Therapeutic Vaccination and Immune Modulation - New Treatment Strategies for the Multidrug-resistant Tuberculosis Pandemic; an Open Label Phase I Clinical Trial of the Therapeutic TB H56:IC31 Vaccine and Cyclooxygenase-inhibitors
Phase: PHASE1
Conditions: Tuberculosis
Sponsor: Anne Margarita Dyrhol Riise

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  !
!
!
Clinical!Study!Protocol!
!
Therapeutic!vaccination!and!immune!modulation!2!
new!treatment!strategies!for!the!multidrug2resistant!
tuberculosis!pandemic!
An!open!label!phase!I!clinical!trial!of!the!therapeutic!TB!H56:IC31!
vaccine!and!cyclooxygenase2inhibitors!!
 
!
Protocol!Identification!Number:!TBCOX2!
EudraCT!Number:!20148004986826!
ClinicalTrials.No:!NCT02503839!
!
SPONSOR:!
Oslo!University!Hospital!
!
PRINCIPAL!INVESTIGATOR!
(PI):!
Professor!Anne!Ma!Dyrhol8Riise!
Oslo!University!Hospital!
Department!of!Infectious!Diseases,!
Oslo,!Norway!
Tel:!+47!92857261!
E8mail:!a.m.d.riise@medisin.uio.no!
!
PROTOCOL!VERSION!6.0!2!1221022016!
!
Confidentiality!Statement!
The!information!contained!in!this!document!is!confidential!and!cannot!be!disclosed!unless!
required!by!governmental!regulation.!!Persons!to!whom!any!portion!of!the!contents!of!this!
document!is!disclosed!must!be!informed!that!the!information!is!confidential!and!may!not!be!
further!disclosed!by!them.!
!
!

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CONTACT!DETAILS!!
Sponsor!
Professor!Dag!Kvale,!MD,!PhD!
Oslo!University!Hospital!
Department!of!Infectious!Diseases,!Oslo,!Norway!
Tel:!+47!95200709!
E8mail:!dag.kvale@medisin.uio.no!!
!
Principal!investigator:!
Professor!Anne!Ma!Dyrhol8Riise,!MD,!PhD!
Oslo!University!Hospital!
Department!of!Infectious!Diseases,!Oslo,!Norway!
Tel:!+47!92857261!
E8mail:!a.m.d.riise@medisin.uio.no!
!
Co2investigator:!
Professor!Kjetil!Taskén,!MD,!PhD!
The!Biotechnology!Centre!
University!of!Oslo,!Oslo,!Norway!
Tel:!+47!90860759!
E8mail:!kjetil.tasken@biotek.uio.no!
!
Co2investigator:!
!
!
!
!
!
!
!
!
!
Co2investigator:!
Morten!Ruhwald,!MD,!PhD!
Head!of!section,!Human!Immunology!
Infectious!Disease!Immunology!
Division!of!vaccine,!Statens!Serum!Institut!
Tel:!+45!3268!3940!!
E8mail:!moru@ssi.dk!
!
Professor!Tehmina!Mustafa,!MD,!PhD!
Dep.!of!Thoracic!Medicine!
Haukeland!University!Hospital,!Bergen,!Norway!
Tel:!+47!97633677!!
E8mail:!tehmina.mustafa@uib.no!

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APPROVAL!PAGE!
I"hereby"declare"that"I"will"conduct"the"study"in"compliance"with"the"Protocol,"ICH"
GCP"and"the"applicable"regulatory"requirements:"
!
Principal!Investigator:!
!
_____________________________________________________________________!
Prof.!Anne!Ma!Dyrhol8Riise,!MD,!PhD!
Date!!
!
Sponsor:!
!
_____________________________________________________________________!
Prof.!Dag!Kvale,!MD,!PhD!!
Date!
!
Co2investigator:!
!
_____________________________________________________________________!
Prof.!Kjetil!Taskén,!MD,!PhD!!
!
!
Date!
!
Co2investigator:!
!
_____________________________________________________________________!
Morten!Ruhwald,!MD,!PhD!!
!
!
Date!
!
Co2investigator:!
!
_____________________________________________________________________!
Tehmina!Mustafa,!MD,!PhD!!
!
!
Date!
!

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PROTOCOL!SYNOPSIS!
Name!of!Sponsor/Company:!Oslo!University!Hospital!!
Name!of!Products:!Arcoxia!(MSD).!Tuberculosis!vaccine:!H56:IC31!
Name!of!Active!Ingredient:!etoricoxib.!H56!antigen!and!IC31!adjuvant.!
Title!of!Study:!Therapeutic+vaccination+and+immune+modulation+2+new+treatment+strategies+for+the+
multidrug2resistant+tuberculosis+pandemic.+A+open+label+phase+I+clinical+trial+of+the+therapeutic+TB+
H56:IC31+vaccine+and+cyclooxygenase2inhibitors+(COX22i)+!
EudraCT!nr:!!20148004986826.!!
Protocol!Identification!Number:!TBCOX2!
Investigators!and!Study!Centre(s):!!!
Professor!Anne!Ma!Dyrhol8Riise,!MD,!PhD,!Oslo!University!Hospital,!Oslo,!Norway!(PI)!
Professor!Dag!Kvale,!MD,!PhD,!Oslo!University!Hospital,!Oslo,!Norway.!
Professor!Kjetil!Taskén,!MD,!PhD,!University!of!Oslo,!Oslo,!Norway.!
Morten!Ruhwald,!MD,!PhD,!Statens!Serum!Institut,!København,!Denmark.!
Professor!Tehmina!Mustafa,!MD,!PhD,!Haukeland!University!Hospital,!Bergen,!Norway.!
Study!centre:!Oslo!University!Hospital.!Haukeland!University!Hospital.!
Phase!of!Development:!Phase!I!
Objectives:!!!
1.! Study!the!safety!and!tolerability!of!etoricoxib!given!for!20!weeks!(day!08140)!alone!and!in!
combination!with!the!therapeutic!TB!vaccine!H56:IC31!given!as!two!immunizations!at!day!84!
and!day!140!in!patients!with!active!TB!disease!treated!with!conventional!268week!anti8TB!
chemotherapy.!
2.! Study!the!immune!effects!of!etoricoxib!given!for!20!weeks!(day!08140)!on!immune!regulation!
and!TB!vaccine!(H56:IC31)!immunogenicity!in!patients!with!active!TB!disease!treated!with!
conventional!268week!anti8TB!chemotherapy.!
Methodology:!Open8label!controlled,!randomized!study!
Number!of!Subjects!Planned:!A!total!of!40!patients!with!active!pulmonary!and/or!extra8pulmonary!
TB!disease!infected!with!drug8sensitive!Mtb!strains!will!be!included!sequentially!in!two!groups!A!and!
B.!Group!A!comprises!the!following!study!arms:!Arm!#1,!etoricoxib!(n=10),!Arm!#2!H56:IC31!TB!
vaccine!(n=10)!and!Arm!#3!as!controls!(n=5.!Following!safety!review!at!day!98!we!will!include!for!part!
B!comprising!Arm!#4!H56:IC31!TB!vaccine!and!etoricoxib!(n=10)!and!the!remainder!of!controls!for!
Arm!#3!(n=5).!!
Diagnosis!and!Main!Criteria!for!Inclusion:!!
1.! Age!between!18!and!70!years!at!the!time!of!randomization!
2.! Microbiologically!confirmed!pulmonary!TB!(culture!and/or!PCR!+!susceptibility!testing)!and/or!!
microbiologically!confirmed!extra8pulmonary!TB!(culture!and/or!PCR!+!susceptibility!testing)!
3.! Drug!sensitive!Mtb!strains!(except!single!resistance!where!fully!adequate!anti8TB!chemotherapy!
regimen!could!be!provided).!!!
4.! Is!willing!and!likely!to!comply!with!the!trial!procedures!and!is!prepared!to!grant!authorized!
persons!access!to!their!medical!record.!
5.! Has!completed!the!written!informed!consent!process!prior!to!the!start!of!screening!evaluations.!
6.! Females:!Ability!to!avoid!pregnancy!during!the!trial.!
Subjects!may!receive!H56:IC31!vaccination!(study!arm!2!and!4)!if!they!meet!the!following!criteria:!
1.! Sputum!obtained!prior!to!1th!immunization!(day!84)!must!be!Mtb+negative!evaluated!by!at!least!
two!consecutive!AFS!or!PCR/GeneXpert!at!least!7!days!apart.!
2.! Documented!reduction!in!the!extent!of!TB!disease!at!the!infectious!site(s)!within!day!84!

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evaluated!by!physical!and/or!radiological!examination!(table!A2).!!
3.! Clinical!improvement!with!normal!vital!signs!(blood!pressure,!temperature!and!pulse),!
improvement!of!any!TB!related!symptoms!to!Grade!183!(table!A2),!stable!or!increased!body8
weight!and!reduced!inflammatory!blood!parameters!(CRP,!ESR!and!WBC!counts)!compared!to!
baseline.!!
Main!exclusion!criteria:!
(i)!Study2specific:!Disseminated!TB.!Evidence!of!a!new!acute!illness!that!may!compromise!the!
safety!of!the!subject!in!the!trial!on!study!day!0.!History!of!autoimmune!disease!or!
immunosuppression.!History!or!laboratory!evidence!of!any!possible!immunodeficiency!state.!Anemia!
(<9!g/100!ml).!HIV!sero8positivity.!Chronic!hepatitis!B!(HBs!antigen!positive)!with!increased!liver!
transaminases!(ASAT,!ALAT)!or!chronic!hepatitis!C!(HCV!RNA!positive).!Concomitant!or!sporadic!
use!of!NSAID!or!corticosteroids!(>2!times!per!week).!Other!immune!modulating!therapies!including!
DMARDS.!Total!cholesterol!>!7!mmol/L.!Hypertension!>140/90!mm!Hg!(treated!or!untreated)!or!
treated!with!>1!antihypertensive!drug!at!any!blood!pressure.!Cardiovascular!events!or!stroke!in!
parents,!siblings!or!off8springs!occurring!<!55!years!of!age.!Serum!creatinine!above!reference!levels!
(females!>!90!µmol/Lm!males!>!105!µmol/L).!Known!diabetes!mellitus!type!I!or!diabetes!mellitus!type!
II!with!HbA1c!>7%.!Pregnancy!(S8hCG!>5!IU/l!for!females!at!childbearing!age).!Breastfeeding.!
(ii)!Exclusion!criteria!for!etoricoxib!according!to!SPC:!Known!hypersensitivity!for!etoricoxib!or!
etoricoxib!tablet!substances.!Known!hypersensitivity!for!sulphonamides.!Active!peptic!ulcer!or!
gastrointestinal!haemorrhage.!History!of!asthma,!acute!rhinitis,!nasal!polyps,!angioneurotic!oedema,!
urticaria!or!other!allergic!reactions!after!taking!acetyl!salicylic!acid!or!NSAID!including!COX82!
inhibitors.!Moderate/severe!deranged!liver!function!(Child8Pugh!>7).!Serum8creatinine!clearance!<30!
ml/min.!Inflammatory!bowel!disease.!Heart!failure!(NYHA!II8IV).!Established!ischaemic!heart!disease,!
peripheral!arteriosclerosis!and/or!cerebrovascular!disease,!including!previous!myocardial!infarction,!
angina!pectoris,!unstable!angina,!PCI!or!coronary!bypass,!previous!transitory!ischemic!attack!or!
apoplexia/stroke.!
iii)!Exclusion!criteria!for!H56:IC31:!Known!hypersensitivity!for!vaccines!or!vaccine!adjuvants.!
Investigational!Product,!Dose!and!Mode!of!Administration:!
!
Arcoxia!(etoricoxib)!tablets!120!mg,!administered!p.o.!at!120!mg!x!1!starting!at!the!same!time!as!
initiation!of!anti8TB!chemotherapy!(study!day!0)!and!for!20!weeks!(day!08140).!If!intolerable!adverse!
reactions!or!clinical!laboratory!evaluation!category!2!occur,!dose!will!be!reduced!to!90!mg!x1!or!drug!
will!be!stopped.!!
H56:IC31!vaccinem!administrated!i.m!at!5!μg!1st!dose!at!study!day!84!and!2nd!dose!at!study!day!140.!!
A!phase!I!trial!(C80328456m!open8label,!dose8escalation!of!latent!TB)!and!a!phase!I/IIa!(C80358456m!
randomized,!placebo8controlled)!with!H56:IC31!show!that!the!vaccine!is!well!tolerated!and!no!safety!
issues!have!been!identified.!A!phase!I/II!clinical!study!of!H56:IC31!(C80378456)!in!patients!treated!for!
active!pulmonary!TB!is!ongoing!in!South8Africa.!The!first!participant!was!dosed!in!January!2015!and!
after!12!first!doses!administered!(19th!February!2015)!no!safety!concerns!have!been!reported.!
Inclusion!in!study!arm!3!and!4!will!not!start!before!all!preliminary!safety!data!from!this!study!is!
available!and!the!vaccine!is!proven!safe!also!in!this!population.!
Study!Duration:"Informed!consent,!inclusion,!baseline!assessments!and!start!of!standard!anti8TB!
chemotherapy!at!day!0!followed!by!20!weeks!of!study!drug!administration!(day!08140),!6!weeks!(or!
according!to!clinical!evaluation)!of!standard!anti8TB!chemotherapy!alone!(day!08182)!and!follow8up!
control!at!day!210!and!end!of!study!visit!day!238."
Criteria!for!Evaluation:!!
Safety:!Tolerability!and!safety!of!etoricoxib!and!the!therapeutic!TB!vaccine!H56:IC31.!Reductions!of!
etoricoxib!dose!or!stop!of!drug,!AE/SAE/SUSAR!including!cardiovascular!events,!blood!pressure,!
clinical!chemistry!and!vaccine!AE/SAE/SUSAR.!!
Pharmacokinetics:!AUC,!Cmax!of!etoricoxib!at!steady!state!after!7!days!(Arm!#1).!!
Primary!Immunogenicity!readouts:!!
1.! Etoricoxib!effect!of!TB!specific!immune!responses:!T!cell!proliferation!and!cytokine!responses!
(change!between!day!0!and!140).!
2.! H56:IC31!vaccine!immunogenicity:!T!cell!proliferation!and!cellular!cytokine!responses!14!
days!post8immunization!(day!98!and!day!154).!!!
3.! Etoricoxib!effect!of!H56:IC31!vaccine!immunogenicity:!T!cell!proliferation!and!cellular!

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cytokine!responses!14!days!post8immunization!(day!98!and!day!154).!!!
Readouts:!1.!WB/PBMC!ICS!(cytokines!responses).!2.!T!cell!proliferation!(cfse),!3.!Tregs/maturity!
(CD25,!FoxP3,!COX82).!4.!Soluble!biomarkers.!5.!Monocyte!responses!(COX82).!6.!RNA!analysis.!!
Statistical!Methods:!Non8parametrical!methods!to!describe!patient!groups!including!matched!pair!
statistics!to!determine!primary!endpoints!within!the!four!study!arms.!

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TABLE!OF!CONTENTS!
!
Page!No.!
CONTACT!DETAILS!.........................................................................................................!2!
APPROVAL!PAGE!...........................................................................................................!3!
PROTOCOL!SYNOPSIS!...................................................................................................!4!
TABLE!OF!CONTENTS!....................................................................................................!7!
LIST!OF!ABBREVIATIONS!............................................................................................!10!
1!
INTRODUCTION!...................................................................................................!11!
1.1!
Background!............................................................................................................!11!
1.1.1!
The!TB!epidemic!.....................................................................................!11!
1.1.2!
Immune!pathogenesis!and!regulation!in!TB!...........................................!11!
1.1.3!
The!cyclooxygenase8prostaglandin!E2!pathway!in!TB!...........................!11!
1.2!
Pre8Clinical!&!Clinical!Experience!with!COX82i!and!H56:IC31!..............................!12!
1.2.1!
Pre8clinical!studies!of!COX82i!in!experimental!animal!TB!models!..........!12!
1.2.2!
Clinical!studies!of!COX82i!.......................................................................!12!
1.2.3!
Pre8clinical!studies!of!the!H56:IC31!TB!vaccine!in!animal!TB!models!...!12!
1.2.4!
Clinical!studies!of!the!H56:IC31!TB!vaccine!...........................................!13!
1.3!
Rationale!for!the!Study!and!Purpose!.....................................................................!13!
1.3.1!
TB!therapeutic!vaccines!as!rescue!therapy!in!MDR8TB!.........................!13!
1.3.2!
COX82i!improves!cellular!vaccine!responses!in+vivo!..............................!14!
1.3.3!
COX82i!improves!TB!specific!immune!responses!and!regulation!in+vitro!14!
1.3.4!
Rationale!for!COX82i!regimen!and!dose!selected!..................................!14!
2!
STUDY!OBJECTIVES!AND!RELATED!ENDPOINTS!.........................................!15!
3!
OVERALL!STUDY!DESIGN!.................................................................................!15!
4!
STUDY!POPULATION!.........................................................................................!17!
4.1!
Selection!of!Study!Population!................................................................................!17!
4.2!
Number!of!Patients!................................................................................................!17!
4.3!
Inclusion!Criteria!....................................................................................................!17!
4.4!
Exclusion!Criteria!...................................................................................................!18!
4.4.1!
Study8specific!exclusion!criteria!..............................................................!18!
4.4.2!
Exclusion!criteria!according!to!the!SPC!on!Arcoxia!!
!
from!Norwegian!Medicines!Agency!........................................................!18!
4.5!
Criteria!for!receiving!H56:IC31!vaccine!..................................................................!19!
4.6!
Withdrawal!and!Termination!Criteria!......................................................................!19!
5!
TREATMENT!........................................................................................................!19!
5.1!
Drug!Identity,!Supply!and!Storage.!........................................................................!20!
5.1.1!
Description!of!Arcoxia®!..........................................................................!20!
5.1.2!
Description!of!H56:IC31!..........................................................................!20!
5.1.3!
Description!of!placebo!............................................................................!20!
5.2!
Dosage!and!Drug!Administration!...........................................................................!20!
5.3!
Duration!of!Therapy!...............................................................................................!21!
5.4!
Clinical!Monitoring!..................................................................................................!21!
5.5!
Drug!dose!Modifications!.........................................................................................!21!
5.6!
Concomitant!Medication!.........................................................................................!21!
5.7!
Drug!Accountability!................................................................................................!22!
5.8!
Treatment!Compliance!...........................................................................................!22!
5.9!
Drug!Labeling!.........................................................................................................!22!
5.10!
Subject!Numbering!and!Randomization!.................................................................!22!
6!
STUDY!PROCEDURES!........................................................................................!23!
6.1!
Table!2.!Trial!flow!chart!!
!
Table!A2.!Evaluation!of!treatment!response!in!extrapulmonal!TB!.........................!24!
6.2!
By!Visit!...................................................................................................................!26!
6.2.1!
Before!Treatment!Starts!.........................................................................!26!
6.2.2!
During!Treatment!....................................................................................!26!
6.2.3!
End!of!Treatment!Visit!............................................................................!27!
6.2.4!
Withdrawal!Visit!......................................................................................!27!
6.2.5!
After!End!of!Treatment!(Follow8up)!........................................................!27!
6.3!
Criteria!for!Patient!Discontinuation!.........................................................................!27!

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6.3.1!
Rules!for!Discontinuing!the!whole!Study!in!an!Individual!Subject!..........!27!
6.3.2!
Specific!Rules!for!Discontinuing!etoricoxib!in!an!Individual!Subject!.......!27!
6.3.3!
Rules!for!Discontinuing!Vaccine!Injections!in!an!Individual!Subject!.......!28!
6.4!
Procedures!for!Discontinuation!..............................................................................!28!
6.4.1!
Patient!Discontinuation!...........................................................................!28!
6.4.2!
Trial!Discontinuation!...............................................................................!28!
6.5!
Laboratory!Tests!....................................................................................................!29!
7!
ASSESSMENTS!...................................................................................................!29!
7.1!
Immunogenicity!and!Immunology!Analyses!...........................................................!29!
7.1.1!
Immunogenicity!and!Immune!variables!..................................................!29!
7.1.1.1!
Flow!cytometry!.....................................................................!29!
7.1.1.2!
ELISPOT!..............................................................................!29!
7.1.1.3!
Transcriptional!(RNA)!biomarker!analysis!............................!29!
7.1.1.4!
Mycobacterial!growth!inhibition!assays!(MGIA):!..................!30!
7.1.1.5!
IgG!and!humoral!immunity.!..................................................!30!
7.1.2!
Summary!of!Immunology!Specimens!and!Assays!(table!3)!...................!30!
7.1.3!
Primary!immunogenicity!Endpoints!........................................................!30!
7.1.4!
Exploratory!immune!studies!...................................................................!31!
7.2!
Safety!and!Tolerability!Assessments!.....................................................................!31!
7.2.1!
Medical!History!.......................................................................................!31!
7.2.2!
Physical!Examination!..............................................................................!31!
7.2.3!
Vital!Signs!...............................................................................................!31!
7.2.4!
Clinical!Laboratory!Evaluation!................................................................!31!
7.2.5!
Pharmacokinetics!...................................................................................!32!
7.2.6!
Radiology!................................................................................................!32!
7.2.7!
Adverse!Events!(AEs)!.............................................................................!32!
8!
SAFETY!MONITORING!AND!REPORTING!........................................................!32!
8.1!
Definitions!..............................................................................................................!32!
8.1.1!
Adverse!Event!(AE)!................................................................................!32!
8.1.2!
Serious!Adverse!Event!(SAE)!.................................................................!33!
8.1.3!
Suspected!Unexpected!Serious!Adverse!Reaction!(SUSAR)!................!33!
8.2!
Expected!Adverse!Events!(EAE)!...........................................................................!34!
8.3!
Disease!Progression/Recurrence!..........................................................................!34!
8.4!
Time!Period!for!Reporting!AE!and!SAE!.................................................................!34!
8.5!
Recording!of!Adverse!Events!.................................................................................!35!
8.6!
Solicited!Adverse!Events!and!Injection!Site!Reactions!..........................................!36!
8.7!
Reporting!Procedure!..............................................................................................!36!
8.7.1!
AEs!and!SAEs!........................................................................................!36!
8.7.2!
SUSARs!..................................................................................................!36!
8.7.3!
Annual!Safety!Report!..............................................................................!37!
8.7.4!
Clinical!Study!Report!..............................................................................!37!
8.8!
Procedures!in!Case!of!Emergency!........................................................................!37!
9!
DATA!MANAGEMENT!AND!MONITORING!........................................................!37!
9.1!
Case!Report!Forms!(CRFs)!...................................................................................!37!
9.2!
Source!Data!...........................................................................................................!37!
9.3!
Study!Monitoring!....................................................................................................!38!
9.4!
Confidentiality!and!database!management!............................................................!38!
10!
STATISTICAL!METHODS!AND!DATA!ANALYSIS!.............................................!39!
10.1!
Determination!of!Sample!Size!................................................................................!39!
10.2!
Randomization!.......................................................................................................!39!
10.3!
Population!for!Analysis!...........................................................................................!39!
10.4!
Statistical!Analysis!.................................................................................................!40!
10.4.1!
Safety!analysis!........................................................................................!40!
10.4.2!
Vital!Signs!...............................................................................................!40!
10.4.3!
Physical!Examinations!............................................................................!40!
10.4.4!
Clinical!Laboratory!Measurements!.........................................................!40!
10.4.5!
Pharmacokinetics!...................................................................................!40!
10.4.6!
Immunogenicity!and!Other!Immunology!Analyses!.................................!40!
10.4.6.1!
Primary!Immunogenicity!endpoints!......................................!40!
10.4.6.2!
Exploratory!Assays!...............................................................!41!
11!
STUDY!MANAGEMENT!.......................................................................................!42!
11.1!
Investigator!Delegation!Procedure!.........................................................................!42!

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11.2!
Investigator’s!Responsibilities!................................................................................!42!
11.3!
Protocol!Adherence!................................................................................................!42!
11.4!
Study!Amendments!................................................................................................!43!
11.5!
Audit!and!Inspections!.............................................................................................!43!
12!
ETHICAL!AND!REGULATORY!REQUIREMENTS!..............................................!43!
12.1!
Competent!Authority!and!Ethics!Committee!Approval!...........................................!43!
12.2!
Handling!and!storage!of!biological!material!...........................................................!44!
12.3!
Informed!Consent!Procedure!.................................................................................!44!
12.4!
Subject!Identification!..............................................................................................!44!
13!
TRIAL!SPONSORSHIP!AND!FINANCING!..........................................................!44!
14!
TRIAL!INSURANCE!.............................................................................................!45!
15!
PUBLICATION!POLICY!.......................................................................................!45!
16!
REFERENCES!......................................................................................................!45!
17!
APPENDIX!............................................................................................................!47!
17.1!
Appendix!1:!Label!Arcoxia!90!mg!..........................................................................!47!
17.2!
Appendix!2:!Label!Arcoxia!120!mg!........................................................................!48!
17.3!
Appendix!3:!Primary!label!H56:IC31!5/500!............................................................!49!
17.4!
Appendix!4:!Secondary!label!H56:IC31!5/500!.......................................................!50!
17.5!
Appendix!5!!Toxicity!Table!.....................................................................................!51!
17.6!
Appendix!6!!!!!!!!!!!!!!!!!DESCRIPTION!OF!STUDY!VISITS!....................................!54!
!

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LIST!OF!ABBREVIATIONS!
AE"
"
?"
adverse"event"
AFS"
"
?"
acid"fast"staining"
ALAT" "
?"
alanine"aminotransferase"
ASA"
"
?"
acetyl"salicylic"acid"
ASAT" "
?"
aspartate"aminotransferase"
ART"
"
?""
antiretroviral"therapy"
cAMP" "
?"
cyclic"adenosine"mono"phosphate"
CFR"
"
?"
code"of"federal"regulations"(USA)"
CHD"
"
?"
coronary"heart"disease"
COX"
"
?"
cyclooxygenase"
COX?2i"
?""
cyclooxygenase?2"inhibitors"
CK"
"
?"
creatine"kinase"
CRF"
"
?"
case"record"form"
CRO" "
?"
contract"research"organization"
CRP"
"
?"
C?reactive"protein"
CSA"
"
?"
Clinical"Study"Agreement"
CTC"
"
?"
Common"Toxicity"Criteria"
CTCAE"
?"
Common"Terminology"Criteria"for"Adverse"Event"
DAE"
"
?"
Discontinuation"due"to"Adverse"Event"
DMARDS"
?""
disease?modifying"anti?rheumatic"drugs"
DOT"
"
?"
directly"observed"therapy"
EC"
"
?"
ethics"committee"
ESR"
"
?"
Erytrocyte"Sedimentation"Rate""
GCP"
"
?"
good"clinical"practice"
HIV"
"
?"
human"immunodeficiency"virus"
hGC"" "
"
human"chorionic"gonadotropin"i"serum"
IB"
"
?"
Investigator’s"Brochure"
ICF"
"
?"
Informed"Consent"Form"
ICH"
"
?"
international"conference"on"harmonization"
ICS"
"
?"
intracellular"cytokine"staining""
IFN"
"
?"
interferon?gamma"
IMP"
"
?"
Investigational"Medicinal"Product""
LTBI" "
?"
latent"TB"infection"
"
LDH"
"
?"
lactate"dehydrogenase"
MDR?TB"
?"
multi?drug"resistant"TB"
Mtb"
"
?"
mycobacterium"tuberculosis""
NSAID""
?"
non?steroid"anti?inflammatory"drug"
NYHA" "
?"
New"York"Heart"Association"
PBMC""
?"
peripheral"blood"mononuclear"cells""
PCI"
"
?"
percutan"coronar"intervention"
PGE"
"
?"
prostaglandin"E"
PKA"
"
?"
protein"kinase"A"
SAE"
"
?"
serious"adverse"event""
SOP"
"
?"
standard"operating"procedure"
SPC"
"
?""
summary"of"product"characteristics"
SUSAR"
?"
Suspected"Unexpected"Serious"Adverse"Reaction"""
TNF"
"
?"
tumor"necrosis"factor"
TB"
"
?"
tuberculosis"
XDR?TB"
?"
extensively"drug?resistant"TB"
"

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1! INTRODUCTION!
1.1!
Background!!
1.1.1! The!TB!epidemic!!
The!World!Health!Organization!estimates!that!there!were!9.0!million!incident!active!tuberculosis!
(TB)!cases!and!1.5!million!deaths!caused!by!TB!in!2013!(1).!A!fifth!of!previously!treated!TB!cases!
with!recurrent!TB!disease!have!multi8drug!resistant!(MDR)8TB!and!extensively!drug8resistant!TB!
(XDR8TB)!has!been!reported!by!84!countries.!MDR8TB!may!take!years!to!treat!with!expensive!and!
toxic!second8line!drugs!with!uncertain!efficacy.!Further,!the!shifting!of!the!TB!epidemic!towards!
XDR8TB!with!very!restricted!treatment!options!could!reverse!many!of!the!major!gains!made!in!TB!
control!and!increase!spread,!morbidity!and!mortality.!This!calls!for!new!treatment!modalities!that!
could!be!affordable!and!simple!alternative!for!a!substantial!number!of!patients!with!MDR8TB!and!
XDR8TB!in!resource8poor!countries.!!
1.1.2! Immune!pathogenesis!and!regulation!in!TB!!
M.+tuberculosis!(Mtb)!normally!enters!the!host!through!mucosal!infection!and!targeting!of!the!
bacteria!to!professional!phagocytic!cells!induces!rapid!innate!inflammatory!responses!with!
subsequent!production!of!cytokines!and!chemokines!and!formation!of!the!primary!granuloma!
surrounded!by!activated!monocytes,!macrophages!and!lymphocytes!(2).!In!the!majority!of!cases,!
TB!infection!is!successfully!contained,!but!persists!as!latent!infection,!whereas!some!succumb!to!
reactivation!and!develop!active!TB,!typically!seen!in!immune!suppressed!patients.!CD4!T!cells!are!
induced!early!in!infection,!whereas!CD8!T!cells,!also!recruited!to!the!lung!and!granulomas!during!
TB!infection,!expand!in!the!late!stages!(3).!Host!control!of!TB!is!dependent!on!the!T!helper!(Th)!1!
cytokines!interferon8gamma!(IFN8γ)!and!tumour!necrosis!factor8alfa!(TNF8α)!as!well!as!proper!
activation!of!macrophages,!since!hyper8activated!macrophages!are!typically!found!in!progressing!
TB!lesions!(4).!The!role!of!TNF8α!is!illustrated!by!the!rapid!reactivation!of!latent!TB!in!humans!
treated!with!TNF8α!receptor!antagonists!(5)!and!the!association!of!TNF8α!production!with!
protection!in!animal!models!(6).!Polyfunctional!T!cell!responses!(IFN8γ+IL82+TNF8α+)!have!
potential!to!serve!as!correlate!for!protective!immunity!since!they!seem!to!dominate!in!contained!TB!
(7,8),!but!the!T!cell!characteristics!required!for!protection!and!optimal!correlates!for!TB!vaccine!
immunogenicity!are!yet!to!be!established!(9).!T!regulatory!cells!(Treg),!a!subset!of!CD4!T!cells!with!
immune!regulatory!properties!that!suppress!Th1!cells!and!IFN8γ!production!are!expanded!in!active!
TB!(10,11)!and!may!suppress!proper!vaccine!responses.!Thus,!the!overall!contribution!to!TB!
immunity!by!all!these!immune!cell!subsets!has!implications!for!both!the!design!and!strategy!of!post!
exposure!vaccines!and!proper!correlates!of!protection!and!needs!to!be!further!studied.!!
1.1.3! The!cyclooxygenase2prostaglandin!E2!pathway!in!TB!!
Prostaglandin!E2!(PGE2)!is!produced!by!cyclooxygenase82!(COX82)!in!inflamed!tissue!and!
deregulates!the!protective!immune!response!against!TB!and!suppresses!T!cell!mediated!immunity+
(12).!Co8investigator!Taskén!and!colleagues!have!established!the!role!of!cyclic!adenosine!
monophosphate!(cAMP)!and!protein!kinase!A!(PKA)!–!Csk!–!Lck!inhibitory!pathway!as!a!general!
mechanism!in!chronic!inflammation!that!inhibits!T!cell!signaling!and!activation!through!antigen!
receptors!on!lymphoid!cells!(13,14).!Peripherally!induced!Tregs!express!COX82,!secrete!PGE2!
and!thus!enhance!cAMP!levels!within!effector!cells!so!this!mechanism!may!also!be!involved!in!the!
inhibitory!function!of!Tregs!(15).!Similarly,!monocytes!and!macrophages!stimulated!with!a!number!
of!bacterial!inflammatory!mediators!potently!induce!T!cell!cAMP!levels!and!T!cell!dysfunction!(16).!
Reduction!of!cAMP!levels!in!T!cells!by!reducing!production!of!PGE2!via!COX82!inhibitors!(COX82i)!
and!thereby!EP!receptor!stimuli!to!T!cells!can!therefore!reverse!this!process!and!restore!T!cell!
responsiveness!to!vaccine!antigens!as!we!have!shown!for!HIV8infected!patients!(17819).!Our!
hypothesis!is!that!inefficacy!of!cellular!immunity!in!TB!lesions!is!closely!linked!to!the!chronic!
inflammation!and!resulting!cAMP8mediated!activation!defects!in!the!T!cells.!Since!human!active!TB!
infection!is!dominated!by!macrophage!activation!in!granulomatous!inflammation,!it!is!relevant!to!
study!whether!hyperexpressed!PGE2!and!COX82!contribute!to!T!cell!dysfunction!and!the!effect!of!
COX82i!in!active!human!TB.!+

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1.2!
Pre2Clinical!&!Clinical!Experience!with!COX22i!and!H56:IC31!!
1.2.1! Pre2clinical!studies!of!COX22i!in!experimental!animal!TB!models!!
Animal!models!support!PGE2!as!a!significant!factor!in!the!pathogenesis!of!a!dysfunctional!hyper8
activated!immune!system!in!TB.!Studies!of!experimental!pulmonary!TB!in!BALB/c!mice!have!
shown!that!during!early!infection!bacilli!are!efficiently!phagocytised!by!lung!macrophages!that!
secrete!pro8inflammatory!cytokines!(TNF8α,!IL81)!and!accordingly!present!bacillary!antigens!to!IL8
12!and!IFN8γ!producing!Th1!cells!(12).!During!progressive!disease!Th2!cells!emerge!and!an!
overproduction!of!anti8inflammatory!and!immunosuppressive!molecules!such!as!cortisol,!PGE2,!
and!transforming!growth!factor8beta!(TGF8β)!takes!place!that!next!downregulate!cell8mediated!
immunity,!enabling!bacilli!growth!and!progressive!tissue!damage.!When!PGE2!production!was!
suppressed!by!COX82i!in!animals!with!advanced!disease,!reductions!in!pulmonary!inflammation!
and!bacillary!load!took!place!in!parallel!with!reversal!to!a!Th1!cell!profile!(12,20).!Further,!the!COX8
2i!celecoxib!improved!the!608day!survival!of!Mtb8infected!mice!to!100%!with!reduced!lung!levels!of!
PGE2,!bacillary!load!and!inhibitory!IL810,!whereas!proinflammatory!IL812,!IFN8γ!and!alveolar!
macrophage!nitric!oxide!synthesis!increased!(21).!Taken!together!inhibiting!the!COX82!activity!
apparently!improves!outcome!in!active!TB.!A!highly!significant!publication!concludes!that!a!human!
intervention!study!with!anti8inflammatory!drugs!to!TB!patients!receiving!standard!chemotherapy!
should!be!designed!based!on!their!murine!data!demonstrating!reduced!Mtb!load!and!lung!lesions!
as!well!as!better!survival!of!animals!treated!with!ibuprofen!(22).!!
1.2.2! Clinical!studies!of!COX22i!!
In!three!clinical!explorative!trials,!we!have!demonstrated!that!COX82i!improves!the!immune!
functions!of!HIV!patients!on!ART!(17819).)!We!have!also!showed!for!the!first!time!that!treatment!
with!a!COX82i!was!able!to!downregulate!chronic!immune!activation!and!improve!T!cell!functions!in!
asymptomatic!HIV8infected!patients!who!did!not!use!antiretroviral!therapy!(19).!In!these!patients,!
chronic!immune!activation!was!dampened!as!demonstratedm!CD38!density!on!CD8+!T!cells!
(primary!endpoint)!decreased!by!24%!by!study!week!12!and!improvement!of!CD4+!T!cell!loss!with!
30!CD4!cells!µl81year8.1.!Celecoxib!further!reduced!the!inhibitory!surface!receptor!programmed!
death!1!(PD81)!on!CD8+!T!cells,!improved!humoral!memory!recall!responses!to!a!T!cell8dependent!
vaccine!and!IL86!tended!to!decrease!in!the!treatment!arm.!In!conclusion,!celecoxib!
downmodulated!the!immune!activation!related!to!clinical!progression!of!chronic!HIV!infection!and!
improved!T!cell8dependent!functions!in+vivo.!There!was!an!acceptable!safety!profile!with!celecoxib!
doses!as!high!as!400!mg!bid!and!no!SAEs!reported!in!any!of!the!studies.!Rash!was!observed!in!
HIV!patients!without!ART!after!receiving!high8dose!celecoxib!in!contrast!to!what!we!found!with!
identical!doses!in!patients!on!ART.!Thus,!it!was!concluded!that!this!was!associated!by!high!HIV8
induced!immune!activation!levels!itself!and!may!have!represented!other!bioprocesses!than!
conventional!drug!allergies!(19).!!
1.2.3! Pre2clinical!studies!of!the!H56:IC31!TB!vaccine!in!animal!TB!models!!
H56!is!a!fusion!protein!of!three!mycobacterial!antigens!(Ag85B,!ESAT86,!Rv2660c).!Both!Ag85B!
and!ESAT86!induce!TB!specific!T!cell!responses!that!protect!animals!from!Mtb+challenge!(23),!
whereas!Rv2660c!is!preferentially!recognized!by!latently!infected!individuals!(24).!The!therapeutic!
post8exposure!vaccine!H56,!developed!at!SSI,!promotes!a!T!cell!response!in!mouse!models!with!a!
high!proportion!of!polyfunctional!CD4!T!cells!that!confers!protective!immunity!and!more!efficient!
containment!of!late8stage!infection!than!its!predecessor!the!H1!(Ag85B8ESAT6)!and!BCG!vaccines!
(23).!This!is!also!the!first!vaccine!that!demonstrates!efficacy!when!administered!post8exposure.!
H56!has!been!tested!pre8clinically!formulated!with!a!range!of!adjuvants,!most!notably!IC31®!
comprised!of!an!oligodeoxynucleotide!ODN1a!complexed!to!a!leucine!and!lysine!containing!
polypeptide!(25).!The!vaccine!candidate!combining!H56!and!IC31®,!termed!H56:IC!(AERAS8456),!
seems!to!be!immunogenic!and!protective!also!in!non8human!primates!(26).!However,!some!
vaccinated!non8human!primates!still!demonstrate!lack!of!H56:IC31!vaccine!recall!responses!and!
experienced!disease!progression!implying!that!strategies!to!boost!vaccine!responses!should!be!
tested.!!!

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1.2.4! Clinical!studies!of!the!H56:IC31!TB!vaccine!!
Three!phase!I!clinical!trials!and!two!phase!II!clinical!trials!of!SSI’s!preceding!and!structurally!
related!vaccine!candidate!H1!(Ag85B/ESAT86):IC31®!have!been!conducted!in!humans!
demonstrating!good!safety!and!tolerability.!
1.! The!first!phase!I!trial!with!H56:IC31,!an!open8label,!dose8escalation!clinical!study!(C80328
456)!in!latent!TB!has!just!been!finalized!and!show!that!the!vaccine!is!immunogenic!and!well!
tolerated.!Further,!in!C80358456,!a!phase!I/IIa!randomized,!placebo8controlled!study!of!HIV8
negative!adults,!no!safety!issues!have!been!identified.!In!these!trials!a!total!of!123!subjects!
have!been!vaccinated,!25!of!whom!have!received!up!to!three!doses!of!H56:IC31.!The!dose!
of!H56:IC31!in!these!trials!ranges!from!5!to!50!μg!H56!with!500!nmol!IC31.!Concerning!
immunogenic!efficacy!for!Ag85B,!the!most!prominent!CD4+!responses!at!Study!Day!70!
were!polyfunctional!(IFN8γ,!IL82,!TNFα),!bifunctional!(IL82!and!TNFα),!and!monofunctional!
(IL82).!For!ESAT86,!the!most!prominent!CD4+!responses!at!Study!Day!14!were!
polyfunctional!(IFN8γ,!IL82,!TNF),!bifunctional!(IFN8γ!and!TNFα),!and!monofunctional!(IFN8γ!
or!TNFα).!CD4+!cells!expressing!IL817!were!rarely!present!after!stimulation!with!either!
antigen!Ag85B!or!ESAT86.!
Thus,!H56:IC31!was!associated!with!an!acceptable!safety!profile!in!subjects!with!and!without!LTBI,!
and!no!vaccine8related!serious!adverse!events!(SAEs)!were!reported.!Vaccination!with!H56:IC31!
was!associated!most!commonly!(≥10%!of!subjects!with!a!related!adverse!event)!with!mild!to!
moderate!injection!site!reactions!of!pain,!warmth,!and!swellingm!mild!to!moderate!systemic!adverse!
events!of!fatigue,!bradycardia,!myalgia,!nausea,!headache,!arthralgia,!and!white!blood!cell!count!
increasedm!and!mild!to!severe!hypertension.!Only!two!SAE!have!been!reported!to!date!in!clinical!
trials!of!H56:IC31,!both!considered!not!related!to!study!vaccine.!One!serious!AE,!unrelated!to!
study!vaccine,!was!reported!in!the!registry!study.!There!are!no!reports!of!deaths!due!to!vaccines!
containing!similar!fusion!proteins!(H1!and!H4)!to!H56!or!containing!IC31!adjuvant.!!
A!phase!I/II!clinical!trial!of!H56:IC31!(C80378456)!in!patients!treated!for!active!pulmonary!TB!has!
started!in!South8Africa!in!2015,!and!no!adverse!events!have!been!reported!after!the!first!12!
subjects!have!been!vaccinated!(by!February!2015).!The!relationship!between!possible!immune8
related!toxicities!to!the!TB!antigens!and!time!since!start!of!anti8TB!chemotherapy!will!be!addressed!
in!C80378456.!The!current!study!will!await!the!inclusion!of!patients!to!the!H56:IC31!arms!until!
preliminary!safety!data!from!this!trial!is!available.!!
In!conclusion,!all!non8clinical!and!clinical!information!supports!the!suitability!of!H56:IC31!as!a!safe!
and!immunogenic!vaccine.!There!is!no!reason!to!believe!that!the!combination!of!COX2i!and!
vaccination!is!unfavorable.!
1.3!
Rationale!for!the!Study!and!Purpose!
1.3.1! TB!therapeutic!vaccines!as!rescue!therapy!in!MDR2TB!
Vaccination!with!Bacillus!Calmette8Guérin!(BCG)!can!limit!disseminated!disease!in!children,!but!
not!the!establishment!of!TB!infection.!Several!prophylactic!TB!vaccines!have!demonstrated!
superiority!to!BCG!in!mouse!models,!although!none!of!them!result!in!sterilizing!immunity!(27,28).!
Recently,!the!first!novel!preventive!TB!vaccine!to!enter!efficacy!testing!(MVA85A)!failed!with!no!
evidence!of!protection!against!TB!disease!or!infection!(29).!These!disappointing!data!has!
intensified!the!search!for!correlates!of!protection!and!to!identify!effective!vaccine!measures!early!
during!development.!It!has!become!clear!that!the!traditional!clinical!development!with!consecutive!
clinical!trials!with!a!final!efficacy!trial!needs!rethinking.!Thus,!therapeutic!vaccines!have!been!listed!
as!an!alternative!approach!as!the!study!design!allows!to!measure!the!biological!effect!of!the!
vaccine!directly!e.g.!by!measuring!bacterial!loads!in!sputum!and!also!open!up!the!possibility!of!
identifying!correlates!of!protection.!Therapeutic!vaccination!alone!or!in!combination!with!other!
types!of!immune!modulation!as!COX82i!may!not!only!boost!and!strengthen!TB!immunity!with!
possibly!better!outcome!especially!for!MDR/XDR8TB,!but!will!also!significantly!improve!on!our!
knowledge!relating!to!clinical!study!design!and!correlates!of!protection.!!

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1.3.2! COX22i!improves!cellular!vaccine!responses!in"vivo!!
Supported!by!the!RCN/Global!Health!program!we!have!shown!for!the!first!time!in!consecutive!
randomized!clinical!trials!that!COX82i!reduce!T!cell!distress!in!HIV81!and!improve!efficacy!of!T!cell8
dependent!vaccines!with!good!safety!(17819).!In!the!study!of!celecoxib,!antibody!levels!to!the!T!
cell8dependent!tetanus!vaccine!were!nearly!three!times!higher!in!COX82i8treated!patients!after!
vaccination!than!in!controls!(19).!This!supports!our!basic!hypothesis!that!COX82i!treatment!indeed!
can!reverse!T!cell!dysfunction!in!infectious!diseases!with!a!chronic!inflammatory!component.!
Furthermore,!the!data!intriguingly!suggest!that!COX82i!treatment!could!improve!vaccine!responses!
as!well!as!improve!T!cell!functions!in!general!and!particularly!in!patients!with!hyper8inflammatory!
lesions!as!in!active!TB.!
1.3.3! COX22i!improves!TB!specific!immune!responses!and!regulation!in"vitro!!
Functional!studies!on!the!effect!of!COX82i!upon!immune!cells,!longitudinally!collected!from!
clinically!characterized!TB!patients!during!therapy!at!our!hospital!and!from!our!national!partners,!
are!currently!in!progress!in!our!lab.!We!have!previously!described!elevated!levels!of!Treg!subsets!
in!active!and!latent!TB!(10).!In!studies!of!active!TB!patients!during!anti8TB!chemotherapy!we!
demonstrate!a!decrease!in!the!fraction!of!Mtb8specific!IFN8γ8producing!T!cells!stimulated!by!TB8
specific!antigens!(ESAT86,!CFP810)!in+vitro!already!after!2!weeks!of!efficient!treatment,!whereas!
the!pool!of!IL82+!cells!increased!over!time+(30).!!The!Treg!was!still!able!to!expand!after!Mtb8
specific!in!vitro!stimulation,!but!a!decline!in!activated!Treg!was!seen!when!COX8i!was!added!to!the!
cells.!These!pilot!findings!indicate!that!COX82i!could!possibly!block!regulatory!T!cells!and!improve!
TB!specific!immunity.!In!the!current!study!these!data!will!form!the!basis!for!additional!in8depth!
exploratory!analysis!of!Tregs!in!TB!infection.!!
1.3.4! Rationale!for!COX22i!regimen!and!dose!selected!
The!immune!modulatory!effects!of!COX82i!are!expected!to!be!dose8dependentm!hence!in!our!
previous!exploratory!trial!of!untreated!HIV!patients!(UUSCOX2,!EudraCT!No!20068001882841,!
approved!by!the!Norwegian!Medicines!Agency),!the!highest!tolerated!dose!of!celecoxib,!400!mg!
bid!for!12!weeks!(dose!approved!by!FDA!in!familial!adenomatous!polyposis),!were!investigated!
and!demonstrated!improved!efficacy!of!T!cell8dependent!vaccines!with!good!safety!(19).!!Further,!
we!have!recently!ended!another!study!of!the!COX82i!etoricoxib!90!mg!OD!given!to!a!HIV!cohort!for!
24!weeks!(OUSCOX2.!EudraCT!No.!20108020382825)!without!any!drug8related!SAE!observed.!!
Etoricoxib!is!generally!well!tolerated,!even!at!doses!above!the!clinical!dose!range!and!could!be!
dosed!once!daily!which!is!very!convenient!in!order!to!secure!compliance.!Multiple!dosing!of!
etoricoxib!up!to!150!mg!OD!has!showed!no!negative!COX818mediated!effects!such!as!
thromboxane!B2,!bleeding!time!or!platelet!aggregation!(31).!Steady8state!pharmacokinetics!of!120!
mg!etoricoxib,!were!consistent!with!linearity!and!achieved!after!7!days!of!once8daily!dosing!in!a!
study!of!24!healthy!subjects!(32).!
The!COX82i!drug!class!has!long!been!approved!and!is!widely!in!use!for!inflammatory!conditions.!
They!are!already!in!use!in!clinical!practice!for!milder!manifestations!of!immune!reconstitution!
syndrome!(IRIS),!predominantly!TB,!in!HIV8patients!where!they!are!preferred!before!steroids!(31).!
The!risk!for!cardiovascular!events!is!low!and!the!mechanism!is!still!unclear!as!COX82i!lowers!pro8
inflammatory!and!prognostic!markers!of!cardiovascular!events!in!patients!with!CHD!(32).!In!our!
last!study,!a!number!of!protrombotic!factors!and!markers!for!endothelial!damage!were!measured,!
finding!only!a!slight!increase!of!D8dimer!in!the!control!group!and!possibly!a!reduction!of!the!pro8
athrogenic!cytokine!IL86!in!the!intervention!group!(19).!However,!also!in!this!trial!we!will!implement!
a!number!of!exclusion!criteria!and!patients!with!typical!high!cardiovascular!risk!will!be!excluded!
and!parameters!reflecting!activated!coagulation!and!endothelial!damage!will!again!be!monitored.!
The!anti8TB!drug!rifampicin!that!is!included!in!the!standard!regimen!for!TB!patients!recruited!to!this!
study!is!a!CYP3A!inducer!in!the!liver!and!will!thus!reduce!the!serum!concentration!of!COX82i.!Co8
administration!of!120!mg!etoricoxib!with!daily!doses!of!600!mg!rifampin!resulted!in!a!mean!65%!
decrease!in!etoricoxib!AUC!and!40%!decrease!in!Cmax!(33).!The!geometric!mean!ratios!(etoricoxib!
with!rifampin/etoricoxib!alone)!for!AUC!(08inf)!and!Cmax!in!these!patients!were:!AUC:!0.35!(90%!

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CI:!(0.31,!0.40)),!with!a!range!of!0.25!8!0.50.!Cmax:!0.60!(90%!CI:!(0.43,!0.84)!with!a!range!of!0.29!
8!0.87).!In!the!same!individuals,!the!ranges!of!AUC's!and!Cmax's!during!rifampin!treatment!were!as!
follows:!AUC!(08inf)!(ug*hr/mL):!2.4186.42!with!a!mean!of!3.80!and!SD!of!1.36.!Cmax!(ng/mL):!3628
1616!with!a!mean!of!733!and!SD!of!394.!Tmax!for!etoricoxib!was!not!significantly!altered!during!
rifampin!treatment,!but!the!apparent!terminal!t½!(hour)!was!significantly!different!(6.8!hours!with!
rifampin!versus!14.4!hours!without).!
Thus,!we!will!use!Arcoxia!120!mg,!the!maximal!dose!approved!(and!recommended!for!acute!artritis!
urica)!to!overcome!too!low!serum!concentrations!when!co8administrated!with!rifampicin!in!TB!
patients.!However,!the!serum!concentration!of!rifampicin!will!not!be!affected!and!there!are!no!
interactions!between!COX82i!and!any!of!the!three!other!anti8TB!drugs!included!in!the!standard!
regimen!(isoniazide,!ethambutol,!pyrazinamide).!!
Analysis!of!serum8concentration!of!COX82i!is!not!routinely!available!and!it!is!thus!not!possible!to!
use!for!drug!monitoring!during!the!study.!However,!pharmacokinetic!parameters!in!serum!after!7!
days!of!etoricoxib!when!steady!state!is!expected!(33)!will!be!analyzed!in!study!arm!#1!in!retrospect!
for!research!purposes!and!correlated!to!tolerance!and!immunogenicity!and!before!inclusion!of!
study!arm!#4!to!achieve!optimal!dosing.!If!intolerable!adverse!reactions!occur!to!etoricoxib!the!
dose!will!be!reduced!to!90!mg!or!stopped.!!
2!
STUDY!OBJECTIVES!AND!RELATED!ENDPOINTS!
Primary:"
"
To!evaluate!the!safety!and!tolerability!of!etoricoxib!alone!and!in!combination!with!the!therapeutic!
TB!vaccine!H56:IC31!in!patients!with!active!TB!disease!treated!with!conventional!268week!anti8TB!
chemotherapy.!
Secondary:"
To!evaluate!the!effect!of!etoricoxib!on!i)!immune!regulation!in!TB!and!ii)!immunogenicity!to!the!
therapeutic!TB!vaccine!(H56:IC31)!in!patients!with!active!TB!disease!treated!with!conventional!268
weeks!anti8TB!chemotherapy.!!
To!investigate!the!pharmacokinetics!of!etoricoxib!in!TB!patients!treated!with!rifampicin.!!!!!
3!
OVERALL!STUDY!DESIGN!
Patients!admitted!to!the!Dep.!of!Infectious!Diseases!or!Dep.!of!Pulmonary!Medicine,!OUS!
(eventually!patients!admitted!to!other!hospitals!in!the!Oslo!region!and!transferred!to!OUS!or!
patients!admitted!to!Haukeland!University!Hospital,!Bergen)!and!with!confirmed!active!pulmonary!
and/or!extrapulmonary!TB!disease!infected!with!drug8sensitive!Mtb!strains!will!be!included!
sequentially!in!an!open!label,!explorative,!randomized,!clinical!phase!I!trial.!!
After!Informed!consent,!inclusion,!baseline!assessments!and!before!start!of!standard!anti8TB!
chemotherapy!(day!08182),!each!patient!will!be!randomized!to!the!following!study!arms:!
Table!1!
Group!
Numbers!
Treatment!
Endpoint!
Arm!1!
10!
Chemotherapy+!COX82i!
Safety!+!immunogenicity!
Arm!2!
10!
Chemotherapy!+!H56:IC31!
Safety!+!immunogenicity!
Arm!3!
10!
Chemotherapy!
Safety!+!immunogenicity!(control)!

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Arm!4!
10!
Chemotherapy!+!H56:IC31!+!COX82i!
Safety!+!immunogenicity!
!
The!study!design!randomizing!patients!will!test:!
1.! Safety!of!etoricoxib!and!H56:IC31!alone!and!in!combination!in!active!TB.!
2.! Effect!of!etoricoxib!on!TB!immunogenicity,!activation!and!regulation!(arm!#1).!!
3.! Pharmacokinetics!of!etoricoxib!in!TB!patients!treated!with!rifampicin!(arm!#1).!
4.! H56:IC31!immunogenicity!after!two!immunizations!in!active!TB!(arm!#2).!!
5.! H56:IC31!immunogenicity!after!pre8treatment!with!etoricoxib!in!active!TB!(arm!#4).!
!
Arm$3
Arm$1
H56:IC31
H56:IC31
Arm$2
Arm$4
Time%line((anti%TB(chemotherapy,(day 0%182)
COX,2i
S:$Sampling$(blood)$
and$clinical visit
S
S
S
S
S
S
182
S
7
14
84
56
0
140
98
154
S
S
210
S
238
H56:IC31
H56:IC31
28
S
!
The!safety!profile!of!COX2i!or!H56:IC31!has!not!yet!been!determined!in!a!population!undergoing!
treatment!for!pulmonary!TB.!Therefore,!we!will!enrol!participants!in!two!groups!separated!by!a!
safety!review.!Group!A!includes!volunteers!for!arm!#1,!arm!#2!and!arm!#3!(2:2:1!randomization).!
First!at!the!completion!of!Study!Day!98!for!all!group!A!participants,!the!“clinical!investigational!
group”!(sponsor,!PI,!collaborators!including!representative!from!the!H56:IC31!vaccine!
manufacturer)!will!meet!and!evaluate!the!cumulative!safety!data!to!determine!if!the!observed!
safety!profile!meets!the!criteria!to!proceed!to!inclusion!of!volunteers!for!group!Bm!arm!#4!and!
remaining!Arm!#3!controls!(2:1!randomization).!
Arm!#1!(n=10):!etoricoxib!treatment!started!at!day!0!and!given!for!20!weeks!(day!08140)!followed!
by!6!weeks!(or!according!to!clinical!evaluation)!of!standard!anti8TB!chemotherapy!alone!(day!08
182)!and!follow8up!control!at!day!210!and!day!238.!!!
Arm!#2!(n=10):!given!anti8TB!chemotherapy!alone!(day!08182)!(or!according!to!clinical!evaluation)!
and!follow8up!control!at!day!210!and!day!238.!TB!vaccine!H56:IC31!will!be!injected!at!day!84!and!
day!140.!!
Arm!#3!(controls,!n=10):!given!anti8TB!chemotherapy!alone!(day!08182)!(or!according!to!clinical!
evaluation)!and!follow8up!control!at!day!210!and!day!238.!!
Arm!#4!(n=10):!etoricoxib!treatment!started!at!day!0!and!given!for!20!weeks!(day!08140)!followed!
by!6!weeks!(or!according!to!clinical!evaluation)!of!standard!anti8TB!chemotherapy!alone!and!
follow8up!control!at!day!210!and!day!238.!TB!vaccine!H56:IC31!will!be!injected!at!day!84!and!day!
140.!!

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4!
STUDY!POPULATION!
4.1!
Selection!of!Study!Population!
Patients!admitted!to!the!Dep.!of!Infectious!Diseases!and!Dep.!of!Pulmonary!Medicine,!OUS!and!
with!confirmed!active!pulmonary!and/or!extrapulmonary!TB!disease!infected!with!drug8sensitive!
Mtb!strains!will!be!included.!If!there!are!difficulties!in!the!recruitment!of!patients!at!OUS,!TB!
patients!will!be!recruited!in!collaboration!with!other!hospitals!in!the!Oslo!region!or!our!partners!from!
Haukeland!University!Hospital.!!
4.2!
Number!of!Patients!
A!total!of!40!patients!will!be!included,!10!in!each!of!the!study!arms.!
4.3!
Inclusion!Criteria!
Subjects!may!be!included!in!the!study!if!they!meet!all!of!the!following!criteria:!
•!
Age!between!18!8!70!years!at!the!time!of!randomization!
•!
Microbiologically!confirmed!pulmonary!and/or!extrapulmonary!TB!as!defined!in!Table!A1!
(culture!and/or!PCR!+!susceptibility!testing).!
•!
Drug!sensitive!Mtb!strains!(except!single!resistance!where!fully!adequate!anti8TB!
chemotherapy!regimen!could!be!provided).!!!
•!
Is!willing!and!likely!to!comply!with!the!trial!procedures!and!is!prepared!to!grant!authorized!
persons!access!to!their!medical!record.!
!
•!
Has!completed!the!written!informed!consent!process!prior!to!the!start!of!screening!evaluations.!
!
•!
Females!at!childbearing!age!must!agree!to!avoid!pregnancy!from!screening!and!during!the!
trial.!!
!
Female!study!participants!at!fertile!age!(not!sterilized!and!still!menstruating!or!within!1!year!of!the!
last!menses!if!menopausal)!will!be!informed!about!the!risk!of!using!the!IMPs!if!pregnant!or!
breastfeeding.!The!study!investigator!will!perform!an!individual!evaluation!of!each!participant!to!
secure!acceptable!methods!of!avoiding!pregnancy!during!the!study.!!
!
Acceptable!methods!of!avoiding!pregnancy!include!a!sterile!sexual!partner,!sexual!abstinence!(not!
engaging!in!sexual!intercourse),!progestogen8only!hormonal!contraception!associated!with!
inhibition!of!ovulation!(oral,!injection,!transdermal!patch,!or!implant),!intrauterine!device!(IUD),!or!a!
combination!of!male!condom!with!either!cap,!diaphragm!or!sponge!with!spermicide!(“double!barrier!
methods”).!
!
Table!A1.!Forms!of!extrapulmonal!TB!that!can!be!included:!
Bone/joint!(including!soft!tissue!affection/abscess)!
Lymphadenitis!!
Pleuritis!
Abdominal!(peritoneal!and!intestinal)!
Urogenital!

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4.4!
Exclusion!Criteria!!
Subjects!must!be!excluded!from!participating!in!this!study!if!they!meet!any!of!the!following!criteria:!
4.4.1! Study2specific!exclusion!criteria!
•!
Disseminated!(miliary)!TB.!
•!
Evidence!of!a!new!acute!illness!that!may!compromise!the!safety!of!the!subject!in!the!trial!on!
study!day!0.!!
•!
History!of!autoimmune!disease!or!immunosuppression.!
•!
History!or!laboratory!evidence!of!any!possible!immunodeficiency!state.!
•!
Anemia!(<!9!g/100!mL)!
•!
HIV!sero8positivity.!
•!
Chronic!hepatitis!B!(HBs!antigen!positive)!with!increased!liver!transaminases!(ASAT,!ALAT).!
•!
Chronic!hepatitis!C!(HCV!RNA!positive).!!
•!
Concomitant!or!sporadic!use!of!NSAID!or!corticosteroids!(>2!times!per!week)!
•!
Other!immune!modulating!therapies!including!DMARDs.!!
•!
Total!cholesterol!>7!mmol/L.!!
•!
Hypertension!>140/90!mm!Hg!(treated!or!untreated)!or!treated!with!>1!antihypertensive!drug!at!
any!blood!pressure.!!
•!
Cardiovascular!events!or!stroke!in!parents,!siblings!or!off8springs!occurring!<55!years!of!age!
•!
Serum!creatinine!above!reference!levels!(females!>90!µmol/Lm!males!>105!µmol/L),!see!
reduced!creatinine!clearance!in!Section!4.4.2).!!!
•!
Known!diabetes!mellitus!type!I!or!diabetes!mellitus!type!II!with!HbA1c!>7%.!
•!
Pregnancy!(documented!S8hCG!>5!IU/l!for!females!at!childbearing!age).!
•!
Breastfeeding.!
•!
Known!hypersensitivity!for!vaccines!or!vaccine!adjuvants.!!
4.4.2! Exclusion!criteria!according!to!the!SPC!on!Arcoxia!from!Norwegian!
Medicines!Agency!
•!
Known!hypersensitivity!for!etoricoxib!or!etoricoxib!tablet!substances!
•!
Known!hypersensitivity!for!sulphonamides!
•!
Active!peptic!ulcer!or!gastrointestinal!haemorrhage!
•!
Patients!with!history!of!asthma,!acute!rhinitis,!nasal!polyps,!angioneurotic!oedema,!urticaria!or!
other!allergic!reactions!after!taking!acetyl!salicylic!acid!or!NSAID!including!COX82i.!
•!
Moderate/severe!deranged!liver!function!(Child8Pugh!>7).!

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•!
Creatinine!clearance!<30!ml/min!
•!
Inflammatory!bowel!disease!
•!
Heart!failure!(NYHA!II8IV)!
•!
Established!ischaemic!heart!disease,!peripheral!arteriosclerosis!and/or!cerebrovascular!
disease,!including!previous!myocardial!infarction,!angina!pectoris,!unstable!angina,!PCI!or!
coronary!bypass,!previous!transitory!ischemic!attack!or!apoplexia/stroke.!!
!
4.5!
Criteria!for!receiving!H56:IC31!vaccine!
Subjects!may!receive!H56:IC31!vaccination!(arm!#2!and!#4)!if!they!meet!the!following!criteria:!
Pulmonary!TB:!!
1.! Sputum!obtained!prior!to!1th!immunization!at!day!84!must!be!Mtb!negative!evaluated!by!at!
least!two!consecutive!AFS!or!PCR/GeneXpert!at!least!7!days!apart.!
2.! Clinical!improvement!with!normal!vital!signs!(blood!pressure,!temperature!and!pulse)!and!
reduced!inflammatory!blood!parameters!(CRP!and!ESR)!compared!to!baseline.!
Extrapulmonary!TB:!!
•!
Documented!reduction!in!the!extent!of!TB!disease!at!the!infectious!site(s)!within!day!84!
evaluated!by!physical!and/or!radiological!examination!(table!A2).!!
•!
Clinical!improvement!with!normal!vital!signs!(blood!pressure,!temperature!and!pulse),!
improvement!of!any!TB!related!symptoms!to!Grade!183!(table!A2),!stable!or!increased!body8
weight!and!reduced!inflammatory!blood!parameters!(CRP,!ESR!and!WBC!counts)!compared!to!
baseline.!!
4.6!
Withdrawal!and!Termination!Criteria!
In!accordance!with!the!Declaration!of!Helsinki,!each!subject!is!free!to!withdraw!from!the!study!at!
any!time!without!further!explanations.!An!investigator!also!has!the!right!to!withdraw!subjects!from!
the!study!in!the!event!of!inter8current!illness,!adverse!events!or!other!reasons!concerning!the!
health!or!well!being!of!the!subject,!or!in!the!case!of!lack!of!cooperation.!!
Should!a!subject!decide!to!withdraw,!or!should!the!investigator!decide!to!withdraw!the!subject,!
efforts!will!be!made!to!complete!and!report!the!observations!up!to!the!time!of!withdrawal!as!
thoroughly!as!possible.!A!complete!final!evaluation!at!the!time!of!the!subject's!withdrawal!should!
be!made!and!an!explanation!given!of!why!the!subject!is!withdrawing!(if!approved!by!the!subject)!or!
being!withdrawn!from!the!study.!
The!reason,!date!and!time!for!withdrawal!will!be!noted!in!the!Case!Record!Form!(CRF).!If!the!
reason!for!withdrawal!is!a!clinical!adverse!event!or!an!abnormal!laboratory!test!result,!monitoring!
will!continue!until!the!outcome!is!evident.!If!possible,!measurements!and!recordings!should!
continue!according!to!the!protocol.!
The!specific!event!or!test!result(s)!being!the!reason!for!withdrawal!will!be!recorded!in!the!CRF.!
5!
TREATMENT!
For!this!study!the!following!are!defined!as!Investigational!Medicinal!Product(s)!(IMP).!
•!
Arcoxia®!blister!tablets!120!mg.!!
•!
H56:IC31!TB!vaccine!5!µg!

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5.1!
Drug!Identity,!Supply!and!Storage.!
5.1.1! Description!of!Arcoxia®!
Contains!the!COX82i!etoricoxib.!Manufacturer!MSD.!
Formulation!of!Arcoxia®:!TABLETTER!120!mg:!Each!tablet!contains:!Etorikoksib!120!mg,!
laktosemonohydrat!5!mg,!supportive!compounds.!Color!compounds:!Indigotin!(E!132),!jernoksid!(E!
172),!titandioksid!(E!171).!
Arcoxia®!Packaging!and!storage:!The!Investigational!product!will!be!bought!by!the!Investigator!
as!ordinary!marketed!product!sealed!in!individual!tablets!and!kept!in!stock.!!
5.1.2! Description!of!H56:IC31!!
H56:IC31!is!a!vaccine!composed!of!the!H56!antigen!and!the!IC31!adjuvant.!!
!
Manufacturer!of!the!H56!Antigen,!IC31!Adjuvant!and!H56:IC31!vaccine!
Name:!Statens!Serum!Institut!!
Address:!5!Artillerivej!!
DK82300!Copenhagen!S,!Denmark!!
Telephone:!+45!3268!3268!!
FAX:!+45!3268!3868!!
!
H56:IC31!Formulations!!
H56:IC31!5/500:!0.8!mL!containing!5!µg/0.5!mL!H56!antigen!and!500!nmol/0.5!mL!IC31!adjuvant.!
H56:IC31!is!formulated!in!a!buffer!consisting!of!4!mM!Glycine,!8!mM!Tris!and!135!mM!NaCl!(the!
vaccine!is!formulated!using!1!part!H56!concentrated!bulk!formulated!in!20!mM!Glycine!and!4!parts!
IC31!1.25!x!concentration!formulated!in!10!mM!Tris!and!168.75!mM!NaCl).!H56:IC31!5/500!
vaccine!will!be!supplied!as!a!final!formulated!vaccine.!!!
!
H56:IC31!Packaging!!
The!vaccine!is!provided!in!clear!type!I!glass!vials!(Schott!Glaskontor)!with!a!20!mm!Flurotec!Plus!
injection,!chlorobutyl!rubber!stopper!(West!Pharmaceutical!Services)!with!a!20!mm!center!tear8off!
aluminum!seal!(West!Pharmaceutical!Services).!The!H56:IC31!vial!contains!0.8!mL!of!
greyish/colorless!final!formulated!vaccine!with!an!extractable!volume!>!0.5!mL.!The!plastic!tops!
are!color!coded.!
!
H56:IC31!(Storage!and!Handling)!!
H56:IC31!vials!will!be!stored!at!the!hospital!pharmacy!at!a!temperature!between!+2°C!and!+8°C!
and!particulate!matter.!Vials!with!visible!particulates!will!be!quarantined!and!the!sponsor!notified.!
Vaccine!doses!for!administration!will!be!drawn!by!the!study!nurse!directly!into!a!1!to!3!mL!
polypropylene!Luer!Lok™!syringe!(similar!to!Becton!Dickinson!#3008962!or!#3098585)!via!a!21!to!
258gauge!needle!using!aseptic!technique.!It!is!important!to!use!a!Luer8Lok™!needle!connection!or!
an!integral!needle!to!avoid!vaccine!spray!exposure!from!accidental!dislodgement!of!the!needle.!
H56:IC31!will!be!administered!by!the!study!nurse!immediately!after!being!drawn!into!the!syringe.!!
!
5.1.3! Description!of!placebo!
No!placebo!for!etoricoxib!or!H56:IC31!will!be!used.!!
!
5.2!
!Dosage!and!Drug!Administration!!
The!following!treatment!will!be!administered:!
1.! Arcoxia®!120!mg!tablets!to!be!administered!once!daily!(120!mg!x!1).!
2.! H56:IC31!vaccine!adm.!intramuscularly!at!5!μg!(1st!dose!day!84!and!2nd!dose!day!140).!

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5.3!
Duration!of!Therapy!
Arcoxia!120!mg!OD!will!be!given!for!20!weeks!(day!08140)!from!initiation!of!standard!anti8TB!
chemotherapy!until!the!second!dose!of!H56:IC31!vaccine!has!been!given!unless!disease!
progression!or!unacceptable!toxicity!are!encountered.!Subjects!may!also!discontinue!protocol!
therapy!in!the!following!instancesm!intercurrent!illness!which!would!in!the!judgment!of!the!
investigator!effect!patient!safety,!the!ability!to!deliver!treatment!or!the!primary!study!endpoints!or!
request!by!the!patient.!!
5.4!
Clinical!Monitoring!!
Regular!visits!performed!by!the!clinical!investigators!and!study!nurse!will!include!registration!of!
compliance,!adverse!events,!routine!clinical!follow8up!and!examinations!(Mtb!cultures/!
microscopy/PCR/Gene!Xpert,!routine!blood!samples!included!biochemical!parameters!associated!
with!organ!toxicity,!X8ray).!S8hCG!will!be!analysed!in!females!to!exclude!pregnancy!(section!6.2.2).!
Sampling!of!biobank!for!primary!immunogenicity!and!exploratory!studies!according!to!time8points!
as!stated!in!section!6.1!(table!1).!!
In!addition,!the!study!nurse!will!after!individual!evaluation!keep!in!contact!with!the!participants!to!
secure!compliance!and!safety!issues.!If!there!is!any!question!of!concern!the!participants!will!be!
seen!at!an!extra!visit!within!few!days!depending!on!the!issue.!!!!!!!!
The!study!arms!receiving!H56:IC31!vaccine!will!be!monitored!for!60!minutes!after!administration!of!
study!vaccine!to!insure!that!no!acute!allergic!events!are!in!process!and!to!see!if!a!febrile!response!
is!developing.!The!participants!will!be!examined!frequently!at!time8points!as!stated!in!section!6.1!
(table!2)!to!evaluate!the!physical!manifestations!of!the!immunization!and!with!blood!samples!to!
assess!the!biochemical!parameters!associated!with!organ!toxicity.!!
5.5!
Drug!dose!Modifications!
If!intolerable!AEs!occur!AND!is!judged!to!be!possibly,!probably,!or!definitely!related!to!etoricoxib!
the!dose!will!be!reduced!from!Arcoxia®!120!mg!OD!to!Arcoxia®!90!mg!tablets!OD!or!the!drug!
stopped!according!to!evaluation!of!the!PI!(see!section!6.3.2).!!
5.6!
Concomitant!Medication!
Concomitant!medication!includes!prescribed!and!non8prescribed!drugs!or!other!treatments!and!
any!vaccines!other!than!the!study!vaccine!given!to!a!subject!within!28!days!before!and!up!to!the!
end!of!the!observation!period.!The!name!of!the!medication,!start!and!stop!dates!(or!‘ongoing’),!
route!of!administration,!and!indication!must!be!recorded!on!the!Concomitant!Medications!eCRF.!
The!indication!recorded!must!correspond!to!a!medical!term/diagnosis!recorded!on!the!AE!eCRF!or!
to!a!pre8existing!condition!noted!in!the!subject’s!medical!history,!or!be!noted!as!prophylaxis,!e.g.,!
dietary!supplement.!
The!patients!will!be!treated!with!the!following!standard!anti8TB!drug!combination!therapy!for!drug8
sensitive!Mtb!throughout!the!study!(184!in!the!first!phase!for!2!months!and!182!for!a!total!of!
minimum!6!months)!dosed!according!to!weight:!
1.! Rifampicin!4508600!mg!
2.! Isoniazid!300!mg!!
3.! Ethambutol!80081600!mg!
4.! Pyrazinamide!100082000!mg!!
The!following!medications!are!not!permitted!during!the!study!in!either!arm:!
Other!NSAIDs,!ASA,!prednisolone,!DMARDS!or!other!immune!modulating!therapies.!
If!the!patient’s!clinical!or!bacteriological!situation!is!changed!during!the!study,!other!therapy!will!be!
instituted!according!to!the!investigator’s!evaluation!and!good!clinical!practice.!

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All!concomitant!medication!(incl.!“over8the8counter”!drugs)!used!by!the!patient!will!be!recorded!in!
the!patient’s!file!and!CRF.!!
5.7!
Drug!Accountability!!
The!investigator!is!responsible!for!ensuring!that!investigational!product!is!correctly!received!and!
recorded,!handled!and!stored!and!used!in!accordance!with!this!protocol.!All!investigational!product!
containers!(opened,!unopened,!or!empty)!must!be!returned!to!the!investigator!after!the!study.!A!
drug!dispensing!log!must!be!prepared!for!each!subject.!At!time8points!as!stated!in!section!6.1!
(table!1)!or!at!any!other!relevant!time8point!the!following!information!must!be!entered!into!the!drug!
dispensing!log:!
8date!of!visit!
8number!of!tablets!and!containers!given!to!the!patient,!including!container!number(s)!
8number!of!containers!returned!from!the!patient,!including!individual!container!number(s)!and!
whether!they!are!unopened,!opened!or!empty!
8the!number!of!tablets!left!in!the!containers!which!are!opened,!but!not!empty!
8explanation!of!any!discrepancies!
8signature!of!the!person!distributing/collecting!the!container(s)!
After!completion!of!the!study,!the!completed!drug!dispensing!logs!must!be!signed!by!the!
investigator.!!!
5.8!
Treatment!Compliance!
Compliance!of!both!study!drug!and!anti8TB!chemotherapy!will!be!calculated!based!on!observations!
from!the!TB!coordinators!(responsible!for!standard!DOT!treatment!given!to!the!individual!patient)!
and!on!the!number!of!returned!tablets!in!the!container!and!pill!organizer!observed!at!every!study!
visit.!
5.9!
Drug!Labeling!
Arcoxia®!TABLETTER!120!mg!and!90!mg!will!be!labeled!by!the!Oslo!University!Hospital!
Pharmacy!Ullevål!according!to!“Forskrift!om!klinisk!utprøving!av!legemidler!til!mennesker!av!
30.10.2009!(FOR8200981083081321)”.!The!label!will!be!affixed!to!the!outside!of!the!container!in!
a!language!that!is!understood!by!the!patient!(Appendix!1!and!2)!
The!H56:IC31!vaccine!vials!will!be!labeled!with!primary!labels!(appendix!3)!and!the!containers!
with!secondary!labels!(appendix!4).!!!!
The!IMPs!labels!will!state!the!patient’s!initials,!study!code,!batch8number,!storage!conditions,!
expiry!date!(for!Arcoxia!already!at!the!original!label),!name!and!contact!information!of!the!
Principal!Investigator!and!that!the!material!is!for!clinical!trial!/!investigational!use!only.!!
5.10!
Subject!Numbering!and!Randomization!
The!subjects!will!be!included!by!consecutive!subject!numbers!from!1!and!upwards.!Step8wise!
inclusion!starting!with!Group!A!and!proceeding!with!Group!B!if!safety!data!are!satisfactory!and!
meet!the!criteria!at!Study!Day!98!for!all!Group!A!participants.!
•!
At!inclusion!day!0,!the!patients!will!be!consecutively!randomized!(2:2:1)!in!groups!
according!to!study!group!descriptionsm!arm!#1!on!etoricoxib!(n=10),!arm!#2!receiving!
H56:IC31!vaccine!(n=10)!and!arm!#3!controls!(n=5).!!!
!

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•!
At!inclusion!day!0,!the!patients!will!be!consecutively!randomized!(2:1)!in!groups!according!
to!study!group!descriptionsm!arm!#4!on!etoricoxib!and!receiving!H56:IC31!vaccine!(n=10!
and!remaining!arm!#3!controls!(n=5).!!
Each!subject!is!identified!in!the!study!by!a!unique!subject!number!that!is!assigned!when!subject!
signs!the!Informed!Consent!Form.!Once!assigned!the!subject!number!cannot!be!reused!for!any!
other!subject.!!
!
6!
STUDY!PROCEDURES

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6.1$
Table$2.$Trial$flow$chart$$
!
Treatment$period$(etoricoxib)$$
Follow;up$period$
End$of$
study$$
Study$day$
Screen$$
0$
7$
14$$
28$
56$
84$
98$
140$
154$
182$
210$
238$
Window$(days)$
$
NA$
±2$
±2$
±7$
±7$
±7$
±3$
±7$
±3$
±7$
±14$
±14$
Informed!consent!
X$
$
$
$
$
$
$
$
$
$
$
$
$
Inclusion/exclusion!
evaluation!
X$
$
$
$
$
$
$
$
$
$
$
$
$
Demographics/!
medical!history!
X$
$
$
$
$
$
$
$
$
$
$
$
$
AFS/Culture/Xpert1)!!
X$
X$
$
X*$
$
X*$
X$
$
X$
$
X$
$
X$
Radiology2)!
X$
$
$
$
$
X$
$
$
$
$
X$
$
$
TB!chemotherapy3)!
$
X$
X$
X$
X$
X$
X$
X$
X$
X$
X$
$
$
Physical!
Examination4)!
X$
X$
X$
X$
X$
X$
X$
X$
X$
X$
X$
X$
X$
Vital!signs5)!
X$
X$
X$
X$
X$
X$
X$
X$
X$
X$
X$
X$
X$
Symptoms10)!
X$
X$
X$
X$
X$
X$
X$
X$
X$
X$
X$
X$
X$
Treatment!
(etoricoxib)!!
$
X$
X$
X$
X$
X$
X$
X$
X$
$
$
$
$
Haematology/clinical!
chemistry6)!
X$
X$
X$
X$
X$
X$
X$
X$
X$
X$
X$
X$
X$
Pharmacokinetics7)!
$
$
X$
$
$
$
$
$
$
$
$
$
$
Adverse!events!
$
$
X$
X$
X$
X$
X$
X$
X$
X$
X$
X$
X$
Con.!Medication!
X$
X$
X$
X$
X$
X$
X$
X$
X$
X$
X$
X$
X$
Vaccine$adm.$(T)8)$
$
$
$
$
$
$
T$$
$
T$$
$
$
$
$
Blood!sampling!for!
exploratory!ssays9)!
$
X$
$
X$
X$
X$
X$
X$
X$
X$
X$
X$
X$
Vaccine!IgG9)!
$
X$
$
$
$
$
X$
X$
X$
X$
$
$
X$
RNA!analysis9)!!
$
X$
$
$
$
$
X$
X$
X$
X$
$
$
X$
PBMC!ICS9)!
$
X$
$
$
$
$
X$
X$
X$
X$
$
$
X$
1). AFS, culture, microscopy, PCR/GeneXpert as part of routine clinical evaluation of TB. 2) Appropriate radiology (chest X-ray/CT/MRI/UL/PET) taken as part of clinical evaluation <1 month before entering the study. 3) Anti-TB chemotherapy: standard 
combination therapy, induction phase day 0-56, continuation phase day 56-182.  4) Physical examination by clinical investigator at every visit, the extent depending on the clinical situation. In the case of glandular TB, the gland(s) are measured. 5) Blood 
pressure, pulse, temperature. 6) Hb, Lpk, monocytes, lymphocytes,Tpk, ESR, CRP, SR, Na, K, Ca, creatinine, ASAT, ALAT, LDH, bilirubin, amylase, CK, cholesterol, glucose, gGT, urine acid, S-hCG) at every visit. QFT-TB at day 0 and 182. 7). Study 

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arm #1:AUC and Cmax after 7 days of etoricoxib when still in-patient at OUS. 8) H56:IC31 vaccine only to study arms #2 and #4. 9) see immunogenicity parameters in section 7.1.2. *). If Mtb detected in sputum either by AFS, culture or PCR, 2 additional 
sputum samples most be performed and proven negative before H56 immunisattion. 10) coughs, arthralgia, sweating, nausea/vomiting, diarrhea, headache, fatigue, myalgia, chestpain (and eventual additional symptoms) are recorded in 5 grades (1.not 
present; 2. no interference with activity; 3. some interference with activity; 4. significant: prevents daily activity, 5. ER visit or hospitalization) 
 
Table$A2.$Evaluation$of$treatment$response$in$extrapulmonal$TB$$
Criteria$for$response$
Timepoint$for$
evaluation$
Subjective!improvement!of!symptoms!(grade!1W3)1!
all!visits!
Reduction!or!within!normal!range!of!ESR,!CRP,!WBC!counts!
all!visits!
Stable!or!increased!weight!(compared!to!weight!at!diagnosis)!
all!visits!
Focal!improvement²!!
all!visits!
Radiological!improvement3!
day!1,!56,!182*!
Clinicians!evaluation!of!improvement4!
all!visits!
1Symptoms!recorded!in!5!grades!(1.!not!present^!2.!no!interference!with!activity^!3.!some!interference!with!activity^!4.!significant:!prevents!daily!
activity,!5.!ER!visit!or!hospitalization),!
2Local!examination!if!appropriate,!i.e.!measuring!(X!x!Y!cm)!enlarged!lymph!glands.!
3Ultrasound,!XWray,!computer!tomography!or!magnetic!resonance!imaging!depending!on!the!manifestation.!
4Overall!conclusive!clinical!evaluation!of!all!examinations!performed!(see!4.5).!
*Additional!timeWpoints!if!progression!of!disease!is!suspected.!
!
 

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6.2$
By$Visit$
Informed)consent)must)be)given)voluntarily)by)each)subject)before)any)trial)specific)
procedures)are)initiated.)All)eligibility)criteria)should)be)assessed)together)with)relevant)
baseline)parameters)prior)to)study)inclusion)(inclusion/exclusion)criteria).))
The)following)examinations/evaluations)will)be)done)at)screening:)
Clinical$status$
Medical)history)(including)disease)history)and)corresponding)treatment)details),)physical)
examination)e.g.)(general)apperance,)BCG)scar,)eyes,)fauces,)thyroid,)heart,)lung,)
abdomen,)peripheral)lymph)node,)basic)CNS)examination,)peripheral)circulation,)skin,)
odema,)eccoIcardiography))and)vital)signs)(blood)pressure,)temperature,)pulse,)weight,)
hight,)BMI).)
Concomitant$medication$
All)concomitant)medication)(incl.)“overItheIcounter”)drugs))used)by)the)subject)within)28)
days)of)treatment)start)must)be)recorded)in)the)CRF.)
Radiology$$$$
Chest)XIray)or)CT)scan/PET)scan)of)thorax)or)other)relevant)organs)to)determine)extent)
and)stage)of)TB)disease)performed)no)more)than)4)weeks)prior)to)inclusion)in)the)study.)
Chest)XIray)as)a)minimum)will)also)be)performed)day)56)and)182)(after)2)months)and)at)
the)end)of)antiITB)chemotherapy))according)to)clinical)guidelines.)
Laboratory$analysis$
Sputum)for)cultures,)microscopy)and)PCR)(i.e)GeneXpert).)Blood)samples)will)be)taken)
to)determine)parameters)of)inflammation,)haematology,)liver)and)kidney)function)(see)
7.2.4).)SIhCG)will)be)analysed)in)females)to)check)for)pregnancy.)QuantiFERONITB)will)
be)obtained)before)inclusion)and)at)day)182)at)the)end)of)antiITB)chemotherapy.))
6.2.1$
Before$Treatment$Starts$$
The)resistance)analyses)of)Mtb)should)be)completed)and)only)patients)with)sensitive)
strains)should)be)included.)The)exception)is)single)resistance)where)fully)adequate)antiI
TB)chemotherapy)regimen)could)be)provided.)Haematology)and)biochemistry)analysis)
should)be)available)and)evaluated)according)to)exclusion)criteria.)Baseline)blood)
samples)for)biobanking)to)assess)immunogenicity)and)exploratory)studies)should)be)
drawn.))
6.2.2$
During$Treatment$
Regular)visits)will)include)registration)of)AE)in)the)CRF)and)secure)vaccinations)and)
sampling)of)plasma)and)PBMC)according)to)protocol)for)exploratory)immune)analysis)at)
timeIpoints)as)stated)in)section)6.1)(Table)2))and)7.1.2)(Table)3).)Standard)clinical)
followIup)(sputum)cultures/AFS,)clinical)examination,)routine)blood)samples,)XIray))will)
be)performed)at)regular)timeIpoints.)SIhCG)will)be)analysed)in)females)in)the)etoricoxib)
treatment)study)arms)at)every)visit)to)check)for)pregnancy)and)in)the)H56:IC31)vaccine)
arms)day)dag)56)and)98)in)addition)to)urineIHCG)day)84)and)day)140)immidiately)before)
immunisation.))
Pharmacokinetic)analysis)(AUC,)Cmax))with)repetitive)serum)sampling)will)be)performed)
during)one)day)in)the)period)between)day)7I14)after)initiation)of)etoricoxib)when)the)
patients)still)are)in)hospital)(arm)#1).))))

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6.2.3$
End$of$Treatment$Visit$$
All)study)arms)will)have)an)“End)of)Treatment)visit”)taking)place)at)day)140)when)
etoricoxib)treatment)will)be)stopped)and/or)last)(2nd))H56:IC31)immunisation)is)given.))
All)study)arms)will)also)have)a)control)at)day)154)and)day)182)(or)at)later)timeIpoint)
according)to)clinical)evaluation)when)antiITB)chemotherapy)will)be)stopped).)
6.2.4$
Withdrawal$Visit$
If)the)patient)is)withdrawn)from)the)study)before)completing)the)study)the)patient)will)still)
be)followed)and)receive)standard)antiITB)chemotherapy)for)26)weeks)or)as)long)as)
needed)as)determined)by)the)responsible)clinician)according)to)clinical)guidelines.)
6.2.5$
After$End$of$Treatment$(FollowIup)$
All)study)arms)will)also)have)final)followIup)controls)and)blood)sampling)for)immune)
analysis)and)chemistry)according)to)protocol)(Table)2))at)day)210)and)238)(10)and)14)
weeks)after)etoricoxib)treatment)is)stopped)and)last)H56:IC31)immunisation)is)performed)
(resp.)4)and)8)weeks)after)antiITB)chemotherapy)is)ended).))
6.3$
Criteria$for$Patient$Discontinuation$$
6.3.1$
Rules$for$Discontinuing$the$whole$Study$in$an$Individual$Subject$$
Patients)may)be)discontinued)from)study)treatment)and)assessments)at)any)time.)Patient)
is)also)at)any)time)free)to)discontinue)his/her)participation)in)the)study,)without)any)
further)explanation)or)prejudice)to)further)treatment.)
Specific)reasons)for)discontinuing)a)patient)for)this)study)are:)
•)
Safety)reason)as)judged)by)the)Principal)Investigator)
•)
Major)protocol)deviation)
•)
Incorrect)enrolment)ie,)the)patient)does)not)meet)the)required)inclusion/exclusion)
criteria)for)the)study)
•)
Patient’s)nonIcompliance)to)study)treatment)and/or)procedures)
)
•)
Patient)lost)to)followIup)
)
•)
A)female)patient)becoming)pregnant)
)
•)
TB)disease)progression))
)
•)
Development)of)autoimmune)disease)or)immunosuppression)
)
•)
Death)
)
•)
Other)
)
6.3.2$
Specific$Rules$for$Discontinuing$etoricoxib$in$an$Individual$Subject$$
•)
An)objective)clinical)or)laboratory)parameter)change)which)meets)Grade)3)or)
Grade)4)severity,)as)defined)in)the)protocol)toxicity)table,)AND)is)judged)to)be)
possibly,)probably,)or)definitely)related)to)etoricoxib.)

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•)
Deterioration) in) the) patients) condition) which) in) the) opinion) of) the) Principal)
Investigator)warrants)study)medication)discontinuation)(to)be)records)as)an)AE)or)
under)Investigator)Discretion).)
6.3.3$
Rules$for$Discontinuing$Vaccine$Injections$in$an$Individual$Subject$
Administration)of)additional)study)injections)will)be)discontinued)for)an)individual)
subject)if)he/she)has)any)of)the)following:)
•)
An)objective)clinical)or)laboratory)parameter)change)which)meets)Grade)3)or)
Grade)4)severity,)as)defined)in)the)protocol)toxicity)table,)AND)is)judged)to)be)
possibly,)probably,)or)definitely)related)to)study)vaccine.)
)
•)
Fever)(oral)temperature)≥39˚C))within)1)week)following)study)injection)which)is)
associated)with)constitutional)symptoms)(myalgia,)arthralgia,)fatigue,)headache,)
anorexia,)hives,)chills))AND)is)judged)to)be)possibly,)probably,)or)definitely)
related)to)study)injection.)
)
•)
Injection)site)reaction)that)involves)severe)induration)(>10)cm,)prevents)daily)
activity)or)necrosis/ulceration),)erythema)(>10)cm)or)necrosis/ulceration/)
exfoliative)dermatitis),)tenderness)(significant)discomfort)at)rest)or)study)site)visit)
or)hospitalization))or)pain)(any)use)of)narcotic)pain)reliever)or)prevents)daily)
activity)or)study)site)visit)or)hospitalization).))
)
•)
Any)event)that)in)the)opinion)of)the)principal)investigator)precludes)administration)
of)any)further)study)injections.)
)
6.4$
Procedures$for$Discontinuation$
6.4.1$
Patient$Discontinuation$
Patients)who)withdraw)or)are)withdrawn)from)the)study,)will)stop)further)etoricoxib)
treatment)and/or)and)not)receive)vaccine)immunization.)The)patient)will)still)be)followed)
and)receive)standard)antiITB)chemotherapy)for)26)weeks)or)as)long)as)needed)as)
determined)by)the)responsible)clinician)according)to)clinical)guidelines.)
If)the)1st)H56:IC31)injection)is)missed)(day)84))due)to)other)reasons)than)in)6.3.3,)the)2nd)
injection)(day)140))can)still)be)given)and)the)patient)continue)to)be)included)in)the)study.)
)
The)reason)for)discontinuation)will)be)recorded.)Any)significant)AE)will)be)followedIup)
until)the)outcome)either)is)recovered)or)resolved.)
)
Patients)who)withdraw)or)are)withdrawn)from)the)study)within)the)first)98)days)of)the)
study)will)be)replaced.)))))
6.4.2$
Trial$Discontinuation$
The)whole)trial)may)be)discontinued)at)the)discretion)of)the)PI)or)the)sponsor)in)the)
event)of)any)of)the)following:)
•)
Occurrence)of)AEs)unknown)to)date)in)respect)of)their)nature,)severity)and)duration)
•)
Medical)or)ethical)reasons)affecting)the)continued)performance)of)the)trial)
•)
Difficulties)in)the)recruitment)of)patients)
•)
Cancellation)of)drug)development))
)

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  Page 29 of 59 
The) sponsor) and) principal) investigator) will) inform) all) investigators,) the) relevant)
Competent)Authorities)and)Ethics)Committees)of)the)termination)of)the)trial)along)with)
the) reasons) for) such) action.) If) the) study) is) terminated) early) on) grounds) of) safety,) the)
Competent)Authorities)and)Ethics)Committees)will)be)informed)within)15)days.)
6.5$
Laboratory$Tests$
Blood)samples)will)be)drawn)by)venepuncture.)Plasma,)serum)and)PBMCs)will)be)
isolated,)frozen)and)stored)in)the)Department)of)Infectious)Diseases,)Oslo)University)
Hospitals)approved)“Research)Biobank)Infectious)Diseases.”)Principles)governing)
biomedical)research)in)humans)as)stated)in)the)Declaration)of)Helsinki)will)be)followed.)
See)Section)7)regarding)the)analysis)to)be)performed))
Routine)sputum,)tissue)and)blood)samples)as)part)of)the)clinical)diagnosis)and)followIup)
of)TB)will)be)collected,)handled)and)analysed)in)accordance)with)hospital/laboratory)
standard)procedures.)
7$
ASSESSMENTS$$
7.1$
Immunogenicity$and$Immunology$Analyses$
A)summary)of)immunologic)assays)to)be)performed)on)blood)specimens)is)shown)in)
Table)3.))Listed)blood)volumes)are)estimates.))Blood)will)be)collected)for)all)assays.))
Required)assays)will)be)performed)on)available)specimens)from)all)listed)subjects)and)
time)points.))Exploratory)assays)may)be)performed)on)specimens)from)certain)subjects)
and)time)points.))
7.1.1$ Immunogenicity$and$Immune$variables$$
7.1.1.1$ Flow$cytometry$$
Immune)responses)to)in&vitro)stimulation)of)whole)blood)or)PBMC)with)H56)antigenic)
peptide)pools)(Ag85B,)ESATI6,)and)Rv2660c))and)with)peptides)representing)nonI
vaccine)MtbIderived)antigens)(CFP10,)TB10.4,)PPD))will)be)analysed)in)all)study)arms)
and)assessed)by:)$
•)
Cytokine)producing)CD4+)and)CD8+)T)cells)(intracellular)cytokine)stainingi)ICS).))
•)
T)cell)proliferation)(cfse)))
•)
Tregulatory)cells)(CD45RA,)CD25,)FoxP3,)PD1)))
•)
Monocyte,)T)cell)and)Treg)COXI2i)expression)
•)
Soluble)cytokines)and)PGE2)levels)in)plasma)and)cell)supernatants)analyzed)by)
multiplex)and)ELISA)
7.1.1.2$ ELISPOT$$
Immune)responses)to)in&vitro)stimulation)of)whole)blood)or)PBMC)with)H56)antigenic)
peptide)pools)(Ag85B,)ESATI6,)and)Rv2660c))and)CFP10:)IFNIγ/ILI2)spotIforming)units)
(SFU))/10
6)
PBMC)preI)and)postIvaccination)and)the)effect)of)COXI2i)will)be)determined.)
7.1.1.3$ Transcriptional$(RNA)$biomarker$analysis$
The)relative)upregulation)of)an)expanded)panel)of)genes)of)interest)will)be)determined)
using)dualIcolor)ReverseITranscriptase)Multiple)LigationIdependent)ProbeIAmplification)
(dcRTIMLPA).)In)brief,)total)RNA)is)extracted)from)PAXgene)blood)collection)tubes)using)
the)PAXgene)Blood)RNA)kit)(PreAnalytiX,)DE))and)relative)expression)is)determined)with)
dcRTIMLPA)assay)and)analyzed)on)a)3730)capillary)sequencer)(Life)Technologies,)US).))

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  Page 30 of 59 
7.1.1.4$ Mycobacterial$growth$inhibition$assays$(MGIA):$$
Vaccine)immunogenicity)will)be)assessed)using)MGIA,)an)in&vitro)challenge)model)
assesses)the)ability)of)immune)cells)to)control)growth)of)Mtb)in)a)controlled)system.)
PBMCs)will)be)infected)with)log)phase)Mtb)and)subsequently,)the)degree)of)
mycobacterial)growth)(BACTEC)MGIT)960),)preI)and)postIvaccination)and)the)effect)of)
COXI2i)will)be)determined.)This)assay)will)be)performed)in)BSL3)facilities)at)OUS)or)with)
collaborating)partners.)
7.1.1.5$ IgG$and$humoral$immunity.$$
AntigenIspecific)IgG)response)to)H56:IC31)will)be)determined)in)plasma)samples)by)
ELISA)preI)and)postIvaccination.)This)assay)will)be)done)at)SSI)in)Denmark.))))
)
)
7.1.2$ Summary$of$Immunology$Specimens$and$Assays$(table$3)$
Assay$
Prority$
Purpose$of$assay$
Location$
Study$
Days$
Volume$
per$time$
ICSi)whole)
blood/PBMC,)
(flow)cytometry))
Required)
Determine)cellular)
immune)response)to)
study)vaccine)and)TB)
OUS,)
Norway)
0,)84)
98,140,)
154,)238)
5)mL)
T)cell)proliferation)
PBMC,)(flow)
cytometry))
Required)
Determine)cellular)
immunogenicity)to)
study)vaccine)and)TB)
OUS,)
Norway)
0,)84,)
98,140,)
154,)238)
5)mL)
IFNIγ/ILI2)PBMC)
(ELISPOT))
Required)
Determine)cellular)
immunogenicity)to)
study)vaccine)and)TB)
OUS,)
Norway)
0,)84,)
98,140,)
154,)238)
5)mL)
Vaccine)IgG)
(ELISA))
Exploratory)
Determine)humoral)
immunogenicity)to)
study)vaccine)
SSI,)
Denmark)
0,)84,)98,)
140,)154,)
238)
4)ml)
(plasma))
MGIA)
Exploratory)
Determine)in)a)in&vitro)
challenge)model)the)
ability)of)immune)cells)
to)control)growth)of)
Mtb)
To)be)
determined)
0,)84,)98,)
140,)154,)
238))
10ml)
PaxGene)for)RNA)
analysis)
(transcriptional)
profiling))
Exploratory)
Identify)early)gene)
signatures)that)can)
predict)immune)
responses)
To)be)
determined)
0,)84,)98,)
140,)154)
3)mL)
PBMC)(flow)
cytometry))
Exploratory)
T)cell)and)monocyte)
regulation,)activation)
cytokine)production)
and)coxI2)expression)
OUS,)
Norway)
0,)14,)28,)
56,)84,)98,)
140,)154,)
182,)210,)
238)
10)mL)
)
7.1.3$ Primary$immunogenicity$Endpoints$
1.) Etoricoxib)effect)of)TB)specific)immunogenicity:)T)cell)proliferation)and)cytokine)
responses)(change)between)day)0)and)140))
)
2.) H56:IC31)vaccine)immunogenicity:)T)cell)proliferation)and)cytokine)responses)14)
days)postIimmunization)(day)98)and)day)154)compared)to)day)84))))

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)
3.) Etoricoxib)effect)of)H56:IC31)vaccine)immunogenicity:)T)cell)proliferation)and)
cytokine)responses)14)days)postIimmunization)compared)to)H56:IC31)alone.)))
7.1.4$ Exploratory$immune$studies$
Several)functional)immune)assays)will)test)timeI)and)drugIdependent)aspects)of)cellular)
immune)responses)to)nonIspecific)and)specific)stimuli.)These)tests)will)be)carried)out)at)
the)different)partner)sites)with)corresponding)technologies)(see)7.1.2,)table)3).))
7.2$
Safety$and$Tolerability$Assessments$$
Safety)will)be)monitored)by)the)assessments)described)below)as)well)as)the)collection)of)
AEs)at)every)visit.)Significant)findings)that)are)present)prior)to)the)signing)of)informed)
consent)will)be)included)in)the)relevant)medical)history/)current)medical)condition)page)of)
the)CRF.)For)details)on)AE)collection)and)reporting)see)Section)8.))
See)Flow)chart)in)Section)6)(table)2))for)assessment)schedule.)
The)“clinical)investigational)group”i)the)sponsor)(Dag)Kvale),)the)PI)(Anne)Ma)DyrholI
Riise))and)the)clinical)study)investigators)will)review)the)safety)data)throughout)the)
course)of)the)study)and)report)as)stated)in)section)8.7.)
7.2.1$ Medical$History$
A)summary)of)the)patient’s)relevant)medical)history)will)be)recorded)on)the)appropriate)
CRF)page(s).)The)following)information)will)be)collected:)
•)
Diagnosis)of)coImorbidities)(i.e)diabetes,)kidney)failure),)coIinfections)(HIV,)Hepatitis)
B)and)C),)incident)events)(i.e)gastric)ulcer,)allergy,)asthma))and)previous)TB.))
•)
Time,)duration,)treatment)and)outcome)of)the)respective)diagnosis.))
7.2.2$ Physical$Examination$
A)qualified)physician)will)conduct)a)physical)examination)including)an)examination)of)
general)appearance,)skin,)neck)(including)thyroid),)fauces,)lymphoid)glandels,)eyes,)
lungs,)heart,)abdomen,)basic)nervous)system)evaluation,)peripheral)circulation.))
Any)pathological)physical)examination)finding)after)start)of)treatment)that)is)classified)by)
the)investigator)as)a)clinically)significant)worsening)compared)to)previous)exam)will)be)
considered)an)AE,)documented)on)the)subject’s)CRF,)and)followed)until)the)outcome)is)
determined.)
7.2.3$ Vital$Signs$
To)be)measured:)Body)temperature,)systolic/diastolic)blood)pressure,)heart)rate,)weight.))
Any)vital)sign)value)after)start)of)treatment)that)is)judged)by)the)investigator)as)a)
clinically)significant)worsening)compared)to)previous)exam)will)be)considered)an)AE,)
documented)on)the)subject’s)CRF,)and)followed)until)the)outcome)is)determined.)
7.2.4$ Clinical$Laboratory$Evaluation$
The)routine)laboratory)analyses)will)be)performed)at)the)Central)Laboratory)at)Oslo)
University)Hospital.))
Haematology)assessments)will)include)the)following)parameters:)haemoglobin,)
leucocytes,)monocytes,)lymphocytes,)platelets,)ESR.)

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Blood)chemistry)assessments)will)include)the)following)parameter:)CRP,)Na,)K,)Ca,)
creatinine,)creatinineIclearance,)ASAT,)ALAT,)LDH,)bilirubin,)amylase,)CK,)gammaGT,)
cholesterol,)glucose,)HbA1C,)urine)acid.)SerumIhCG)and)urineIhCG)for)females.)
Results)from)clinical)laboratory)tests)obtained)as)part)of)the)study)will)be)reviewed)by)a)
medically)qualified)study)team)member)and)treated)in)accordance)with)site)policies.))
Any)laboratory)value)that)is)judged)by)the)investigator)as)a)clinically)significant)
worsening)compared)to)previous)exam)or)has)increased)in)toxicity)grade)after)start)of)
treatment)with)IMPs)(see)Appendix)for)toxicity)grading)scales))must)be)reported)as)an)
AE,)documented)on)the)subject’s)CRF,)and)followed)until)the)outcome)is)determined.)
The)signed)and)interpreted)laboratory)results)will)be)kept)together)with)the)subject’s)CRF)
as)supplemental)pages.)
7.2.5$ Pharmacokinetics$$
The)AUC)and)Cmax)of)etoricoxib)at)steady)state)after)7)days)of)treatment)will)be)
analyzed)in)Arm)#1)in)order)to)study)the)degree)of)interaction)between)etoricoxib)and)
rifampicin.)Blood)samples)will)be)collected)in)heparinized)tubes)at)regular)intervals)
during)96)hours)as)previously)described)(32).)The)blood)samples)will)be)protected)from)
light)and)stored)on)ice)until)the)plasma)could)be)separated.)The)separated)plasma)was)
stored)at)–20°C)until)analysis)for)etoricoxib.)
7.2.6$ Radiology$
Routine)chest)XIray)or)CT/PET)scan)will)be)performed)at)Dep.)of)Radiology,)Oslo)
University)Hospital)before)initiation)of)the)study)and)at)least)at)day)56)and)day)182)and)
in)addition)according)to)clinical)evaluation.)
7.2.7$ Adverse$Events$(AEs)$
The)adverse)drug)reaction)(ADR))profiles)for)etoricoxib)give)reason)to)expect)
gastrointestinal)AEs,)especially)nausea,)as)the)most)common)(see)section)8.2).)
Headache)may)also)occur.)In)addition,)study)personnel)must)remain)vigilant)for)the)
occurrence)of)any)event)related)to)the)patients’)TB)diagnosis)and)antiITB)chemotherapy)
where)gastrointestinal)ADRs)are)the)most)common)as)well)as)to)all)other)types)of)AEs.)
8$
SAFETY$MONITORING$AND$REPORTING$
The)investigator)is)responsible)for)the)detection)and)documentation)of)events)meeting)
the)criteria)and)definition)of)an)adverse)event)(AE))or)serious)adverse)event)(SAE).)Each)
patient)will)be)instructed)to)contact)the)investigator)immediately)should)they)manifest)any)
signs)or)symptoms)they)perceive)as)serious.)
The)methods)for)collection)of)safety)data)are)described)below.)
8.1$
Definitions$
8.1.1$
Adverse$Event$(AE)$
An)AE)is)any)untoward)medical)occurrence)in)a)patient)administered)a)pharmaceutical)
product)and)which)does)not)necessarily)have)a)causal)relationship)with)this)treatment.))
An)adverse)event)(AE))can)therefore)be)any)unfavorable)and)unintended)sign)(including)
an)abnormal)laboratory)finding),)symptom,)or)disease)temporally)associated)with)the)use)
of)a)medicinal)(investigational))product,)whether)or)not)related)to)the)medicinal)
(investigational))product.))

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The)term)AE)is)used)to)include)both)serious)and)nonIserious)AEs.)
If)an)abnormal)laboratory)value/vital)sign)are)associated)with)clinical)signs)and)
symptoms,)the)sign/symptom)should)be)reported)as)an)AE)and)the)associated)laboratory)
result/vital)sign)should)be)considered)additional)information)that)must)be)collected)on)the)
relevant)CRF.)
All)conditions)that)exist)prior)to)administration)of)the)study)vaccine)(preIexisting)
conditions))will)be)recorded)in)the)subject’s)medical)history)to)establish)baseline.)DayItoI
day)fluctuations)in)preIexisting)conditions)that)do)not)represent)a)clinically)significant)
change)in)the)subject’s)status)will)not)necessarily)be)reported)as)AE.)
Any)adverse)change)from)the)subject’s)baseline)condition)that)occurs)following)the)
administration)of)the)IMPs)will)be)considered)an)AE.)This)includes)the)occurrence)of)a)
new)AE)or)the)worsening)of)a)baseline)condition,)whether)or)not)considered)related)to)
the)IMPs.)Intermittent)conditions)such)as)headaches)may)be)present)on)Study)Day)0)but)
may)represent)an)AE)if)the)intensity)or)duration)of)the)event)is)worse)than)usual)following)
receipt)of)IMPs.)AE)include,)but)are)not)limited)to:)adverse)changes)from)baseline)that)
represent)increases)in)toxicity)grade)according)to)the)Toxicity)Table)adverse)changes)in)
the)general)condition)of)the)subject,)signs)and)symptoms)noted)by)the)subject,)
concomitant)disease)with)onset)or)increased)severity)and)changes)in)laboratory)safety)
parameters)occurring)after)administration)of)IMPs.)
8.1.2$
Serious$Adverse$Event$(SAE)$
Any untoward medical occurrence that at any dose:  
)
•)
Results in death 
•)
Is immediately life-threatening 
•)
Requires in-patient hospitalization or prolongation of existing hospitalization  
•)
Results in persistent or significant disability or incapacity  
•)
Is a congenital abnormality or birth defect   
•)
Is an important medical event that may jeopardize the subject or may require medical intervention 
to prevent one of the outcomes listed above. 
Medical)and)scientific)judgment)is)to)be)exercised)in)deciding)on)the)seriousness)of)a)
case.)Important)medical)events)may)not)be)immediately)lifeIthreatening)or)result)in)death)
or)hospitalization,)but)may)jeopardize)the)subject)or)may)require)intervention)to)prevent)
one)of)the)listed)outcomes)in)the)definitions)above.)In)such)situations,)or)in)doubtful)
cases,)the)case)should)be)considered)as)serious.)Hospitalization)for)administrative)
reason)(for)observation)or)social)reasons))is)allowed)at)the)investigator’s)discretion)and)
will)not)qualify)as)serious)unless)there)is)an)associated)adverse)event)warranting)
hospitalization.)
8.1.3$
Suspected$
Unexpected$
Serious$
Adverse$
Reaction$
(SUSAR)$$
Adverse Reaction: all untoward and unintended responses to an investigational medicinal product related to 
any dose administered; 
 
Unexpected Adverse Reaction: an adverse reaction, the nature or severity of which is not consistent with the 
applicable product information. 
 

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Suspected Unexpected Serious Adverse Reaction: SAE (see section 8.1.2) that is unexpected as defined in 
section 8.2 and possibly related to the investigational medicinal product(s). 
 
8.2$
Expected$Adverse$Events$(EAE)$
Etoricoxib:)Gastrointestinal)EAE)and)headache)are)the)most)commonly)occurring.)
≥1/100)til)<1/10:)abdominal)pain,)constipation,)gastritis,)reflux,)gas,)diarréa,)dyspeptic)
discomfort,)nausea,)vomiting,)eosophagitis,)palpitations,)arythmia,)hypertention,)alveolar)
osteitis,)increase)in)liver)enzymes)(ALAT/ASAT),)bronchospasm,)dizziness,)headache,)
oedema,)fatigue)(text)from)Arcoxia,)MSD,)ATCInr.:)M01A)H05)in)Felleskatalogen).)The)
EAEs)will)be)recorded)in)the)CRF.)
H56:IC31:$Vaccination)with)H56:IC31)has)been)associated)most)commonly)(≥10%)of)
subjects)with)one)or)several)of)the)AE))with)mild)to)moderate)injection)site)reactions)of)
pain,)warmth,)and)swelling,)mild)to)moderate)systemic)adverse)events)of)fatigue,)
bradycardia,)myalgia,)nausea,)headache,)arthralgia,)and)white)blood)cell)count)
increasedi)and)mild)to)severe)hypertension)(Table)5I8,)page)72,)Statens)Serum)Institut)
Investigator’s)Brochure).))
There)have)been)no)suspected)unexpected)serious)adverse)reactions)(SUSARs))
reported)to)date)in)clinical)trials)of)H56:IC31.)
8.3$
Disease$Progression/Recurrence$$
Progression)of)TB)disease)during)the)study)is)not)expected)since)only)patients)infected)
with)drug)sensitive)Mtb)isolates)given)appropriate)antiITB)chemotherapy)are)included.))
It)is)expected)that)some)few)patients)could)experience)initial)worsening)of)symptoms)due)
to)the)nature)of)the)TB)disease.)Events)definitely)explained)as)caused)by)TB,)will)not)be)
reported)as)an)AE/SAE.)However,)if)the)investigator)considers)that)there)is)a)causal)
relationship)between)the)IMPs)and)the)disease)progression)or)increase)in)symptoms)
then)this)must)be)reported)as)an)SAE.)
Death)due)to)progressive)disease)is)to)be)recorded)on)a)specific)from)in)the)CRF,)but)
not)as)an)SAE.)
8.4$
Time$Period$for$Reporting$AE$and$SAE$$
For)each)patient)the)standard)time)period)for)collecting)and)recording)AE)and)SAEs)will)
begin)at)baseline)(day)0))when)antiITB)chemotherapy)and)study)drug)etoricoxib)are)
started)and)continue)until)day)238)(14)weeks)after)the)last)dose)of)etoricoxib)and)last)
H56:IC31)immunization)is)given).))
For)H56:IC31)specific)AEs)will)be)reported)through)14)days)after)each)vaccination,)
injection)site)assessments)performed)through)14)days)after)each)vaccination)and)SAE)
and)SUSARs)reported)until)end)of)study.)The)monitor)will)review)unblinded)safety)data)
and)make)a)formal)recommendation)on)the)continued)conduct)of)the)trial)after)each)
safety)review.)
During)the)course)of)the)study)all)AEs)and)SAEs)will)be)proactively)followed)up)for)each)
patienti)events)should)be)followed)up)to)resolution,)unless)the)event)is)considered)by)the)
investigator)to)be)unlikely)to)resolve)due)to)the)underlying)disease.)Every)effort)should)
be)made)to)obtain)a)resolution)for)all)events,)even)if)the)events)continue)after)
discontinuation/study)completion.)

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  Page 35 of 59 
8.5$
Recording$of$Adverse$Events$
If)the)patient)has)experienced)or)hospital)personnel)have)observed)AEs)the)investigator)
will)record)the)following)information)in)the)CRF:)
Date)and)time)of)onset)and)resolution)(duration),)severity)(defined)below),)the)nature)of)
the)event)described)by)the)investigator)in)precise)standard)medical)terminology)
(MedDRA)Version)18.0),)whether)it)required)treatment)or)action)taken,)outcome,)
relationship)to)the)patient’s)TB)diagnosis)or)treatment)and)whether)the)AE)caused)
withdrawal)from)the)study.)
The)severity)of)all)AE,)including)clinical)findings)and)abnormal)laboratory)values)will)be)
classified)as)one)of)the)following)grades)using)the)following)definitions:))
1)) Mild: 
 
Tolerable 
2)) Moderate: 
Interferes with normal activity 
3)) Severe:  
Incapacitating (causes inability to perform usual activity or work). 
In)addition,)a)Toxicity)Table)(US&FDA&guidance:&Toxicity&Grading&Scale&for&Healthy&Adult&and&
Adolescent&Subjects&Enrolled&in&Preventive&Vaccine&Clinical&Trials,&September&2007))is)provided)
in)the)protocol)appendix)for)the)grading)of)severity)of)specified)AE.)For)AE)not)listed)in)
the)Toxicity)Table)determination)of)severity)requires)some)level)of)interpretation)as)
outlined)above.)The)degree)of)incapacity)caused)by)the)AE)and)the)level)of)medical)
intervention)required)for)treatment)may)be)helpful)in)assessing)the)overall)severity)of)the)
AE.)
The)causal,relationship)of)the)event)to)the)study)medication)will)be)assessed)as)one)of)
the)following:)
Unrelated: 
There)is)not)a)temporal)relationship)to)investigational)product)administration)(too)
early,)or)late,)or)investigational)product)not)taken),)or)there)is)a)reasonable)causal)
relationship)between)nonIinvestigational)product,)concurrent)disease,)or)
circumstance)and)the)AE.)
)
Unlikely:  
There)is)a)temporal)relationship)to)investigational)product)administration,)but)there)is)
not)a)reasonable)causal)relationship)between)the$investigational)product)and)the)AE.)
$
Possible:  
There)is)reasonable)causal)relationship)between)the)investigational$product)and)the)
AE.)Dechallenge)information)is)lacking)or)unclear.)
$
Probable:  
There)is)a)reasonable)causal)relationship)between)the)investigational)product)and)
the)AE.)The)event)responds)to)dechallenge.)Rechallenge)is)not)required.)
)
Definite:  
There)is)a)reasonable)causal)relationship)between)the)investigational)product)and)
the)AE.))
)
The)outcome)of)all)adverse)events)will)be)classified)as)one)of)the)following:)
)
1.) On-going 
2.) Resolved  

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  Page 36 of 59 
3.) Resolved with sequelae 
4.) Death 
5.) Unknown 
)
8.6$
Solicited$Adverse$Events$and$Injection$Site$Reactions$
Solicited)AE)are)events)the)subject)is)specifically)asked)about.))These)AE)are)commonly)
observed)soon)after)receipt)of)vaccines.)For)this)study,)solicited)AE)to)be)collected)
include:))
Local:)
injection)site)pain,)injection)site)erythema,)injection)site)swelling)
Systemic:) fatigue,)myalgia,)arthralgia,)pyrexia,)chills,)nausea.)
8.7$
Reporting$Procedure$
8.7.1$
AEs$and$SAEs$
All)adverse)events)and)serious)adverse)events)that)should)be)reported)as)defined)in)
section)8.1.1)will)be)recorded)in)the)patient's)CRF.)
SAEs)must)be)reported)by)the)investigator)to)the)sponsor,)the)medical)expert)Dag)Kvale,)
either)directly)or)by)phone,)within)24)hours)after)the)site)has)gained)knowledge)of)the)
SAE.)Every)SAE)must)be)documented)by)the)investigator)on)the)SAE)pages)of)the)CRF.)
The)Serious)Adverse)Event)Report)Form)must)be)completed)and)signed)in)the)eCRF.)
The)medical)expert)will)review)the)report)in)the)eCRF.)The)initial)report)shall)promptly)be)
followed)by)detailed,)written)reports)if)necessary.)The)initial)and)followIup)reports)shall)
identify)the)trial)subjects)by)unique)code)numbers)assigned)to)the)latter.)
All)SAE)reports)will)be)collected)and)communicated)annually)to)the)National)Regulatory)
Authority)(Norwegian)Medicines)Agency).)SAEs)will)be)recorded)if)they)occurred)as)
follows:)
•)
between)the)first)administration)of)the)study)drug)and)the)completion)of)the)last)
followIup)evaluation,)whether)or)not)considered)related)to)the)investigational)product.)
•)
at)any)time)after)completion)of)the)last)followIup)evaluation,)and)came)to)the)
investigator’s)attention)and)were)judged)to)be)related)to)the)subject’s)participation)in)
the)study.)
8.7.2$
SUSARs$
SUSARs)will)be)reported)to)the)Norwegian)Medicines)Agency)according)to)national)
regulation)(“Forskrift)om)klinisk)utprøving)av)legemidler)til)mennesker)av)30.10.2009)
(FORI2009I10I30I1321)”).)The)following)timelines)should)be)followed:)
The)sponsor)(Dag)Kvale))will)ensure)that)all)relevant)information)about)suspected)
serious)unexpected)adverse)reactions)that)are)fatal)or)lifeIthreatening)is)recorded)and)
reported)as)soon)as)possible)to)the)Norwegian)Medicines)Agency)in)any)case)no)later)
than)seven)(7))days)after)knowledge)by)the)sponsor)of)such)a)case,)and)that)relevant)
followIup)information)is)subsequently)communicated)within)an)additional)eight)(8))days.)
All)other)suspected)serious)unexpected)adverse)reactions)will)be)reported)to)the)
Competent)Authority)concerned)as)soon)as)possible)but)within)a)maximum)of)fifteen)(15))
days)of)first)knowledge)by)the)sponsor.)SUSARs)will)be)reported)using)in)“paper)form”)or)
by)the)the)CIOMS)form)since)OUS)is)not)connected)to)EudraVigilance.))
Both)SAEs)and)SUSARs)related)to)the)H56:IC31)will)be)reported)to)SSI)within)the)same)
deadlines)by)cryptic)eImail)clin.pv@ssi.dk)or)fax.nr.)+45)32)68)82)47.)

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8.7.3$
Annual$Safety$Report$
Once)a)year)throughout)the)clinical)trial,)the)sponsor)will)provide)the)Competent)
Authority)with)an)annual)safety)report.)The)format)will)comply)with)national)requirements.))
8.7.4$
Clinical$Study$Report$
The)adverse)events)and)serious)adverse)events)occurring)during)the)study)will)be)
discussed)in)the)safety)evaluation)part)of)the)Clinical)Study)Report.)
8.8$
Procedures$in$Case$of$Emergency$
The)investigator)is)responsible)for)assuring)that)there)are)procedures)and)expertise)
available)to)cope)with)emergencies)during)the)study.)The)study)will)take)place)at)the)
outpatient)clinic)at)Dep.)of)Infectious)Diseases,)Oslo)University)Hospital)where)
emergencies)can)be)taken)care)of)during)H56:IC31)immunization.)When)the)patient)is)
home)he)will)be)given)information)about)telephone)numbers)to)phone)in)case)of)
emergencies.))
9$
DATA$MANAGEMENT$AND$MONITORING$$$
9.1$
Case$Report$Forms$(CRFs)$
The)investigator)will)keep)a)screening)log,)recording)all)subjects)who)were)screened)and)
whether)they)were)enrolled)or)not.)A)separate)Subject)Identification)List)will)be)kept,)
showing)code)numbers,)names,)and)dates)of)birth)to)allow)unambiguous)identification)of)
each)subject)included)in)the)study.)
The)designated)investigator)staff)will)enter)the)data)required)by)the)protocol)into)the)
electronic)Case)report)forms)(CRF).)The)Principal)Investigator)is)responsible)for)assuring)
that)data)entered)into)the)CRF)is)complete,)accurate,)and)that)entry)is)performed)in)a)
timely)manner.)The)signature)of)the)investigator)will)attest)the)accuracy)of)the)data)on)
each)CRF.)If)any)assessments)are)omitted,)the)reason)for)such)omissions)will)be)noted)
on)the)CRFs.)Corrections,)with)the)reason)for)the)corrections)will)also)be)recorded.)
The)principal)investigator)will)sign)the)last)page)of)the)CRF.)Any)corrections)to)the)data)
will)be)made)in)a)manner)that)does)not)obscure)the)original)entry)and)will)be)dated)and)
initialed)by)the)investigator)or)assigned)designee)
9.2$
Source$Data$$
The)medical)records)for)each)patient)should)contain)information)important)for)the)
patient’s)safety)and)continued)care,)and)to)fulfil)the)requirement)that)critical)study)data)
should)be)verifiable.))
To)achieve)this,)the)medical)records)of)each)patient)should)clearly)describe)at)least:)
•)
That the patient is participating in the study, e.g. by including the enrollment number and the study code 
or other study identification; 
•)
Date when Informed Consent was obtained from the patient and statement that patient received a copy 
of the signed and dated Informed Consent; 
•)
Results of all assessments confirming a patient’s eligibility for the study; 
•)
Diseases (past and current; both the disease studied and others, as relevant); 
•)
Surgical history, as relevant; 

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  Page 38 of 59 
•)
Treatments withdrawn/withheld due to participation in the study; 
•)
Results of assessments performed during the study; 
•)
Treatments given, changes in treatments during the study and the time points for the changes;  
•)
Visits to the clinic / telephone contacts during the study, including those for study purposes only; 
•)
Non-Serious Adverse Events and Serious Adverse Events (if any) including causality assessments;  
•)
Date of, and reason for, discontinuation from study treatment;  
•)
Date of, and reason for, withdrawal from study; 
•)
Date of death and cause of death, if available; 
•)
Additional information according to local regulations and practice. 
9.3$
Study$Monitoring$$
The)investigator)will)be)visited)on)a)regular)basis)by)the)Clinical)Study)Monitor,)who)will)
check)the)following:)
•)
Informed)consent)process)
•)
Reporting)of)adverse)events)and)all)other)safety)data)
•)
Adherence)to)protocol)
•)
Maintenance)of)required)regulatory)documents)
•)
Study)Supply)accountability)
•)
Facilities)and)equipment’s)
•)
Data)completion)on)the)CRFs)including)source)data)verification)(SDV))
The)monitor)will)review)the)relevant)CRFs)for)accuracy)and)completeness)and)will)ask)
the)site)staff)to)adjust)any)discrepancies)as)required.))
When)the)responsible)study)monitor)has)checked)and)verified)the)CRFs,)the)unidentified)
data)(verified)by)study)code))will)be)entered)into)a)computer)database)at)the)approved)
scientific)server)at)OUS)for)further)handling)and)statistical)evaluation.)The)code)key)will)
be)stored)at)another)approved)server.))
Sponsor’s)representatives)(e.g.)monitors,)auditors))and/or)competent)authorities)will)be)
allowed)access)to)source)data)for)source)data)verification)in)which)case)a)review)of)
those)parts)of)the)hospital)records)relevant)to)the)study)may)be)required.))
9.4$
Confidentiality$and$database$management$
All)information)concerning)the)study)will)be)stored)in)a)safe)place)inaccessible)to)
unauthorized)personnel.)The)entry)of)data)and)coding)will)be)secured)by)two)study)
nurses.)The)following)information)will)be)retained)at)the)investigator’s)site)for)at)least)15)
years)after)final)patient)visit)according)to)“Forskrift)om)klinisk)utprøving)av)legemidler)til)
mennesker)av)30.10.2009)(FORI2009I10I30I1321)”.))
•)
Source)documents)

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  Page 39 of 59 
•)
CRFs)
•)
Copies)of)protocols))
•)
Protocol)amendments)
•)
Drug)accountability)forms)
•)
Correspondence)
•)
Subject)identification)lists)
•)
Informed)consent)forms)
•)
Copies)of)study)reports)
)
10$
STATISTICAL$METHODS$AND$DATA$ANALYSIS$
10.1$
Determination$of$Sample$Size$
This)is)a)first)of)its)kind)exploratory)open)label)phase)I)study.)Primary)efficacy)data)of)
COXI2i)as)well)as)the)H56:IC31)vaccine)in)patients)with)active)TB)are)nonIexisting.)
Further,)it)is)not)optimal)to)extrapolate)efficacy)data)from)H56:IC31)studies)of)latent)TB)
patients.)Thus,)a)sample)size)calculation)is)therefore)not)performed.)Still,)H56:IC31)
studies)have)shown)significant)differences)in)vaccine)immunogenicity)with)10)patients)in)
each)arm)and)we)have)proven)differences)in)immune)activation)(CD38))in)a)HIV)cohort)
after)12)weeks)on)high)dose)celecoxib)(Pettersen)et)al.,)2010))with)13)and)14)patients)in)
the)study)and)control)groups,)respectively.)
10.2$
Randomization$$
We)will)include)10)patients)in)each)of)the)three)study)arms)and)10)in)the)control)arm.)By)
open)label)randomization)TB)patients)meeting)the)inclusion)criteria)will)be)included)in)a)
2:2:1)fashion)in)the)arms)#1,)#2)and)#3.)When)the)last)patient)have)reached)study)day)
98)(end)of)etoricoxib)treatment),)arms)#4)and)rest)of)controls)arm)#3)will)be)recruited)in)a)
2:1)fashion)if)safety)issue)are)satisfactory)in)arms)#1,)#2)and)#3.))
10.3$
Population$for$Analysis$
A)table)will)be)provided)with)the)following)information:)
•)
number)of)subjects,)both)screened)and)enrolled,)included)in)the)study)
•)
number)of)subjects)included)in)the)immunogenicity)analysis)
•)
number)of)subjects)included)in)the)safety)analysis)
•)
number)of)subjects)withdrawn)from)the)study)and)the)reason)for)withdrawal)
The)following)populations)will)be)considered)for)the)analyses:))
I)
Intention)to)treat)(ITT))population:)All)randomized)participants,)regardless)of)
protocol)adherence.)))
I)
PerIprotocol)population)(PP):)Includes)all)subjects)who)have)received)at)least)
one)dose)of)etoricoxib)and/or)H56:IC31.)
I)
Safety)population:)Includes)all)subjects)who)have)received)at)least)one)dose)of)
etoricoxib)and/or)H56:IC31.)Subjects)who)withdraw)from)the)study)will)be)

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  Page 40 of 59 
included)in)the)safety)analysis.)A)list)of)withdrawn)subjects,)preferably)with)the)
reasons)for)withdrawal,)will)be)made.)
10.4$
Statistical$Analysis$
Groups)will)be)compared)with)nonIparametrical)statistical)methods)throughout)with)twoI
ways)tests)using)pIvalues)equal)to)or)below)0.05)as)significant.)No)adjustments)due)to)
multiple)comparisons)will)be)performed.))
Deviation)from)the)original)statistical)plan)will)be)described)and)justified)in)the)Clinical)
Study)Report.)The)investigators)can)make)the)decision)regarding)individual)values)
belonging)to)a)subject)to)be)excluded)from)the)statistical)evaluations,)but)only)when)a)
protocol)violation)is)considered)to)weaken)any)of)the)scientific)aspects)of)the)study.)
Missing)data)will)not)be)substituted)by)estimated)values,)but)will)be)treated)as)missing)
data)by)the)method)used.))
10.4.1$ Safety$analysis$
The)number)and)percentages)of)patients)with)at)least)one)AE)will)be)tabulated.)
Occurrence)of)particular)AEs)and)their)severity)and)relationship)to)study)drug)will)be)
summarized.)))
10.4.2$ Vital$Signs$
Categorical)data)will)be)summarized)by)treatment)and)as)a)total)using)count)and)
percentages)of)patients.)Continuous)data)will)be)summarized)by)treatment)and)as)a)total)
using)medians,)quartiles)and)ranges.))
10.4.3$ Physical$Examinations$
Categorical)data)will)be)summarized)by)treatment)and)as)a)total)using)count)and)
percentages)of)patients.)Continuous)data)will)be)summarized)by)treatment)and)as)a)total)
using)median,)quartiles)and)ranges.))
10.4.4$ Clinical$Laboratory$Measurements$
Categorical)data)will)be)summarized)by)treatment)and)as)a)total)using)count)and)
percentages)of)patients.)Continuous)data)will)be)summarized)by)treatment)and)as)a)total)
using)median,)quartiles)and)ranges.)
10.4.5$ Pharmacokinetics$$
The)AUC)and)Cmax)of)etoricoxib)at)steady)state)after)7)days)of)treatment)will)be)
analyzed)and)statistics)performed)as)previously)described)(32).)
10.4.6$ Immunogenicity$and$Other$Immunology$Analyses$
All)immunogenicity)analyses)will)be)based)on)subjects)who)has)received)etoricoxib)until)
the)sample)timeIpoint)in)question)and/or)received)at)least)one)dose)of)study)vaccine)
H56:IC31.)Immunogenicity)will)be)summarized)for)all)time)points)as)collected)and)as)
available.)No)imputation)for)missing)data)will)be)performed.)Data)will)be)transformed)as)
appropriate)prior)to)analysis.)))
10.4.6.1$Primary$Immunogenicity$endpoints$
The)primary)variables)of)interest)for)assessment)of)immune)response)to)vaccine)will)be)
the)percentage)of)CD4+)and)CD8+)T)cells)that)produce)any)of)selected)cytokines.)The)
immunogenicity)of)H56:IC31)in)this)study)will)be)evaluated)by)PBMC)ICS,)TIcell)
proliferation)and)ILI2/IFNIγ)ELISPOT.)Due)to)the)exploratory)nature)of)immunogenicity)
endpoints,)the)primary)evaluation)will)be)based)on)descriptive)summaries)and)no)formal)
hypothesis)testing)will)be)performed.)

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  Page 41 of 59 
PBMC/whole$blood$ICS$Assay$
Assessment)of)immune)response)by)PBMC)or)whole)blood)ICS)will)be)based)on)the)
percentage)of)cytokine)producing)CD4+)and)CD8+)T)cells)in)response)to)stimulation)with)
H56)protein)antigen)and)antigenic)peptide)pools)(Ag85B,)ESATI6,)Rv2660c,)CFPI10).)
ICS)parameters)will)include)cytokines)such)as)IFNIγ,)ILI2)and)TNFIα,)and)may)include)
other)cytokines)to)identify)T)cells)of)specific)functionality.)Additional)cell)surface)markers,)
cytokines,)or)functional)markers)may)also)be)analysed.)Median)controlIsubtracted)
cytokine)responses)and)associated)95%)confidence)intervals)(CIs))or)other)descriptive)
statistics)as)appropriate)will)be)used)to)summarize)the)percentage)of)antigenIspecific)
CD4)and)CD8)T)cell)responses)by)all)study)group)and)treatment)assignment)at)all)
available)time)points.))Summaries)of)T)cell)responses)will)be)presented)by)T)cell)type)
(CD4)and)CD8),)by)stimulation)antigen(s),)and)by)cytokine)profile.)Summaries)will)
include)immune)responses)at)all)available)preI)and)postI)etoricoxib)and)preI)and)postI
vaccination)time)points.)Exploratory)assessment)of)antigen)specific)CD4+)and)CD8+)T)
cell)responses)in)relation)to)the)magnitude)of)QFT)positivity)pre)and)postIstudy)may)also)
be)performed.)
T$cell$proliferation$$
Assessment)of)T)cell)proliferation)will)be)based)on)the)percentage)of)CD4+)and)CD8+)T)
cells)expressing)the)proliferation)marker)cfse)in)response)to)stimulation)with)H56)protein)
antigen)and)antigenic)peptide)pools)(Ag85B,)ESATI6,)Rv2660c,)CFPI10).)Fraction)of)cell)
subsets)and)responses)and)associated)95%)confidence)intervals)(CIs))or)other)
descriptive)statistics)as)appropriate)will)be)used)to)summarize)the)percentage)of)antigenI
specific)CD4+)and)CD8+)T)cell)responses)by)all)study)group)and)treatment)assignment)
at)all)available)time)points.))Summaries)of)T)cell)responses)will)be)presented)by)T)cell)
type)(CD4)and)CD8))and)by)stimulation)antigen(s))at)all)available)preI)and)postI)
etoricoxib)and)preI)and)postIvaccination)timeIpoints.))
ELISPOT$
Assessment)of)immune)response)by)ELISPOT)will)be)based)on)the)number)of)ILI2/IFNIγ)
spotIforming)units)(SFU))per)106)PBMC)in)response)to)stimulation)with)H56)antigen)and)
antigenic)peptide)pools)(Ag85B,)ESATI6,)Rv2660c,)CFPI10).)Geometric)mean)and)
associated)95%)CIs)will)be)used)to)summarize)the)number)of)ILI2/IFNIγ)SFU)per)106)
PBMC)by)study)group)and)treatment)assignment)at)all)available)time)points.)Summaries)
of)the)number)of)ILI2/IFNIγ)SFU)per)106)PBMC)will)be)presented)by)stimulation)
antigen(s))and)will)include)immune)response)at)all)available)preI)and)postI)etoricoxib)and)
preI)and)postIvaccination)timeIpoints.)
QuantiFERONITB$Gold$Test$
Results)for)the)QuantiFERONITB)Gold)test)at)baseline)day)0)and)day)182)will)be)
summarized)using)subject)count)(percentage))summaries)and)descriptive)statistics.)
10.4.6.2$Exploratory$Assays$
dcRTIMLPA$(RNA$Analysis)$
As)an)exploratory)endpoint)for)examining)RNA)gene)expression)signatures,)RNA)
expression)will)be)performed.))RNA)will)be)isolated)from)whole)blood.))Signatures)of)
gene)expression)changes)after)vaccination)may)be)determined)using)computational)
systems)biology)tools.))
Antibody$IgG$ELISA$

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Geometric)mean)titers)for)antibody)ELISA)to)Ag85B,)ESATI6,)and)Rv2660c)and)
associated)95%)CIs)will)be)summarized)at)all)preI)and)postIvaccination)timeIpoints.)
PBMC$flow$cytometry$Assay$
Assessment)of)immune)phenotyping)and)responses)by)PBMC)will)be)based)on)the)
percentage)of)CD4+)and)CD8+)T)cells)and)monocytes)expressing)various)markers)of)
activation,)regulation,)maturity)and)COXI2)ex&vivo)and)in)response)to)stimulation)with)
H56)protein)antigen)and)antigenic)peptide)pools)(Ag85B,)ESATI6,)Rv2660c))and)
eventually)with)peptides)representing)nonIvaccine)MtbIderived)antigens)(TB10.4,)
CFP10,)PPD).)Fraction)of)cell)subsets)and)responses)and)associated)95%)confidence)
intervals)(CIs))or)other)descriptive)statistics)as)appropriate)will)be)used)to)summarize)the)
percentage)of)antigenIspecific)CD4+)and)CD8+)T)cell)responses)by)all)study)group)and)
treatment)assignment)at)all)available)time)points.)Summaries)of)T)cell)responses)will)be)
presented)by)T)cell)type)(CD4)and)CD8),)by)stimulation)antigen(s),)and)by)marker)profile)
at)all)available)preI)and)postI)etoricoxib)and)preIand)postIvaccination)timeIpoints.))
11$
STUDY$MANAGEMENT$
11.1$
Investigator$Delegation$Procedure$
The)principal)investigator)is)responsible)for)making)and)updating)a)“delegation)of)tasks”)
listing)all)the)involved)coIworkers)and)their)role)in)the)project.)He)will)ensure)that)
appropriate)training)relevant)to)the)study)is)given)to)all)of)these)staff,)and)that)any)new)
information)of)relevance)to)the)performance)of)this)study)is)forwarded)to)the)staff)
involved.)
11.2$
Investigator’s$Responsibilities$
The)investigator(s))is)responsible)for)performing)the)study)in)accordance)with)this)
protocol)and)the)ICH)guidelines)on)GCP,)and)for)collecting,)recording,)and)reporting)the)
data)accurately)and)properly.))Agreement)of)the)investigator)to)conduct)and)administer)
this)study)in)accordance)with)the)protocol)will)be)documented)in)a)separate)study)
agreement.)
The)investigator)has)the)overall)responsibility)for)the)conduct)and)administration)of)the)
study)at)the)centre,)and)for)contacts)with)study)centre)management,)the)EC)and)with)
local)authorities.)
The)investigator)is)responsible)for)giving)information)about)the)study)to)all)staff)members)
involved)in)the)study)or)in)any)element)of)subject)management,)both)before)starting)the)
practical)performance)of)the)study)and)during)the)course)of)the)study)(e.g.,)when)new)
staff)become)involved).)
The)investigator(s))is)responsible)for)ensuring)the)privacy,)health,)and)welfare)of)the)
subjects)during)and)after)the)study.))The)investigator)must)be)familiar)with)the)
background)and)requirements)of)the)study)and)with)the)properties)of)the)study)drugs)as)
described)in)the)package)insert.)
Authorised)personnel)of)the)Regulatory)Authority)inspector(s))or)their)agents)will)be)
given)direct)access)to)source)data)and)documentation)(e.g.,)medical)charts/records,)
laboratory)results,)printouts,)etc.))for)source)data)verification,)provided)that)subject)
confidentiality)is)maintained.)
11.3$
Protocol$Adherence$
Investigators)ascertain)they)will)apply)due)diligence)to)avoid)protocol)deviations.))

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All)significant)protocol)deviations)will)be)recorded)and)reported)in)the)Clinical)Study)
Report)(CSR).)
11.4$
Study$Amendments$
If)it)is)necessary)for)the)study)protocol)to)be)amended,)the)amendment)and/or)a)new)
version)of)the)study)protocol)(Amended)Protocol))must)be)notified)to)and)approved)by)
the)Competent)Authority)and)the)Ethics)Committee)according)to)EU)and)national)
regulations.)
A)Toxicity)Table)(US&FDA&guidance:&Toxicity&Grading&Scale&for&Healthy&Adult&and&
Adolescent&Subjects&Enrolled&in&Preventive&Vaccine&Clinical&Trials,&September&2007))will)
be)amended.)No)other)substantial)changes)from)the)final)approved)(signed))protocol)will)
be)initiated)without)the)EC’s)and)the)Regulatory)Authority’s)prior)written)approval)or)
favorable)opinion)of)a)written)amendment,)except)when)necessary)to)eliminate)
immediate)hazards)to)the)subjects)or)when)the)change)involves)only)logistics)or)
administration.))The)investigator)will)sign)the)protocol)amendment.))Any)significant)
deviation)from)the)protocol)when)no)approved)amendment)exists)will)be)regarded)as)a)
protocol)violation,)and)will)be)addressed)as)such)during)the)reporting)of)the)study.))
Before)any)subjects)are)enrolled)in)the)study,)a)list)of)potential)protocol)violations)and)
deviations)will)be)created,)with)corresponding)actions)to)be)taken.))))
11.5$
Audit$and$Inspections$
Authorized)representatives)of)a)Competent)Authority)and)Ethics)Committee)may)visit)the)
centre)to)perform)inspections,)including)source)data)verification.)Likewise,)the)
representatives)from)sponsor)may)visit)the)centre)to)perform)an)audit.)The)purpose)of)an)
audit)or)inspection)is)to)systematically)and)independently)examine)all)studyIrelated)
activities)and)documents)to)determine)whether)these)activities)were)conducted,)and)data)
were)recorded,)analyzed,)and)accurately)reported)according)to)the)protocol,)Good)
Clinical)Practice)(ICH)GCP),)and)any)applicable)regulatory)requirements.)The)principal)
investigator)will)ensure)that)the)inspectors)and)auditors)will)be)provided)with)access)to)
source)data/documents.)The)investigators)may)engage)an)internal)or)external)monitor.)))
12$
ETHICAL$AND$REGULATORY$REQUIREMENTS$
The)study)will)be)conducted)in)accordance)with)ethical)principles)that)have)their)origin)in)
the)Declaration)of)Helsinki)and)are)consistent)with)International&Conference&on&
Harmonisation&(ICH)/Good&Clinical&Practice&(GCP))and)applicable)regulatory)
requirements.)Registration)of)patient)data)will)be)carried)out)in)accordance)with)national)
personal)data)laws)and)regulations)for)clinical)researchi)“Forskrift&om&klinisk&utprøving&av&
legemidler&til&mennesker&av&30.10.2009&(FORV2009V10V30V1321)”.)
The)protocol)will)be)registered)in)www.clinicaltrials.gov)before)start)of)the)study.)
12.1$
Competent$Authority$and$Ethics$Committee$Approval$
Before)starting)this)study)the)protocol)will)be)submitted)to)the)National)Regulatory)
Authority)(Statens&Legemiddelverk&/&Norwegian&Medicines&Agency).)The)study)will)not)
start)before)the)Regulatory)Authority)give)approval)or)a)favorable)opinion.)
The)study)protocol,)including)the)patient)information)and)informed)consent)form)to)be)
used,)must)be)approved)by)the)regional)ethics)committee)(Regional&komite&for&medisinsk&
forskningsetikk,&Helseregion&Sør,&REK&II))before)enrolment)of)any)patients)into)the)study.)

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  Page 44 of 59 
The)investigator)is)responsible)for)informing)the)National)Regulatory)Authority)of)any)
serious)and)unexpected)adverse)events)and)EC)also)or)major)amendments)to)the)
protocol)as)per)national)requirements.)
12.2$
$Handling$and$storage$of$biological$material$
Blood)cells)and)serum/plasma)for)immunological)analysis)will)be)frozen)and)stored)in)an)
approved)research)biobank)entitled)“Forskningsbiobank&Infeksjonssykdommer”&(REK&
1.2006.1811&V&SV0885,&SHDNR.&09/513))at)The)Department)of)Infectious)Diseases,)Oslo)
University)Hospital)HF)at)the)Ullevål)site.)The)research)biobank)will)contain)only)patient)
codes,)i.e.)nonIidentifiable)information.))
12.3$
Informed$Consent$Procedure$
Written)informed)consent)will)be)obtained)from)each)subject)before)any)procedures)or)
assessments)are)done)and)after)the)aims,)methods,)anticipated)benefits,)and)potential)
hazards)are)explained)and)in)accordance)with)the)national)and)local)regulatory)
requirements.)It)will)be)emphasized)that)the)participation)is)voluntary)and)that)the)patient)
is)allowed)to)refuse)further)participation)in)the)protocol)whenever)she/he)wants.)This)will)
not)prejudice)the)patient’s)subsequent)care.))
The)subject’s)willingness)to)participate)in)the)study)will)be)documented)in)writing)in)a)
consent)form,)which)will)be)individually)dated)and)signed)by)the)subject)and)by)the)
person)conducting)the)informed)consent)process.)The)investigator)will)keep)the)original)
consent)forms)and)copies)will)be)offered)to)the)patients.)
Written)and)verbal)information)about)the)study)in)a)language)understandable)by)the)
subject)will)be)given)to)all)subjects.))The)information)provided)must)include)an)adequate)
explanation)of)the)aims,)methods,)anticipated)benefits,)potential)hazards,)and)insurance)
arrangements)in)force.)
They)will)be)informed)as)to)the)strict)confidentiality)of)their)patient)data,)but)that)their)
medical)records)may)be)reviewed)for)trial)purposes)by)authorized)individuals)other)than)
their)treating)physician.))
12.4$
Subject$Identification$
The)investigator)is)responsible)for)keeping)a)list)of)all)patients)(who)have)received)study)
treatment)or)undergone)any)study)specific)procedure))including)patient’s)date)of)birth)
and)personal)number,)full)names)and)last)known)addresses.))
The)investigator)will)assure)that)the)privacy)of)the)subjects,)including)their)personal)
identity)and)all)personal)medical)information,)will)be)maintained)at)all)times.))In)CRFs)
and)other)documents)submitted)to)the)sponsor,)subjects)will)not$be)identified)by)their)
names,)but)by)initials)and)allocation)number.)
Personal)medical)information)may)be)scrutinized)for)the)purpose)of)verifying)data)
recorded)in)the)CRF.)This)may)be)done)by)the)regulatory)authorities.)Personal)medical)
information)will)always)be)treated)as)confidential.)
13$
TRIAL$SPONSORSHIP$AND$FINANCING$
The)study)is)financed)by:)The$Norwegian$Research$Council)through)the)“GlobVac”)
program)assigned)14.01.2015)(Grant&234493&“Therapeutic&vaccination&and&immune&
modulation&V&new&treatment&strategies&for&the&multidrugVresistant&tuberculosis&pandemic”)&
and&by&Oslo&University$Hospital$and)the$University$of$Oslo.)

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  Page 45 of 59 
The)principle)investigator)(or)investigating)institution))will)certify)that)the)investigators)
and/or)the)investigating)institutions)do)not)have))
•)
compensation)for)participation)in)the)study)from)study)drug)manufacturer)
•)
significant)payments)of)other)sorts)from)study)drug)manufacturer)
The)principal)investigator)has)no)proprietary)interest)in)the)study)drug)or)H56)vaccine.))
No)initiatives)towards)agreements)or)discussions)with)the)pharmaceutical)companies)
that)have)patent)rights)and)regulatory)approvals)for)production)and)sale)of)COXI2i)will)be)
taken.)COXI2i)go)off)patent)in)2014)to)2017)and)based)on)experience)with)a)second)
medicinal)indication)patent)on)use)of)COXI2i)in)HIV)(Taskén)et)al,)WO)2002/07721),)the)
remaining)patent)life)is)considered)too)short)for)a)potential)use)patent)on)TB)to)have)
value.)Rather)generic)sale)of)COXI2i)will)make)this)class)of)drugs)cheap)and)available.)
However,)any)new)findings)and)potential)inventions)arising)from)the)project)work)will)be)
considered)for)patent)protection)and)development)in)line)with)the)IPRIpolicy)and)practise)
of)the)participating)institutions.)SSI)has)the)exclusive)rights)to)use)IC31®)from)Intercell)
within)the)field)of)TB.)The)H56)vaccine)is)proprietary)to)SSI.)
14$
TRIAL$INSURANCE$
The)Principal)investigator)has)insurance)coverage)for)this)study)through)membership)of)
the)Drug)Liability)Association.))
The)clinical)study)subjects)are)insured)by)membership)i)“Legemiddelansvarsforeningen”.)
15$
PUBLICATION$POLICY$
Upon)study)completion)and)finalization)of)the)study)report)the)results)of)this)study)will)
either)be)submitted)for)publication)and/or)posted)in)a)publicly)assessable)database)of)
clinical)study)results.))
The)results)of)this)study)will)also)be)submitted)to)the)Competent)Authority)and)the)Ethics)
Committee)according)to)EU)and)national)regulations.)
All)personnel)who)have)contributed)significantly)with)the)planning)and)performance)of)
the)study)(Vancouver)convention)1988))may)be)included)in)the)list)of)authors.)
16$
REFERENCES$
World)health)organization.)Global)Tuberculosis)report)2014.)
http://www.who.int/tb/publications/global_report/en/.)
GonzalezIJuarrero)M)et)al,)Infect)Immun)2001i)69:1722I8.))
Hoang)TT)et)al.)PLoS)One.)2009)Jun)16i4(6):e5928.))
Ottenhoff)TH.)Int)J)Tuberc)Lung)Dis.)2012)Novi16(11):1424I32.)Review.))
Keane)J)et)al.)N)Engl)J)Med)2001i)345:1098I104.))
Flynn)JL)et)al.)Immunity)1995i)2:561I72.2526.))
Harari)A)et)al.)Nat)Med.)2011)Mari17(3):372I6.))
Scanga)CA)et)al.)J)Exp)Med)2000i)192:347I58.))
Dintwe)OB)et)al.,)Eur)J)Immunol.)2013)Jun)5)doi:)10.1002/eji.201343454.))
Wergeland)I)et)al.)Scand)J)Immunol.)2011)Mari73(3):234I42.))
GuyotIRevol)V)et)al.)Am)J)Respir)Crit)Care)Med)2006)Apr)1i173(7):803I10.))
Rangel)Moreno)J)et)al.)Immunology.)2002)Juni106(2):257I66.))
Torgersen)KM)et)al.)Handb.)Exp.)Pharmacol.)2008i)186:327I363.))
Brudvik)KW,)Taskén)K.)Br)J)Pharmacol.)2012)Mayi166(2):411I9.)Review.))
Mahic)M)et)al.)J)Immunol.)2006i177:246I54.))
Bryn)T)et)al.)Int)Immunol.)2008i20(2):235I45.))
Johansson,)CC)et)al.)AIDS)2004i)18:)6I7.)1)

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  Page 46 of 59 
Kvale)D)et)al.)AIDS)2006i)20:813I820.))
Pettersen)FO)et)al.)J)Virol.)2011)Juli85(13):6557I66.))
HernándezIPand)et)al.,)Clin)and)Exp)Immunology)2006,)144:)264–272.))
PeresIBuzalaf)et)al.,)Prostaglandins)Leukot)Essent)Fatty)Acids.)2011i85(2):75I81.))
Vilaplana)C)et)al.)J)Infect)Dis.)2013)Jul)15i208(2):199I202.))
Aagaard)C)et)al.)Nat)Med.)2011)Febi17(2):189I943.))
Govender)L)et)al.)Vaccine.)2010)Dec)10i29(1):51I7.))
van)Dissel)JT)et)al.)I.)Vaccine.)2011)Mar)3i29(11):2100I9.))
Lin)PL)et)al.)J)Clin)Invest.)2012)Jan)3i122(1):303I14.)
Andersen,)P.)Nat.)Rev.)Microbiol.)5,)484–487)(2007).))
Olsen,)A.W)et)al.)Infect.)Immun.)69,)2773–2778)(2000).))
Tameris)MD)et)al.)Lancet.)2013)23i381(9871):1021I8.))
Feruglio)SL,)Tonby)K,)Kvale)D,)DyrholIRiise)AM.)Clin)Exp)Immunol.)2014)
Dallob)A)et)al,)J)Clin)Pharmacol.)2003)Juni43(6):573I85.)
Agrawal)NG)et)al.)J)Clin)Pharmacol.)2003)Mari43(3):268I76.)
Agrawal)NG)et)al.)J)Clin)Pharmacol.)2004)Octi44(10):1125I31.)
Surendra)K)et)al.)Indian)J)Med)Res.)2011)134(6):)866–877.))
Bogaty)P)et)al.,)Circulation)2004i)110:934I939.)

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  Page 47 of 59 
17$ APPENDIX$
17.1$
Appendix$1:$Label$Arcoxia$90$mg$
)
)
 
 
 
TIL$KLINISK$UTPRØVING$
Studie$kode:$TBCOX2$$$$$$$$$$$$$$$$$)
Pasient$initialer$og$kode$no:)____________)
)
1$TABLETT$(90$mg)$DAGLIG$$$
$
Lagres$ved$rom$temperatur))
Oppbevares)utilgjengelig)for)barn))
$
Prosjektansvarlig:$Prof.)Anne)Ma)DyrholIRiise)
Infeksjonsmedisinsk)avdeling,)Oslo)
universitetssykehus,)Kirkeveien)166,)0407)Oslo)
Tel:)+4722119100))/+47)92857261)
)
TA)MED)PAKNINGEN)VED)NESTE)KONTROLL))
Ikke)kast)tomme)pakninger.) 
 
 
)
)

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  Page 48 of 59 
17.2$
Appendix$2:$Label$Arcoxia$120$mg$$
)
)
 
 
 
TIL$KLINISK$UTPRØVING$
Studie$kode:$TBCOX2$$$$$$$$$$$$$$$$$)
Pasient$initialer$og$kode$no:)____________)
)
1$TABLETT$(120$mg)$DAGLIG$$$
$
Lagres$ved$rom$temperatur))
Oppbevares)utilgjengelig)for)barn))
$
Prosjektansvarlig:$Prof.)Anne)Ma)DyrholIRiise)
Infeksjonsmedisinsk)avdeling,)Oslo)
universitetssykehus,)Kirkeveien)166,)0407)Oslo)
Tel:)+4722119100))/+47)92857261)
)
TA)MED)PAKNINGEN)VED)NESTE)KONTROLL))
Ikke)kast)tomme)pakninger.) 
 
 
)

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  Page 49 of 59 
17.3$
Appendix$3:$Primary$label$H56:IC31$5/500$$
)
)
 
 
 
 
 
!
!
!
!
 
!
!
!
!
!
 
!
!
H56:IC31 5/500 
!
Study code: TBCOX2 
Subject initials and no: ________________ 
5 µg antigen H56 + IC31 (500 nmol KLK/20 
nmol ODN1a)/0.5 mL/dose. 
 
For Single Use Only.   For IM Injection Only. 
Prepare according to Protocol.  
For clinical trial use only. 
 
Store cold at 2°C - 8°C  
Manufactured by Statens Serum Institut 
Batch: XXXXXX Use by date: YYYY.MM.DD!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
)

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  Page 50 of 59 
17.4$
Appendix$4:$Secondary$label$H56:IC31$5/500$
)
 
 
 
 !
H56:IC31 5/500 
 
 
 
Study code: TBCOX2                 10 single-use vials 
H56:IC31 5 + 500/20 (0.8 mL sterile solution/vial) 
5 µg H56 antigen + IC31 (500 nmol KLK/20 nmol 
ODN1a)/0.5 mL/dose 
For IM injection only          For clinical trial use only 
Prepare according to Study Protocol  
PI: Prof. MD Anne Ma Dyrhol-Riise, Oslo 
University Hospital, Department of Infectious 
Diseases, Kirkeveien 166, 0407 Oslo, Norway,  
Tel: +47 92857261 
Manufactured by: Statens Serum Institut,  
5 Artillerivej, 2300 Copenhagen S, Denmark. 
Store cold at 2°C – 8°C 
Batch: XXXXXX      Use by date: YYYY.MM.DD 
 
 
 
!
 !
 !
)

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  Page 51 of 59 
17.5$
Appendix$5$
$Toxicity$Table$
)
Note:)From)final)US)FDA)guidance:)“Toxicity)Grading)Scale)for)Healthy)Adult)and)Adolescent)Subjects)
Enrolled)in)Preventive)Vaccine)Clinical)Trials)(September)2007))and)for)some)values)“Division)of)AIDS)
(DAIDS))Table)for)Grading)the)Severity)of)Adult)and)Pediatric)Adverse)Events)Version)2.0”)(November)
2014).)The)laboratory)values)provided)in)the)tables)serve)as)guidelines)and)are)dependent)upon)institutional)
normal)parameters)laboratory)values.))
)
Local$Reaction$to)
Injectable$Product)
Mild$
(Grade$1))
Moderate$
(Grade$2))
Severe$
(Grade$3))
Potentially$Life)
Threatening)
(Grade$4))
Pain)
Does)not)
interfere)with)
activity))
Repeated)use)of)
nonInarcotic)
pain)reliever)>)
24)hours)or)
interferes)with)
activity))
Any)use)of)
narcotic)pain)
reliever)or)
prevents)daily)
activity))
Emergency)
room)(ER))visit)
or)
hospitalization))
Tenderness))
Mild)discomfort)
to)touch))
Discomfort)with)
movement))
Significant)
discomfort)at)
rest))
ER)visit)or)
hospitalization))
Erythema/Redness*))
2.5)–)5)cm))
5.1)–)10)cm))
>)10)cm))
Necrosis)or)
exfoliative)
dermatitis))
Induration/Swelling**))
2.5)–)5)cm)and)
does)not)
interfere)with)
activity))
5.1)–)10)cm)or)
interferes)with)
activity))
>)10)cm)or)
prevents)daily)
activity))
Necrosis))
*"In"addition"to"grading"the"measured"local"reaction"at"the"greatest"single"diameter,"the"measurement"""
should"be"recorded"as"a"continuous"variable.""
**"Induration/Swelling"should"be"evaluated"and"graded"using"the"functional"scale"as"well"as"the"actual"measurement."
"
Vital$Signs$*)
Mild$
(Grade$1))
Moderate$
(Grade$2))
Severe$
(Grade$3))
Potentially$Life)
Threatening)
(Grade$4))
Fever)(°C))**))
38.0)–)38.4))
38.5)–)38.9))
39.0)–)40))
>)40))
Tachycardia)–)
beats)per)minute))
101)–)115))
116)–)130))
>)130))
ER)visit)or)
hospitalization)
for))
arrhythmia))
Bradycardia)–))
beats)per)minute***))
50)–)54))
45)–)49))
<)45))
ER)visit)
orhospitalization)
for)arrhythmia))
Hypertension)(systolic))I))
mmHg))
141)–)150))
151)–)155))
>)155))
ER)visit)or)
hospitalization)
for)malignant)
hypertension))
Hypertension)(diastolic))I))
mmHg))
91)–)95))
96)–)100))
>)100))
ER)visit)or)
hospitalization)
for)malignant)
hypertension))
Hypotension)(systolic))–))
mmHg))
85)–)89))
80)–)84))
<)80))
ER)visit)or)
hospitalization)
for)hypotensive)
hypotensive)
shock))
Respiratory)Rate)–))
breaths)per)minute))
17)–)20))
21)–)25))
>)25))
Intubation))
!
*!Subject!should!be!at!rest!for!all!vital!sign!measurements.!!
**!Body!temperature,!measured!by!ear!thermometer!!
***!When!resting!heart!rate!is!between!60!–!100!beats!per!minute.!Use!clinical!judgement!when!characterizing!!
bradycardia!among!some!healthy!subject!populations,!for!example,!conditioned!athletes.)
)

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  Page 52 of 59 
Systemic$(General))
Mild$
(Grade$1))
Moderate$
(Grade$2))
Severe$
(Grade$3))
Potentially$
Life)
Threatening)
(Grade$4))
Nausea/vomiting))
No)interference)
with)activity)or)1)
–)2)episodes/24)
hours))
Some)interference)
with)activity)or)>)2)
episodes/24)hours))
Prevents)daily)
activity,)requires)
outpatient)IV)
hydration))
ER)visit)or)
hospitalization)
for)hypotensive)
shock))
Diarrhea))
2)–)3)loose)stools)
or)<)400g/24)
hours)
4)–)5)stools)or)400)
–)800g/24)hours))
6)or)more)watery)
stools)or)>)
800g/24)hours)or)
requires)
outpatient)IV)
hydration))
ER)visit)or)
hospitalization))
Headache))
No)interference)
with)activity))
Repeated)use)of)
nonInarcotic)pain)
reliever)>24h)or)
some)interference)
with)activity))
Significanti)any)
use)of)narcotic)
pain)reliever)or)
prevents)daily)
activity))
ER)visit)or)
hospitalization))
Fatigue))
No)interference)
with)activity))
Some)interference)
with)activity))
Significanti)
prevents)daily)
activity))
ER)visit)or)
hospitalization))
Myalgia))
No)interference)
with)activity))
Some)interference)
with)activity))
Significanti)
prevents)daily)
activity))
ER)visit)or)
hospitalization))
Illness)or)clinical)adverse)
event)(as)defined)according)to)
applicable)regulations))
No)interference)
with)activity)
Some)interference)
with)activity)not)
requiring)medical)
intervention)
Prevents)daily)
activity)and)
requires)medical)
intervention)
ER)visit)or)
hospitalization)
)
Serum$
Mild$$$$$$$$$$$$
(Grade$1)$
Moderate$$$
(Grade$2)$
Severe$$$$
(Grade$3)$
Potentially$
Life$
Threatening$
(Grade$4)$
SodiumIhyponatremia,)
mmol/L*$
130I134$
125I129$
121I124$
≤)120$
SodiumIhypernatremia,)
mmol/L*)
146I149)
150I153)
154I159)
≥)160)
PotassiumIhyperkalemia,)
mmol/L*)
5.6I5.9)
6.0I6.4)
6.5I6.9)
≥7)
PotassiumIhypokalemia,)
mmol/L*)
3.0I3.4)
2.5I2.9)
2.0I2.4)
<2.0)
GlucoseIhypoglycemia,)
mmol/L)(random))**)
3.6I3.8)
3.0I3.5)
2.5I2.9)
<2.5)
GlucoseIhyperglycemia,)
mmol/L)(random))**)
6.1I6.8)
6.9I11.0)
>11.0)
Insulin)
requirement)or)
hyperosmolar)
coma)
Creatinine)(µmol/L)**)
K:)96I145.))))))))))
M:)106I145)
146I170)
171I208))))))
>)208)or)
requires)
dialysis)
CalciumIhypocalcemia)
mmol/L**)
2.00I2.10)
1.87I1.99)
1.75I1.86)
<1.75)
Calcium)Ihypercalcemia)
mmol/L**)
2.63I2.76)
2.77I2.88)
2.89I3.00)
>3.00)

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  Page 53 of 59 
Creatinine)Kinase)(CK),)U/L***)
1.25)–)1.59)x)ULN)
1.6I3.0)x)ULN)
3.1I10)x)ULN)
>10)x)ULN)
ASAT)(U/L),)Increased)by)
factor***)
1.1I2.5)x)ULN)
2.6I5.0)x)ULN)
5.1I10)x)ULN)
>10)x)ULN)
ALAT)(U/L),)Increased)by)
factor)***)
1.1I2.5)x)ULN)
2.6I5.0)x)ULN)
5.1I10)x)ULN)
>10)x)ULN$
Lactate)dehydrogenase)(LD))
U/L**)
1.1I2.5)x)ULN)
2.6I5.0)x)ULN)
5.1I10)x)ULN)
>10)x)ULN$
Bilirubin,)µmol/L***)
1.1I1.5)x)ULN)
1.6I2.0)x)ULN)
2.1I3.0)x)ULN)
>3.0)x)ULN)
Cholesterol,)mmol/L*)
6.0I6.3))
6.4I7.8))
>7.8)
NA)
Pancreatic)enzyme)(amylase),)
U/L***)
1.1I1.5)x)ULN)
1.6I2.0)x)ULN)
2.1I5.0)x)ULN)
>5.0)x)ULN)
Uric)acid)(µmol/L)*)
500I599)
600I719)
720I889)
>890)
Hematology$
Mild$(grade$1)$
Moderate$
(Grade2))
Severe$$$$
(Grade$3))
Potentially$
Life$
Threatening$
(Grade$4)$
Hemoglobin)(g/100mL))I)
(Female)*)
10.0I10.9)
9.0I9.9)
7.0I8.9)
<7)
Hemoglobin)(g/100mL))I)
(Female))change&from&
baseline&value***)
Any)decrease)I1.5)
1.6I2.0)
2.1I5.0)
>5.0)
Hemoglobin)(g/100mL))I(Male))
**)
12.0I13.0)
10.5I11.9)
8.5I10.4)
<8.5)
Hemoglobin)(g/100mL),)(Male))
change&from&baseline&value***)
Any)decrease)I1.5)
1.6I2.0)
2.1I5.0)
>5.0)
WBC)(109/L))I)increase***)
10.8I15.0)
15.1I20.0)
20.1I25.0)
>25.0)
WBC)(109/L))I)decrease***)
2.5I3.5)
1.5I2.4)
1.0I1.4)
<1.0)
Platelets)(109/L))I)decrease***)
125I140)
100I124)
25I99)
<25)
Lymphocytes)(109/L))I
decrease***)
0.8I1.0)
0.5I0.7)
0.3I0.4)
<0.3)
!
ULN=!Upper!Level!Limit!of!Normal!range!!
*!Division!of!AIDS!(DAIDS)!Table!for!Grading!the!Severity!of!Adult!and!Pediatric!Adverse!Events.!Version!2.0!S!
November!2014.!Modified!according!to!local!laboratory!reference!ranges!for!Cholesterol!and!Uric!acid.!
**!Modified!FDA!according!to!local!laboratory!reference!ranges.!
***!FDA;!Guidance!for!Industry.!Toxicity!Grading!Scale!for!Healthy!Adult!and!Adolescent!Volunteers!enrolled!in!
preventive!vaccine!clinical!trials.!US!Department!of!health!and!Human!Services.!Food!and!Drug!Administration.!Center!
for!biologics!Evaluation!and!Research.!September!2007.!

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  Page 54 of 59 
17.6$ Appendix$6$$$$$$$$$$$$$$$$$DESCRIPTION$OF$STUDY$VISITS$$
&
(If&baseline&day&is&the&same&day&as&screening&day&combine&all&examinations&and&
blood&samples).&&
$
Screening:$$
1.) Inclusion/Exclusion)evaluation)(confirm)that)study)eligibility)criteria)are)met).)
2.) Written)informed)consent))
3.) Assignment)of)subject)identification)number)
4.) Medical)history)(confirm)methods)of)contraception)for)females).))
5.) Concomitant)medication:)All)concomitant)medication)(including)“overItheIcounter”)
drugs))used)by)the)subject)within)28)days)of)treatment)start)must)be)recorded)in)
the)CRF)
6.) Physical)examination)(focused)physical)examination)by)medical)practitioner))
including)general)apperance,)BCG)scar,)eyes,)fauces,)thyroid,)heart,)lung,)
abdomen,)peripheral)lymph)node,)basic)CNS)examination,)peripheral)circulation,)
skin,)oedema.)
7.) Vital)signs)(blood)pressure,)pulse)and)temperature),)height,)weight)and)BMI.)
8.) Appropriate)radiology)(chest)XIray/CT/MRI/UL/PET)))
9.) Sputum)samples))
10.$Blood$collection$for:)$
a.$ Serum)chemistry/hematology:)includes)hgb,)leucocytes,)monocytes,)
lymphocytes,)platelets,)ESR,)CRP,)NA,)K,)CA,)Kreatinin,)GFR,)Asat,)Alat,)
LD,)Bilirubin,)Amylase,)CK,)gammaGT,)Kolesterol,)Glukose,)HbA1C,)Urat,)
Quantiferon)TB.$Serum)HCG)for)females)at)childbearing)age.)$
b.$ 1$EDTA$tube$(4$ml),$1$serum$tube$(5$ml),$3$(one$set)$Quantiferon$TB$
tubes.$
11.$ECG$
)
Visit$1IBaseline)(day$0)$
1.) Confirm)abscence)of)acute)illness)and)significant)syptomatic)infection)
2.) Update)medical)history)including)use)of)concomitant)medications)
3.) Focused)physical)examination)by)medical)practitioner)if)indicated)based)on)
history)
4.) Vital)signs:)Blood)pressure,)pulse,)temperature.)Weight.)
5.$ Blood$collection/number$of$tubes:$$
a.$ Serum)chemistry/hematology:)1$EDTA$tube$(4$ml),$1$serum$tube$(5$ml).$
b.$ Biobank:)1$Natrium$heparin$tube*(=WHOLE$BLOOD),$4$CPT$tubes,$1$
Pax$gene$tube.$
6.) Confirm)continued)eligibility)for)study)entry)and)vaccination)including)negative)
hcg)(for)all)females)of)childIbearing)potential).)
7.) Randomize)
8.) Studydrug)dispensing:)Hand)out)and)record)study)medication)(Etoricoxib))for)
study)arms)#1)and)#4.)Register)in)drug)accountability)log.)
9.) Anti)TB)chemotherapy:)standard)combination)therapy.)Register)medication)in)
CRF.)
10.)Sputum)samples.)
)
)

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  Page 55 of 59 
)
Visit$2I$(day$7)$
1.) Record)any)adverse)events,)including)serious)adverse)events)and)adverse)
events)of)special)interest)occuring)since)previous)evaluationi)record)any)
concomitant)medications)taken)associated)with)treatment)of)the)adverse)event.)
2.) Focused)physical)examination)by)medical)practitioner)if)indicated)based)on)
history)
3.) Vital)signs:)Blood)pressure,)pulse,)temperature.)Weight)
4.) Blood$collection/number$of$tubes:))
a.) Serum)chemistry/hematology.)1$EDTA$tube$(4$ml),$1$serum$tube$(5$ml).))
b.) Blood)hcg)for)all)females)of)childbearing)potential.)
c.) Study)arm#1:)Pharmacokinetics&after&7V14&days&of&etoricoxib&(see&
protocol).)
5.) Anti)TB)chemotherapy:)standard)combination)therapy.)Register)any)changes)in)
medication)in)CRF)
6.) Study)drug)dispensing)and)collecting:)Collect)and)record)any)excessive)study)
medication)and)empty)medicine)containers)and)if)needed:)hand)out)new)study)
medication)(Etoricoxib))for)study)arms)#1)and)#4.)Register)in)drug)accountability)
log.)
$
Visit$3I$(day$14)$
1.) Record)any)adverse)events,)including)serious)adverse)events)and)adverse)
events)of)special)interest)occuring)since)previous)evaluationi)record)any)
concomitant)medications)taken)associated)with)treatment)of)the)adverse)event.)
2.) Focused)physical)examination)by)medical)practitioner)if)indicated)based)on)
history)
3.) Vital)signs:)Blood)pressure,)pulse,)temperature.)Weight.)
4.) Sputum)samples))
5.$ Blood$collection/number$of$tubes:)$
a.$ Serum)chemistry/hematology.)1$EDTA$tube$(4$ml),$1$serum$tube$(5$ml).$
b.$ Blood)hcg)for)all)females)of)childbearing)potential.$
c.$ Biobank)4$CPT$tubes$
6.) Anti)TB)chemotherapy:)standard)combination)therapy.)Register)any)changes)in)
medication)in)CRF)
7.) Drug)dispensing)and)collecting:)Collect)and)record)any)excessive)study)
medication)and)empty)medicine)containers)and)if)needed:)hand)out)new)study)
medication)(Etoricoxib))for)study)arms)#1)and)#4.)Register)in)drug)accountability)
log.)
)
Visit$4I$(day$28)$
1.) Record)any)adverse)events,)including)serious)adverse)events)and)adverse)
events)of)special)interest)occuring)since)previous)evaluationi)record)any)
concomitant)medications)taken)associated)with)treatment)of)the)adverse)event.)
2.) Focused)physical)examination)by)medical)practitioner)if)indicated)based)on)
history)
3.) Vital)signs:)Blood)pressure,)pulse,)temperature.)Weight)
4.) Blood$collection/number$of$tubes:))
a.) Serum)chemistry/hematology.)1$EDTA$tube$(4$ml),$1$serum$tube$(5$ml).)
b.) Blood)hcg)for)all)females)of)childbearing)potential.)
c.) Biobank:)4$CPT$tubes.)

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  Page 56 of 59 
5.) Anti)TB)chemotherapy:)standard)combination)therapy.)Register)any)changes)in)
medication)in)CRF)
6.) Drug)dispensing)and)collecting:)Collect)and)record)any)excessive)study)
medication)and)empty)medicine)containers,)and)if)needed:)hand)out)new)study)
medication)(Etoricoxib))for)study)arms)#1)and)#4.)Register)in)drug)accountability)
log.)
)
Visit$5I$(day$56)$
1.) Record)any)adverse)events,)including)serious)adverse)events)and)adverse)events)of)
special)interest)occuring)since)previous)evaluationi)record)any)concomitant)
medications)taken)associated)with)treatment)of)the)adverse)event.)
2.) Focused)physical)examination)by)medical)practitioner)if)indicated)based)on)history)
3.) Weight)
4.) Vital)signs:)Blood)pressure,)pulse,)temperature)
5.) Sputum)samples))
6.) Blood$collection/number$of$tubes:))
a.) Serum)chemistry/hematology.)1$EDTA$tube$(4$ml),$1$serum$tube$(5$ml).)
b.) Blood)hcg)for)all)females)of)childbearing)potential.)
c.) Biobank:)4$CPT$tubes.)
7.) Anti)TB)chemotherapy:)standard)combination)therapy.)Register)any)changes)in)
medication)in)CRF)
8.) Sputum)samples))
9.) Appropriate)radiology)(chest)XIray/CT/MRI/UL/PET),)but)limited)to)chest)XIray)if)the)
disease)is)limited)to)pulmonary)TB.)
10.)Drug)dispensing)and)collecting:)Collect)and)record)any)excessive)study)medication)
and)empty)medicine)containers)and)if)needed:)hand)out)new)study)medication)
(Etoricoxib))for)study)arms)#1)and)#4.)Register)in)drug)accountability)log.)
)
Visit$6I$(day$84)$
1.) Record)any)adverse)events,)including)serious)adverse)events)and)adverse)
events)of)special)interest)occuring)since)previous)evaluationi)record)any)
concomitant)medications)taken)associated)with)treatment)of)the)adverse)event.)
2.) Focused)physical)examination)by)medical)practitioner)if)indicated)based)on)
history)
3.) Vital)signs:)Blood)pressure,)pulse,)temperature.)Weight.)
4.) Sputum)samples)
5.) Urine$collection:)Confirm)continued)eligibility)for)vaccination)including)negative)
hcg)(urine)pregnancy)test))for)all)females)of)childIbearing)potential)
6.$ Blood$collection/number$of$tubes:$
a.$ Serum)chemistry/hematology:)1$EDTA$tube$(4$ml),$1$serum$tube$(5$ml).$
b.$ Blood)hcg)for)all)females)of)childbearing)potential.$
c.$ Biobank:)1$Natrium$heparine$tube*(=WHOLE$BLOOD),$4$CPT$tubes,$1$
Pax$gene$tube.$$
7.) Anti)TB)chemotherapy:)standard)combination)therapy.)Register)any)changes)in)
medication)in)CRF)
8.) Vaccine&administration&study&arms&#2&and&#4:)Confirm)subject)
identificationnumber,)check)if)patient)is)elligible)to)receive)the)study)vaccine)
according)to)specific)criterias.)Check)subject)initials,)date)and)time)of)dose)
preparation.)Administer)study)vaccine)to)deltoid)area)by)intramuscular)injection.)
Record)date)and)time)of)vaccination)and)which)arm)was)vaccinated.)Monitor)
subject)for)acute)adverse)events)for)at)least)60)minutes)after)vaccination.))
9.) Examine)site)of)vaccination)60)+/I)10)minutes)postIimmunization.))

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  Page 57 of 59 
10.)Drug)dispensing)and)collecting:)Collect)and)record)any)excessive)study)
medication)and)empty)medicine)containers)and)if)needed:)hand)out)new)study)
medication)(Etoricoxib))for)study)arms)#1)and)#4.)Register)in)drug)accountability)
log.)
)
Visit$7I$(day$98)$
1.) Record)any)adverse)events,)including)serious)adverse)events)and)adverse)
events)of)special)interest)occuring)since)previous)evaluationi)record)any)
concomitant)medications)taken)associated)with)treatment)of)the)adverse)event.)
2.) Focused)physical)examination)by)medical)practitioner)if)indicated)based)on)
history)
3.) Vital)signs:)Blood)pressure,)pulse,)temperature.)Weight)
4.$ Blood$collection/number$of$tubes:$
a.$ Serum)chemistry/hematology:)1$EDTA$tube$(4$ml),$1$serum$tube$(5$ml).$
b.$ Blood)hcg)for)all)females)of)childbearing)potential.$
c.$ Biobank:)1$Natrium$heparine$tube*(=WHOLE$BLOOD),$4$CPT$tubes,$1$
Pax$gene$tube.$
5.$ Anti)TB)chemotherapy:)standard)combination)therapy.)Register)any)changes)in)
medication)in)CRF$
6.) Drug)dispensing)and)collecting:)Collect)and)record)any)excessive)study)
medication)and)empty)medicine)containers)and)if)needed:)hand)out)new)study)
medication)(Etoricoxib))for)studyarms)#1)and)#4.)Register)in)drug)accountability)
log.)
7.) Examine)site)of)vaccination,)study)arms)#2)and)#4)
$
Visit$8I$(day$140)$
1.) Record)any)adverse)events,)including)serious)adverse)events)and)adverse)
events)of)special)interest)occuring)since)previous)evaluationi)record)any)
concomitant)medications)taken)associated)with)treatment)of)the)adverse)event.)
2.) Focused)physical)examination)by)medical)practitioner)if)indicated)based)on)
history)
3.) Vital)signs:)Blood)pressure,)pulse,)temperature.)Weight)
4.) Urine$collection:)Confirm)continued)eligibility)for)vaccination)including)negative)
hcg)(urine)pregnancy)test))for)all)females)of)childIbearing)potential)
5.$ Blood$collection/number$of$tubes:$
a.$ Serum)chemistry/hematology:)1$EDTA$tube$(4$ml),$1$serum$tube$(5$ml).$
b.$ Blood)hcg)for)all)females)of)childbearing)potential.$
c.$ Biobank:)1$Natrium$heparine$tube*(=WHOLE$BLOOD),$4$CPT$tubes,$1$
Pax$gene$tube.$
6.) Anti)TB)chemotherapy:)standard)combination)therapy.)Register)any)changes)in)
medication)in)CRF)
7.) Sputum)samples))
8.) Drug)collecting/)END)OF)TREATMENT:)Collect)any)excessive)study)medication)
and)empty)medicine)containers)(Etoricoxib))for)study)arms)#1)and)#4.)Register)in)
drug)accountability)log)
9.) Vaccine&administration&study&arms&#2&and&#4:)Confirm)subject)
identificationnumber,)check)if)patient)is)elligible)to)recieve)the)studyvaccine)
according)to)specific)criterias.)Check)subject)initials,)date)and)time)of)dose)
preparation.)Administer)study)vaccine)to)deltoid)area)by)intramuscular)injection.)
Record)date)and)time)of)vaccination)and)which)arm)was)vaccinated.)Monitor)
subject)for)acute)adverse)events)for)at)least)60)minutes)after)vaccination.)
10.)Examine)site)of)vaccination)60)+/I)10)minutes)postIimmunization.)

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  Page 58 of 59 
$
$
Visit$9I$(day$154)$
1.) Record)any)adverse)events,)including)serious)adverse)events)and)adverse)
events)of)special)interest)occuring)since)previous)evaluationi)record)any)
concomitant)medications)taken)associated)with)treatment)of)the)adverse)event.)
2.) Focused)physical)examination)by)medical)practitioner)if)indicated)based)on)
history)
3.) Vital)signs:)Blood)pressure,)pulse,)temperature.)Weight)
4.$ Blood$collection/number$of$tubes:$
a.$ Serum)chemistry/hematology:)1$EDTA$tube$(4$ml),$1$serum$tube$(5$ml).$
b.$ Blood)hcg)for)all)females)of)childbearing)potential.$
c.$ Biobank:)1$Natrium$heparine$tube*(=WHOLE$BLOOD),$4$CPT$tubes,$1$
Pax$gene$tube.$
5.$ AntiITB)chemotherapy:)standard)combination)therapy.)Register)any)changes)in)
medication)in)CRF$
6.) Examine)site)of)vaccination,)study)arms)#2)and)#4.)
)
Visit$10I$(day$182)$
1.) Record)any)adverse)events,)including)serious)adverse)events)and)adverse)
events)of)special)interest)occuring)since)previous)evaluationi)record)any)
concomitant)medications)taken)associated)with)treatment)of)the)adverse)event.)
2.) Focused)physical)examination)by)medical)practitioner)if)indicated)based)on)
history)
3.) Vital)signs:)Blood)pressure,)pulse,)temperature.)Weight)
4.) Sputum)samples))
5.$ Blood$collection/number$of$tubes:)$
a.$ Serum)chemistry/hematology.)1$EDTA$tube$(4$ml),$1$serum$tube$(5$ml).$$
b.$ 3$QuantiferonITB$tubes$(one$set)$
c.$ Blood)hcg)for)all)females)of)childbearing)potential.$
d.$ Biobank)4$CPT$tubes.$1$Pax$gene$tube.$
6.) Anti)TB)chemotherapy:)standard)combination)therapy.)Register)any)changes)in)
medication)in)CRF.)
7.) Appropriate)radiology)(chest)XIray/CT/MRI/UL/PET),)but)limited)to)chest)XIray)if)
the)disease)is)limited)to)pulmonary)TB.)
$
Visit$11I$(day$210)$
1.) Record)any)adverse)events,)including)serious)adverse)events)and)adverse)
events)of)special)interest)occuring)since)previous)evaluationi)record)any)
concomitant)medications)taken)associated)with)treatment)of)the)adverse)event.)
2.) Focused)physical)examination)by)medical)practitioner)if)indicated)based)on)
history)
3.) Vital)signs:)Blood)pressure,)pulse,)temperature.)Weight.)
4.) Blood$collection/number$of$tubes:))
a.$ Serum)chemistry/hematology.)1$EDTA$tube$(4$ml),$1$serum$tube$(5$ml).$
b.$ Blood)hcg)for)all)females)of)childbearing)potential.$
c.$ Biobank)4$CPT$tubes$
)

TBCOX2 V6.0 12.10.2016 / EudraCTno-2014-004986-26  Page 59 of 59 
)
)
Visit$12I$End$of$study$(day$238)$
1.) Record)any)adverse)events,)including)serious)adverse)events)and)adverse)
events)of)special)interest)occuring)since)previous)evaluationi)record)any)
concomitant)medications)taken)associated)with)treatment)of)the)adverse)event.)
2.) Focused)physical)examination)by)medical)practitioner)if)indicated)based)on)
history.)
3.) Vital)signs:)Blood)pressure,)pulse,)temperature.)Weight.)
4.) Sputum)samples))
5.$ Blood$collection/number$of$tubes:$
a.$ Serum)chemistry/hematology:)1$EDTA$tube$(4$ml),$1$serum$tube$(5$ml).$
b.$ Blood)hcg)for)all)females)of)childbearing)potential.$
c.$ Biobank:)1$Natrium$heparine$tube*(=WHOLE$BLOOD),$4$CPT$tubes,$1$
Pax$gene$tube.$
6.) Fill)out)”End)of)study)form”)in)eCRF.)
$
*$Na)heparin)tube)(green):)Write)time)of)sampling)on)the)tube.)To)be)processed)in)the)
LAB)within)75)min)after)collected)from)patient.)
)
)
)
)