ongoing, and no preliminary results are available. 
4.4.2 Phase II Studies  
Currently there are two clinical phase II studies with MV-CHIK going on. One in Europe (MV-
CHIK-202; 
EudraCT: 2015-004037-26) 
and 
one 
in 
Puerto 
Rico 
(MV-CHIK-204; 
NCT03101111). 
MV-CHIK-202: 
This phase II study of MV-CHIK is being conducted at four sites across Austria and Germany. 
It is comparing 2 doses (5×104 and 5×105 TCID50) of MV-CHIK administered at two different 
intervals (1 month and 6 months). Each of these four cohorts will have 70 consented subjects 
of which 60 will receive MV-CHIK and 10 will receive a licensed MMR vaccine as a comparator. 
In addition, two cohorts of 20 consented subjects each will receive MMR either one month or 
6 months before MV-CHIK in order to assess the effect of recently boosted immunity to 
Measles on Chikungunya immunogenicity.  
A database snapshot was performed in August 2017, providing preliminary interim safety and 
immunogenicity data up to study day 56.  
Safety Analysis: 
Until the database snapshot, overall 624 adverse events (AEs) were observed in 263 treated 
subjects, whereas 456 AEs [73.1%] were solicited by the means of a subjects’ diaries and 168 
unsolicited [26.9%], reported spontaneously. The intensity was mostly assessed as mild in 468 
cases [75.0%] or moderate in 145 cases [23.2%] and 11 cases [1.8%] were classified as 
severe, disregarding relatedness. 
Solicited AEs occurred more often in MV-CHIK group (91 subjects [72.7%]) compared to the 
control group (17 subjects [34.0%]) but unsolicited AEs were seen more frequently in the 
control group (17 subjects [34.0%] and 69 subjects [32.4%] in the MV-CHIK group 
respectively). 
The most common solicited, systemic adverse event after immunisation was headache, which 
was reported by 42 subjects [19.7%] of the MV-CHIK group and by 10 subjects [20.0%] of the 
 
 
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control group. The severity of headache was mostly reported as mild (52 cases [65.0%]) or 
moderate (23 [28.8%]), 2 subjects reported severe headache. 
After headache the most common solicited, systemic adverse events were observed in the 
following number of subjects: fatigue (33 [14.4%] MV-CHIK; 3 [8.8%] control group), flu like 
symptoms (16 [7.9%] MV-CHIK; 1 [2.9%] control group), nausea (14 [6.1%] MV-CHIK; 3 [8.8%] 
control group) and myalgia (14 [6.1%] MV-CHIK; 3 [8.8%] control group). Taken together, the 
frequency of solicited systemic AEs was equally distributed between MV-CHIK and control 
group. 
Arthralgia, regarded as adverse event of special interest, was solicited and observed in 9 
subjects [3.9%] treated with MV-CHIK and in 2 subjects [5.9%] of the control group. 
The general local tolerability was assessed one hour after each vaccination by the investigator 
and additionally recorded in a diary by the subjects for 7 days upon treatment.  
The most common local side effects were tenderness (57 subjects [26.8%] MV-CHIK; 4 
subjects [8.0%] control group), pain (38 [17.4%] MV-CHIK; 4 [8.0%] control group), induration 
(19 [8.9%] MV-CHIK; 0 [0.0%] control group) and erythema (16 [7.5%] MV-CHIK; 1 [2.0%] 
control group) with higher reporting rates after MV-CHIK administration. 
In addition, no clinical relevant abnormalities were detected in haematology or clinical 
chemistry laboratory results in either treatment group and no case of anaphylactic reaction 
occurred in the study population up to visit 3. 
One serious adverse event was reported for a 49-year old male subject, who underwent 
surgery for umbilical hernia 120 days after his last vaccination. As this subject already had a 
medical history of umbilical hernia, the event was assessed as not related to MV-CHIK or 
control vaccine.  
Overall the interims analysis of safety and tolerability data up to study visit 3, showed that the 
MV-CHIK vaccine is well tolerated and safe. 
Immunogenicity Analysis: 
Preliminary PRNT50 conducted after completion of the primary endpoint, 28 days after one or 
two immunisations (day 56) clearly demonstrated that immunisation with one or two MV-CHIK 
doses (at either dose level) induced high levels of neutralising antibodies and a seroconversion 
rate of up to 95% in the prime/boost groups. The immunisation with a single MV-CHIK dose 
was less potent, however, higher titres and seroconversion rates were achieved in the high 
dose groups. 
 
 
 
Figure 2: MV-CHIK 202 preliminary data.  
Neutralising antibodies as determined by PRNT50 after one or two immunisations. 
 
28
56
28
56
0
28
56
0
28
56
28
56
1
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PRNT50 GMT (95% CI)
LOW
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2-dose
LOW
1-dose
HIGH
1-dose
Control 
Vaccine
 
 
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MV-CHIK-204: 
This clinical phase II study (NCT03101111) initiated in May-2017 and currently conducted in 
Puerto Rico, a previously epidemic area, evaluates the safety and immunogenicity of MV-CHIK 
in 100 subjects. The main objective is to determine the safety of MV-CHIK administered in 2 
doses (5×104 and 5×105 TCID50) separated by 28 days in previously exposed versus 
unexposed individuals. The subjects will be randomised in a double-blind fashion to receive 
either MV-CHIK or the licensed active measles, mumps, and rubella vaccine (Priorix) in a 4:1 
ratio. Additionally, immunogenicity of MV-CHIK will be investigated in previously exposed 
versus unexposed individuals by a neutralisation assay.  
 
4.5 
Study Rationale 
The current phase II trial is designed to investigate the immunogenicity, safety and tolerability 
of MV-CHIK as well as the long-term durability of anti-Chikungunya antibody response after 
administration of different dose levels of MV-CHIK in three different formulations. 
The concentrations of the evaluated doses are 5x104 (± 0.5 log) TCID50 /dose, 1x105 (± 0.5 log) 
TCID50 /dose and 1x106 (± 0.5 log) TCID50 /dose and the compared formulations are lyophilised, 
liquid frozen and liquid SPS® (Stabilising and Protecting Solution), respectively. 
The induction of functional anti-Chikungunya antibodies by MV-CHIK will be investigated in 
healthy adults aged 18 to 55 years, by means of immunoassays like ELISA and T-cell assay 
and PRNT50. The timepoint day 28 and day 56 after immunisation were found to be suitable 
for immunogenicity analyses to reveal valuable information on future treatment 
recommendations (single shot treatment vs. double immunisation). 
A randomised, observer-blinded study design was chosen to allow an objective recording and 
assessment of all adverse events. 
The MV-CHIK doses used in previous clinical trials (phase I and phase II) was calculated 
between 1,5x104 (± 0.5 log) - 5x105 (± 0.5 log) TCID50 /dose. This dose was efficient to induce 
a seroconversion rate of up to 96% in the study population. To further investigate the capacity 
of the vaccine to induce sufficiently high neutralising titres and seroconversion rates after a 
single immunisation, an increased dose 1x106 (± 0.5 log) TCID50 /dose will be administered 
once or twice.  
The different vaccination schedules, two MV-CHIK vaccinations on days 0 and 28 or one MV-
CHIK vaccination on day 0 and placebo on day 28, allow to compare the immunogenicity of 
these dosing regimens. A single shot or two vaccinations within a short period of time are 
desirable to allow for a quick immunisation before travelling to areas with active transmission 
of the Chikungunya virus. 
In addition to the previously tested liquid frozen and lyophilised formulations, Themis has an 
ongoing project to improve the product stability in a variety of potential formulations. Recently, 
a liquid formulation (stored at 2-8°C) showed promising stability data. Clearly, a liquid 
formulation will substantially decrease the costs of good and will facilitate the use of the vaccine 
throughout the world. Thus, a group of subjects will receive the SPS formulation and safety 
and immunogenicity will be analysed. 
The induction of virus specific T cells is a critical step in the generation of a functional immune 
response. For this purpose, the rate of Chikungunya virus specific T cells will be analysed in 
vitro. 
 
 
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Additionally, the study design will allow for the first time to gather data on the long-term stability 
of specific antibodies, by testing serum samples 6 months and 1 year after the first 
immunisation with MV-CHIK. 
Up to now the level of protective anti-Chikungunya-Ab titre could only be estimated. Therefore, 
it is of special interest to evaluable and proof Ab titres that are able to prevent CHIKV infections. 
The design of the study will allow to collect human serum samples, to verify efficacy, by passive 
transfer of antibodies to non-human primates in future investigations. 
This study was designed according to the Note for Guidance on Clinical Evaluation of New 
Vaccines (CHMP/VWP/164653/2005), where applicable, and will be conducted in compliance 
with the protocol, Good Clinical Practice (GCP) as set forth in the International Council on 
Harmonisation (ICH) guidelines on GCP (ICH E6), and applicable local regulatory 
requirements.  
 
4.6 
Benefit/Risk Assessment 
General 
Potential risks that are frequently associated with vaccination are the occurrence of local 
reactions such as oedema, induration and erythema, transient local pain or tenderness at the 
injection site as well as mild to moderate headache, myalgia, flu-like symptoms or fatigue. 
Vaccines have been known to induce allergic and anaphylactic reactions apart from reactions 
at the vaccination site and systemic flu-like reactions. Additionally, needle picks for blood 
sampling may cause discomforts and local reactions. 
MV-CHIK Related  
As described above, adverse events (AEs) previously reported with MV-CHIK include injection 
site pain, headache, fatigue, and joint pain or arthralgia. Refer to the current version of the 
Investigators’ Brochure for more detail.  
Potential for Severe Adverse Reaction  
In the past, a live virus vaccine against Chikungunya virus, which was based on an attenuated 
Chikungunya-strain was associated with mild, transient arthralgia in immunised individuals. 
The MV-CHIK vaccine is based on live measles virus and contains no live Chikungunya virus. 
Therefore, induction of chikungunya-like symptoms is not expected. However, the subjects will 
be monitored for occurrence of arthralgia, an adverse event of special interest (AESI).  
Potential Benefit 
If the clinical development of MV-CHIK is successful, the potential benefit of MV-CHIK 
vaccination would be life-long protection against Chikungunya infection helping people, who 
are at risk of acquiring a possibly life-threatening infection with CHIKV.  
A boost in measles immunity may be an additional benefit. 
Conclusion 
The benefit risk ratio is considered favourable. 
 
 
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5. 
TRIAL OBJECTIVES AND MEASUREMENTS 
5.1 
Primary Objective 
• 
To investigate immunogenicity and safety of MV-CHIK in different dose regiments, 28 days 
after one or two vaccinations  
The immunogenicity will be determined by means of PRNT50 28 days after a single shot 
treatment at Visit 3 (study day 28) and 28 days after two treatments with MV-CHIK at Visit 5 
(study day 56). Local and systemic AEs will be recorded and assessed. 
 
5.2 
Secondary Objectives 
• 
To compare immunogenicity, safety and tolerability between different doses and 
formulations of MV-CHIK during the treatment period up to day 56 
 
• 
To investigate the immunogenicity and safety of a novel liquid vaccine formulation 
To cover this objective immunogenicity will be determined by means of PRNT50 at the following 
timepoints during the treatment period: Visit 1 (day 0), Visit 3 (day 28) and Visit 5 (day 56). 
Solicited and unsolicited AEs will be recorded at each visit during the treatment period. 
 
• 
To evaluate cellular responses induced by one or two immunisations 
The cellular response will be investigated by T cell analysis of PBMCs isolated at Visit 1(day 
0), Visit 2 (day 14), Visit 3 (day 28), Visit 4 (day 42) and Visit 5 (day 56) 
 
• 
To evaluate the long-term immunogenicity of MV-CHIK up to one year after the first 
MV-CHIK treatment.  
The long-term immunogenicity will be observed by means of PRNT50 detecting anti-
Chikungunya antibodies 6 months and one year after the first treatment with MV-CHIK (at Visit 
6 and Visit 7). 
 
• 
To collect human sera for future efficacy evaluation, by passive transfer of 
anti-Chikungunya antibodies to virus susceptible non-human primates 
On study day 0 (Visit 1), day 28 (Visit 3), day 56 (Visit 5) and day 365 (Visit 7) blood samples 
will be collected for isolation of anti-Chikungunya antibody containing human serum.  
 
 
 
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6. 
TRIAL DESIGN 
6.1 
Overall Study Design 
This is a prospective, interventional, observer-blinded, block-randomised, phase II trial, 
comparing different dose levels of MV-CHIK in three different formulations (lyophilised, liquid 
frozen and liquid SPS) to evaluate immunogenicity, safety and tolerability of this novel 
Chikungunya vaccine. Placebo (physiological saline solution) will be applied to blind two 
different treatment schedules, evaluating single shot versus double shot treatment.  
The study will be conducted at a single study site, Celerion in Belfast (United Kingdom) and is 
registered online at http://www.ClinicalTrials.gov under EudraCT number 2018-000211-25. 
After the screening procedures, 60 healthy male and female volunteers aged 18-55 years will 
be randomly assigned to one of five treatment groups (A, B, C, D or E). Subjects will be 
observed for safety and immunogenicity for 56 days during the treatment period, starting with 
the first MV-CHIK vaccination at Visit 1 (day 0) up to Visit 5 (day 56). After this treatment period 
subjects will return to site at Visit 6 (after 6 months) and at Visit 7 (after 1 year) for collection 
of serum to follow up the durability of specific antibodies against Chikungunya. 
The investigator and site personnel assessing AEs, all subjects, as well as the sponsor’s 
representatives involved in the monitoring and conduct of the study will be blinded to which 
vaccine was administered. Only the site personnel performing randomisation, preparation and 
administration of IMP will be unblinded. 
6.2 
Study Endpoints 
6.2.1 Primary Endpoint 
• 
Immunogenicity 28 days after the last MV-CHIK vaccination confirmed by the presence of 
functional antibodies as determined by the plaque reduction neutralisation test (PRNT50) 
6.2.2 Secondary Endpoints 
• 
Rate of solicited and unsolicited adverse events during the treatment period until day 56  
• 
Serious adverse events during the treatment period until study day 56 
• 
Immunogenicity on days 0, 28 (group A, B, C, and D), days 0, 56 (group E) and long-term 
immunogenicity on day 182 (6 Mo) and 365 (12 Mo), confirmed by the presence of 
functional antibodies as determined by the plaque reduction neutralisation test (PRNT50). 
• 
Measurement of anti-Chikungunya antibodies on days 0, 28, 56, 182 and 365 determined 
by enzyme linked immunosorbent assay (ELISA)  
• 
Measurement of anti-Measles antibodies on days 0, 28, 56 determined by enzyme linked 
immunosorbent assay (ELISA) 
• 
Induction of Chikungunya specific immune responses on days 0, 14, 28, 42 and 56 
determined by T-cell assay. 
 
 
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• 
Safety laboratory parameters (haematology, serum chemistry, coagulation, urinalysis)  
6.3 
Treatment Groups 
After the screening procedure, 60 subjects eligible for the study will be randomised to one of 
the following 5 treatment groups: 
Group A:  
two vaccinations with MV-CHIK lyophilised formulation, low dose, on day 0 and day 28 
Group B:  
two vaccinations with MV-CHIK liquid frozen formulation, low dose, on day 0 and day 28 
Group C:  
two vaccinations with MV-CHIK liquid SPS® formulation, low dose, on day 0 and day 28  
Group D: 
two vaccinations with MV-CHIK liquid frozen formulation, high dose, on day 0 and day 28 
Group E:  
one vaccination with MV-CHIK liquid frozen formulation, high dose on day 0 and placebo on 
day 28 
The concentration of different MV-CHIK dose levels per treatment group are: 
Group A:  
low dose: 5x104 0.5 log TCID50 /dose 
Group B+C: 
low dose: 1x105 0.5 log TCID50 /dose 
Group D+E: 
high dose: 1x106 0.5 log TCID50 /dose  
The actual vaccine dosages are dependent on the manufacturing process, specifying and 
allowing a window of 0.5 log. The five different treatment groups, group sizes and vaccination 
schedules are summarised in table 1.  
 
Table 1: Treatment Groups and Vaccination Schedule 
Treatment 
Group 
N 
Vaccine 
Formulation 
Vaccine 
on day 
Placebo 
on day 
A 
12 
MV-CHIK 5x104 (0.5 log) TCID50 
lyophilised 
0 + 28 
 
B 
12 
MV-CHIK 1x105 (0.5 log) TCID50 
liquid frozen 
0 + 28 
 
C 
12 
MV-CHIK 1x105 (0.5 log) TCID50 
liquid SPS® 
0 + 28 
 
D 
12 
MV-CHIK 1x106 (0.5 log) TCID50 
liquid frozen 
0 + 28 
 
E 
12 
MV-CHIK 1x106 (0.5 log) TCID50 
liquid frozen 
0 
28 
 
 
 
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6.4 
Study Flowchart 
 
 
 
 
 
 
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6.5 
Study Procedures 
Table 2: Study Procedures 
 
 
Screening 
Treatment Period 
Follow up Period 
 
Visit 
VS 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
ET 
Study Day 
-28 to -1 
0 
14 ±1 
28 ±5 
42 ±5 
56 ±5 182 ±14 365 ±14 
(7) 
Informed Consent 
x 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
x 
 
 
 
 
 
 
 
Medical History 
x 
x 
 
 
 
 
 
 
 
Vaccination History 
x 
 
 
 
 
 
 
 
 
Vital Signs (1) 
x 
x 
 
x 
 
x 
 
 
x 
Physical Examination (2) 
x 
x 
 
x 
 
x 
 
 
x 
Adverse Events (3) 
 
x 
x 
x 
x 
x 
 
 
x 
Concomitant Medication (4) 
x 
x 
x 
x 
x 
x 
 
 
x 
Clinical Laboratory (5) 
x 
 
 
x 
 
x 
 
 
x 
Pregnancy Test 
x 
x 
 
x 
 
x 
 
 
x 
Study Treatment (8) 
 
x 
 
x 
 
 
 
 
 
Dispense subject diary 
 
x 
 
x 
 
 
 
 
 
Collect subject diary 
 
 
x 
 
x 
 
 
 
x 
Local Tolerability (6) 
 
x 
x 
x 
x 
x 
 
 
x 
Immunogenicity (PRNT50) 
 
x 
 
x 
 
x 
x 
x 
x 
T-cell Immunity 
 
x 
x 
x 
x 
x 
 
 
x 
CHIKV-antibodies (ELISA) 
 
x 
 
x 
 
x 
x 
x 
x 
Measles-antibodies (ELISA) 
 
x 
 
x 
 
x 
 
 
x 
Serum collection for 
passive transfer 
 
x 
 
x 
 
x 
 
x 
x 
 
(1) Assessment of vital signs will include systolic and diastolic blood pressure, pulse rate and body temperature 
(2) A full physical examination will be performed at screening and a system based physical examination will be done 
at Visit 1, 3 and 5, if necessary according to findings in a symptom-directed physical examination   
(3) Conditions/symptoms noted prior to first IMP administration will be reported as medical history and not as AEs, 
At Visit 6 and 7 AEs will not be recorded as subjects are allowed to participate in other clinical studies during the 
follow-up period. 
(4) Medications administered within 30 days prior to screening until end of treatment period will be documented as 
concomitant medication. 
(5) Clinical Laboratory parameters include:  
- Virology: HB s-Ag, anti-HB c-Ab, anti-HC-Ab, HIV-Ab (only once at screening) 
- Haematology: haemoglobin, haematocrit, erythrocyte count, differential and total white blood count, platelets 
- Chemistry: creatinine, potassium, sodium, calcium, AST, ALT, alkaline phosphatase, bilirubin 
- Coagulation parameter: prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen  
- Urinalysis: pH-value, glucose, protein, bilirubin, urobilinogen, blood, leucocytes esterase, nitrite, ketone and 
specific gravity. In case of abnormal findings, a microscopy will be done for confirmation.  
Please refer to section 8.11.1 
(6) Local tolerability to be investigated 2 hours after each vaccination and additionally at the subsequent visits and 
prior to IMP administration. 
(7) If the early termination occurs within the treatment period (at or before Visit 5), subjects shall perform all 
procedures as defined for Visit 5. If the early termination occurs within the follow up period (after Visit 5), subjects 
shall perform all procedures defined for Visit 7 
(8) Administration of IMP will be performed according to allocated treatment group, after randomisation at Visit 1 
 
 
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7. 
PARTICIPANT IDENTIFICATION 
7.1 
Trial Participants 
Healthy male and female volunteers will be screened for inclusion and exclusion criteria and 
randomised to one of 5 treatment groups in case of eligibility.  
60 subjects will be enrolled if all of the following inclusion criteria and none of the following 
exclusion criteria apply: 
7.2 
Inclusion Criteria 
1. 
Signed informed consent obtained before any trial-related activities 
2. 
Healthy men or women aged 18 to 55 years on the day of consenting 
3. 
Ability to comprehend the full nature and purpose of the study, including possible risks 
and side effects; ability to cooperate with the investigator and to comply with the 
requirements of the entire study 
4. 
All female subjects must have a negative serum pregnancy test at screening  
5. 
Willingness not to become pregnant or to father a child during the entire study period by 
practicing reliable methods of contraception as specified in protocol section 8.11.4 
6. 
Availability during the duration of the trial 
7.3 
Exclusion Criteria 
The subject may not be enrolled in the study if any of the following applies: 
1. Participation in another clinical study (including exposure to an investigational medicinal 
product ore device) within one month before the screening visit or planned concurrent 
participation in another clinical study before completion of the treatment period (day 56) 
2. History of immunodeficiency, known human immunodeficiency virus (HIV) infection or 
current hepatitis B/C infection 
3. History of drug addiction including alcohol dependence within the last 2 years  
4. Inability or unwillingness to avoid intake of more than around 20g alcohol per day during 
48 hours after each vaccination (equals roughly 0.5 L beer or 0.25 L of wine) 
5. Vaccination within 4 weeks prior to first vaccination or planning to receive any non-study 
vaccine until end of treatment period (day 56)  
6. Prior receipt of any Chikungunya vaccine 
7. History of moderate or severe arthritis or arthralgia within the past 3 months prior to 
Screening Visit 
8. Recent infection within 1 week prior to Screening Visit (possibility of deferral) 
 
 
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9. Blood donations including plasma donations, 90 days prior to Screening Visit and 
anticipated blood, plasma, tissue, sperm or organ donation, throughout the study until 
end of treatment period (day 56) 
10. Clinically relevant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory, 
skin, haematological, endocrine, inflammatory, autoimmune or neurological diseases or 
clinically relevant abnormal laboratory values, that in the opinion of the investigator may 
interfere with the aim of the study 
11. History of neoplastic disease (excluding non-melanoma skin cancer that was 
successfully treated) within the past 5 years or a history of any haematological 
malignancy 
12. Behavioural, cognitive, or psychiatric condition that in the opinion of the investigator 
affects the ability of the participant to understand and cooperate with the study protocol 
13. History of severe adverse reactions to vaccine administration, including anaphylaxis and 
related symptoms, such as urticaria, respiratory difficulty, angioedema and abdominal 
pain to vaccines, or history of allergic reaction likely to be exacerbated by any 
component of the vaccine 
14. History of anaphylaxis to drugs or other allergic reactions, which the investigator 
considers compromising the safety of the volunteer 
15. Use of medication during 2 weeks before the first vaccination and throughout the study, 
which the investigator considers affecting the validity of the study, except hormonal 
contraception or hormonal replacement therapy in female subjects. (Prior to taking any 
medication within 72 h before study vaccination, the subject should consult the 
investigator) 
16. Use of immunosuppressive drugs like corticosteroids (excluding topical preparations) 
within 30 days prior to the first vaccination or anticipated use before completion of the 
treatment period (day 56) 
17. Receipt of blood products or immunoglobulins within 120 days prior to the Screening 
Visit or anticipated receipt of any blood product or immunoglobulin before completion of 
the treatment period (day 56) 
18. Pregnancy (positive pregnancy test at screening or during the treatment period) or 
lactation at screening, or planning to become pregnant during the treatment period 
19. Unreliable contraception methods (for details please refer to protocol section 8.11.4) 
20. Persons in a direct relationship with the sponsor, an investigator or other study team 
members. Direct dependent relationships include close relatives (i.e. children, parents, 
partner/spouse, siblings) as well as employees of the study site or the sponsor 
 
 
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8. 
TRIAL PROCEDURES 
8.1 
Informed Consent  
Before any trial specific procedures are performed subjects will be informed about the exact 
nature of the trial, what it will involve for the participant, all procedures as determined by the 
clinical protocol, the known side effects and any risks involved in taking part. It will be clearly 
stated that the subject is free to withdraw from the trial at any time for any reason without 
prejudice to future care, without affecting their legal rights and with no obligation to give the 
reason for withdrawal. 
The participant will be allowed as much time as needed to consider the information, and the 
opportunity to question the investigator or other independent parties to decide whether they 
will participate in the trial. 
Written informed consent will then be obtained by means of participant’s dated signature and 
dated signature of the qualified and experienced person who presented and obtained the 
informed consent. A copy of the signed informed consent will be provided to the subject and 
the original signed form will be retained at the site.  
 
8.2 
Randomisation 
At Visit 1 (day 0) 60 eligible subjects will be randomly assigned to one of five treatment groups 
(A, B, C, D or E) by means of randomisation envelopes provided by data management.  
Each subject will be assigned a unique three-digit randomisation number, stated on the 
envelope in ascending order. Only trained members of the unblinded study team will be 
authorised to open one envelope per subject, containing the information about the allocated 
treatment group. 
Upon opening, the randomisation envelope shall be signed with date and time of randomisation 
and the number of the randomised subject shall be written down on it. 
All 60 subjects will be equally distributed between the 5 groups using a randomisation ratio of 
1 : 1 : 1 : 1 : 1 = A : B : C : D : E 
A subject will be considered enrolled once the first IMP administration has been performed 
according to randomisation. 
 
8.3 
Blinding and Code-breaking  
As this study will be conducted in an observer-blinded manner, unblinded study team members 
responsible for randomisation, preparation and administration of IMP, will otherwise not be 
involved in the conduct of the study. 
 
 
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All subjects, the investigator and site personnel performing study related assessments, as well 
as the sponsor’s representatives involved in the monitoring and conduct of the study, will be 
blinded to treatment assignment. 
Besides one set of randomisation envelopes, the site will receive an additional set of 
emergency envelopes stored in the ISF for unblinding purposes. As the knowledge of the 
subject’s treatment might become mandatory (e.g. in case of emergency) the investigator has 
the possibility to open the emergency envelope identified with the subject’s randomisation 
number and unblind the subject.  
Please note that this code-breaking should only be done by the investigator if the knowledge 
of the subject’s treatment influences the decision on further procedures. If unblinding would 
not make any difference for further treatment, the study team should remain blinded. 
 
8.4 
Screening Procedures 
8.4.1 Screening Visit, (VS, 1-28 days prior to Visit 1)  
After subjects have signed the informed consent form the screening visit will be performed 
within four weeks prior to Visit 1. 
During this visit, all subjects will be checked for inclusion and exclusion criteria, undergo a full 
physical examination and evaluation of vital signs (systolic and diastolic blood pressure, pulse 
rate and body temperature). Medical history, vaccination history (covering the last three years 
prior to screening), prior/concomitant medication within 30 days prior to screening and 
demographic data will be recorded. 
Blood and urine samples will be collected for clinical laboratory assays (HIV, hepatitis B and 
C, haematology, coagulation parameters, clinical chemistry and urinalysis). HIV tests with 
available results performed up to 30 days before screening are acceptable. For details on 
laboratory sampling and testing, see section 8.11.1.  
A serum β-HCG pregnancy test will be performed in all women.  
All subjects eligible for the clinical study will be asked to return to the study site within 28 days 
after the screening visit for Visit 1. 
 
8.5 
Treatment Period 
8.5.1 Visit 1 (day 0) 
Subjects found to be eligible will return to site for Visit 1 within 28 days after the screening visit. 
Inclusion and exclusion criteria will be checked again and (in case of changes since the 
screening visit) the medical history will be updated. Symptom-directed physical examination, 
system-based assessment (only if necessary according to findings in symptom-directed 
physical exam) and vital signs (systolic and diastolic blood pressure, pulse and body 
temperature) will be recorded. In addition, the subjects will be asked regarding changes in 
 
 
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concomitant medications since the last visit. A serum pregnancy test will be performed in all 
women. 
Blood samples for baseline immunogenicity assessments (measles and Chikungunya antibody 
ELISA, PRNT50) and isolation of serum for passive transfer will be drawn from an appropriate 
forearm or cubital vein. For T-cell assays blood samples will be collected and peripheral blood 
mononuclear cells (PBMCs) will be prepared. For details on laboratory sampling and testing, 
see section 8.11. 
Subjects will be randomised to treatment group A, B, C, D or E and receive their first MV-CHIK 
vaccination. 
The subjects’ diaries will be explained and handed over. Subjects will be asked to report their 
body temperature and any adverse event in these diaries for 7 days, starting 6 hours after the 
injection. 
After observation of the subjects for two hours, local reactions and adverse events (if any 
occurred) will be recorded.  
Blood pressure and pulse rate will be checked, and participants will be discharged only if the 
investigating physician considers it to be safe for them to leave the department.  
The subjects are invited to return to study site for Visit 2 on study day 14 (± 1 day). 
 
8.5.2 Visit 2 (day 14 1 day) 
Subjects will be requested to return to site for Visit 2, 13 to 15 days after the first vaccination. 
The investigator or designee will assess local tolerability (of previous vaccination site) and ask 
about any new concomitant medications or AEs occurred since the last visit. The subject’s 
diary will be collected and checked for completeness.  
A blood sample will be collected and PBMCs will be prepared for T cell analysis. 
The subjects will be asked to return to study site for Visit 3 on study day 28 (± 5 days). 
 
8.5.3 Visit 3 (day 28 5 days) 
Subjects will be invited to return to site for Visit 3, 23 to 33 days after Visit 1. 
The investigator or designee will examine local tolerability (of previous vaccination site) and 
ask about any new concomitant medications or AEs occurred since the last visit.  
In addition, symptom-directed physical examination, system-based assessment (only if 
necessary according to findings in symptom-directed physical exam) and vital signs (systolic 
and diastolic blood pressure, pulse rate and body temperature) will be recorded.  
A serum pregnancy test will be performed in all women. 
Blood samples will be taken for clinical chemistry, haematology and coagulation parameters 
and a urine sample will be collected for urinalysis. 
 
 
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Additional blood samples for immunogenicity assessments (measles and Chikungunya ELISA, 
PRNT50) and isolation of serum for passive transfer will be drawn from an appropriate vein. For 
T-cell assays blood samples will be collected and PBMCs will be prepared. For details on 
laboratory sampling and testing, see section 8.11. 
Subjects will receive their second vaccination of MV-CHIK or placebo, according to their 
randomised treatment group. 
The subjects’ diaries will be explained and handed over. Subjects will be asked to report their 
body temperature and any adverse event in these diaries for 7 days, starting 6 hours after the 
injection.  
After observation of the subjects for two hours, local reactions and adverse events (if any 
occurred) will be recorded.  
Blood pressure and pulse rate will be measured, and participants will be discharged only if the 
investigating physician considers it to be safe for them to leave the department.  
The subjects are invited to return to study site for Visit 4 on study day 42 (± 5 days). 
 
8.5.4 Visit 4 (day 42 5 days) 
Subjects will be asked to return for Visit 4, 37 to 47 days after Visit 1. 
The investigator or designee will assess local tolerability (of previous vaccination site) and ask 
about any new concomitant medications or AEs occurred since the last visit. The subject’s 
diary will be collected and checked for completeness.  
A blood sample will be collected and PBMCs will be prepared for T cell analysis. 
The subjects are invited to return to study site for Visit 5 on study day 56 (± 5 day). 
 
8.5.5 Visit 5 (day 56 5 days) 
Subjects will be asked to return to site for Visit 5, 51 to 61 days after Visit 1. 
The investigator or designee will examine and document local tolerability (of the previous 
vaccination site) and ask about any new concomitant medications or AEs occurred since the 
last visit. 
Symptom-directed physical examination, system-based assessment (only if necessary 
according to findings in symptom-directed physical exam) and vital signs (systolic and diastolic 
blood pressure, pulse rate and body temperature) will be recorded. A serum pregnancy test 
will be performed in all women. 
Blood samples will be taken for clinical chemistry, haematology, coagulation parameters and 
urine samples will be collected for urinalysis. 
Additionally, blood samples for immunogenicity assessments (measles and Chikungunya 
ELISA, PRNT50) and isolation of serum for passive transfer will be drawn from an appropriate 
 
 
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vein. For T-cell assays blood samples will be collected and PBMCs will be prepared. For details 
on laboratory sampling and testing, see section 8.11. 
Upon Visit 5, the treatment period of this study will be completed. Subjects will be allowed to 
participate in other clinical trials after all procedures of Visit 5 will have been performed.  
Blood pressure and pulse rate will be measured before participants will be discharged, and 
subjects are invited to return to study site for follow up Visit 6 on study day 182 (± 14 days). 
8.6 
Follow up Period 
8.6.1 Visit 6 (day 182 14 days) 
Subjects will be asked to return to site for follow up Visit 6, 168 to 196 days (6 months) after 
Visit 1. 
Blood samples will be collected for immunogenicity assessments (Chikungunya antibody 
ELISA and PRNT50). For details on laboratory sampling and testing, see section 8.11. 
The subjects are invited to return to study site for the final Visit 7 on study day 365 (± 14 days). 
8.6.2 Visit 7 (day 365 14 days), termination visit 
Subjects will be asked to return for the final Visit 7, 351 to 379 days (1 year) after Visit 1. 
Blood samples will be collected for immunogenicity assessments (Chikungunya antibody 
ELISA and PRNT50) and for isolation of serum for passive transfer. For details on laboratory 
sampling and testing, see section 8.11. 
 
8.7 
Early Termination Visit (ET) 
Subjects who are withdrawn or wish to discontinue the study prematurely for any reason shall 
be asked to attend an early termination visit.  
If the early termination occurs within the treatment period (at or before Visit 5), subjects shall 
perform all procedures as defined for Visit 5. If the early termination occurs within the follow 
up period (after Visit 5), subjects shall perform all procedures defined for Visit 7. 
8.8 
Unscheduled Visits 
Unscheduled visits can be conducted whenever deemed necessary. The extent of the 
examination performed at an unscheduled visit is at the discretion of the investigator. All 
procedures completed during an unscheduled visit should be documented in the source data 
and should also be entered to the electronic case report form (eCRF). 
 
 
 
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8.9 
Discontinuation/Withdrawal of Subjects 
Subjects may withdraw from participation in the study at any time.  If a subject withdraws or is 
withdrawn prior to completion of the study, the reason for this decision should be recorded in 
the electronic case report forms (eCRFs) although it is recognised that the subject may refuse 
to provide a reason.  
Generally, any enrolled/vaccinated subject may withdraw or be withdrawn from the study for 
the following reasons: 
• 
The subject withdraws consent 
• 
The subject fails to comply with the requirements of the protocol 
• 
At the discretion of the investigator 
• 
For an adverse event, which at the discretion of the investigator requires discontinuation 
of the subject or results in inability to continue to comply with trial procedures 
• 
if the administration of a drug, which is not permitted by the study protocol, becomes 
necessary (this should be discussed and agreed between the investigator and the sponsor) 
• 
violation of exclusion criteria 1, 4, 5, 7, 12, 15, 16, 17, 18, 19 or 20 during the study (this 
should be discussed and agreed between the investigator and the sponsor) 
All subjects who withdraw or are withdrawn prematurely from the study will undergo an early 
termination visit (see section 8.7). 
8.9.1 Safety Stopping Rules 
Stopping rules are established at subject level and entire study level. 
Individual Subjects Stopping Rules 
The following are specific criteria for discontinuing individual subjects from further vaccination, 
but not from completing scheduled follow-up assessments, unless the subject is explicitly 
withdrawn from the study: 
- Subjects who develop serious adverse reaction (SAR) at the discretion of the 
investigator 
- Subjects who develop a potentially life-threatening (grade 4) solicited systemic adverse 
reaction that occurs without alternative etiology within 7 days after the study vaccination 
- Subjects who develop a medical condition for which continued participation, in the 
opinion of the investigator, would pose a risk to the subject or would be likely to 
confound interpretation of the results 
- Subjects who become pregnant during the treatment phase of the study 
- Subjects who experience anaphylaxis within 24 hours or generalised urticaria within 72 
hours after administration of the study vaccine  
If any of these occur, appropriate measures to treat the subject will be taken and the sponsor 
or the sponsor designee will be notified immediately. 
 
 
 
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Entire Study Stopping Rules 
The study will be stopped (no new enrolments and no additional vaccine administered) pending 
a safety review by the investigator and the sponsor, if any of the following occurs: 
- One or more subjects experience a serious adverse reaction (SAR), based on the 
current reference safety information (Investigator’s Brochure) 
- One or more subjects’ deaths assessed by the investigator, safety manager or 
sponsor as related to investigational product 
- One or more subjects develop laryngospasm, bronchospasm or anaphylaxis within 24 
hours of vaccine administration 
- Three or more subjects develop injection-site ulceration, abscess or necrosis 
- Three or more subjects experience generalised urticaria within 72 hours after 
administration of study product 
Upon completion of this review, the sponsor will determine if study enrolment or treatment 
should be discontinued, or if study enrolment and treatment may continue according to the 
protocol.  
Irrespective of the stopping rules the study may be temporarily suspended or prematurely 
terminated at any time if there is sufficient reasonable cause, and if agreed to by both the 
investigator and the sponsor as being in the best interests of subjects and justified on either 
medical or ethical grounds. In terminating the study, the sponsor, the CRO, and the investigator 
will ensure that adequate consideration is given to the protection of the subjects’ interests. 
Whenever the study is stopped the competent authorities and ethical committees will be 
informed. 
In case the entire study has to be discontinued prematurely, all concerned subjects should be 
asked to perform an early termination visit. 
 
8.9.2 Replacement of Subjects 
Subjects who are discontinued before randomisation will be regarded as screening failures 
and screening will be continued until 60 subjects will be randomised. 
Subjects who withdraw or are withdrawn after randomisation will not be replaced. This may 
result in a decreased number of subjects in the predefined sample size. 
 
8.10 End of Study 
The end of study will be defined as the date of the last visit of the last subject. The study will 
then be stopped. For premature termination or suspension of the study, refer to section 8.9.1 
 
 
 
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8.11 Handling of Samples 
The procedures of sample collection, preparation and storage will be described in detail in a 
study specific Lab-Manual. Blood sampling kits and labels will be supplied by the CRO 
supply vendor. Timepoints and blood volumes are summarised in Table 3. 
 
8.11.1 
Samples for Safety Laboratory Parameters 
Safety laboratory parameters will be analysed by local laboratories according to applicable 
laboratory SOP 
The following parameters will be measured to evaluate inclusion and exclusion criteria only 
once at screening visit (SV).  
- Virology: Hepatitis B surface-Ag, anti-Hepatitis B core-Ab, anti-Hepatitis C-Ab, HIV Ab. HIV 
tests that were performed up to 30 days before screening and where results are available 
are acceptable and do not require a new test. 
 
The following laboratory parameters will be assessed for subject’s safety at screening, Visit 3, 
Visit 5 and additionally at Early Termination (if applicable) as depicted in Table 2. 
- Haematology: haemoglobin, haematocrit, erythrocyte count, differential and total white 
blood count, platelets 
- Chemistry: creatinine, potassium, sodium, calcium, AST, ALT, alkaline phosphatase, 
bilirubin 
- Coagulation parameter: prothrombin time (PT), activated partial thromboplastin time 
(aPTT), fibrinogen  
- Urinalysis: a standard urine test dipstick for determining pH-value, glucose, protein, 
bilirubin, urobilinogen, blood, leucocytes esterase, nitrite, ketone and specific gravity will 
be used. In case of abnormal findings, a microscopy will be done for confirmation.  
- Laboratory values deviating from the normal ranges defined by the local laboratory will be 
evaluated by the investigator. Clinically relevant deviations have to be reported as adverse 
events and graded according to the FDA Guidance for Industry (Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, 
Sept. 2007) 
 
8.11.2 
Immunogenicity Samples 
Plaque reduction neutralisation assay (PRNT50) 
Humoral systemic immune response will be determined by anti-Chikungunya neutralisation 
assay. The 50% plaque reduction neutralisation titre (PRNT50) will be measured to identify 
immunogenicity in sera of all subjects. 
 
 
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At Visits 1, 3, 5, 6 and 7 a volume of 8-10 ml blood will be collected, to isolate serum and freeze 
two aliquots (0.5-1.2 ml /vial) at -80°C, for determination of anti-Chikungunya antibodies by 
PRNT50. 
 
Enzyme linked immunosorbent assay (ELISA) 
In addition, humoral systemic immune response mediated by serum IgG antibodies against 
Chikungunya and against Measles will be determined by IgG ELISA.  
At Visits 1, 3, 5, 6 and 7 a volume of 8-10 ml blood will be collected, to isolate serum and freeze 
two aliquots (3-4 ml /round bottom cryovial) at -80°C, for determination of anti-Chikungunya 
antibodies by ELISA. 
Anti-Measles antibodies will be determined by ELISA out of the same samples collected at 
Visit 1, 3 and 5. Therefor no additional blood sapling will be required for this assay. 
 
T cell Analysis 
Cellular immunogenicity will be determined by evaluation of T cell immune response. 
Therefore, PBMCs will be isolated from fresh blood within 8 hours after blood draw, aliquoted 
in 3-5 cryovials (0.8 ml /vial) and frozen at -80°C for further analysis. The T cells will be re-
stimulated in vitro with Chikungunya virus structural protein peptides to determine the number 
of Chikungunya virus specific T cells after one or two immunisations. 
At Visits 1, 2, 3, 4 and 5 a volume of 24-30 ml blood will be collected for isolation of peripheral 
blood mononuclear cells (PBMCs).  
 
 
8.11.3 
Serum Samples for Passive Transfer 
At Visit 1, a volume of 50 ml and at Visit 3, 5 and 7, a volume of 200 ml blood will be collected 
for isolation of human serum and frozen at -80°C for future efficacy evaluation of the MV-CHIK 
vaccine. Sera of different anti-Chikungunya antibody titres will be transferred to non-human 
primates to investigate protective potential against Chikungunya virus challenge. 
 
 
 
 
 
 
 
 
 
 
 
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Table 3: Blood Sample Collection 
Test 
Type of Vials 
Volume 
ml 
Visits 
Total 
Volume ml 
Virology (HIV, HBV, HCV) 
serum 
* 0  
 VS 
* 0 
β-HCG Pregnancy Test 
serum 
*0, 1x 3-5  
 VS, V1, V3, V5 
 3-5  
Haematology 
EDTA 
3 - 5  
VS, V3, V5 
9-15 
Coagulation 
citrate tubes 
3 - 5  
VS, V3, V5 
9-15 
Clinical Chemistry 
serum 
8 - 10 
VS, V3, V5 
24-30 
PRNT50 
serum 
8 - 10 
V1, V3, V5, V6, V7 
40-50 
ELISA CHIKV 
serum 
8 - 10 
V1, V3, V5, V6, V7 
40-50 
ELISA Measles 
serum 
** 0 
V1, V3, V5 
** 0 
PBMCs for T-cell Analysis  
citrate tubes 
24-30 
V1, V2, V3, V4, V5 
120-150 
Passive Transfer 
serum 
50 + 3x 200 
V1, V3, V5, V7 
650 
 
895-965 
 
 
* 0 ml: Virology testing at screening and pregnancy testing at screening, V3 and V5 will be performed from the 
same sample as Clinical Chemistry, no additional blood draw will be necessary 
** 0 ml: ELISA for determination of Measles antibodies will be performed from the same sample as the ELISA for 
CHIK-Ab, no additional blood draw will be necessary 
 
Total blood volume collected during the entire study duration of one year will be 895-965 ml 
 
8.11.4 
Pregnancy Test – Contraception 
Pregnancy will be determined by evaluation of β-HCG in serum at screening, Visit 1, 3 and 5 
(or at early termination) for all women.  
A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and 
until becoming post-menopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a post-menopausal state in women not using hormonal contraception or 
hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient. 
Only females with a negative result will be allowed to receive study vaccinations. 
Subjects with a positive pregnancy test will be excluded from further treatments and the 
Investigator will inform the CRO immediately by completing a pregnancy report from. Please 
see section 10.6. 
After the last IMP use (Day 56) all subjects will be follow up until Day 365.  
Contraception 
 
 
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Birth control methods which may be considered as highly effective are those that can achieve 
a failure rate of less than 1% per year when used consistently and correctly are considered as 
highly effective birth control methods. Such methods include: 
_ combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
• 
Oral 
• 
Intravaginal 
• 
transdermal 
_ progestogen-only hormonal contraception associated with inhibition of ovulation: 
• 
oral 
• 
injectable 
• 
implantable  
_ intrauterine device (IUD) 
_ intrauterine hormone-releasing system (IUS) 
_ bilateral tubal occlusion  
_ vasectomised partner 
_ sexual abstinence  
 
Acceptable birth control methods which may not be considered as highly effective are those 
that result in a failure rate of more than 1% per year include: 
_ progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action 
_ male or female condom with or without spermicide  
_ cap, diaphragm or sponge with spermicide 
 
Birth control methods which are considered unacceptable include:  
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable 
methods of contraception. Female condom and male condom should not be used together 
8.11.5 
Labelling, Storage and Transport of Samples  
Please refer to the study specific Lab-Manual for detailed information about labelling, storage 
and transport of study serum sample vials. 
Labelling of Samples 
Each sample tube will be clearly and unequivocally identified by a label resistant to the storage 
temperature which contains at least the following information:  
study code, subject number, visit code, test allocation (e.g. ELISA, PRNT50) 
Samples Storage  
Aliquots of samples will be stored at -80°C in a temperature monitored freezer. The 
temperature will be controlled either by a connected central monitoring system or a min/max 
thermometer, which will be controlled and documented each working day. 
Transport of Samples  
 
 
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Study samples packed in sufficient dry ice will be shipped by an authorised courier from the 
study site to the sponsor, a dedicated analytical laboratory or a sample storage facility. Pick 
up of serum samples will be organised together with the site personnel at the end of the study 
or during the study as necessary. 
 
 
 
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9. 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) 
9.1 
Investigational Medicinal Product Description 
9.1.1 MV-CHIK vaccine – test product 
The MV-CHIK vaccine candidate is a recombinant live attenuated viral vectored vaccine, 
based on the backbone of the measles Schwarz virus strain for prophylaxis of Chikungunya 
infection. The heterologous antigens are derived from the Chikungunya virus. 
Nucleotide sequences encoding Chikungunya structural proteins were inserted into the 
Measles virus Schwarz strain to produce the candidate vaccine MV-CHIK expressing 
Chikungunya virus antigens.  
The MV-CHIK vaccine is provided by the sponsor in three different formulations in glass 
vials: 
(1) as lyophilised powder for suspension in water for injection:   
• MV-CHIK 5x104 (± 0.5 log) TCID50/ dose 
 
(2) as liquid frozen suspension for injection in two concentrations: 
• MV-CHIK 1x105 (0.5 log) TCID50 / dose  
• MV-CHIK 1x106 (0.5 log) TCID50 / dose  
 
(3) suspension in stabilising and protecting solution (SPS) for injection: 
• MV-CHIK 1x105 (0.5 log) TCID50 / dose  
 
(1) The lyophilised product will be reconstituted in 0.5 ml/ dose injection grade water and 0.4ml/ 
dose will be administered i.m. Following excipients are present: D-sorbitol, sucrose, sodium 
phosphate, sodium chloride, hydrolysed gelatine and recombinant human serum albumin 
(HAS). No adjuvants are added. The solvent for suspension will be provided by the study sites. 
(2) The frozen formulation will be thawed at room temperature for about 30 min before 0.4 ml 
will be drawn up into a syringe for i.m. administration.  
(3) The solution stabilised in protective SPS formulation will be kept outside the fridge for 
about 10 min to adapt to room temperature before i.m. administration of 0.4 ml 
For a detailed description of the vaccine construct and mechanism of action please refer to the 
current version of the MV-CHIK Investigators’ Brochure. 
For detailed description of receipt, storage, preparation, accountability and destruction of IMP 
please refer to the study specific IMP-Manual. 
9.1.2 Placebo 
A sterile physiological saline solution will be used as placebo to ensure blinding of the 
treatment schedule in case of single vaccination regimen (treatment group E). The 
 
 
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physiological saline solution (0.9% NaCl) is a clear colourless solution ready to use, stored at 
room temperature and provided by the study site.  
 
9.2 
Packaging and Labelling 
Individual cardboard boxes will contain single 2 ml amber glass vials, with rubber stopper and 
aluminium seal, containing either lyophilised powder, frozen liquid or cooled SPS liquid. The 
labels on vials and boxes will be in English language.  
The ready to use IMP syringe will be labelled fulfilling all requirements of EudraLex Volume 4, 
GMP Annex 13, 2010.  
For further details of IMP labelling, please refer to the study specific IMP-Manual. 
 
9.3 
Dose Regimen 
All 60 eligible subjects will receive their first treatment with MV-CHIK at Visit 1 (day 0) and 4 
weeks later their second treatment with MV-CHIK or placebo at Visit 3 (day 28 ±5)  
 
Visit 
VS 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Study Day 
 
0 
14 ±1 
28 ±5 
42 ±5 
56 ±5 
182 ±14 
365 ±14 
Study Treatment 
 
 
 
 
 
 
 
 
 
The 5 treatments groups (A, B, C, D and E) differ in the concentration and formulation of 
MV-CHIK as well as in single or double shot treatment regimen. 
 
Group A: 
Lyophilised formulation  
 
 
 
2x low dose MV-CHIK 5x104 (0.5 log) TCID50/dose  
day 0 and day 28  
 
Group B: 
Liquid frozen formulation  
 
 
 
2x low dose MV-CHIK 1x105  (0.5 log) TCID50/dose  
day 0 and day 28  
 
 
 
 
Group C:  
Liquid SPS formulation 
 
 
 
2x low dose MV-CHIK 1x105  (0.5 log) TCID50/dose 
day 0 and day 28  
 
 
 
 
Group D: 
Liquid frozen formulation 
 
 
 
2x high dose MV-CHIK 1x106 (0.5 log) TCID50/dose 
day 0 and day 28 
  
Group E: 
Liquid frozen formulation  
 
 
 
1x high dose MV-CHIK 1x106 (0.5 log) TCID50 /dose  
day 0  
 
 
 
1x placebo  
 
 
 
 
 
 
day 28 
 
 
 
 
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Table 4: Dose Regimen 
Treatment 
Group 
N 
Vaccine 
Formulation 
Vaccine 
on day 
Placebo 
on day 
A 
12 
MV-CHIK  5x104  /0.4 ml 
lyophilised 
0 + 28 
 
B 
12 
MV-CHIK  1x105  /0.4 ml 
liquid frozen 
0 + 28 
 
C 
12 
MV-CHIK  1x105  /0.4 ml 
liquid SPS® 
0 + 28 
 
D 
12 
MV-CHIK  1x106  /0.4 ml 
liquid frozen 
0 + 28 
 
E 
12 
MV-CHIK  1x106 /0.4 ml 
liquid frozen 
0 
28 
 
9.4 
Storage and Transport Conditions 
The IMP has to be stored under continuously temperature-controlled condition in a lockable 
room, or lockable freezer with limited access. 
The minimum and maximum temperature will be recorded daily in the temperature logs 
throughout the study, except on weekends and holidays if min/max thermometer will be used. 
In case the freezer/fridge is connected to an alarm system and corresponding copies of the 
readout can be filed, a min/max temperature does not need to be recorded daily. It is 
acceptable to use a site-specific temperature log, which covers all the required information.  
MV-CHIK has to be kept in the outer package to be protected from light. 
The lyophilised formulation of MV-CHIK will be stored and transported at -20°C and shall be 
administered within 30 min after preparation, the ready to use formulation can be stored at 
2-8°C for up to 1 hour.  
The liquid frozen formulation of MV-CHIK will be stored and transported at -80°C and shall be 
administered within 30 min after preparation, the ready to use formulation can be stored at 
2-8°C for up to 1 hour.  
The liquid SPS® formulation of MV-CHIK will be stored and transported at 2°- 8°C and shall be 
administered within 30 min after preparation, the ready to use formulation can be stored at 
2-8°C for up to 1 hour.  
The 0.9% saline solution and sterile water diluent will be stored according to instruction leaflet. 
It is under the site’s responsibility to ensure the storage conditions according to the summary 
product characteristics. 
After administration, all used containers properly labelled with subject ID and appropriate visit 
identifier (e.g. visit number, date of administration) will be stored at site until checked by the 
unblinded monitor. 
 
9.5 
IMP Preparation and Distribution 
MV-CHIK and placebo will be prepared and administered by unblinded, authorised and 
qualified staff members (investigator, pharmacist or nurse) otherwise not involved in the 
conduct of the trial after randomisation. Preparation of MV-CHIK for injection will be performed 
in a dedicated lab appropriate for handling of GMOs applying biosafety level 2 (BSL2) 
 
 
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standards although MV-CHIK is assessed as a biosafety level 1 product. BSL2 is applied 
because there is a negative system biological safety level 2 cabinet available within a 
containment room, which usually is used for preparing IMPs. 
MV-CHIK and placebo will be exclusively used for the present clinical trial and will only be 
administered to subjects enrolled in the study.  
For detailed description of receipt, storage, preparation, accountability and destruction of IMP, 
please refer to the study specific IMP-Manual. 
 
9.6 
GMO Handling 
MV-CHIK vaccine is a genetically modified organism requiring biosafety level 1 standards. 
Nevertheless, preparation and disposal of IMP will be performed in a dedicated lab according 
to applicable hygiene standards of biosafety level 2. Needles and syringes that have been in 
contact with MV-CHIK, as well as all other potentially contaminated materials, will be collected 
in dedicated containers and will be destroyed in a safe manner.  
This study will be conducted under regulations for contained use of a GMO.  
 
9.7 
Route and Method of Administration of IMP 
All subjects will receive intra muscular (i.m.) injections of MV-CHIK vaccine or placebo in the 
deltoid region of the non-dominant arm (preferred) or the dominant arm. In case of ongoing 
local AEs from previous vaccinations at the respective injection site, vaccination in the contra-
lateral arm should be performed. 
 
9.8 
Treatment Compliance 
The study medication will be prepared at site and administered during the study Visit 1 and 3. 
Each treatment will be documented in the subject’s charts, the eCRF, an IMP Preparation Log 
and an IMP Inventory Log. Subjects must receive all assigned vaccinations to be considered 
compliant. 
 
9.9 
Study Drug Accountability 
IMP accountability will be performed throughout the entire study, starting with the initial receipt 
of medication. 
The authorised, unblinded study staff members will confirm the number and condition of 
received vials, by signing and dating an IMP receipt form.  
Upon receipt an IMP inventory log will be kept current by the site, detailing the batch numbers, 
dates and quantity of IMP obtained, used for administration on a per subject basis and 
 
 
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destroyed or returned to the sponsor. This documentation will only be available to an unblinded 
monitor verifying drug accountability during the study.  
At the end of the study, all unused and used MV-CHIK vials (marked with subject ID and visit 
number) will be returned to the sponsor or destroyed by the investigator in a confidential 
manner, after final reconciliation and confirmation of correctness of drug accountability. 
 
9.10 Prior and Concomitant Therapy 
9.10.1 
Permitted Prior and Concomitant Therapy 
Any prior vaccination within the last three years prior screening and any medication within 30 
days prior screening has to be documented.  
Any medication taken during the study up to Visit 5 (study day 56) has to be reported to the 
investigator and will be documented.  
Additionally, any treatment that will be considered necessary for the subject’s welfare may be 
given at the discretion of the Investigator. All concomitant medications must be reported in the 
appropriate section of the eCRF along with dosage information, dates of administration, and 
reasons for use. Generic names for concomitant medication should be preferred, if possible. 
All concomitant medications will be coded using the WHO Drug Dictionary. 
9.10.2 
Forbidden Prior and Concomitant Therapy 
Treatments with non-study licensed vaccines within 4 weeks prior to first study vaccination 
until the end of the treatment period (day 56) are not allowed. 
Use of immunosuppressive drugs like corticosteroids (excluding topical preparations) within 
30 days prior to the first vaccination or anticipated use before completion of the treatment 
period (day 56) is not allowed. 
Receipt of blood products or immunoglobulins within 120 days prior to the Screening Visit or 
anticipated receipt of any blood product or immunoglobulin before completion of the treatment 
period (day 56) is not allowed.  
Subjects have to be asked about concomitant medication and vaccinations at each visit. Any 
concomitant medication or vaccination has to be documented. 
 
 
 
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10. SAFETY REPORTING 
10.1 Definitions 
10.1.1 
Adverse Event (AE) 
Any untoward medical occurrence in a participant to whom an investigational medicinal product 
(IMP) has been administered, not necessarily caused by or related to that product. 
An AE can therefore be any unfavourable or unintended sign, abnormal laboratory finding, 
symptom or disease temporally associated with the use of an IMP whether or not considered 
related to the IMP. 
10.1.2 
Adverse Reaction (AR) 
An untoward and unintended response in a participant to an investigational medicinal product 
which is at least possibly related to any dose administered to that participant. 
All cases judged by either the reporting medically qualified professional or the sponsor as 
having a reasonable suspected causal relationship to the trial medication qualify as adverse 
reactions. 
10.1.3 
Serious Adverse Event (SAE) 
A serious adverse event is any untoward medical occurrence that: 
• 
results in death 
• 
is life-threatening 
• 
requires inpatient hospitalisation or prolongation of existing hospitalisation 
• 
results in persistent or significant disability/incapacity 
• 
consists of a congenital anomaly or birth defect 
Other ‘important medical events’ may also be considered serious if they jeopardise the 
participant or require an intervention to prevent one of the above consequences. 
The term "life-threatening" in the definition of "serious" refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event which 
hypothetically might have caused death if it were more severe. 
Any pregnancy occurring during the clinical trial and the outcome of the pregnancy will be 
recorded and followed up for congenital abnormality or birth defect, at which point it would fall 
within the definition of “serious”. 
NOTE: to avoid confusion or misunderstanding of the difference between the terms “serious” 
and “severe”, the following note of clarification is provided: “Severe” is used to describe the 
intensity of a specific adverse event, while “seriousness” is used for defining regulatory 
reporting obligations as supplied above. 
 
 
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10.1.4 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A serious adverse reaction, the nature, severity or outcome of which is not consistent with the 
applicable product information.  
10.1.5 
Causality 
The relationship of each AE to the IMP must be determined by a medically qualified person 
according to the following definitions: 
Definitely: Temporal relationship to the administration of the study drug and course following a 
known reaction pattern 
Probably: Good reasons and sufficient documentation to assume a causal relationship 
Possibly: A causal relationship is conceivable and cannot be dismissed 
Unlikely: The event is most likely related to an etiology other than the trial treatment 
Not Related: No temporal relationship to the administration of the drug or other factors have 
caused the event 
10.1.6 
Severity 
AEs must be graded by a medically qualified person as being mild, moderate, severe or life-
threatening and their approximate duration given. Definitions of severity are as follows: 
Mild: an AE that requires minimal or no treatment and does not interfere with daily activities; 
Moderate: an AE that is sufficiently discomforting to interfere with normal activities; 
Severe: an AE that is incapacitating or prevents normal activities and may require systemic 
drug therapy or other treatment. 
Potentially life threatening:  an AE that requires immediate intervention to prevent death.  
"life-threatening" refers to an AE in which the subject was at risk of death at the time of the 
event, it does not refer to an AE which hypothetically might have caused death if it were more 
severe.  
Please see Appendix 1 for stencil to be used for grading local injection site reactions and Table 
5 and 6 for grading of systemic and local reactions. 
 
10.1.7 
Expectedness 
Expectedness will be determined considering the current Investigators’ Brochure. 
Expected: an AE that is listed in the current Investigator's Brochure of MV-CHIK. 
Unexpected: an AE that is not listed in the current Investigator's Brochure or differs due to 
greater severity or greater specificity. 
 
 
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All SAEs assessed as unexpected and suspected to be related to the IMP qualify for a SUSAR 
(suspected unexpected serious adverse reaction) and require expedited reporting. 
10.1.8 
Outcome  
Recovered: A subject has recovered from an AE, when all signs or symptoms returned to 
normal. 
Stabilised: An AE is stabilised when, according to the investigator, the subject is in a clinically 
stable condition. This term should only be used for chronic conditions and for a given subject 
only when he/she has completed the study. 
Recovered with sequelae: As a result of the SAE, the subject is suffering from persistent or 
significant disability/incapacity (e.g. became blind, deaf, paralysed). Any AE recovered with 
sequelae should be rated as an SAE since an SAE criterion is fulfilled. 
Not Recovered: An AE currently ongoing. 
Ongoing at final examination: An AE ongoing at the subject’s last visit. 
Died: An AE that caused death. 
 
10.2 Recording of Adverse Events 
All AEs occurring during the treatment period starting after the first vaccination at Visit 1 until 
termination of Visit 5 (day 56) observed by the investigator or reported by the subject (verbally 
or in the subject diary), will be recorded, whether or not related to the study treatment. 
AEs will be requested at each visit during the treatment period up to Visit 5 (day 56) and 
additionally solicited by a subject’s diary for 7 days after each vaccination. (see section 11.7) 
The subjects will be asked generally (e.g. "How are you?") as well as specifically (e.g. “Have 
you experienced any problems since the last visit?”).  
The investigator must record all adverse events in the eCRF. One single adverse event page 
must be used per adverse event, from start to resolution, stating the following information:  
AE description, date of onset and end date, severity, relatedness, seriousness and action 
taken. Please consider definitions of section 10.1. Follow-up information should be provided 
as necessary.  
If possible, the investigator should record the diagnosis. If a diagnosis is not available, the 
investigator should record each sign and symptom as individual adverse events. However, as 
soon as a diagnosis becomes available, all signs and symptoms should be summarised and 
replaced by the underlying adverse event term (e.g. common cold instead of separate AEs for 
headache, rhinorrhoea, arthralgia, fever etc.) 
The AE should be documented stating the highest severity (i.e. if an AE goes from mild severity 
to moderate severity or vice versa, the whole episode of the AE should be reported with the 
moderate severity). Please consider Table 5 and 6 for grading local injection site reactions and 
systemic reactions. 
 
 
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Pr ot o c ol M V -C HI K -2 0 5  
   E u dr a C T 2 0 1 8 -0 0 0 2 1 1 -2 5  V er si o n 1. 4 , 0 8 -A u g u st -2 0 1 8  
P a g e 4 9 /6 8  
F or c a u s alit y r e p orti n g p ur p o s e s, t h e c at e g ori e s " d ef i nit el y", " pr o b a bl y" a n d " p o s si bl y" q u alif y 
a n e v e nt a s " s u s p e ct e d" a d v er s e r e a cti o n. A E s wit h mi s si n g c a u s alit y a s s e s s m e nt will b e 
r e g ar d e d a s p o s si bl y r el at e d u nl e s s f urt h er s p e cifi e d. 
A n y m e di c al c o n diti o n t h at i s pr e s e nt at s cr e e n i n g will b e c o n si d er e d a s m e di c al hi st or y  a n d 
n ot r e p ort e d a s a n A E. H o w e v er, if t h e s u bj e ct’ s  c o n diti o n d et eri or at e s at a n y ti m e d uri n g t h e 
st u d y, it will b e r e c or d e d a s a n A E.  
It will b e l eft t o t h e in v e sti g at or’ s cli ni c al j u d g m e nt t o d e ci d e w h et h er a n A E  re q uir e s  t h e 
s u bj e ct’ s r e m o v al fr o m t h e st u d y. I n c a s e of di s c o nti n u ati o n, t h e s u bj e ct  will u n d er g o a n e arl y 
t er mi n ati o n vi sit. 
 
1 0. 3  R e p orti n g of  S eri o u s A d v er s e E v e nt s  
T h e i n v e sti g at or s h o ul d r e p ort all S A E s o c c urri n g d uri n g t h e tr e at m e nt p eri o d ( w h et h er or n ot 
r el at e d t o t h e I M P) wit hi n 2 4 h o ur s of t h e sit e st u d y t e a m b e c o mi n g a w ar e of t h e e v e nt , t o t h e 
A s si g n S af et y D e s k b y c o m pl eti n g a n  S A E R e p ort F or m . 
T h e c o m pl et e d S A E R e p ort F or m s h o ul d b e s u b mitt e d t o t h e A s si g n S af et y D e s k eit h er b y f a x 
or a s p df p er e -m ail:  
F a x:  
 
E m ail:  
 
 
F or ur g e nt q u e sti o n s, pl e a s e c all t h e  2 4 -h o ur s S af et y H otli n e:  
 
U n d er c ert ai n cir c u m st a n c e s, t h e fir st n o tifi c ati o n c a n b e d o n e b y p h o n e,  n e v ert h el e s s, a 
writt e n S eri o u s A d v er s e E v e nt R e p ort F or m s h o ul d b e s u b mitt e d f or c o nfir m ati o n t o A s si g n 
S af et y D e s k.  
Aft er t h e i niti al  S A E r e p ort t h e i n v e sti g at or will  f oll o w u p pr o a cti v el y e a c h s u bj e ct a n d pr o vi d e 
f urt h er i nf or m ati o n li k e c o pi e s of h o s pit al c a s e r e p ort s, l a b or at or y r e p ort s or a ut o p s y r e p ort s , 
t o t h e A s si g n S af et y D e s k wit hi n 2 4 h aft er r e c ei pt.  
A s si g n  S af et y D e s k  will a s s e s s i niti al a n d f oll o w -u p S A E r e p ort s fr o m t h e sit e f or e x p e ct e d n e s s, 
w hi c h will b e d et er mi n e d b a s e d o n  t h e m o st r e c e nt e diti o n of t h e I n v e sti g at or’ s Br o c h ur e.   
R e p ort s of s u s p e ct e d u n e x p e ct e d s eri o u s a d v er s e re a cti o n s ( S U S A R s) will b e  r e p ort e d i n a n 
e x p e dit e d m a n n er t o t h e r e g ul at or y a ut h oriti e s a s r e q uir e d p er l o c al r e g ul ati o n s wit hi n t h e 
r e q uir e d ti m e fr a m e.  
T h e ori gi n al c o p y of t h e S A E R e p ort F or m a n d t h e f a x c o nfir m ati o n s h e et m u st b e k e pt wit h 
t h e d o c u m e nt ati o n at t h e st u d y sit e. E a c h S A E h a s al s o t o b e d o c u m e nt e d i n t h e e C R F a s a 
s eri o u s a d v er s e e v e nt i n t h e c orr e s p o n di n g A E s e cti o n.  
 
1 0. 4  F oll o w -u p of A d v er s e E v e nt s  
D uri n g a n d f oll o wi n g a s u bj e ct’ s p arti ci p ati o n i n a c li ni c al tri al, t h e i n v e sti g at or will e n s ur e t h at 
a d e q u at e m e di c al c ar e i s pr o vi d e d t o t h e s u bj e ct f or a n y a d v er s e e v e nt s, i n cl u di n g cli ni c all y 
si g nifi c a nt l a b or at or y v al u e s r el at e d t o t h e tri al.  
 
 
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All n o n -s eri o u s a n d s eri o u s a d v er s e e v e nt s will  b e f oll o w e d u ntil t h e  s u bj e ct h a s r e c o v er e d, 
st a bili s e d, r e c o v er e d wit h s e q u el a e or di e d u ntil e n d of t h e st u d y .  
F oll o w -u p i nf or m ati o n a b o ut a pr e vi o u sl y r e p ort e d S A E m u st al s o b e r e p ort e d wit hi n 2 4 h o ur s 
of t h e i n v e sti g at or r e c ei vi n g it. T h e i niti al S A E r e p ort f or m s h o ul d b e u s e d, st ati n g t h at t hi s i s a 
f oll o w-u p r e p ort t o t h e pr e vi o u sl y r e p ort e d S A E a n d gi vi n g t h e n u m b er a n d d at e of t h e f oll o w -
u p r e p ort. T h e i nf or m ati o n pr o vi d e d s h o ul d d e s cri b e w h et h er t h e e v e nt h a s r e s ol v e d or 
c o nti n u e s, if a n d h o w it w a s tr e at e d, a n d w h et h er t h e s u bj e ct c o nti n u e d or di s c o nti n u e d st u d y 
p arti ci p ati o n, if n ot alr e a d y st at e d i n t h e i n iti al r e p ort.  
 
1 0. 5  R e p orti n g  of S U S A R s  
A s eri o u s a d v er s e r e a cti o n  t h at i s n ot e x p e ct e d a c c or di n g t o t h e c urr e nt I B a n d w er e t h e 
c a u s alit y i s a s s e s s e d a s " d efi nit el y", " pr o b a bl y" or  " p o s si bl y", q u alifi e s a s " s u s p e ct e d" 
u n e x p e ct e d s eri o u s a d v er s e r e a cti o n.  
O n b e h alf of t h e s p o n s or , A s si g n S af et y D e s k will b e  r e s p o n si bl e t o f ulfil t h e r e q uir e m e nt s of 
e x p e dit e d r e p orti n g of all S U S A R s ( s u s p e c t e d u n e x p e ct e d s eri o u s a d v er s e re a cti o n s ) t o t h e 
C o m p et e nt A ut h oriti e s, Et hi c s C o m mitt e e s a n d pri n ci p al i n v e sti g at or s c o n c er n e d a c c or di n g t o 
n ati o n al a n d E ur o p e a n l a w a n d r e g ul ati o n s.  
F or f at al a n d lif e -t hr e at e ni n g S U S A Rs , t hi s will b e d o n e n o l at er t h a n 7 c al e n d ar d a y s aft er t h e 
s p o n s or or d el e g at e i s fir st a w ar e of t h e r e a cti o n. A n y a d diti o n al r el e v a nt i nf or m ati o n t o t h e 
i niti al r e p ort t h at w a s n ot a v ail a bl e wit hi n t h e 7 c al e n d ar d a y s will b e r e p ort e d wit hi n  8 a d diti o n al 
c al e n d ar d a y s. All ot h er S U S A R s will b e r e p ort e d wit hi n 1 5 c al e n d ar d a y s.  
Tr e at m e nt c o d e s will b e u n bli n d e d f or s p e cifi c p arti ci p a nt s.  
Pri n ci p al in v e sti g at or s will b e i nf or m e d of all S U S A R s r el at e d t o t h e r el e v a nt I M P f or all st u di e s 
c o n d u ct e d wit h t h e s a m e I M P, w h et h er or n ot t h e e v e nt o c c urr e d i n t h e c urr e nt tri al. 
 
1 0. 6  R e p orti n g of Pr e g n a n ci e s  
W o m e n s h o ul d n ot b e c o m e pr e g n a nt d uri n g t h e 
tr e at m e nt p eri o d of t h e st u d y. If a s u bj e ct 
b e c o m e s pr e g n a nt wit hi n t h e tr e at m e nt p eri o d u p t o d a y 5 6 , s h e s h o ul d i m m e di at el y i nf or m 
t h e i n v e sti g at or a b o ut  t h e pr e g n a n c y.  
T h e i n v e sti g at or will c o m pl et e a c orr e s p o n di n g Pr e g n a n c y R e p ort F or m a n d s e n d t h e f o r m 
wit hi n 2 4 h o ur s aft er b e c o mi n g a w ar e t o A s si g n S af et y D e s k vi a f a x  or a s p df p er e -m ail:   
F a x:  
 
E m ail:  
 
 
T h e fir st n otifi c ati o n c a n b e d o n e vi a p h o n e  2 4 -h o ur s S af et y H otli n e: 
 
N e v ert h el e s s,  a writt e n Pr e g n a n c y R e p ort F or m m u st b e s u b mitt e d f or c o nfir m ati o n. T h e 
s u bj e ct s h o ul d att e n d f oll o w -u p vi sit s a s pl a n n e d. I n a d diti o n, s u bj e ct s w h o b e c o m e pr e g n a nt 
wit hi n t h e tr e at m e nt p eri o d u p t o d a y 5 6  (a n d w h o r e c ei v e d at l e a st o n e d o s e) will b e f oll o w e d 
u ntil t h e pr e g n a n c y o ut c o m e, e v e n if t hi s o c c ur s aft er t h e st u d y i s c o m pl et e d.  
 
 
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Pregnancy itself is not regarded as an AE unless there is a suspicion that the IMP may have 
interfered with the effectiveness of a contraceptive medication. However, the outcome of all 
pregnancies that begin before day 56 (spontaneous miscarriage, elective termination, normal 
birth or congenital abnormality) will be followed up and documented even if the subject was 
discontinued from the study. 
A pregnancy outcome of a congenital abnormality/birth defect would qualify as an SAE and 
will be reported to Assign Safety Desk for processing to the regulatory authority. A pregnancy 
outcome of an elective abortion without evidence of complications would not be processed as 
an AE. 
 
10.7 Development Safety Update Reports 
Assign Data Management and Biostatistics GmbH will submit a DSUR once a year throughout 
the clinical trial to the competent authority (MHRA), ethics committee, HRA (where required) 
and Host NHS trust according to applicable regulations and requirements. 
 
 
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11. ASSESSMENT OF SAFETY  
Adverse event rates compared between 5 different treatment groups will be used to evaluate 
the secondary study objective. Please also refer to Table 2, summarising study procedures 
including safety assessments.  
 
11.1 Safety Laboratory Parameter Assessments 
Haematology, blood chemistry, coagulation parameters and urinalysis will be assessed for 
subject’s safety at screening, Visit 3, Visit 5 and additionally at Early Termination (if applicable). 
Please refer to section 8.11.1  
 
11.2 Symptom-directed Physical Examination  
A full physical exam will be performed at screening and a system based physical examination 
will be done, if necessary according to findings in a symptom-directed physical examination at 
Visit 1, 3 and 5. This means if a symptom is reported by the subject, a system-based 
assessment will be performed, if needed, for a detailed check of the affected body system.  
Any symptom reported after first vaccination, including worsening of pre-existing conditions 
(i.e. medical history/concomitant diseases), will be recorded as AE. 
 
11.3 System-based Physical Examination 
All subjects will undergo a system-based physical examination, including but not limited to 
assessment of general appearance and skin, head/eyes/ears/nose/throat, respiratory system, 
cardiovascular system, abdominal and gastrointestinal system, musculoskeletal system, 
neurological system and lymph nodes. 
This system-based physical examination will only be performed if necessary according to 
findings of the symptom-directed physical exam at Visit 1, 3 and 5. 
 
11.4 Vital Signs and Body Temperature 
Systolic and diastolic blood pressure and pulse rate as well as body temperature will be 
recorded at screening and Visit 1, 3 and 5 with the subject at rest in a sitting position. 
 
11.5 Post Vaccination Reactogenicity Assessments 
All subjects enrolled in the study and who receive at least one study treatment (MV-CHIK or 
placebo) will be followed up 28 days after each study treatment. Solicited and unsolicited AEs 
will be recorded at each visit until the end of the treatment phase at Visit 5. 
 
 
 
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11.6 Local and Systemic Tolerability 
The local tolerability (i.e. injection site reactions) will be inspected and evaluated by the 
investigator two hours after each IMP administration.  
Additionally, local tolerability (i.e. inspection of the previous injection site) will be assessed at 
the following visits and prior to application of the subsequent vaccination at Visit 3 (day 28). 
Furthermore, local tolerability will be evaluated by the subjects in the subject diaries for 7 days 
starting 6 hours after each treatment.  
The grading of local reaction will be performed by means of a stencil (provided to the subject 
as shown in Appendix 1) and per "Guidance for Industry: Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials", modified, 
reflecting the guidance of the Brighton Collaboration (Table 5). 
Findings in the local tolerability examination by the investigator as well as local tolerability 
findings recorded in the subject diary will be covered as adverse events in the eCRF.  
 
11.7 Subject Diary 
The subjects will be instructed to complete a diary for 7 days after each vaccination to 
document local and systemic tolerability as well as body temperature. 
Solicited local and solicited systemic AEs will be assessed by the subjects themselves by 
checking for presence of the listed symptoms and measuring the size of the affected area 
where appropriate (a template will be provided for local reaction grading, as shown in Appendix 
1). The diary will also provide space for recording unsolicited AEs and concomitant medication.  
Recording should be done approximately at the same time each day, starting on the day of 
vaccination. The first entry should be made 6 hours 1h after vaccination at Visit 1 and Visit 3.  
The subjects’ diaries will be collected and verified for completeness by the investigator at 
Visit 2 and Visit 4. Any AE recorded in the subject diaries will be entered in the eCRF by the 
investigator or authorised delegates. The investigator will re-evaluate the severity of the 
reported local and systemic AEs according to the below Tables 5 and 6. 
Diary solicited systemic AEs include: nausea, vomiting, headache and fatigue, also to be 
documented in the eCRF.  
In addition, body temperature will be recorded daily for 7 days and fever will be graded by the 
investigator according to the FDA Guidance for Industry. For details see below Table 6. 
 
 
 
 
 
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Table 5: Grading of Local Reactions 
Local reaction 
to injectable 
product 
Mild  
(grade 1) 
Moderate  
(grade 2) 
Severe  
(grade 3) 
Potentially life 
threatening 
(grade 4) 
Pain 
Does not 
interfere with 
activity 
Interfere with activity 
or repeated use of 
non-narcotic pain 
reliever 
Prevents daily activity 
or repeated use of non-
narcotic pain reliever 
Emergency room 
(ER) visit or 
hospitalisation 
Tenderness 
Mild pain to touch 
Pain with movement 
Significant pain at rest 
ER visit or 
hospitalisation 
Erythema/ 
Redness1 
≤ 5 cm 
5.1–10 cm 
> 10 cm 
Necrosis or exfoliate 
dermatitis 
Swelling2 
≤ 5 cm and does 
not interfere with 
activity  
5.1–10 cm or 
interfere with activity 
> 10 cm or prevents 
daily activity 
Necrosis 
Itching 
Does not 
interfere with 
activity 
Interferes with activity 
or repeated use of 
non-narcotic pain 
reliever 
Prevents daily activity 
or repeated use of anti-
inflammation and pain-
relieving ointment 
Emergency room 
(ER) visit or 
hospitalisation 
Induration1 
≤ 1 cm 
Does not 
interfere with 
activity 
> 1 to < 3 cm 
Interferes with activity 
or repeated use of 
non-narcotic pain 
reliever 
≥ 3 cm 
Prevents daily activity 
or repeated use of anti-
inflammation and pain-
relieving ointment 
Not applicable 
1 In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a 
 continuous variable. 
2  Swelling should be evaluated and graded using the functional scale as well as the actual measurement. 
 
 
 
Table 6: Grading of Systemic Reactions 
Systemic 
Reaction 
(General) 
Mild  
(grade 1) 
Moderate  
(grade 2) 
Severe  
(grade 3) 
Potentially life 
threatening 
(grade 4) 
Nausea/ 
vomiting 
No interference with 
activity or 1-2 
episodes/ 24 hours 
Some interference 
with activity or >2 
episodes/ 24 hours 
Prevents daily activity, 
requires outpatient IV 
hydration 
Emergency room 
(ER) visit or 
hospitalisation for 
hypotensive shock 
Diarrhoea 
2-3 loose stools or < 
400 gms/ 24hours 
4-5 stools or < 400-
800 gms/ 24hours 
6 or more watery 
stools or >800 gms/ 
24 hours or requires 
outpatient IV 
hydration 
ER visit or 
hospitalisation 
Headache 
No interference with 
activity 
Repeated use of 
non-narcotic pain 
reliever >24 hours or 
some interference 
with activity 
Significant; any use 
of narcotic pain 
reliever or prevents 
daily activity 
ER visit or 
hospitalisation 
Fatigue 
No interference with 
activity 
Some interference 
with activity 
Significant; prevents 
daily activity 
ER visit or 
hospitalisation 
Myalgia 
No interference with 
activity 
Some interference 
with activity 
Significant; prevents 
daily activity 
ER visit or 
hospitalisation 
Illness or 
clinical AE 
(as defined 
according to 
applicable 
regulations) 
No interference with 
activity 
Some interference 
with activity not 
requiring medical 
intervention 
Prevents daily 
activity and requires 
medical intervention 
ER visit or 
hospitalisation 
Fever (°C) 
38.0 - 38.4 
38.5 - 38.9 
39.0 - 40.0 
>40.0 
 
 
 
 
 
 
 
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12. STATISTICS 
The data will be analysed by Assign Data Management and Biostatistics GmbH. A Statistical 
Analysis Plan (SAP) will be finalised before database snapshot/closure providing a detailed 
description on the statistical methods and evaluation of study results. 
An interim analysis will be performed after all subjects completed the treatment period and the 
final analysis will be conducted after the last subject completed the last visit. 
 
12.1 Interim Analysis 
A preliminary analysis including safety and immunogenicity data will be performed after all 
subjects completed Visit 5 (day 56) and therefore terminated the treatment period of the study. 
The purpose of this analysis is to provide highly valuable data for further Chikungunya vaccine 
development including the efficacy evaluation, by passive transfer of anti-Chikungunya 
antibodies to virus susceptible non-human primates. 
Results from this interim analysis will not have any impact on the study design or the subjects 
during the follow up period of the study.  
 
12.2 Methods of Statistical Immunogenicity Analysis 
The immunogenicity analysis will compare the anti-Chikungunya PRNT50 antibody geometric 
mean titre (GMT) 28 days after the last MV-CHIK vaccination in the Per Protocol (PP) analysis 
population between the treatment groups. GMTs and GMT ratios will be estimated by applying 
an analysis of variance including the factor treatment group. This will be done using log10 
transformed data and taking the anti-log of the resulting point estimates for the least squares 
means, least squares means differences and the corresponding 2-sided 95% CIs.  
P-values will also be provided to compare GMTs between the treatment groups adjusted for 
multiple comparisons according to Tukey-Kramer. Likewise, seroconversion rates will be 
compared between groups.  
Seroconversion will be defined as anti-Chikungunya PRNT50 titres ≥10. 
Measles- and Chikungunya- ELISA titres will be analysed as described above.  
In addition, the long-term stability of anti-Chikungunya antibodies determined by PRNT50 and 
ELISA, 6 months and one year after the first immunisation, will be analysed compared between 
the five treatment groups. 
 
12.3 Methods of Statistical Safety Analysis 
The analysis of safety will be performed by means of descriptive measures in the Safety 
Population. Solicited and unsolicited AEs (local and systemic) will be analysed descriptively. 
AEs and concomitant diseases will be coded using the MedDRA coding dictionary.  
 
 
 
 
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Solicited AEs (reactogenicity):  
Solicited local and systemic AEs gathered by the subjects’ diaries will be summarised for the 
7-day period, by AE grading (mild, moderate, severe) and by treatment group. The number 
and percentage of subjects with AEs will be presented. Fisher exact tests will be provided for 
a comparison of AE rates between treatment groups in summary tables. 
Unsolicited AEs:  
Separately, the number and percentage of subjects with unsolicited/spontaneous adverse 
events (AEs), medically-attended AEs (MAEs) and serious adverse events (SAEs) will be 
presented for each treatment group overall, and by system organ class/preferred term, by AE 
grade, and relatedness. Fisher exact tests will be provided for a comparison of AE rates 
between treatment groups. 
Laboratory values and vital signs as well as changes in laboratory values from baseline will be 
analysed descriptively by time point and treatment group.  
 
12.4  Determination and Justification of Sample Size 
A formal sample size calculation was not conducted. The sample size of 60 subjects has been 
determined based on prior experience in evaluating the safety and immunogenicity of vaccines 
and is typical for early phase clinical studies. Sample size for this study was determined on 
grounds of feasibility and common practice in similar trials. 
 
12.5  Analysis Populations 
12.5.1 
Safety Population 
All safety analyses will be based on the safety population, defined as subjects who entered 
into the study and received at least one IMP administration. All analysis based on the Safety 
Population will be carried out using the actual treatment received.  
12.5.2 
Modified Intent-to-Treat (mITT) Population 
The secondary immunogenicity analyses will be based on the modified ITT population. The 
modified intent-to-treat (mITT) analysis population is defined to include all subjects randomised 
who receive at least one IMP administration. Subjects will be analysed according to the 
treatment group they had been allocated to, rather than by the actual treatment they received. 
12.5.3 
Per-Protocol (PP) Population 
As a primary analysis, immunogenicity will be assessed on the per-protocol (PP) population. 
The PP population includes subjects without protocol deviations that could impact immune 
response. Examples that may lead to exclusion from the PP population are provided here 
(further criteria may be defined in the SAP): 
 
 
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- Immunosuppressive drugs: Use of corticosteroids (excluding topical preparations) or 
immunosuppressive drugs within 30 days prior to first IMP administration, or anticipated 
use during the trial. 
- Subjects with any confirmed immunosuppressive or immunodeficient condition, 
including human immunodeficiency virus (HIV), hepatitis A, B or C infection or a family 
history of congenital or hereditary immunodeficiency 
- Subjects who received the wrong or no IMP 
These criteria for potential protocol violation are identified at the time of planning the study. 
However, during the course of the trial unforeseen events may occur or new scientific 
knowledge may become available, therefore final decisions on whether any protocol violation 
could impact immune response and thus lead to exclusion from the PP population will be made 
by the sponsor on a case by case basis in a blinded manner (and prior to study unblinding). 
Sample testing issues may also lead to exclusion from the PP population for particular time 
points.  
 
12.6 Statistical Analysis Plan 
A Statistical Analysis Plan (SAP) will be written and finalised prior to any lock of the study 
database. The SAP will provide a detailed description of the statistical methods and expand 
on the details provided in the protocol. Additional analyses may be added.  
 
12.7  Missing Data 
All attempts will be made to prevent missing data and generally, missing will not be imputed, 
and analysis will be limited to observed values. However, for missing data in AE evaluation 
(e.g. missing information about severity or causality) a worst-case approach will be applied.  
 
 
 
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1 3.  Q U A LI T Y C O N T R O L A N D  Q U A LI T Y A S S U R A N C E  
T h e tri al will b e c o n d u ct e d i n a c c or d a n c e wit h t h e c urr e nt a p pr o v e d pr ot o c ol, I C H G C P 
g ui d eli n e s , r el e v a nt r e g ul ati o n s a n d st a n d ar d o p er ati n g pr o c e d ur e s. 
 
1 3. 1  P eri o di c M o nit ori n g  
A d e si g n at e d Cli ni c al R e s e ar c h A s s o ci at e  ( C R A) will m o nit or st u d y pr o gr e s s b y s c h e d uli n g 
a n d p erf or mi n g o n -sit e st u d y vi sit s t hr o u g h o ut t h e st u d y i n cl u di n g sit e i niti ati o n vi sit, s e v er al 
sit e 
m o nit ori n g vi sit s a n d sit e cl o s e o ut vi sit. A t r e g ul ar i nt er v al s t hr o u g h o ut t h e st u d y 
m o nit ori n g vi sit s will b e  p erf or m e d t o v erif y c o m pl et e n e s s , a c c ur a c y a n d c o n si st e n c y of d at a  
i n t h e e C R F s , pr ot o c ol a d h er e n c e , a d h er e n c e t o G C P 
a n d t h e a p pli c a bl e r e g ul at or y 
r e q uir e m e nt s. Fr e q u e n c y a n d s c o p e of s o ur c e d at a v erifi c ati o n  will b e d et er mi n e d b ef or e st u d y 
st art a n d d et ail e d i n t h e M o nit ori n g Pl a n.  
T h er ef or e,  th e m o nit or m u st  h a v e a c c e s s t o all s o ur c e r e c or d s n e e d e d t o v erif y t h e e ntri e s o n 
t h e e C R F s. T h e i n v e sti g at or will c o o p er at e wit h t h e m o nit or t o e n s ur e t h at a n y di s cr e p a n ci e s 
i d e ntifi e d ar e r e s ol v e d. 
T h e p eri o di c m o nit ori n g will b e p erf or m e d b y C e leri o n, 2 2 -2 4 Li s b ur n R o a d, B elf a st B T 9 6 A D  
T el: 
 
 
1 3. 2  A u dit a n d I n s p e cti o n  
U p o n r e q u e st, t h e i n v e sti g at or will m a k e all st u d y -r el at e d s o ur c e d at a a n d r e c or d s a v ail a bl e t o 
a q u alifi e d q u alit y a s s ur a n c e a u dit or m a n d at e d b y t h e s p o n s or or t o r e g ul at or y i n s p e ct or s.  
T h e 
in v e sti g at or 
or 
d e si g n e e 
s h o ul d 
c o nt a ct t h e 
s p o n s or/ C R O i m m e di at el y  u p o n 
a n n o u n c e m e nt of a n a u dit b y t h e r e g ul at or y a ut h orit y. H e/ s h e  f urt h er a gr e e s t o f ull y c o o p er at e 
wit h r e g ul at or y a ut h oriti e s a n d p arti ci p at e wit h a u dit s c o n d u ct e d at a c o n v e ni e nt ti m e i n a 
r e a s o n a bl e m a n n er. 
T h e m ai n p ur p o s e s of a n a u dit or i n s p e cti o n ar e t o c o nfir m t h at t h e ri g ht s a n d w elf ar e of t h e 
s u bj e ct s h a v e b e e n a d e q u at el y pr ot e ct e d , to a s s e s s w h et h er et hi c s, r e g ul at or y a n d q u alit y 
r e q uir e m e nt s ar e m et a n d t o v erif y t h at all d at a r el e v a nt f or t h e a s s e s s m e nt of s af et y a n d 
i m m u n o g e ni cit y of t h e i n v e sti g ati o n al pr o d u ct h a v e a p pr o pri at el y b e e n r e p ort e d t o t h e s p o n s or.  
 
 
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14. ETHICS 
14.1 Ethical Conduct of the Study 
This study will be conducted in compliance with relevant regulatory requirements, ICH GCP 
guidelines of the Declaration of Helsinki for biomedical research involving human subjects and 
the EU directive 2005/28/EC. 
 
14.2 Independent Ethics Committees (IEC) 
Prior to initiation of the study, the protocol, subject informed consent form, any other written 
information to be provided to the subject, any proposed advertising material, investigator’s 
brochure (IB), information about payments and compensation available to subjects if not 
mentioned in the subject information, investigator’s current CV and other documentation 
evidencing qualifications, and other documents as required by the independent ethics 
committee should be submitted.  
Written approval/favourable opinion must be obtained from the IEC prior to commencement of 
the study. This approval should include a statement that these documents comply with GCP 
requirements and must identify the documents and versions reviewed. 
During the trial, the investigator must promptly report the following to the IEC: amendments to 
the protocol, updates to IB, unexpected SAEs where a causal relationship cannot be ruled out, 
notes of administrative changes, deviations to the protocol implemented to eliminate 
immediate hazards to the trial subjects, new information that may affect adversely the safety 
of the subjects or the conduct of the trial, annually written summaries of the trial status, and 
other documents as required by the local IEC. 
Amendments must not be implemented before approval/favourable opinion, unless necessary 
to eliminate immediate hazards to the subjects. 
 
14.3 Regulatory Authority 
The regulatory authority will receive the protocol, amendments, reports on SAEs, and related 
relevant safety information, including the final report according to EU Directive and national 
regulations. 
Written approval/favourable opinion must be obtained from the regulatory authorities prior to 
commencement of the study and for all substantial amendments to the original documents 
before implementation. 
 
 
 
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15. DATA HANDLING AND RECORD KEEPING 
15.1 Source Data and Records 
Source documents are where data are first recorded and from which subjects’ eCRF data are 
obtained. These include, but are not limited to, original charts (subjects’ records), laboratory 
and pharmacy printouts, diaries, and data from automated instruments. On all trial-specific 
documents, other than the signed consent, the participant will be referred to by subject number, 
not by name. 
 
At least the following data will be documented in the source records: 
- Study identification, date of subject’s study entry and termination  
- Subject number 
- Documentation of informed consent procedure 
- Date of each study visit  
- Medical history, demographic data 
- Any examination findings, including local injection site reactions 
- Adverse events 
- Concomitant medication intake 
- Early withdrawal date and withdrawal reason, if applicable 
- Treatment dates  
- Completed subject diaries 
 
Source data entries must be made in accordance with GCP and local requirements.  
The investigator will permit study-related monitoring, audits, IRB/IEC review and regulatory 
inspections, by providing direct access to source data. Source records should be preserved 
for the maximum period of time required by local regulations. 
 
15.2 Access to Data 
Direct access to source data and documents will be granted to authorised representatives from 
the sponsor, host institution and the competent authorities to permit trial-related monitoring, 
IRB/IEC review, audits and inspections. 
 
 
15.3 Data Collection 
During each study visit, the investigator will collect and maintain notes in the subject’s study 
records to document all procedures, significant observations and assessments, which are 
regarded as source data. Additionally, diaries and laboratory result reports signed and dated 
by the investigator, have to be kept within the subject’s records. Changes to information in the 
study record and other source documents will be initiated and dated on the day the change is 
made. All documents will be stored safely under confidential conditions. 
 
 
 
 
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15.4 Electronic Case Report Forms (eCRFs) 
15.4.1 
eCRF Entries 
Information from the subjects’ study records and other source documents will be entered into 
a 21 CFR Part 11-compliant validated electronic Case Report Form (eCRF) as soon as 
possible after each visit. The participants will be identified by a unique trial specific subject 
number. The name or any other identifying detail will NOT be included in the eCRF. 
Entries and corrections in the eCRF may only be performed by the investigator or authorised 
study site staff via personal user account and password for access. This password must be 
kept confidential and must only be used by the person to whom it was assigned to ensure that 
each entry/change can be allocated to the person who performed the entry/change. 
An automatic audit trail will log each data entry/change performed in the eCRF. 
The eCRF system includes internal quality checks, to identify data that appear inconsistent, 
incomplete or inaccurate. Maintenance of the eCRF and the study database will be performed 
by the data management centre at Assign Data Management and Biostatistics GmbH. 
15.4.2 
Changes to eCRF Data 
Necessary data changes of the eCRF data may be identified as follows: 
Entries are checked by the eCRF during data entry or when the eCRF page has been 
submitted/saved. If the data does not fulfil particular quality criteria, a message will specify the 
type of problem and assist in its correction. 
Monitors may ask for correction of data during monitoring (e.g., if the eCRF entry does not 
match the source data). 
Computerised data-check programs and/or manual checks will identify clinical data 
discrepancies. Corresponding queries aiming at the resolution of these discrepancies will be 
created within the eCRF system and the study site will be informed about new issues to be 
resolved on-line. 
All discrepancies will be resolved on-line directly by the investigator or by authorised staff. 
As long as an eCRF page is not locked, required data changes can be conducted by the 
investigator or authorised site staff at any time. 
15.4.3 
eCRF Entry Validation 
The principal investigator or the authorised delegate will thoroughly review the eCRF data and 
will finally certify the contents of the eCRF by electronically signing the eCRFs within the data 
capturing system directly. If a correction was made to the eCRF data after the investigator’s 
approval, the certification must be repeated after the changes were performed. 
 
 
 
 
 
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15.5 Confidentiality of Subject’s Data 
The investigator will ensure that all subject’s information obtained during the conduct of the 
study will be kept confidential maintaining subject’s anonymity. 
On eCRFs or any other documents submitted to the sponsor, subjects will only be identified 
by subject number and therefore remain confidential in all reports or publications related to the 
study. Documents revealing subject’s identification, e.g. subject identification log and original 
informed consent forms, will be maintained by the investigator in strict confidence, except to 
the extent necessary to allow checking by CRAs, the Sponsor or competent authorities. 
 
15.6 Record Maintenance, Archiving and Destruction 
The investigator is responsible for compiling and keeping all essential documents in the 
Investigator Site File (ISF) during the study and for the maximum period of time in accordance 
with ICH GCP guidelines and local regulatory requirements.  
The ISF has to be stored in a safe and secure location with restricted access to staff personnel 
only and will include all essential documents like the clinical protocol, competent authorities’ 
approvals, original informed consent forms, source data, IMP dispensing and accountability 
logs, subjects’ logs and all correspondence pertaining to the study.  
The investigator will agree to archive the study documentation and will not dispose of any 
records relevant to this study without prior written permission from the sponsor. If an 
investigator moves, withdraws, or retires, the responsibility for maintaining the records may be 
transferred to another person upon sponsor’s agreement. 
The sponsor or their representative will notify the investigator when study documents need no 
longer be retained. 
 
 
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16. CHANGES IN THE CONDUCT OF THE STUDY 
16.1 Protocol Amendments 
Any proposed changes to the protocol must be covered in a written amendment to the protocol 
and submitted to the appropriate ethics committees or regulatory authorities. Amendments 
may only be implemented after approval of the appropriate ethics committees or regulatory 
authorities has been obtained except where necessary to eliminate apparent immediate 
hazard to subjects. 
 
16.2 Study Termination 
If the sponsor or the investigator decides to terminate the study before it is completed, they will 
notify each other in writing stating the reasons for early termination. In terminating the study, 
the sponsor and the investigator will ensure that adequate consideration is given to the 
protection of the subjects’ interest. The investigator, sponsor or CRO will notify the relevant 
ethics committee and regulatory authority in writing in accordance with local requirements. 
Documentation will be submitted for filing in Central File and Investigator File. 
 
 
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17. DEVIATIONS FROM THE PROTOCOL  
17.1 Relevant Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, ICH GCP, manuals or 
local requirements. The noncompliance may be either on the part of the subject, the 
Investigator, or the study site staff. Consequently, corrective actions are to be developed and 
implemented promptly.  
Important protocol deviations are deviations that might significantly affect the completeness, 
accuracy and/or reliability of the study data or that might significantly affect a subject’s rights, 
safety or well-being. 
Inclusion of subjects not satisfying the entry criteria will be subject to prior discussion with the 
sponsor and written approval from the sponsor. Subjects developing exclusion criteria during 
the study will be withdrawn, exceptions need prior discussion and written approval from the 
sponsor.  
All protocol deviations will be listed in the study report and assessed as to their influence on 
the quality of the study analysis. No deviations from the protocol of any type will be made 
without complying with all the ethics committee’s or regulatory authority’s established 
procedures in accordance with applicable regulations. 
 
17.2 Serious Breaches 
The Medicines for Human Use (Clinical Trials) Regulations contain a requirement for the 
notification of "serious breaches" to the MHRA within 7 days of the sponsor becoming aware 
of the breach. 
A serious breach is defined as “A breach of GCP or the trial protocol which is likely to affect to 
a significant degree:  
- the safety or physical or mental integrity of the subjects of the trial, or 
- the scientific value of the trial”. 
If a serious breach is suspected the sponsor must be contacted within 1 working day. In 
collaboration with the principal investigator, the serious breach will be reviewed by the sponsor 
and, if appropriate, the sponsor will report it to the REC committee, Regulatory Authority and 
the NHS host organisation within 7 calendar days. 
 
17.3 Premature Subject Withdrawal 
Subjects have the right to withdraw from the study at any time for any reason, without the need 
to justify. The investigator also has the right to withdraw subjects in case of AEs, protocol 
violations or administrative reasons. Please refer to section 8.9 for details. 
Since an excessive rate of withdrawal can render the study inconclusively, the unnecessary 
withdrawal of subjects must be avoided. 
 
 
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18. FINANCE AND INSURANCE 
18.1 Contractual and Financial Details 
The investigator, the sponsor and CRO will sign a clinical study agreement prior to the start of 
the study outlining overall sponsor and investigator responsibilities in relation to the study. The 
contract will describe costs for pharmacy, laboratory and other protocol-required services.  
Financial Disclosure Statements will be completed, as required by 21 CFR part 54. 
 
18.2 Insurance 
All subjects participating in this clinical study will be insured through Themis Biosciences 
GmbH. The Insurance will be contracted by the assigned CRO. 
 
 
19. REPORTING AND PUBLICATION 
19.1 Clinical Study Report 
After all subjects terminated their study participation (either by completion of Visit 7 (day 365) 
or prematurely by early termination or are confirmed as lost to follow up), a clinical study report 
will be prepared by the sponsor or delegate in accordance with relevant guidelines. 
 
19.1 Publication Policy 
All results generated in this study will be considered to be strictly confidential. The investigators 
may not submit the results for publication or presentation without prior written permission of 
the sponsor. Authorship for any publication will be determined in mutual agreement. 
 
 
 
 
 
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20. REFERENCES 
CDC/PAHO. Preparedness and Response for Chikungunya virus introduction in the Americas. 
www.paho.org/hq/index.php?option=com_docman&task=doc_download&gid=16984&Itemid=
&lang=en 
Brandler S, Lucas-Hourani M, Moris A, Frenkiel MP, Combredet C, Février M, Bedouelle H, 
Schwartz O, Desprès P, Tangy F. Pediatric measles vaccine expressing a dengue antigen 
induces durable serotype-specific neutralizing antibodies to dengue virus. PLoS Negl Trop Dis. 
2007;1(3):e96. 
Brandler S, Marianneau P, Loth P, Lacôte S, Combredet C, Frenkiel MP, Desprès P, Contamin 
H, Tangy F. Measles vaccine expressing the secreted form of West Nile virus envelope 
glycoprotein induces protective immunity in squirrel monkeys, a new model of West Nile virus 
infection. J Infect Dis. 2012;206:212-9.  
Brandler S, Ruffie C, Najburg V, Frenkiel MP, Bedouelle H, Desprès P, Tangy F. Pediatric 
measles vaccine expressing a dengue tetravalent antigen elicits neutralizing antibodies 
against all four dengue viruses. Vaccine. 2010;28:6730-9.  
Brandler S, Ruffié C, Combredet C, Brault JB, Najburg V, Prevost MC, Habel A, Tauber E, 
Desprès P, Tangy F. A recombinant measles vaccine expressing chikungunya virus-like 
particles is strongly immunogenic and protects mice from lethal challenge with chikungunya 
virus. Vaccine. 2013;31(36):3718-25.  
Cao-Lormeau VM et al, Emerg Infect Dis 2013; 20: 1085–86.  
Cauchemez S et al, The Lancet 2016  
Combredet C, Labrousse V, Mollet L, Lorin C, Delebecque F, Hurtrel B, McClure H, Feinberg 
MB, Brahic M, Tangy F. A molecularly cloned Schwarz strain of measles virus vaccine induces 
strong immune responses in macaques and transgenic mice. J Virol. 2003;77(21):11546-54.  
Commission Directive 2005/28/EC laying  down  principles  and  detailed  guidelines  for  good  
clinical  practice  as  regards  investigational medicinal   products   for   human   use,   as   well   
as   the   requirements   for   authorisation   of   the manufacturing  or importation  of such 
products; see 
https://ec.europa.eu/health/files/eudralex/vol-1/dir_2005_28/dir_2005_28_en.pdf 
Committee for Human Medicinal Products (CHMP): Note for Guidance on the Clinical 
Evaluation 
of 
Vaccines 
(CHMP/VWP/164653/2005); 
see: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC50
0003875.pdf 
Desprès P, Combredet C, Frenkiel MP, Lorin C, Brahic M, Tangy F. Live measles vaccine 
expressing the secreted form of the West Nile virus envelope glycoprotein protects against 
West Nile virus encephalitis. J Infect Dis. 2005;191(2):207-14.  
Dick GWA et al, Trans R Soc Trop Med Hyg 1952; 46: 509–20 
Enserik M (2008) Entomology. A mosquito goes global. Science 320: 864-866 
FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers 
Enrolled 
in 
Preventive 
Vaccine 
Clinical 
Trials 
(Sept. 
2007) 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guid
ances/Vaccines/ucm074775.htm 
Gerardin P, Barau G, Michault A, Bintner M, Randrianaivo H, et al. (2008) Multidisciplinary 
prospective study of mother-to-child chikungunya virus infections on the island of La Reunion. 
PLoS Med 5: e60. doi:10.1371/journal.pmed.0050060 
 
 
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International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use: ICH Harmonised Tripartite Guideline: Guideline for Good 
Clinical 
Practice 
E6 
(R1); https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products 
/Guidelines /Efficacy/E6/E6_R1_Guideline.pdf 
Jain M, Rai S, Chakravarti A (2008) Chikungunya: a review. Trop Doct 38: 70-72 
Lorin C, Mollet L, Delebecque F, Combredet C, Hurtrel B, Charneau P, Brahic M, Tangy F. A 
single injection of recombinant measles virus vaccines expressing human immunodeficiency 
virus (HIV) type 1 clade B envelope glycoproteins induces neutralizing antibodies and cellular 
immune responses to HIV. J Virol. 2004;78(1):146-57.  
Msaouel P, Opyrchal M, Domingo Musibay E, Galantis E. Expert Oncolytic measles virus 
strains as novel anticancer agents Opin Biol Ther. 2013 Apr;13(4):483-502. 
Paul BJ, Pannarkady G, Moni SP, Thachil EJ. Clinical profile and long-term sequelae of 
Chikungunya fever. Indian Journal of Rheumatology. Volume 6, Issue 1, March 2011, 12–19. 
Ramsauer K, Schwameis M, Firbas C, Müllner M, Putnak RJ, Thomas SJ, Desprès P, Tauber 
E, Jilma B, Tangy F. Immunogenicity, safety, and tolerability of a recombinant measles-virus-
based chikungunya vaccine: a randomised, double-blind, placebo-controlled, active-
comparator, first-in-man trial. Lancet Infect Dis. 2015 May;15(5):519-27.  
Rezza G, Nicoletti L, Angelini R, Romi R, Finarelli AC, et al. (2007) Infection with chikungunya 
virus in Italy: an outbreak in a temperate region. Lancet 370:1840-1846 
Schilte C, Staikowsky F, Couderc T, Madec Y, Carpentier F, Kassab S, Albert ML, Lecuit M, 
Michault A. Chikungunya virus-associated long-term arthralgia: a 36-month prospective 
longitudinal study. PLoS Negl Trop Dis. 2013;7(3):e2137. 
Simon F, Parola P, Grandadam M, Fourcade S, Oliver M, Brouqui P, Hance P, Kraemer P, Ali 
Mohamed A, de Lamballerie X, Charrel R, Tolou H. Chikungunya infection: an emerging 
rheumatism among travelers returned from Indian Ocean islands. Report of 47 cases. 
Medicine (Baltimore). 2007 May;86(3):123-37. 
Staples JE, Breiman RF, Powers AM. Chikungunya fever: an epidemiological review of a re-
emerging infectious disease. Clin Infect Dis. 2009 Sep 15;49(6):942-8. 
Stebbings R, Février M, Li B, Lorin C, Koutsoukos M, Mee E, et al. Immunogenicity of a 
recombinant measles-HIV-1 clade B candidate vaccine. PLoS One. 2012;7:e50397.  
Tsetsarkin KA, Vanlandingham DL, McGee CE, Higgs S (2007) A single mutation in 
chikungunya virus affects vector specifity and epidemic potential. PLoS Pathog 3: e201. 
doi:10.1371/journal.ppat.0030201 
Vazeille M, Moutailler S, Coudrier D, Rousseaux C, Khun H, et al. (2007) Two Chikungunya 
isolates from the outbreak of La Reunion (Indian Ocean) exhibit different patterns of infection 
in the mosquito, Aedes albopictus. PLoS ONE 2: e1168. doi:10.1371/journal.pone.0001168 
Wang E, Volkova E, Adams AP, Forrester N, Xiao SY, et al. (2008) Chimeric alphavirus 
vaccine candidates for chikungunya. Vaccine 26: 5030-5039 
WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human 
Subjects; JAMA. 2013;310(20):2191-2194.  
WHO. Guillain-Barré syndrome – El Salvador. Jan 21, 2016. http://www.who.int/csr/don/21-
january-2016-gbs-el-salvador/en/ (accessed Feb 5, 2016).  
 
 
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21. APPENDICES 
 
Appendix 1: Template distributed to subjects to assess local reaction 
 
 
 
 
 
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Page 1 of 29 
STAT03_A Statistical Analysis Plan 
Version 6.0, Effective Date 16-Feb-2018 
Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
 
 
 
Statistical Analysis Plan 
Preliminary and Final Analysis 
 
 
Observer blinded, randomised study to investigate safety, tolerability 
and long-term immunogenicity of different dose regimens and 
formulations of MV-CHIK in healthy volunteers 
 
Protocol: MV-CHIK-205 
 
 
Confidential 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor: 
Themis Bioscience GmbH, Vienna, Austria 
 
 
MV-CHIK-205
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Final 2.0
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STAT03_A Statistical Analysis Plan 
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Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
Table of Contents 
 
1. 
OVERVIEW 
6 
1.1 
Study Design 
6 
1.2 
Study Objectives 
7 
1.2.1 
Primary Objective 
7 
1.2.2 
Secondary Objectives 
7 
1.3 
Endpoints 
7 
1.3.1 
Primary Endpoint 
7 
1.3.2 
Secondary Endpoints 
7 
1.4 
Sample Size Calculation 
8 
1.5 
Flowchart 
8 
1.6 
Schedule of Assessments 
9 
2. 
GENERAL CONSIDERATIONS 
10 
2.1 
Conduct of Analysis 
10 
2.2 
Statistical Software and Quality Control 
10 
2.3 
Applicable Standard Operation Procedures 
10 
2.4 
Blinding and Randomization 
11 
2.5 
Descriptive Analyses 
11 
2.6 
Inferential Analyses 
11 
2.7 
Center and Country Effect 
12 
2.8 
Handling Missing Data 
12 
2.9 
Protocol Deviations 
12 
2.10 
Medical Coding 
13 
2.11 
Analysis Populations 
13 
2.11.1 
Safety Population 
13 
2.11.2 
Modified Intent-to-Treat (mITT) Population 
13 
2.11.3 
Per-Protocol (PP) Population 
13 
2.12 
Subject-Level Data Listings 
14 
2.13 
Changes in the Conduct of the Study or Planned Analysis 
14 
3. 
OVERALL STUDY INFORMATION 
14 
4. 
BASELINE EVALUATION 
14 
4.1 
Data Points 
14 
4.2 
Derivations and Definitions 
15 
5. 
IMMUNOGENICITY ANALYSIS 
15 
5.1 
Data Points 
15 
5.2 
Derivations and Definitions 
15 
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STAT03_A Statistical Analysis Plan 
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Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
6. 
SAFETY ANALYSIS 
16 
6.1 
Extent of Exposure 
16 
6.1.1 
Data Points 
16 
6.1.2 
Derivations and Definitions 
16 
6.2 
Adverse Events 
16 
6.2.1 
Data Points 
16 
6.2.2 
Derivations and Definitions 
16 
6.3 
Laboratory Parameters 
17 
6.3.1 
Data Points 
17 
6.3.2 
Derivations and Definitions 
19 
6.4 
Other Safety Parameters 
19 
7. 
LIST OF TABLES, DATA LISTINGS AND FIGURES 
20 
7.1 
List of Tables 
20 
7.2 
List of Data Listings 
25 
 
 
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M V- C HI K- 2 0 5
Cli ni c al St u dy R e p ort, S e cti o n 1 6
Fi n al 2. 0
 4 0 6 of 1 0 9 3
1 8-J a n- 2 0 2 1
0 6 CJ D X
0 6 CJ D X
P P D
P P D
0 6 D Y D R

SAP (MV-CHIK-205, FINAL 1.0, 20-Feb-2019) 
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STAT03_A Statistical Analysis Plan 
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Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
List of Abbreviations 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase  
ANOVA 
Analysis of Variance 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase  
ATC 
Anatomical Therapeutic Chemical 
BDRM 
Blind Data Review Meeting 
CI 
Confidence Interval 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
DRM 
Data Review Meeting 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme Linked Immunosorbent Assay  
GMFI 
Geometric Mean Fold Increase 
GMT 
Geometric Mean Titer 
HIV 
Human Immunodeficiency Virus 
IMP 
Investigational Medicinal Product  
IMP 
Investigational Medical Product 
LLOQ 
Lower Limit of Quantification 
mITT 
Modified Intent-to-Treat 
PP 
Per-Protocol 
PRNT50 
Plaque Reduction Neutralization Test 50 % 
PT 
Prothrombin Time 
SOP 
Standard Operating Procedure 
SPS® 
Stabilizing and Protecting Solutions  
TLF 
Tables Listings and Figures 
 
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STAT03_A Statistical Analysis Plan 
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Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
1. 
OVERVIEW 
1.1 
Study Design 
MV-CHIK-205 is a prospective, interventional, observer blinded, block-randomized phase II trial, comparing 
different dose levels of MV-CHIK in three different formulations ((lyophilized, liquid frozen and liquid Stabilizing 
and Protecting Solutions (SPS®)) to evaluate immunogenicity, safety and tolerability of this novel Chikungunya 
vaccine in 60 healthy volunteer female and male subjects. Placebo (physiological saline solution) will be applied to 
blind two different treatment schedules, evaluating single shot versus double shot treatment. The study will be 
conducted as a single study site.  
After completion of screening procedures, subjects will be randomized to one of five treatment groups (A, B, C, D 
or E) and will receive injections according to the scheme outlined in the study flow chart (see Section 1.5). 
Group A: 12 subjects will receive two low dose treatments with MV-CHIK 5x104 (±0.5 log) TCID50 /dose on day 0 
and 28 (lyophilized formulation). 
Group B: 12 subjects will receive two low dose treatments with MV-CHIK 1x105 (±0.5 log) TCID50 /dose on day 0 
and 28 (liquid frozen formulation). 
Group C: 12 subjects will receive two low dose treatments with MV-CHIK 1x105 (±0.5 log) TCID50 /dose on day 0 
and 28 (liquid SPS® formulation).  
Group D: 12 subjects will receive two high dose treatments with MV-CHIK 1x106 (±0.5 log) TCID50 /dose on day 0 
and 28 (liquid frozen formulation).  
Group E: 12 subjects will receive one high dose treatment with MV-CHIK 1x106 (±0.5 log) TCID50 /dose on day 0 
(liquid frozen formulation) and placebo on day 28.  
Subjects will be observed for safety and immunogenicity for 56 days during the treatment period, starting with the 
first MV-CHIK vaccination at day 0 (Visit 1), day 14 (Visit 2), day 28 (Visit 3), day 42 (Visit 4) and day 56 (Visit 5). 
After this treatment period subjects will return to site at day 182 (Visit 6) and at day 365 (Visit 7) for collection of 
serum to follow up the durability of specific antibodies against Chikungunya. Serum samples for passive transfer 
will be collected on days 0, 28, 56 and 365.  
Study duration per subject will be 12 months, comprising of 8 weeks treatment period from study day 0 (Visit 1) 
until day 56 (Visit 5) and 44 weeks follow up period, including Visit 6 and Visit 7 (post day 56 until day 365). Study 
subjects are free to participate in other clinical studies after completion of the treatment period on day 56. The 
end of study will be defined as date of the last visit of the last subject. 
 
 
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Adapted from: 
 
Page 7 of 29 
STAT03_A Statistical Analysis Plan 
Version 6.0, Effective Date 16-Feb-2018 
Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
1.2 
Study Objectives 
1.2.1 
Primary Objective 
 
To investigate immunogenicity and safety of MV-CHIK in different dose regiments, 28 days after one or 
two vaccinations  
The immunogenicity will be determined by means of Plaque Reduction Neutralization Test 50 % (PRNT50) 28 days 
after a single shot treatment at Visit 3 (study day 28) and 28 days after two treatments with MV-CHIK at Visit 5 
(study day 56). Local and systemic AEs will be recorded and assessed. 
1.2.2 
Secondary Objectives 
 
To compare immunogenicity, safety and tolerability between different doses and formulations of MV-CHIK 
during the treatment period up to day 56  
 
To investigate the immunogenicity and safety of a novel liquid vaccine formulation  
 
To evaluate cellular responses induced by one or two immunizations  
 
To evaluate the long-term immunogenicity of MV-CHIK up to one year after the first MV-CHIK treatment  
 
To collect human sera for future efficacy evaluation, by passive transfer of anti-Chikungunya antibodies to 
virus susceptible non-human primates  
1.3 
Endpoints 
1.3.1 
Primary Endpoint 
 
Immunogenicity 28 days after the last MV-CHIK vaccination confirmed by the presence of functional 
antibodies as determined by the plaque reduction neutralization test (PRNT50)  
1.3.2 
Secondary Endpoints 
 
Rate of solicited and unsolicited adverse events (AEs) during the treatment period until day 56  
 
Serious adverse events during the treatment period until study day 56  
 
Immunogenicity on days 0, 28 (group A, B, C, and D), days 0, 56 (group E) and long-term immunogenicity 
on day 182 (6 Month) and 365 (12 Month), confirmed by the presence of functional antibodies as 
determined by the plaque reduction neutralization test (PRNT50).  
 
Measurement of anti-Chikungunya antibodies on days 0, 28, 56, 182 and 365 determined by enzyme 
linked immunosorbent assay (ELISA)  
 
Measurement of anti-Measles antibodies on days 0, 28, 56 determined by enzyme linked immunosorbent 
assay (ELISA)  
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Page 8 of 29 
STAT03_A Statistical Analysis Plan 
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Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
 
Induction of Chikungunya specific immune responses on days 0, 14, 28, 42 and 56 determined by T-cell 
assay.  
 
Safety laboratory parameters (hematology, serum chemistry, coagulation, urinalysis)  
1.4 
Sample Size Calculation 
A formal sample size calculation was not conducted. The sample size of 60 subjects has been determined based 
on prior experience in evaluating the safety and immunogenicity of vaccines and is typical for early phase clinical 
studies. Sample size for this study was determined on grounds of feasibility and common practice in similar trials. 
1.5 
Flowchart 
 
 
 
 
 
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STAT03_A Statistical Analysis Plan 
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Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
1.6 
Schedule of Assessments 
 
(1) Assessment of vital signs will include systolic and diastolic blood pressure, pulse rate and body temperature  
(2) A full physical examination will be performed at screening and a system based physical examination will be done at Visit 1, 
3 and 5, if necessary according to findings in a symptom-directed physical examination  
(3) Conditions/symptoms noted prior to first IMP administration will be reported as medical history and not as AEs, At Visit 6 
and 7 AEs will not be recorded as subjects are allowed to participate in other clinical studies during the follow-up period.  
(4) Medications administered within 30 days prior to screening until end of treatment period will be documented as 
concomitant medication.  
(5) Clinical Laboratory parameters include:  
- 
Virology: HB s-Ag, anti-HB c-Ab, anti-HC-Ab, HIV-Ab (only once at screening)  
- 
Hematology: hemoglobin, hematocrit, erythrocyte count, differential and total white blood count, platelets  
- 
Chemistry: creatinine, potassium, sodium, calcium, AST, ALT, alkaline phosphatase, bilirubin  
- 
Coagulation parameter: prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen  
- 
Urinalysis: pH-value, glucose, protein, bilirubin, urobilinogen, blood, leucocytes esterase, nitrite, ketone and specific 
gravity. In case of abnormal findings, a microscopy will be done for confirmation.  
Please refer to CSP section 8.11.1  
(6) Local tolerability to be investigated 2 hours after each vaccination and additionally at the subsequent visits and prior to IMP 
administration.  
(7) If the early termination occurs within the treatment period (at or before Visit 5), subjects shall perform all procedures as 
defined for Visit 5. If the early termination occurs within the follow up period (after Visit 5), subjects shall perform all 
procedures defined for Visit 7  
(8) Administration of IMP will be performed according to allocated treatment group, after randomization at Visit 1 
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S A P ( M V - C HI K-2 0 5 , FI N A L 1. 0, 2 0 - F e b-2 0 1 9 ) 
A d a pt e d fr o m: 
 
P a g e 1 0  of 2 9  
S T A T 0 3 _ A St ati sti c al A n aly si s Pl a n 
V er si o n 6. 0, Eff e ctiv e D at e 1 6 - F e b- 2 0 1 8 
C o nfi d e nti al a n d i nt ell e ct u al pr o p erty of A s si g n D M B. N o p art of t hi s d o c u m e nt or it s c o nt e nt s m ay b e d u pli c at e d, r ef er e n c e d, p u bli s h e d or 
ot h er wi s e di s cl o s e d i n a ny f or m or by a ny m e a n s wit h o ut pri or writt e n c o n s e nt of A s si g n D M B. 
2.2.  
G E N E R A L C O N SI D E R A TI O
G E N E R A L C O N SI D E R A TI O N S
N S  
2. 1  
C o n d u ct of A n aly si s 
A pr eli mi n ary a n aly si s i n cl u di n g s af ety a n d i m m u n o g e ni city d at a will b e p erf or m e d aft er all s u bj e ct s c o m pl et e d 
Vi sit 5 ( d ay 5 6) a n d t h er ef or e t er mi n at e d t h e tr e at m e nt p eri o d of t h e st u dy. T h e p ur p o s e of t hi s a n aly si s i s t o 
pr o vi d e hi g hly v al u a bl e d at a f or f urt h er C hi k u n g u ny a v a c ci n e d ev el o p m e nt i n cl u di n g t h e effi c a cy ev al u ati o n, by 
p a s siv e tr a n sf er. T h u s, i m m u n o g e ni city a n aly si s f or P R N T 5 0  a n d E LI S A r e s ult s f or c hi k u n g u ny a a nti b o di e s i n t h e 
pr eli mi n ary a n aly si s will b e p erf or m e d f or Vi sit 1 ( d ay 0), Vi sit 3 ( d ay 2 8), a n d Vi sit 5 ( d ay 5 6). All s af ety a n aly si s 
will b e d o n e i n t h e pr eli mi n ary a n aly si s. R e s ult s fr o m t hi s pr eli mi n ary a n aly si s will n ot h a v e a ny i m p a ct o n t h e 
st u dy d e si g n or t h e s u bj e ct s d uri n g t h e f oll o w u p p eri o d of t h e st u dy.  
T h e fi n al a n aly si s will b e c o n d u ct e d o n c e t h e l a st s u bj e ct h a s c o m pl et e d t h e st u dy. All d at a of t h e st u dy will 
alr e a dy b e a v ail a bl e at t h e pr eli mi n ary a n aly si s ex c e pt t h e i m m u n o g e ni city d at a fr o m Vi sit 6 a n d Vi sit 7, e n d of 
st u dy d at a a s w ell a s ot h er a n aly s e s r e q u e st e d fr o m Vi sit 1 t o Vi sit 5 f or w hi c h n o l a b or at ory r e s ult s ar e a v ail a bl e 
at t h e ti m e of t h e D ay 5 6 a n aly si s ( T- c ell a n aly si s a n d E LI S A r e s ult s f or m e a sl e s). T h u s o nly t h e s e d at a will b e 
a n alyz e d at t h e fi n al a n aly si s. If u n ex p e ct e d c h a n g e s o c c ur e. g. i n t h e b a s eli n e or a d v er s e e v e nt d at a, a n aly s e s 
m ay al s o b e r e p e at e d at t h e fi n al a n aly si s.  
2. 2  
St ati sti c al S oft w ar e a n d Q u ality C o ntr ol 
All st ati sti c al a n aly s e s will b e p erf or m e d u si n g S A S ® v er si o n 9. 3 or hi g h er. T a bl e s, fi g ur e s a n d d at a li sti n g s will b e 
g e n er at e d i n Mi cr o s oft ® W or d ® a s w ell a s P D F ® f or m at. 
Q u ality c o ntr ol of S A S ® pr o gr a m s will i n cl u d e a r e vi e w of t h e w h ol e pr o c e s s of r e s ult g e n er ati o n: 
 
R evi e w of all a n aly si s S A S ® pr o gr a m s 
 
R evi e w of S A S ® l o g f or err or s, w ar ni n g s a n d ot h er n ot e s t h at c o ul d i n di c at e mi st a k e s i n t h e pr o gr a m s 
 
R evi e w of all t a bl e s, li sti n g s a n d fi g ur e s f or c o m pl et e n e s s a n d c orr e ct n e s s 
2. 3  
A p pli c a bl e St a n d ar d O p er ati o n Pr o c e d ur e s 
M V- C HI K- 2 0 5
Cli ni c al St u dy R e p ort, S e cti o n 1 6
Fi n al 2. 0
 4 1 2 of 1 0 9 3
1 8-J a n- 2 0 2 1
0 6 CJ D X
0 6 CJ D X
C CI
0 6 D Y D R

SAP (MV-CHIK-205, FINAL 1.0, 20-Feb-2019) 
Adapted from: 
 
Page 11 of 29 
STAT03_A Statistical Analysis Plan 
Version 6.0, Effective Date 16-Feb-2018 
Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
2.4 
Blinding and Randomization 
At Visit 1 (day 0) 60 eligible subjects will be randomly assigned to one of five treatment groups (A, B, C, D or E) by 
means of randomization envelopes provided by data management. All of these subjects will be equally distributed 
between the 5 groups using a randomization ratio of 1:1:1:1:1=A:B:C:D:E. A subject will be considered enrolled 
once the first IMP administration has been performed according to randomization. 
As this study will be conducted in an observer-blinded manner, unblinded study team members responsible for 
randomization, preparation and administration of IMP, will otherwise not be involved in the conduct of the study. 
All subjects, the investigator and site personnel performing study related assessments, as well as the sponsor’s 
representatives involved in the monitoring and conduct of the study, will be blinded to treatment assignment. 
The primary endpoint as well as most of the secondary endpoints will be covered in the preliminary analysis after 
Day 56. The sponsor personnel and ADMB statisticians (blinded statistician) that perform and review the 
preliminary analysis will be unblinded at this point in time, but after the Blind Data Review Meeting (Section 2.9). 
2.5 
Descriptive Analyses 
Descriptive analyses of continuous variables (summary statistics) will be described with the number of non-
missing observations, arithmetic mean, standard deviation (±SD), median, quartiles (Q1 and Q3) and range 
(minimum and maximum). 
Descriptive analysis of continuous immunogenicity variables (i.e. tables for the GMT and GMFI) will be described 
with the number of non-missing observations, geometric mean, confidence intervals for the geometric mean, 
standard deviation of logarithmic values, median, quartiles (Q1 and Q3) and range (minimum and maximum). 
Categorical variables (frequency statistics) will be described with the number of non-missing observations and 
percentages (%). Percentages will be calculated within each stratum on the total number of non-missing 
observations, if not stated otherwise. 
2.6 
Inferential Analyses 
The immunogenicity analysis will compare the functional anti-Chikungunya PRNT50 antibody geometric mean titer 
(GMT) 28 days after the last MV-CHIK vaccination between the treatment groups. The significance level will be 
0.05. All p-values will be two-sided and rounded to four decimal places. 
GMTs and GMT ratios will be estimated by applying an analysis of variance (ANOVA) including the factor treatment 
group. This will be done using log10 transformed data and taking the anti-log of the resulting point estimates for 
the least squares means, least squares means differences and the corresponding 2-sided 95% Confidence 
Intervals (CI). P-values will also be provided to compare GMTs between treatment groups adjusted for multiple 
comparisons according to Tukey-Kramer.  
Measles- and Chikungunya-ELISA titers as well as long-term stability of anti-Chikungunya antibodies determined by 
PRNT50 and ELISA will be analyzed likewise.  
Seroconversion rates will be compared between groups using a Fisher-Freeman-Halton test.  
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Adapted from: 
 
Page 12 of 29 
STAT03_A Statistical Analysis Plan 
Version 6.0, Effective Date 16-Feb-2018 
Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
For the safety analysis Fisher exact tests will be provided for a comparison of AE rates between treatment groups. 
2.7 
Center and Country Effect 
Not applicable since this is a single-center study. 
2.8 
Handling Missing Data 
Generally, missing values of immunogenicity variables will not be imputed, and the analysis will be limited to 
observed values. For missing data in AE evaluation concerning seriousness, severity or causality a worst case 
approach will be applied. In case of missing assignment to solicited or unsolicited, this AE will neither be counted 
in tables for solicited AEs nor in tables for unsolicited AEs but in tables for all AEs. 
2.9 
Protocol Deviations 
Protocol deviations will be collected only for the preliminary analysis. A listing of the potential protocol deviations 
will be prepared by Assign Data Management and Biostatistics GmbH using information from the eCRF 
documentation and monitoring reports. These protocol deviations will be classified into major or minor protocol 
deviations based on their possible impact on the study results in a Blind Data Review Meeting (BDRM) prior to the 
preliminary analysis attended by Assign Data Management GmbH and Themis Bioscience GmbH (sponsor).  
Major protocol deviations will include but are not limited to the following: 
 
Subjects with any confirmed immunosuppressive or immunodeficient condition, including human 
immunodeficiency virus (HIV), hepatitis A, B or C infection or a family history of congenital or hereditary 
immunodeficiency 
 
Subjects who received the wrong or no IMP  
 
Subjects who received less than the protocol-defined number of vaccinations 
 
Subjects who received a wrong dose other than they were randomized to 
 
Subjects who entered the study even though they did not satisfy the entry criteria 
 
Subjects with substantial time window violations on vaccination visits 
 
Subjects who received an forbidden prior or concomitant medication 
o 
Immunosuppressive drugs: Use of corticosteroids (excluding topical preparations) or 
immunosuppressive drugs within 30 days prior to first IMP administration, or anticipated use 
during the trial 
o 
Treatments with non-study licensed vaccines within 4 weeks prior to first study vaccination until 
the end of the treatment period (day 56) 
o 
Receipt of blood products or immunoglobulins within 120 days prior to the Screening Visit or 
anticipated receipt of any blood product or immunoglobulin before completion of the treatment 
period (day 56) 
 
Further protocol deviations that could impact immune response that have not been described above 
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Adapted from: 
 
Page 13 of 29 
STAT03_A Statistical Analysis Plan 
Version 6.0, Effective Date 16-Feb-2018 
Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
These criteria for potential protocol violation are identified at the time of planning the study. However, during the 
course of the trial unforeseen events may occur or new scientific knowledge may become available, therefore final 
decisions on whether any protocol violation could impact immune response and thus lead to exclusion from the 
per-protocol (PP) population will be made by the sponsor on a case by case basis in a blinded manner (and prior to 
study unblinding). 
All protocol deviations will be listed in the analysis and described in the Clinical Study Report (CSR). 
It is not planned to define a second PP population prior before database closure since it is not expected that 
protocol deviations after day 56 affect the primary immunogenicity endpoint. In case of unexpected changes or 
further protocol deviations documented after the BDRM, it may be discussed in a second DRM prior to database 
closure which analyses may be repeated for the final analysis.  
2.10 Medical Coding 
Adverse events and medical history will be coded using MedDRA in the most current version. Concomitant 
medications and vaccination history will be coded using WHO Drug Reference List and Anatomical Therapeutic 
Chemical (ATC) Classification System in the most current version.  
2.11 Analysis Populations 
2.11.1 Safety Population 
The safety population is defined to include all subjects who entered into the study and received at least one IMP 
administration. All analysis based on the safety population will be carried out using the actual treatment received. 
Subjects with vaccination protocol deviations will be allocated to a treatment group after a case-by-case review in 
the Blind Data Review Meeting. If a subject received different doses at different visits, the minimum dose received 
will decide the treatment group. 
2.11.2  Modified Intent-to-Treat (mITT) Population 
The modified intent-to-treat (mITT) population is defined to include all randomized subjects who receive at least 
one IMP administration. Subjects will be analyzed according to the treatment group they had been allocated to, 
rather than by the actual treatment they received. 
2.11.3 Per-Protocol (PP) Population 
The per-protocol (PP) population is defined as mITT population including subjects with at least one major protocol 
deviation that might have an impact on the immune response, see Section 2.9. The PP population is the primary 
population for the immunogenicity analysis and will be defined in the BDRM that is conducted before preliminary 
analysis.  
 
 
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Adapted from: 
 
Page 14 of 29 
STAT03_A Statistical Analysis Plan 
Version 6.0, Effective Date 16-Feb-2018 
Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
2.12 Subject-Level Data Listings 
All treated subjects will be included in listings if not stated otherwise. Data listings will include the subject number 
as identifier (and parameter and/or visit if available) and will be sorted by subject number (and parameter and/or 
visit if available). Columns that indicate the treatment group will be shown in all listings. 
2.13 Changes in the Conduct of the Study or Planned Analysis 
All statistical analyses will be performed according to the CSP. In case of analyses deviate from SAP, all changes 
will be described and justified in the CSR.  
3. 
OVERALL STUDY INFORMATION 
The following information will be analyzed descriptively and corresponding details on the subject level will be 
provided in data listings: 
 
Subject overview 
 
Vaccination 
 
Visit attendance 
 
Protocol deviations 
 
Study status (incl. drop-outs and reason) 
 
Screening failures 
Specifications on TLFs are provided in Section 7. 
4. 
BASELINE EVALUATION 
For the preliminary analysis baseline data (screening visit, VS) will be presented for the Safety and mITT 
population by treatment group and overall. For the final analysis all tables will be repeated for the PP population. 
In case populations do not differ, tabulations will not be repeated. 
4.1 
Data Points 
The following information will be analyzed descriptively in tables and corresponding details on the subject level will 
be provided in data listings:  
 
Demographic information (age, sex, race) 
 
Physical examination (will be listed only) 
 
Vaccination history  
 
Virology (will be listed only) 
 
Medical history 
 
Prior and concomitant medications 
Pregnancy test will be only listed in the safety section. Specifications on TLFs are provided in Section 7. 
 
 
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SAP (MV-CHIK-205, FINAL 1.0, 20-Feb-2019) 
Adapted from: 
 
Page 15 of 29 
STAT03_A Statistical Analysis Plan 
Version 6.0, Effective Date 16-Feb-2018 
Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
4.2 
Derivations and Definitions 
 
Medications stopped clearly prior (<) to Day 0 (Visit 1) will be considered prior medications, all other 
medications are considered to be concomitant. Medications with a missing or incomplete stop date where 
it cannot clearly be decided if the stop date was before or after Day 0 will be considered concomitant. 
5. 
IMMUNOGENICITY ANALYSIS 
The immunogenicity analysis will be performed for the mITT and PP population. All tables will be presented by 
treatment group and overall. Data from the early termination visit or unscheduled visits will be listed only and will 
not be shown in summary tables by time point. 
5.1 
Data Points 
The following information will be analyzed by visit descriptively in tables and corresponding details on the subject 
level will be provided in data listings:  
 
GMT of anti-Chikungunya PRNT50 antibody (incl. ANOVA with fixed treatment group) 
 
Seroconversion rate for Anti-Chikungunya PRNT50 antibody  
 
GMT of Chikungunya-ELISA antibodies (incl. ANOVA with fixed treatment group) 
 
Seroconversion rate for Chikungunya-ELISA antibodies  
 
GMT of Measles-ELISA antibodies  
 
T cell results (will be listed only) 
 
Sampling details for PRNT50, ELISA CHIK, ELISA measles; T-cells and passive transfer (will be listed only) 
Specifications on TLFs are provided in Section 7. 
5.2 
Derivations and Definitions 
 
For the preliminary analysis, only PRNT50 will be analyzed included time points Visit 1 (day 0), Visit 3 (day 
28) and Visit 5 (day 56). For the final analysis all immunogenicity parameters will be analyzed at all 
available time points except passive transfer. 
 
Analysis of passive transfer results are not described in this SAP. 
 
The primary analysis compares the PRNT50 titer 28 days after last MV-CHIK vaccination between 
treatment groups. Therefore, titers from Day 56 in Groups A-D will be considered and the titer at Day 28 
for Group E. 
 
Seroconversion rate for anti-Chikungunya PRNT50 titers is defined as proportion of subjects achieving 
anti-Chikungunya PRNT50 titers ≥ 10 at a certain time point. 
 
Seroconversion rate for Chikungunya-ELISA is defined as proportion of subjects achieving Chikungunya-
ELISA titers ≥ 16 at a certain time point. 
 
The lower limit of quantification (LLOQ) are not known for immunogenicity parameters at SAP 
development and therefore the following general rules will apply:  
o 
In data listings, the original reported value “<LLOQ” will be displayed. 
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Adapted from: 
 
Page 16 of 29 
STAT03_A Statistical Analysis Plan 
Version 6.0, Effective Date 16-Feb-2018 
Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
O For calculations the half of the true LLOQ value will be used for such values.  
6. 
SAFETY ANALYSIS 
All safety analyses will be performed for the safety population.  
6.1 
Extent of Exposure 
6.1.1 
Data Points 
The following information will be analyzed descriptively in tables and corresponding details on the subject level will 
be provided in data listings:  
 
Treatment duration 
 
Study duration 
 
Study vaccine administration (will be listed only) 
6.1.2 
Derivations and Definitions 
 
Treatment duration [days] = date of last administered vaccine – date of first vaccination +1 
 
Study duration [days] = date of last attended visit (or date of study discontinuation, if applicable) – date 
of signed informed consent + 1 
6.2 
Adverse Events 
6.2.1 
Data Points 
The following analyses will be provided for all Adverse Events: 
 
Adverse event overview for solicited and unsolicited events (e.g. any AE, any SAE, any related AE). This 
table will include a statistical test for comparison of treatment groups (see Section 2.6). 
 
Solicited Adverse Events by symptom 
 
Solicited Adverse Events by symptom and severity 
 
Unsolicited Adverse Events by SOC and PT, overall and for specific types of Adverse Events (e.g. SAEs, 
related AEs) 
 
Unsolicited Adverse Events by severity and for specific types of Adverse Events 
 
Unsolicited Adverse Events by causality and for specific types of Adverse Events 
Specifications of TLFs are provided in Section 7. 
6.2.2 
Derivations and Definitions 
 
All solicited and unsolicited Adverse Events up to day 56 (Visit 5) will be analyzed for the preliminary 
analysis. AE reporting and documentation is completed at Day 56. Thus all AE in the database are 
considered for the adverse event endpoints. In case of unexpected data change, new reported AEs or 
follow-up information, affected tables and/or listings may be repeated for the final analysis. Otherwise, 
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Page 17 of 29 
STAT03_A Statistical Analysis Plan 
Version 6.0, Effective Date 16-Feb-2018 
Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
adverse event tables are not repeated at the final analysis. This decision may be done in a DRM prior to 
database closure, see Section 2.9. 
 
Percentages for AE rates are based on N (treatment group totals). 
 
Medical Conditions/symptoms noted prior to first IMP administration will be reported as medical history 
and not as adverse events. In case of an incomplete start date where it cannot clearly be decided if the 
Adverse Event started before the first IMP the Adverse Event will be considered to be started before first 
IMP.  
 
An Adverse Events is considered to be related to study treatment if “Relationship to Study Treatment” is 
answered with “definitely”, “probably” or “possibly” or the causality is missing. 
 
Adverse Events where an action was taken are considered if “Action taken with Study Treatment” is 
answered with “Second IMP Administration Delayed” or “Second IMP not Administered”. 
 
Tables showing “severe” events will include events with grade 3 or 4 or missing grade. 
 
In tables showing subjects with AEs by maximum severity, subjects will be counted only in the highest 
grading category, but events will be counted in each reported grading category. 
 
In tables showing AEs by causality, subjects will be counted only in the strongest relationship category, 
but events will be counted in each category. 
6.3 
Laboratory Parameters 
Data from the early termination visit or unscheduled visits will be listed only and will not be shown in summary 
tables by time point. All tables will be presented by treatment group and overall. Laboratory data from scheduled 
visits (VS, Visit 3 and Visit 5) will be tabulated by time point. Specifications on TLFs are provided in Section 7. 
6.3.1 
Data Points 
 
Hematology 
o 
Hemoglobin 
o 
Hematocrit 
o 
Erythrocytes 
o 
Leukocytes 
o 
Neutrophils 
o 
Lymphocytes 
o 
Monocytes 
o 
Basophils 
o 
Eosinophils 
o 
Neutrophils/Leukocytes 
o 
Lymphocytes/Leukocytes 
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Page 18 of 29 
STAT03_A Statistical Analysis Plan 
Version 6.0, Effective Date 16-Feb-2018 
Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
o 
Monocytes/Leukocytes 
o 
Basophiles/Leukocytes 
o 
Eosinophils/Leukocytes 
o 
Platelets 
 
Clinical Chemistry 
o 
Creatinine 
o 
Potassium 
o 
Sodium 
o 
Calcium 
o 
Aspartate Aminotransferase 
o 
Alanine Aminotransferase 
o 
Alkaline Phosphatase 
o 
Bilirubin 
 
Coagulation 
o 
Prothrombin Time 
o 
Activated Partial Thromboplastin Time 
o 
Fibrinogen 
 
Urinalysis 
o 
pH 
o 
Specific gravity 
o 
Glucose 
o 
Protein 
o 
Bilirubin 
o 
Urobilinogen 
o 
Erythrocytes 
o 
Leukocyte Esterase 
o 
Nitrite 
 
Urinalysis (Micro) 
o 
Ketones 
o 
Leukocytes 
o 
Erythrocytes 
o 
Casts 
o 
Bacteria 
The following parameters will be analyzed descriptively by time point: 
 
Number of subjects with laboratory samples drawn for hematology, clinical chemistry, coagulation and 
urinalysis 
 
Absolute values (summary statistics for hematology, clinical chemistry and coagulation) 
MV-CHIK-205
Clinical Study Report, Section 16
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Adapted from: 
 
Page 19 of 29 
STAT03_A Statistical Analysis Plan 
Version 6.0, Effective Date 16-Feb-2018 
Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
 
Absolute change from baseline (Screening) (summary statistics for hematology, clinical chemistry and 
coagulation) 
 
Number of subjects with values above/below normal range (for hematology, clinical chemistry and 
coagulation) 
 
Urinalysis results (summary statistics for quantitative parameters, frequency statistics for qualitative 
parameters) 
6.3.2 
Derivations and Definitions 
 
No conversion of laboratory parameters will be performed. The parameters listed above will be tabulated 
and listed in the units reported by the study site.  
 
Absolute change from baseline will be calculated as difference from value of the current visit and 
baseline value (screening). 
6.4 
Other Safety Parameters 
Data from the early termination visit or unscheduled visits will be listed only and will not be shown in summary 
tables by time point. All tables will be presented by treatment group and overall. Vital signs will be analyzed for 
Screening, Visit 3 and Visit 5:  
 
Diastolic blood pressure 
 
Systolic blood pressure 
 
Pulse rate 
 
Temperature 
The following data will be listed only:  
 
Pregnancy test 
 
Local tolerability 
 
Local tolerability – post vaccination 
 
Symptom-directed physical examination 
 
System-based physical examination 
MV-CHIK-205
Clinical Study Report, Section 16
Final 2.0
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SAP (MV-CHIK-205, FINAL 1.0, 20-Feb-2019) 
Adapted from: 
 
Page 20 of 29 
STAT03_A Statistical Analysis Plan 
Version 6.0, Effective Date 16-Feb-2018 
Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
7. 
LIST OF TABLES, DATA LISTINGS AND FIGURES 
7.1 
List of Tables 
No. for IA No. for FA 
Legend 
Content 
Overall Subject Information 
1.1.1.1 
2.1.1.1 
Subject Overview (Safety 
Population) 
 
Randomized 
 
Safety Population 
 
mITT Population 
 
PP Population 
1.1.1.2 
2.1.1.2 
Subjects by Visit (Safety 
Population) 
 
1.1.1.3 
n/a 
Vaccinated Subjects and 
Reason for missed Vaccinations 
(Safety Population) 
 
Number of subjects that received 
first vaccination 
 
Number of subjects that received 
second vaccination 
 
Number of subjects that missed 
any vaccination 
 
Reason for missing any vaccination 
1.1.1.4 
2.1.1.4 
Protocol Deviations by Deviation 
Type (Safety Population) 
 
Any major PD 
 
Any major PD by category 
 
Any minor PD 
 
Any minor PD by category 
1.1.1.5 
2.1.1.5 
Study Status (Safety Population) 
 
Visit attendance status 
 
Primary reason for early 
termination 
1.1.1.6 
n/a 
Number of Screening Failures 
and Reasons 
 
Number of screening failures 
 
Reason for screening failure 
1.1.2.2- 
1.1.2.5 
2.1.2.2- 
2.1.2.5 
Repeat tables x.1.1.1-x.1.1.5 for 
mITT population (if not the same 
as Safety Population) 
 
1.1.3.2- 
1.1.3.5 
n/a 
Repeat tables x.1.1.1-x.1.15 for 
PP population  
 
Baseline Evaluation 
1.2.1.1 
n/a 
Summary Table of Demographic 
Information (Safety Population) 
 
Age 
 
Gender 
 
Race 
 
Height [cm] 
 
Weight [kg] 
1.2.1.2 
n/a 
Vital Signs at Baseline (Safety 
Population) 
 
Systolic blood pressure [mmHg] 
 
Diastolic blood pressure [mmHg] 
 
Pulse rate [beats/min] 
 
Temperature [C] 
1.2.1.3 
n/a 
Medical History Entry by SOC 
and PT (Safety Population) 
 
1.2.1.4 
n/a 
Prior Medications by ATC Level 2 
and 3 (Safety Population) 
 
1.2.1.5 
n/a 
Concomitant Medications and 
by ATC Level 2 and 3 (Safety 
Population) 
 
1.2.1.6 
n/a 
Vaccination History by ATC Level 
2 and Level 3 (Safety 
Population) 
 
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Clinical Study Report, Section 16
Final 2.0
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Adapted from: 
 
Page 21 of 29 
STAT03_A Statistical Analysis Plan 
Version 6.0, Effective Date 16-Feb-2018 
Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
1.2.2.1- 
1.2.2.6 
n/a 
Repeat tables x.2.1.1-x.2.1.6 for 
mITT population (if not the same 
as Safety Population) 
 
1.2.3.1- 
1.2.3.6 
n/a 
Repeat tables 2.1.1-x2.1.6 for 
PP population (if not the same 
as Safety Population) 
 
Immunogenicity Results 
Primary Endpoint 
1.3.1.1 
2.3.1.1 
GMT of anti-Chikungunya 
PRNT50 Antibody 28 days after 
last MV-CHIK vaccination (mITT 
Population)  
 
1.3.1.2 
2.3.1.2 
ANOVA with fixed factor 
treatment group for GMT of anti-
Chikungunya PRNT50 Antibody 
28 days after last MV-CHIK 
vaccination (mITT Population) 
 
Anti-Chikungunya PRNT50 Antibody 
1.3.1.3 
2.3.1.3 
GMT of anti-Chikungunya 
PRNT50 Antibody by Visit (mITT 
Population)  
 
Preliminary Analysis: Visit 1, 3 and 
5 
 
Final Analysis : All available time 
points 
1.3.1.4 
2.3.1.4 
ANOVA for GMT of anti-
Chikungunya PRNT50 Antibody 
between treatment groups by 
Visit (mITT Population) 
 
Preliminary Analysis: Visit 1, 3 and 
5 
 
Final Analysis : All available time 
points 
1.3.1.5 
2.3.1.5 
Seroconversion rate for Anti-
Chikungunya PRNT50 Antibody 
by Visit (mITT Population) 
 
Preliminary Analysis: Visit 1, 3 and 
5 
 
Final Analysis : All available time 
points 
Chikungunya-ELISA Antibodies 
1.3.1.6 
2.3.1.6 
GMT of Chikungunya-ELISA 
Antibodies 28 days after last 
MV-CHIK vaccination (mITT 
Population)  
 
1.3.1.7 
2.3.1.7 
ANOVA for GMT of Chikungunya-
ELISA Antibodies between 
treatment groups 28 days after 
last MV-CHIK vaccination (mITT 
Population) 
 
n/a 
2.3.1.8 
GMT of Chikungunya-ELISA 
Antibodies by Visit (mITT 
Population) 
 
All available time points 
n/a 
2.3.1.9 
ANOVA for GMT of Chikungunya-
ELISA Antibodies between 
treatment groups by Visit (mITT 
Population) 
 
All available time points 
n/a 
2.3.1.10 
Seroconversion rate of 
Chikungunya-ELISA Antibodies 
by Visit (mITT Population) 
 
All available time points 
Measles-ELISA antibodies 
n/a 
2.3.1.11 
GMT of Measles-ELISA 
Antibodies 28 days after last 
MV-CHIK vaccination (mITT 
Population) 
 
All available time points 
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STAT03_A Statistical Analysis Plan 
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Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
1.3.1.1 –  
1.3.1.7 
1.3.2.1 –  
1.3.2.11 
Repeat tables for PP Population  
Safety Results 
Extent of Exposure 
1.4.1. 
2.4.1 
Extent of Exposure (Safety 
Population) 
 
Study duration 
 
Treatment duration 
Adverse Events 
1.4.2 
n/a 
Summary Table of solicited and 
unsolicited Adverse Events 
(Safety Population) 
Number of subjects with: 
 
Any AEs 
 
Any related AEs 
 
Any severe AEs 
 
Any related severe AEs 
 
Any SAEs 
 
Any related SAEs 
 
Any medically attended AEs 
 
Any related medically attended AEs 
 
Any AEs leading to study 
discontinuation 
 
Any AEs leading to second 
vaccination not administered 
1.4.3 
n/a 
Summary Table of solicited 
Adverse Events (Safety 
Population) 
 
Any solicited AEs 
 
Any related solicited AEs 
 
Any severe solicited AEs 
 
Any related severe solicited AEs 
 
Any solicited SAEs 
 
Any related solicited SAEs 
 
Any medically attended solicited 
AEs 
 
Any related medically attended 
solicited AEs 
 
Any solicited AEs leading to study 
discontinuation 
 
Any solicited AEs leading to second 
vaccination not administered 
1.4.4 
n/a 
Summary Table of solicited local 
Adverse Events (Safety 
Population) 
 
Any solicited local AEs 
 
Any related solicited local AEs 
 
Any severe solicited local AEs 
 
Any related severe solicited local 
AEs 
 
Any solicited local SAEs 
 
Any related solicited local SAEs 
 
Any medically attended solicited 
local AEs 
 
Any related medically attended 
solicited local AEs 
 
Any solicited local AEs leading to 
study discontinuation 
 
Any solicited local AEs leading to 
second vaccination not 
administered 
1.4.5 
n/a 
Summary Table of solicited 
systemic Adverse Events (Safety 
Population) 
 
Any solicited systemic AEs 
 
Any related solicited AEs 
 
Any severe solicited AEs 
MV-CHIK-205
Clinical Study Report, Section 16
Final 2.0
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Adapted from: 
 
Page 23 of 29 
STAT03_A Statistical Analysis Plan 
Version 6.0, Effective Date 16-Feb-2018 
Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
 
Any related severe solicited 
systemic AEs 
 
Any solicited systemic SAEs 
 
Any related solicited systemic SAEs 
 
Any medically attended solicited 
systemic AEs 
 
Any related medically attended 
solicited systemic AEs 
 
Any solicited systemic AEs leading 
to study discontinuation 
 
Any solicited systemic AEs leading 
to second vaccination not 
administered 
1.4.6 
n/a 
Summary Table of unsolicited 
Adverse Events (Safety 
Population) 
 
Any unsolicited AEs 
 
Any related unsolicited AEs 
 
Any severe unsolicited AEs 
 
Any serious unsolicited AEs 
 
Any medically attended unsolicited 
AEs 
 
Any related severe unsolicited AEs 
 
Any related serious unsolicited AEs 
 
Any related medically attended 
unsolicited AEs 
 
Any unsolicited AEs leading to 
second vaccination not 
administered 
 
Any unsolicited AEs caused study 
discontinuation 
1.4.7 
n/a 
Subjects with at least one 
Adverse Event classified by 
Maximum Severity (Safety 
Population) 
 
Solicited Adverse Events 
1.4.8 
n/a 
Subjects with solicited local 
Adverse Events by Symptom 
(Safety Population) 
 
1.4.9 
n/a 
Subjects with solicited systemic 
Adverse Events by Symptom 
(Safety Population) 
 
1.4.10 
n/a 
Subjects with solicited Adverse 
Events classified by Maximum 
Severity (Safety Population) 
 
1.4.11 
n/a 
Subjects with solicited local 
Adverse Events by Symptom 
classified by Maximum Severity 
(Safety Population) 
 
1.4.12 
n/a 
Subjects with solicited systemic 
Adverse Events by Symptom 
classified by Maximum Severity 
(Safety Population) 
 
Unsolicited Adverse Events 
1.4.13 
n/a 
Subjects with unsolicited 
Adverse Events by SOC and PT 
(Safety Population) 
 
1.4.14 
n/a 
Subjects with related unsolicited  
MV-CHIK-205
Clinical Study Report, Section 16
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STAT03_A Statistical Analysis Plan 
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Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
Adverse Events by SOC and PT 
(Safety Population) 
1.4.15 
n/a 
Subjects with severe unsolicited 
Adverse Events by SOC and PT 
(Safety Population) 
 
1.4.16 
n/a 
Subjects with serious 
unsolicited Adverse Events by 
SOC and PT (Safety Population) 
 
1.4.17 
n/a 
Subjects with medically 
attended unsolicited Adverse 
Events by SOC and PT (Safety 
Population) 
 
1.4.18 
n/a 
Subjects with related severe 
unsolicited Adverse Events by 
SOC and PT (Safety Population) 
 
1.4.19 
n/a 
Subjects with related serious 
unsolicited Adverse Events by 
SOC and PT (Safety Population) 
 
1.4.20 
n/a 
Subjects with related medically 
attended unsolicited Adverse 
Events by SOC and PT (Safety 
Population) 
 
1.4.21 
n/a 
Subjects with unsolicited 
Adverse Events leading to 
second Vaccination not 
administered (Safety 
Population) 
 
1.4.22 
n/a 
Subjects with unsolicited 
Adverse Events caused study 
discontinuation (Safety 
Population) 
 
1.4.23 
n/a 
Subjects with at least one 
unsolicited 
Adverse Event by Maximum 
Severity (Safety Population) 
 
1.4.24 
n/a 
Subjects with at least one 
medically attended unsolicited 
Adverse Event by Maximum 
Severity (Safety Population) 
 
1.4.25 
n/a 
Subjects with at least one 
unsolicited 
Adverse Event by Causality 
(Safety Population) 
 
1.4.26 
n/a 
Subjects with at least one 
medically attended unsolicited 
Adverse Event by Causality 
(Safety Population) 
 
1.4.27 
n/a 
Subjects with at least one 
serious unsolicited Adverse 
Event by Causality (Safety 
Population) 
 
Laboratory Parameters 
1.4.28 
n/a 
Absolute Values for Hematology 
Parameters by Parameter and 
Visit (Safety Population) 
 
1.4.29 
n/a 
Absolute Values for Clinical 
 
MV-CHIK-205
Clinical Study Report, Section 16
Final 2.0
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Adapted from: 
 
Page 25 of 29 
STAT03_A Statistical Analysis Plan 
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otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
Chemistry Parameters by 
Parameter and Visit (Safety 
Population) 
1.4.30 
n/a 
Absolute Values for Coagulation 
Parameters by Parameter and 
Visit (Safety Population) 
 
1.4.31 
n/a 
Absolute Changes from Baseline 
for Hematology Parameters by 
Parameter and Visit (Safety 
Population) 
 
1.4.32 
n/a 
Absolute Changes from Baseline 
for Clinical Chemistry 
Parameters by Parameter and 
Visit (Safety Population) 
 
1.4.33 
n/a 
Absolute Changes from Baseline 
for Coagulation Parameters by 
Parameter and Visit (Safety 
Population) 
 
1.4.34 
n/a 
Subjects with Hematology 
Parameters Outside Normal 
Range by Parameter and Visit 
(Safety Population) 
 
1.4.35 
n/a 
Subjects with Clinical Chemistry 
Parameters Outside Normal 
Range by Parameter and Visit 
(Safety Population) 
 
1.4.36 
n/a 
Subjects with Coagulation 
Parameters Outside Normal 
Range by Parameter and Visit 
(Safety Population) 
 
1.4.37 
n/a 
Urine Laboratory Results by 
Parameter and Visit (Safety 
Population) 
 
1.4.38 
n/a 
Absolute Changes from Baseline 
for pH and Specific Gravity by 
Visit (Safety Population) 
 
Other Safety Parameters 
1.4.38 
n/a 
Systolic Blood Pressure [mmHg] 
by Visit (Safety Population) 
 
1.4.39 
n/a 
Diastolic Blood Pressure 
[mmHg] by Visit (Safety 
Population) 
 
1.4.40 
n/a 
Pulse Rate [beats/min] by Visit 
(Safety Population) 
 
1.4.41 
n/a 
Body Temperature [°C] by Visit 
(Safety Population) 
 
7.2 
List of Data Listings 
No for IA No for FA 
Legend 
Content 
Overall Subject Information 
1.1 
2.1 
Analysis Population Details 
Subject number, Treatment (Safety), Treatment 
(mITT), Safety Population, Reason not in Safety 
Population, mITT Population, Reason not in mITT 
Population, PP Population, Reason not in PP 
Population 
MV-CHIK-205
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SAP (MV-CHIK-205, FINAL 1.0, 20-Feb-2019) 
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STAT03_A Statistical Analysis Plan 
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otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
1.2 
2.2 
Screening Failures with Reason 
Subject number, Date of informed consent, 
Subject’s withdrawal of consent, In/Ex criterion not 
satisfied, Other, Specification other reason 
1.3 
2.3 
Violated Entry Criteria 
Subject number, Visit, Criterion ID not met, Criterion 
description 
1.4 
2.4 
Attended Visits with Dates (Safety 
Population) 
Subject number, Treatment (Safety), Visit, Reason 
for unscheduled visit, Date, Reason out of time 
window 
1.5 
n/a 
Protocol Deviations (Safety Population) 
Subject number, Treatment (Safety), PD Category, 
Classification, Reason for classification, PD 
Description 
1.6 
2.6 
Study Status (Safety Population) 
Subject number, Treatment (Safety), Visit 
attendance status, Primary reason early 
termination/treatment discontinuation, Other 
reason specification, AE Term, Death date, Primary 
cause of death, Date of study discontinuation 
Baseline Evaluation 
1.2.1 
2.2.1 
Demographic Information (Safety 
Population) 
Subject number, Treatment (Safety), Date of birth, 
Age [years], Gender, Childbearing potential, Race, 
Specification other race 
1.2.3 
2.2.3 
Full Physical Examination at Visit 0 
(Safety Population) 
Subject number, Treatment (Safety), Examination 
performed, Reason not performed, Exam Date 
1.2.4 
2.2.4 
Medical History (Safety Population) 
Subject number, Treatment (Safety), MH Term, 
Preferred Term (MedDRA [Version]), SOC (MedDRA 
[Version]), Started prior to study, Start date, End 
date, Ongoing, Ongoing at first IMP administration 
1.2.6 
2.2.6 
Prior Medications (Safety Population) 
Subject number, Treatment (Safety), Medication, 
ATC Level 2 (WHODD [Version]), ATC Level 3 
(WHODD [Version]), Active Ingredients, Indication 
category, Indication, Dose, Dose Unit, Frequency, 
Route, Taken prior to study, Start date, End date, 
Ongoing, Ongoing at final examination 
1.2.7 
2.2.7 
Concomitant Medications (Safety 
Population) 
Subject number, Treatment (Safety), Medication, 
ATC Level 2 (WHODD [Version]), ATC Level 3 
(WHODD [Version]), Active Ingredients, Indication 
category, Indication, Dose, Dose Unit, Frequency, 
Route, Taken prior to study, Start date, End date, 
Ongoing, Ongoing at final examination 
1.2.5 
2.2.5 
Vaccination History (Safety Population) 
Subject number, Treatment (Safety), Vaccination 
within 3 years prior screening, Date, 
Vaccination/Indication, ATC Level 2 (WHODD 
[Version]), ATC Level 3 (WHODD [Version]), 
1.2.8 
2.2.8 
Virology 
Subject number, Treatment (Safety), Virology test, 
Test performed, Result, Date 
Immunogenicity Analysis 
1.3.1 
2.3.1 
Functional Antibodies Assessment 
(PRNT50) (ITT Population) 
Subject number, Country, Treatment group, 
Visit, Sample performed, Reason not performed, 
Sample ID, Date/Time of sample, Titer [IU/ml], 
Serconversion 
1.3.2 
2.3.2 
Functional Antibodies Assessment 
(ELISA) (ITT Population) 
Subject number, Country, Treatment group, 
Visit, Sample performed, Reason not performed, 
Sample ID, Date/Time of sample, Titer [IU/ml] , 
Serconversion 
n/a 
2.3.3 
Measles Antibodies Assessment (ITT 
Population) 
Subject number, Country, Treatment group, 
Visit, Sample performed, Reason not performed, 
Sample ID, Date/Time of sample, Titer [IU/ml] 
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Page 27 of 29 
STAT03_A Statistical Analysis Plan 
Version 6.0, Effective Date 16-Feb-2018 
Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
n/a  
2.3.4 
T-cell details (ITT Population) 
Subject number, Country, Treatment group, 
Visit, Sample performed, Reason not performed, 
Sample ID, Date/Time of sample, Titer [IU/ml] 
n/a 
2.3.5 
Serum collection for passive transfer 
(ITT Population) 
Subject number, Country, Treatment group, 
Visit, Sample performed, Reason not performed, 
Sample ID, Date/Time of sample 
Safety Analysis 
Extent of Exposure 
1.4.1 
2.4.1 
Extent of Exposure (Safety Population) 
Subject number, Treatment (Safety), Date first 
vaccination, Date second vaccination, Treatment 
duration [days], Date informed consent, Date of last 
attended visit, Study duration [days] 
1.4.2 
2.4.2 
Study Medication Details (Safety 
Population) 
Subject number, Treatment (Safety), Visit, IMP 
administered, Reason IMP not administered, 
Date/Time, Package label barcode 
Adverse Events 
1.4.3 
n/a 
Adverse Events Part 1 (Safety 
Population) 
Subject number, Treatment (Safety), Record ID, AE 
Term, MedDRA PT, MedDRA SOC, AE type, Start 
date/time, End date/time, Medically attended, 
Severity, Serious AE, SAE Criteria, Causality 
1.4.4 
n/a 
Adverse Events Part 2 (Safety 
Population) 
Subject number, Treatment (Safety), Record ID, AE 
Term, AE type ,Action taken with Study Treatment, 
Other Action taken, Outcome, Ongoing at final 
examination, Caused study discontinuation 
1.4.5 
n/a 
Unsolicited Adverse Events Part 1 
(Safety Population) 
Subject number, Treatment (Safety), Record ID, AE 
Term, MedDRA PT, MedDRA SOC, Start date/time, 
End date/time, Medically attended, Severity, 
Serious AE, SAE Criteria, Causality 
1.4.6 
n/a 
Unsolicited Adverse Events Part 2 
(Safety Population) 
Subject number, Treatment (Safety), Record ID, AE 
Term, Action taken with Study Treatment, Other 
Action taken, Outcome, Ongoing at final 
examination, Caused study discontinuation 
1.4.7 
n/a 
Related Unsolicited Adverse Events Part 
1 (Safety Population) 
See Listing 1.4.5 
1.4.8 
n/a 
Related Unsolicited Adverse Events Part 
2 (Safety Population) 
See Listing 1.4.6 
1.4.9 
n/a 
Severe Unsolicited Adverse Events Part 
1 (Safety Population) 
See Listing 1.4.5 
1.4.10 
n/a 
Severe Unsolicited Adverse Events Part 
2 (Safety Population) 
See Listing 1.4.6 
1.4.11 
n/a 
Serious Unsolicited Adverse Events Part 
1 (Safety Population) 
See Listing 1.4.5 
1.4.12 
n/a 
Serious Unsolicited Adverse Events Part 
2 (Safety Population) 
See Listing 1.4.6 
1.4.13 
n/a 
Medically attended unsolicited Adverse 
Events Part 1 (Safety Population) 
See Listing 1.4.5 
1.4.14 
n/a 
Medically attended unsolicited Adverse 
Events Part 2 (Safety Population) 
See Listing 1.4.6 
1.4.15 
n/a 
Unsolicited Adverse Events caused 
Study Discontinuation Part 1 (Safety 
Population) 
See Listing 1.4.5 
1.4.16 
n/a 
Unsolicited Adverse Events caused 
Study Discontinuation Part 2 (Safety 
Population) 
See Listing 1.4.6 
1.4.17 
n/a 
Unsolicited Adverse Events leading to 
second Vaccination not administered 
See Listing 1.4.5 
MV-CHIK-205
Clinical Study Report, Section 16
Final 2.0
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Page 28 of 29 
STAT03_A Statistical Analysis Plan 
Version 6.0, Effective Date 16-Feb-2018 
Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
Part 1 (Safety Population) 
1.4.18 
n/a 
Unsolicited Adverse Events leading to 
second Vaccination not administered 
Part 2 (Safety Population) 
See Listing 1.4.6 
1.4.19 
n/a 
Solicited Adverse Events Part 1 (Safety 
Population) 
Subject number, Treatment (Safety), Record ID, AE 
Term, Start date/time, End date/time, Medically 
attended, Severity, Serious AE, SAE Criteria, 
Causality 
1.4.20 
n/a 
Solicited Adverse Events Part 2 (Safety 
Population) 
Subject number, Treatment (Safety), Record ID, AE 
Term, Action taken with Study Treatment, Other 
Action taken, Outcome, Ongoing at final 
examination, Caused study discontinuation 
1.4.21 
n/a 
Related Solicited Adverse Events Part 1 
(Safety Population) 
See Listing 1.4.19 
1.4.22 
n/a 
Related Solicited Adverse Events Part 2 
(Safety Population) 
See Listing 1.4.20 
1.4.23 
n/a 
Severe Solicited Adverse Events Part 1 
(Safety Population) 
See Listing 1.4.19 
1.4.24 
n/a 
Severe Solicited Adverse Events Part 2 
(Safety Population) 
See Listing 1.4.20 
1.4.25 
n/a 
Serious Solicited Adverse Events Part 1 
(Safety Population) 
See Listing 1.4.19 
1.4.26 
n/a 
Serious Solicited Adverse Events Part 2 
(Safety Population) 
See Listing 1.4.20 
1.4.27 
n/a 
Medically attended Solicited Adverse 
Events Part 1 (Safety Population) 
See Listing 1.4.19 
1.4.28 
n/a 
Medically attended Solicited Adverse 
Events Part 2 (Safety Population) 
See Listing 1.4.20 
1.4.29 
n/a 
Solicited Adverse Events caused Study 
Discontinuation Part 1 (Safety 
Population) 
See Listing 1.4.19 
1.4.30 
n/a 
Solicited Adverse Events caused Study 
Discontinuation Part 2 (Safety 
Population) 
See Listing 1.4.20 
1.4.31 
n/a 
Solicited Adverse Events leading to 
second Vaccination not administered 
Part 1 (Safety Population) 
See Listing 1.4.19 
1.4.32 
n/a 
Solicited Adverse Events leading to 
second Vaccination not administered 
Part 2 (Safety Population) 
See Listing 1.4.20 
Laboratory Parameters 
1.4.33 
n/a 
Hematology Values outside Normal 
Range (Safety Population) 
Subject number, Treatment (Safety), Visit, 
Date/Time, Parameter, Value, Unit, Not done, 
Reason not done, Clinically significant, Likely 
cause, Change from baseline 
1.4.34 
n/a 
Clinical Chemistry Values outside 
Normal Range (Safety Population) 
Subject number, Treatment (Safety), Visit, 
Date/Time, Parameter, Value, Unit, Not done, 
Reason not done, Clinically significant, Likely 
cause, Change from baseline 
1.4.35 
n/a 
Coagulation Values outside Normal 
Range (Safety Population) 
Subject number, Treatment (Safety), Visit, 
Date/Time, Parameter, Value, Unit, Not done, 
Reason not done, Clinically significant, Likely 
cause, Change from baseline 
1.4.36 
n/a 
Urinalysis Values outside Normal Range 
(Safety Population) 
Subject number, Treatment (Safety), Visit, 
Date/Time, Parameter, Result, Not done, Reason 
not done, Clinically significant, Likely cause 
MV-CHIK-205
Clinical Study Report, Section 16
Final 2.0
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SAP (MV-CHIK-205, FINAL 1.0, 20-Feb-2019) 
Adapted from: 
 
Page 29 of 29 
STAT03_A Statistical Analysis Plan 
Version 6.0, Effective Date 16-Feb-2018 
Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
Other Safety Parameters 
1.4.37 
n/a 
Vital Signs (Safety Population) 
Subject number, Treatment (Safety), Visit, Vital 
signs collected, Reason not collected, Date, Test, 
Result, Unit, Clinically significant, not done 
1.4.38 
n/a 
Symptom-directed Physical Exam 
(Safety Population) 
Subject number, Treatment (Safety), Exam 
performed, Reason not performed, Exam date 
1.4.39 
n/a 
System Based Physical Exam (Safety 
Population) 
Subject number, Treatment (Safety), Exam 
performed, Exam date 
1.4.40 
n/a 
Local Tolerability (Safety Population) 
Subject number, Treatment (Safety), Assessment 
performed, Reason not performed, Exam 
Date/Time, Time recorded 
1.4.41 
n/a 
Local Tolerability – Post Vaccination 
(Safety Population) 
Subject number, Treatment (Safety), Assessment 
performed, Reason not performed, Exam 
Date/Time, Time recorded 
1.4.42 
n/a 
Pregnancy test (Safety Population) 
Subject number, Treatment (Safety), visit, 
Pregnancy test performed, Reason not performed, 
Date, Result 
 
MV-CHIK-205
Clinical Study Report, Section 16
Final 2.0
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