Phase IIa Prospective Study to Evaluate the Safety and Measure Efficacy of Anti-chlamydophila Antibiotic Combination (ACAC) Therapy Comprising 100mg Doxycycline, 500mg Azithromycin and 300mg Rifabutin in the Treatment of Patients With Coronary Heart Disease (CHD)
Phase: PHASE2
Conditions: Coronary Heart Disease, Chlamydophila Pneumoniae Infections
Sponsor: Cadrock Pty. Ltd.

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STUDY NO. NC10/C01 
PROTOCOL NO.: Version 8.2 dated 22 July 2018 
 
“Phase IIa, Prospective  
Study to evaluate the safety and measure efficacy of anti-
Chlamydophila antibiotic combination (ACAC) therapy comprising 
100mg doxycycline, 500mg azithromycin and 300mg rifabutin in the 
treatment of patients with Coronary Heart Disease (CHD)” 
 
Chief / Principal Investigators 
Prof John French 
BMed Sc MBChB PhD FRACP FESC FACC FCSANZ 
Liverpool Hospital,  
 
Elizabeth St, Liverpool NSW 2170, Sydney, Australia. 
 
Dr Henry Newman        
MBBS, FRACP, DDU, FCSANZ, FACC 
Liverpool Hospital 
Liverpool, Sydney 
NSW 2170 Australia 
 
 
Prof Thomas Borody 
 
BMedSc MBBS, MD, PhD, FRACP, FACG, FACP, FACG 
 
Centre for Digestive Diseases 
 
Level 1,229 Great North Road, Five Dock, NSW Australia 2046 
 
Associate / Co-Investigators  
 
Assoc. Prof Rohan Rajaratnam  
MBBS(Syd),FRACP,FCSANZ, FACC 
Liverpool Hospital 
Liverpool, Sydney 
NSW 2170 Australia 
 
 
Dr Sidney Lo 
MBBS, FRACP, FCSANZ 
Liverpool Hospital  
Liverpool Sydney  
NSW 2170 
 
 
 
Dr Oliver Gibbs 
BSc, MBBS (Hons), MPhil, FRACP 
Liverpool Hospital 
Liverpool, Sydney 
NSW 2170 Australia 
 
 
Dr Amir Faour 
BSc, MBBS, FRACP 
Liverpool Hospital 
Liverpool, Sydney 
NSW 2170 Australia 
 
 
Assoc. Prof Craig Juergens 
MBBS, FRACP, FACC 
Liverpool Hospital 
Liverpool, Sydney 
NSW 2170 Australia 
 
 
Assoc. Prof Gillian Heller 
BSc (Cape Town),  
PhD (Cape Town), MSc (S. Af.) 
 
E4A 533, Department of Statistics  
Macquarie University 2109 
NSW Australia 
 
 
Dr Aiden O’Loughlin 
BSc(Med)(Hons), MBBS, MBiostat, PhD, 
FRACP 
Liverpool Hospital 
Liverpool, Sydney 
NSW 2170 Australia 
 
 
Dr David Taylor 
MBBS, FRACP, FCSANZ 
Liverpool Hospital 
Liverpool, Sydney 
NSW 2170 Australia 
 
 
Dr Bernard Hudson 
MBBS, DTPH, FACTM, 
FAFPHM, FRCPA, FRACP 
Royal North Shore Hospital 
St Leonards 2065  
 NSW Australia 
 
 
A/Prof Kalaeb Asrress 
MA, BM BCh, MRCP, PhD 
Liverpool Hospital 
Liverpool, Sydney 
NSW 2170 Australia 
 
 
 
 
 
Sponsor 
 
NEWCURE Pty Ltd  
 
Unit 6, 3 Central Avenue 
 
 
Thornleigh, NSW, 2120 
 
 
P: +61 2 9847 4900 
F: +61 2 9980 2499 

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TABLE OF CONTENTS 
APPENDICES .............................................................................................................................................. 4 
PROTOCOL SYNOPSIS .............................................................................................................................. 5 
STUDY SCHEDULE ..................................................................................................................................... 6 
PATIENT FLOW DIAGRAM ........................................................................... Error! Bookmark not defined. 
ABBREVIATIONS AND DEFINITIONS ....................................................................................................... 8 
1. 
INTRODUCTION AND STUDY RATIONALE ................................................................................ 10 
1.1 Introduction ............................................................................................................................................. 10 
1.2 RATIONALE ......................................................................................................................................... 13 
2.  
STUDY OBJECTIVES .................................................................................................................... 14 
2.1 
Primary Objectives .............................................................................................................................. 14 
2.2 
Secondary Objectives.......................................................................................................................... 14 
2.3 
Exploratory Objectives......................................................................................................................... 14 
3.  
STUDY DESIGN ............................................................................................................................. 14 
4. 
SELECTION OF STUDY POPULATION ....................................................................................... 14 
4.1 
Inclusion Criteria .................................................................................................................................. 14 
4.2  
Exclusion Criteria ............................................................................................................................ 15 
4.3 
Recruitment ......................................................................................................................................... 16 
4.4   
Number of Subjects ......................................................................................................................... 16 
4.5   
Randomisation and Randomisation Schedule ................................................................................ 16 
4.6   
Blinding Procedures ........................................................................................................................ 16 
5. 
STUDY PRODUCT ......................................................................................................................... 17 
5.1  
Dosage Schedule ............................................................................................................................ 17 
5.2  
Supplies and Accountability ............................................................................................................ 17 
5.3  
Packaging and Labeling .................................................................................................................. 18 
5.4 
Compliance .......................................................................................................................................... 18 
6.   
PRIOR AND CONCOMITANT ILLNESSES AND TREATMENTS ................................................ 19 
6.1 
Prior and Concomitant Illnesses .......................................................................................................... 19 
6.2 
Prior and Concomitant Treatments ..................................................................................................... 19 
6.3 
Prohibited medication .......................................................................................................................... 19 
7. 
INVESTIGATIONAL PROCEDURES AND SCHEDULE .............................................................. 19 
7.1 
Description of Study Schedule ............................................................................................................ 19 
7.1.1  
Visit 1 Screening and Baseline .............................................................................................. 19 
7.1.2 
Visit 2 (Day 30 ± 7)................................................................................................................. 20 
7.1.3 
Visit 3 – End of Treatment (Day 90 ± 21) .............................................................................. 20 
7.1.4 
Visit 4 Final Follow up ............................................................................................................ 21 
7.1.5 
Phone Contact (Day 150) ...................................................................................................... 21 
7.2 
Methods of Data Collection ................................................................................................................. 21 
7.2.1 
Efficacy data ........................................................................................................................... 21 
7.2.1.1 Laboratory Studies ............................................................................................................ 22 
7.2.1.2 Symptomatology ................................................................................................................ 22 
7.2.1.3 Other .................................................................................................................................. 22 
7.2.1.4 Electrocardiogram (ECG) .................................................................................................. 22 

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7.2.1.5 Fractional Flow Reserve (FFR) Study ............................................................................... 22 
7.2.1.6 Intra-coronary Imaging (IVUS and OCT) ........................................................................... 23 
7.2.2 
Safety data ............................................................................................................................. 23 
7.2.2.1 Laboratory Studies ............................................................................................................ 23 
7.2.2.2 Adverse Events ................................................................................................................. 23 
8.  
ADVERSE EVENTS ....................................................................................................................... 23 
8.1  
Definitions........................................................................................................................................ 23 
8.1.1 Adverse event ............................................................................................................................ 23 
8.2.2 Serious adverse event ............................................................................................................... 24 
8.2 
Period of observation........................................................................................................................... 25 
8.3  
Documentation and Reporting of Adverse Events by the Investigator ........................................... 25 
8.4  
Immediate Reporting by Investigator to Sponsor ............................................................................ 26 
8.5 
 Data and Safety Monitoring Board ..................................................................................................... 26 
9. WITHDRAWALS AND DEFAULTERS .................................................................................................. 27 
10.  
EMERGENCY PROCEDURES ...................................................................................................... 28 
10.1  
Emergency Sponsor Contact .......................................................................................................... 28 
10.2  
Emergency Treatment ..................................................................................................................... 28 
11.  
STATISTICAL PROCEDURES ...................................................................................................... 28 
11.1 
Analysis Variables ........................................................................................................................... 28 
11.2 
Interim Analysis ............................................................................................................................... 28 
11.3 
Sample Size Justification ................................................................................................................ 28 
12.  
ETHICAL AND LEGAL ASPECTS ................................................................................................ 28 
12.1 
Good Clinical Practice ..................................................................................................................... 29 
12.2 
Delegation of Investigator Responsibilities ..................................................................................... 29 
12.3 
Subject Information and Informed Consent .................................................................................... 29 
12.4 
Confidentiality .................................................................................................................................. 29 
12.5 
Protocol Amendments ..................................................................................................................... 29 
12.6 
Approval of the Study Protocol and Amendments .......................................................................... 30 
12.7 
Ongoing Information for HREC ....................................................................................................... 30 
12.8 
Premature Closure of the Study ...................................................................................................... 30 
12.9 
Record Retention ............................................................................................................................ 30 
12.10 
 Liability and Insurance ................................................................................................................... 31 
12.11 
 Ongoing Access to Study Drug ...................................................................................................... 31 
13.   
ADMINISTRATION ........................................................................................................................ 31 
13.1 
Case Report Forms (CRFs) ............................................................................................................ 31 
13.2 
Monitoring........................................................................................................................................ 32 
13.2.1 Study monitoring ...................................................................................................................... 32 
13.3 
Source Data Verification and On-site Audits................................................................................... 32 
13.4 
Archiving.......................................................................................................................................... 32 
13.5  
Use of Study Findings ..................................................................................................................... 32 
13.6 
Report and Publications .................................................................................................................. 32 
14. 
STUDY DURATION AND DATES ................................................................................................. 33 

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15. 
DECLARATION OF SPONSOR AND INVESTIGATOR ............................................................... 33 
15.1 
Declaration of Sponsor .................................................................................................................... 33 
15.2 
Declaration of Investigator .............................................................................................................. 34 
16. 
REFERENCES ............................................................................................................................... 35 
APPENDIX 1: 
  STUDY LABORATORY TESTS ................................................................................ 36 
APPENDIX 2 – LIST OF RESTRICTED MEDICATIONS .......................................................................... 37 
APPENDIX 3:  SERIOUS ADVERSE EVENT REPORT FORM ............................................................... 38 
APPENDIX 4: DEFINITIONS OF CAUSALITY AND SEVERITY OF ADVERSE EVENTS ..................... 41 
APPENDIX 5 – DECLARATION OF HELSINKI 2008 ............................................................................... 43 
 
 
 
APPENDICES 
 
 
 
 
APPENDIX 1 
STUDY LABORATORY TESTS 
 
APPENDIX 2 
LIST OF PROHIBITED MEDICATIONS 
 
APPENDIX 3 
SERIOUS ADVERSE EVENT FORM  
 
APPENDIX 4 
DEFINITIONS OF CAUSALITY AND SEVERITY OF ADVERSE EVENTS 
 
APPENDIX 5 
DECLARATION OF HELSINKI 2008 
 
 
 
 
 
 

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PROTOCOL SYNOPSIS 
 
Title 
A Phase IIa, prospective study to evaluate the safety and efficacy of anti-Chlamydophila 
antibiotic combination (ACAC) therapy comprising 100mg doxycycline, 500mg azithromycin 
and 300mg rifabutin in the treatment of patients with Coronary Heart Disease (CHD) 
Study Sites 
Liverpool Hospital/ Sydney Southwest Private Hospital  
Objectives 
Primary objectives:  
1. To evaluate the effect of an antibiotic combination therapy on fractional flow reserve 
(FFR) (coronary arterial flow) in participants with Coronary Heart Disease  
Secondary objectives:  
1. To evaluate the effect of an antibiotic combination therapy on plaque morphology 
and volume as assessed with intra-coronary imaging (IVUS and/or OCT) in culprit 
and non-culprit arteries in a substudy 
2. To evaluate angiographic stenoses changes using Quantitative Coronary 
Angiography (QCA) during ACAC therapy. 
3. To evaluate morbidity and clinical improvement during the ACAC therapy. 
4. To record major adverse clinical events (MACE). Including death, recurrent 
myocardial infarction, stroke and major bleeding. 
Exploratory objectives: 
1. To evaluate the use of loop-mediated isothermal amplification (LAMP) for the 
detection of Chlamydophila pneumoniae in blood samples, compared with standard 
titers and cell culture  
2. To evaluate changes in indices of pressure and flow (as measured with coronary 
pressure/flow guidewire) in culprit and non-culprit coronary arteries 
Design 
Phase IIa, multicenter, randomised, placebo-controlled trial 
Population 
Subjects with symptomatic coronary heart disease on medical therapy who have a culprit 
artery lesion suitable for percutaneous coronary intervention (PCI) and another stenosis 
potentially suitable for staged PCI, with FFR ≤0.80. Or subjects who have a single non-
critical culprit artery of intermediate severity with a clinically indicated FFR ≤0.80 which is 
suitable for staged PCI. 
Sample Size 
60 subjects  
Treatment  
All subjects will be assigned to either active treatment or matching placebo. They will receive 
ACAC in conjunction with standard medical therapy for 3 months. 
Efficacy Data 
FBC, ESR, Electrolytes/Urea/Creatine, Liver Function tests, Lipid Studies ,CK-MB, High 
Sensitivity Troponin T, Chlamydophila pneumoniae titer, Chlamydophila pneumoniae 
macrophage culture, Chlamydophila pneumoniae (c. pneumoniae) DNA detection 
(exploratory), hs CRP, symptomatology, Functional Status – New York Heart Association 
Class, Quantitative Coronary Angiography (QCA); FFR and Coronary pressure/flow indices, 
plaque volume, plaque composition, fibrous cap thickness, macrophage content. 
Safety data 
Adverse event reports, Blood tests (standard haematology, serum chemistry and 
pregnancy) and Physical Examination, compliance and major adverse cardiac events 
MACE 
Statistical 
procedures 
Results will be presented as mean +/-SD for continuous normally distributed variables, as 
median (interquartile range) for continuously non-normally distributed data and as 
percentages for categorical data. Significant changes in clinical symptom improvement, 
arterial flow and biochemical variables over time will be assessed using ANOVA for 
repeated measurements. A P value <0.05 will be considered statistically significant. 
 
Study duration 
& dates 
 
Total of 24-month recruitment period. From Q1 - 2018 to Q3 - 2019. Study duration is 6 
months from the initial angiographic procedure 
 
 

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PATIENT FLOW DIAGRAM 
 
Patient	with	CHD	undergoing	Angiography	+/- PCI	
has	a	Non-critical	Lesion	which	would	otherwise	
be	Suitable	for	Staged	PCI
FFR	of	Lesion	≤0.8
Consent	and	
Randomisation
Placebo
Anti-Chlamydophilia
Antibiotic	Combination	
(ACAC)	Therapy
(Doxycycline	50mg	BD,
Azithromycin	250mg	BD,
Rifabutin 150mg	BD)
Repeat	Angiography	and	FFR	
+/- PCI	of	Lesion
Usual	Care	+	Follow	up
n=60
3/12

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STUDY SCHEDULE  
Assessments and Recordings 
V1 
V2 
Phone 
Call 
V3 
Phone 
Call 
Phone 
Call 
V4 
Screening 
and 
Baseline 
Day 30 
(+7 
days) 
Day 
60 
Day 
90 
(+21 
days) 
Day 
120 
Day 
150 
 
Day 
180 
(+ 21 
days) 
Subject Information 
X 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Confirmation of eligibility 
X 
 
 
 
 
 
 
Laboratory tests 
 
FBC 
 
X 
 
X 
 
 
X 
 
 
 
 
ESR  
X 
X 
 
X 
 
 
 
 
EUC 
X 
X 
 
X 
 
 
 
 
Liver Function Tests  
X 
X 
 
X 
 
 
 
 
Lipid Studies 
X 
X 
 
X 
 
 
 
 
CK-MB 
X 
X 
 
X 
 
 
 
 
 High Sensitivity Troponin T 
X 
X 
 
X 
 
 
 
 
High Sensitivity CRP 
X 
X 
 
X 
 
 
 
 
Pregnancy testing  
X 
 
 
 
 
 
 
 
C. pneumoniae macrophage 
cultures  
X 
 
 
X 
 
 
 
 
C. pneumoniae titers 
X 
 
 
X 
 
 
 
              C. pneumoniae DNA 
detection 
X 
 
 
X 
 
 
 
Physical Examination 
X 
X 
 
X 
 
 
 
Vital Signs 
X 
X 
 
X 
 
 
 
Quantitative Coronary Angiogram 
X 
 
 
X 
 
 
 
ECG  
X 
 
 
X 
 
 
 
New York Heart Association 
Functional Class 
X 
X 
 
X 
 
 
 
Fractional Flow Reserve, 
Pressure/flow wire measurements 
and intracoronary imaging (IVUS + 
OCT)  
X 
 
 
X 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Concomitant illnesses 
X 
X 
X 
X 
X 
X 
X 
Medication dispense/collection 
X 
 
 
X 
 
 
 
Medication review/Accountability 
 
X 
 
X 
 
 
 
Participant Symptomatology Diary 
X 
X 
 
X 
 
 
 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
 
 

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ABBREVIATIONS AND DEFINITIONS 
 
 
ACAC  
Anti-Chlamydophila Antibiotic Combination 
ACS 
 
Acute Coronary Syndrome 
AE 
 
Adverse Event 
CANTOS 
Canakinumab Antiinflammatory Thrombosis Outcome Study 
CDD 
 
Centre for Digestive Diseases 
CAD 
 
Coronary Artery Disease 
CHD 
 
Coronary Heart Disease 
CK-MB 
Creatine Kinase MB 
CRF 
 
Case Report Form 
CRP   
C-Reactive Protein 
CTN 
 
Clinical Trials Notification (Scheme) 
ECG 
 
Electrocardiogram 
EOT 
 
End of Trial 
EUC 
 
Electrolytes, Urea, Creatinine 
FBC 
 
Full Blood Count 
FFR 
 
Fractional Flow Reserve 
GCRP  
Good Clinical Research Practice 
HREC  
Human Research Ethics Committee 
HMR  
Hyperaemic Microvascular Resistance 
HSR 
 
Hyperaemic Stenosis Resistance 
ICH 
 
International Conference for Harmonisation 
IMR 
 
Index of Microvascular Resistance 
IVUS  
Intra-Vascular Ultrasound 
JUPITER 
Justification for the Use of statins in Primary prevention: an Intervention 
Trial Evaluating Rosuvastatin 
LAMP  
Loop-mediated isothermal amplification (of DNA) 
LDL 
 
Low density lipoprotein 

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MACE  
Major Adverse Cardiovascular Events 
NHMRC 
National Health and Medical Research Council 
OCT 
 
Optical Coherence Tomography 
PCI 
 
Percutaneous Coronary Intervention 
SAE 
 
Serious Adverse Event 
SD 
 
Standard Deviation 
TGA 
 
Therapeutic Goods Administration 
TWAR  
Taiwan Acute Respiratory Agent 
QCA   
Quantitative Coronary Angiography 
V1 
 
Visit 1 
V2 
 
Visit 2 
V3 
 
Visit 3 
V4 
 
Visit 4 
 
 
For Laboratory tests please see Appendix 1. 
 

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1. 
INTRODUCTION AND STUDY RATIONALE 
 
1.1 Introduction 
 
Coronary artery disease (CAD) describes the pathologic process of accumulation of atheromatous 
plaques within the walls of arteries responsible for supply of oxygen and nutrients to the myocardium. 
These plaques usually consist of cholesterol deposits, calcium minerals and various amounts of 
connective tissue and inflammatory cells, and this atheroma eventually reduces the rate of blood flow 
to the heart1. Atheromatous plaques originate from the chronic inflammatory responses to many 
cytokine stimuli, including oxidized Low-Density Lipoprotein (LDL) particles coming into contact with 
arterial walls.  The consequent damage and accumulation of cholesterol results in atherosclerosis 
and stenosis of arteries2.  
 
CHD events result in approximately 6.9 million deaths each year worldwide. In Australia, CHD 
remains the leading cause of death and is a major contributor to permanent disability. CHD accounted 
for approximately 48,500 deaths in Australia in 2008 (34% of all mortalities)3. Whilst CHD is usually 
diagnosed in its advanced stages, a majority of subjects with CAD remain asymptomatic and 
demonstrate no visible evidence of the disease before a major cardiac event occurs. The prevalence 
of CHD increases with age and is gender and lifestyle-related. Available data has shown a higher 
incidence of CHD amongst those aged over 40 years, and men have been shown to be twice as likely 
to present with CHD compared to women. Tobacco smoking, hypertension, hypercholesterolaemia, 
family history, diabetes, lack of physical exercise and significant weight gain are associated with an 
increased risk of developing CHD4.  
 
The presence of cholesterol in plaque has directed research efforts towards the development of 
various groups of drugs to treat hypercholesterolaemia, together with diets and lifestyle changes. 
Though increased C-reactive protein (CRP) levels have been associated with increased rates of 
events, there is debate as to whether the JUPITER [Justification for the Use of Statins in Primary 
Prevention: An Intervention Trial Evaluating Rosuvastatin] trial supports the concept of therapeutic 
intervention to “reduce inflammation”5. The landmark Canakinumab Antiinflammatory Thrombosis 
Outcome Study (CANTOS) trial which compared Canakinumab, a monoclonal antibody to the pro-
inflammatory cytokine interleukin-1, with placebo, showed that anti-inflammatory therapy lead to a 
significant reduction in cardiovascular events compared to placebo6. Certainly there is an established 
and growing body of evidence suggesting that atherosclerosis is a chronic inflammatory disease. This 
has lead to the exploration of potential instigators and propagators of inflammation being considered, 
including the concept of a chronic infection in the arterial wall leading to chronic inflammation. Though 
antigens of several candidate infective agents have been identified antigenically, only Chlamydia 
pneumoniae TWAR has been identified in viable form. Furthermore, C. pneumoniae has been shown 
to be a mediator of foam cell formation laden with lipopolysaccharide, as an infective peri-
phenomenon of the Chlamydia infection7. Chlamydia terminology has recently been refined and 
Chlamydia pneumoniae has been moved to Chlamydophila pneumoniae genus. For the present both 
terminologies are being used interchangeably.   
 
 
Chlamydophila pneumoniae 
 
Chlamydophila pneumoniae is an obligate intracellular pathogen which requires another cell in order 
to complete its replication. C. pneumoniae exists as a non-biologically active ‘elementary body’ 
outside a host, only transforming into a ‘reticulate body’ in endosomes upon phagocytosis and utilises 
the host’s replication mechanisms for proliferation. The consequent replicate reticulate bodies are 
converted back into elementary bodies and released for further infection into new host cells8. 
 
The presence of C. pneumoniae in atheromatous plaque specimens and in vitro animal models have 
implicated C. pneumoniae as a potential infectious agent in the pathogenesis and progression of CAD 
particularly as there is no commensal form of C.pneumoniae. C. pneumoniae is a common cause of 
pneumonia and respiratory infection worldwide and has been shown to infect and propagate in human 

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smooth muscle and endothelial cells of coronary arteries which can be cultured from circulating 
macrophages. Antibodies to C. pneumoniae have been detected in elevated levels in subjects with 
atherosclerosis though this is non-specific. Some suggest that coronary arterial infection stems from 
the migration and proliferation of infected macrophages into the intimal layer of the arterial wall after 
an initial functional alteration or injury to the endothelium9.  
 
While numerous studies have demonstrated the presence of C. pneumoniae in atherosclerotic 
arteries and endarterectomy specimens, a lack of standardisation of current diagnostic methods may 
be responsible for inconsistent detection of C. pneumoniae. Indeed detection methods have been 
largely concentrated on serological studies due to the complexity and difficulty in obtaining tissue 
cultures. However, accumulating evidence indicates that detection through serological investigations 
has not been as specific as previously assumed10. Although cell culture studies remain the gold 
standard in C. pneumoniae detection, isolation and proliferation of C. pneumoniae in tissue samples 
remain a difficult problem resulting in inconsistent results11.  
 
Current Treatment  
 
In subjects with stable coronary heart disease (CHD) and inducible ischemia, percutaneous coronary 
interventions (PCI) can improve symptoms. As coronary angiography is often inexact in accurately 
determining the functional significance of non-critical coronary stenoses, fractional flow reserve (FFR) 
can assess their physiological significance12. For subjects with acute coronary syndromes and 
multivessel disease undergoing an early invasive strategy, performing PCI in the culprit vessel and 
‘staging’ possible treatment allows measurement of non culprit FFR at initial angiography. While non-
culprit FFR in Acute Coronary Syndrome (ACS) subjects may worsen acutely due to endothelial 
dysfunction, randomisation should minimise confounding. Return for planned staged PCI as guided 
by angiography has been standard practice in such subjects, and increasingly, revascularisation is 
FFR guided. We plan to perform another FFR study to evaluate flow changes over a three month 
period.  
 
The coronary circulation is comprised of two major components: the major epicardial coronary arteries 
which have a capacitance function; and the microvascular circulation comprised of pre-arterioles and 
arterioles which provide a metabolic interface with cardiac myocytes.13 Both components of the 
circulation have been implicated in coronary ischaemia By measuring pressure and flow in the 
epicardial coronary artery, indices to assess the microcirculation can be calculated such as CFR, 
IMR, HSR, HMR at the same time as calculating the FFR value. This provides a comprehensive 
physiological assessment of the entire coronary circulation14. We plan to record pressure and flow 
indicies at the time of measurement of FFR in the culprit and non-culprit arteries. 
 
Intra-coronary imaging such as Intravascular Ultrasound (IVUS) and Optical Coherence Tomography 
(OCT) allow direct visualisation and characterisation of coronary plaque in vivo.15 Due to the unique 
characteristics of the energy source utilised for image acquisition, the resolution and penetration 
capabilities of IVUS (ultrasound) and OCT (infra-red light) differ. The combination of the two 
modalities allow for comprehensive assessment of atherosclerotic plaque including: atheroma 
volume, cap thickness, arterial remodelling, calcification, lipid pool/necrotic core, macrophage 
accumulation and neovascularisation.15 Intracoronary imaging has been shown to be safe in routine 
practice and is able to predict clinical events according to lesion characteristics and improve outcomes 
following PCI however its routine use is limited by cost and reimbursement.15,16 We plan on assessing 
plaque with OCT and IVUS at the time of initial and staged PCI in the culprit and non-culprit coronary 
arteries in a sub-study.  
 
Other current treatment methodologies have been directed at reduction of cholesterol accumulation 
in arteries and hence reduction of the associated inflammation. As such, lipid-modifying therapies 
have reduced mortality and clinical events17.   
 
Antibiotics and coronary heart disease 
 
Previous trial designs examining the effects of antibiotics in subjects with CHD have been focused on 
treatment studies with serological and clinical symptoms as primary endpoints. However previous 

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trials have not yielded reproducible changes in clinical outcomes, likely due to small subject 
populations, inadequate dosing, and particularly the use of a single antibiotic rather than a multiple 
treatment drug regimen, coupled with a short duration of treatment18-22.  
 
Results of human trials and meta-analyses performed demonstrate that the use of single antibiotics 
has little or no beneficial effect in reducing subsequent acute cardiac events19-22. In CLARICOR trial 
of 13,702 subjects in Denmark, there was evidence of significantly higher mortality rates in subjects 
who received two weeks of treatment with clarithromycin (Odds ratio 1.45, 95% confidence intervals 
1.09 to 1.92; P=0.01)19. On the contrary, results from the only multiple antibiotic STAMINA trial 
reported the treatment of 325 subjects directed against C. pneumoniae and Helicobacter pylori 
showed a significant 36% reduction in the incidence of coronary events at 12 weeks and 12 months. 
The effect was independent of the presence of antibody to C. pneumoniae or to H. pylori22. However 
the use of combined multiple antibiotics in subjects with CHD has not been investigated. Thus, one 
cannot entirely exclude the importance of antibiotics in the role of CHD treatment. 

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1.2 RATIONALE 
 
Chlamydophila pneumoniae has been evaluated as one potential underlying cause of CHD. The 
strongest evidence supporting this hypothesis comes from multiple investigators who enrolled over 
19,217 subjects in ‘Anti-Chlamydia trials’17. However, these studies can be questioned on the basis 
of the type and duration of therapy. The recent change of the genus no longer permits treatment of 
C. pneumoniae as if it were Chlamydia trachomatis - which can generally be cured with a short course 
of macrolides [azithromycin, roxithromycin or clarithromycin] used in the majority of subjects analysed 
in this meta-analysis23. C. pneumoniae is largely intra-cellular and its preferred locations (arterial 
muscle cells and macrophages) may contribute to its persistence in the body17. C. pneumoniae can 
be refractory to antibiotic treatment24 in spite of in vitro susceptibility to various macrolides and 
ansamycins likely due to the use of sub-optimal dosages, which has been shown to encourage or 
induce persistence of C. pneumoniae in vitro25. Rupp et al (2009) reported C. pneumoniae to infiltrated 
poptotic neutrophils that are subsequently taken up by monocyte-derived macrophages, thereby 
preventing clearance by the body’s immune system and preventing susceptibility in the presence of 
antibiotics26.  
  
The previously reported trials have used short-term or recurrent treatment23. The rationale for 
combined antibiotic long-term therapy stems from experience with other intracellular bacteria e.g. 
Mycobacterium tuberculosis, characterized by its dormant forms and affinity for developing 
resistance. The presence of infection in arterial cells with associated fibrosis and calcification for a 
considerable time may warrant prolonged treatment to enable antibiotic penetration into infected 
spaces. The occurrence of dormant forms also requires long-term treatment to anticipate the 
‘awakening’ of dormant bacterial cells so that antibiotics can be effective during their division phase. 
The use of a combination therapy rather than a single agent to address dormant forms is concurrent 
with experience with other chronic and multiple resistant strain infections such as H. pylori, M. 
tuberculosis, and Mycobacterium avium paratuberculosis which are treated with combination 
antibiotics to minimise the development of resistant strains. Indeed, in the C. pneumoniae/CHD trials, 
the only trial that showed marked improvement in primary end points was the trial that used multiple 
antibiotics albeit for 7 days22. Hence, it would be reasonable to trial an appropriate multiple-antibiotic 
regimen in CHD  
  
In this trial, antibiotics against C. pneumoniae known to be active within cells will be used. The three 
drugs will be administered simultaneously to minimise resistance development, and these will be used 
for a minimum of 3 months. At this stage ideal duration of treatment is not known.   
  
In preliminary clinical experience of 5 subjects, with 3-6 month treatment using clarithromycin, 
rifabutin and doxycycline, subjects noted reduced shortness of breath, angina episodes, and marked 
improvement in claudication. The dosage schedule for this trial will be initiated as half doses in the 
first week followed by full dosages from week two onwards. This is designed as to minimize the onset 
of potential adverse effects in subjects. The dose-escalating schedule allows introduction of the 
medications into the body and maximizing bioavailability yet minimizing the potential adverse events. 
  
The experience with long term use of a combination of three antibiotics in Mycobacterium avium 
paratuberculosis and Crohn’s disease has been largely in younger subjects who did not receive anti-
platelet agents as concomitant therapies, and thus, macrolide anti-platelet agent interactions have 
not been observed.  In the proposed group of subjects with CHD disease, clarithromycin has a known 
interaction with anti-platelet agents and therefore in this group, clarithromycin will be substituted by 
azithromycin, a similar macrolide that demonstrates the same intracellular activity against C. 

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pneumoniae but does not exhibit such interaction with anti-platelet agents.  The azithromycin dose 
will be reduced due to its longer half-life, resulting in longer bioavailability duration in the body. Due 
to reported occasional QT-prolongation at high doses of azithromycin, ECG monitoring of the QT-
interval will be carried out.     
 
 
2.  
STUDY OBJECTIVES 
 
2.1 
Primary Objectives 
 
1. To evaluate the effect of antibiotic combination therapy on objective measures of 
improvement in coronary flow as determined by fractional flow reserve (FFR) in subjects 
undergoing PCI with non-critical lesions in non-culprit arteries.  
 
 
2.2 
Secondary Objectives 
 
1. 
To evaluate the effect of an antibiotic combination therapy on plaque morphology and volume as 
assessed with intra-coronary imaging (IVUS and OCT) in a substudy. 
2. 
To evaluate angiographic stenoses changes (QCA) during the ACAC trial. 
3. 
To examine safety and major adverse clinical events (MACE) during the ACAC therapy. 
4. 
To record major adverse clinical events (MACE). Including death, recurrent myocardial 
infarction, stroke and major bleeding. 
 
2.3 
Exploratory Objectives 
 
1. 
To evaluate the use of LAMP for the detection of C. pneumoniae in blood samples. 
2. 
To evaluate the changes in indices of pressure and flow (as measured with the pressure/flow 
FFR wire) in the culprit and non-culprit coronary arteries 
 
3.  
STUDY DESIGN  
 
This is a Phase II a, prospective study comprising of 60 subjects referred to Liverpool Hospital 
and Sydney Southwest Private Hospital who have paired FFR assessments. To achieve this 
number, assuming a dropout rate of 25%, approximately 80 subjects will be approached. 
These subjects will be undergoing investigation for symptomatic CHD. Once consent has 
been obtained and the subject has met all the inclusion criteria without exclusions, they will 
be included in the study. The study is a randomised, placebo controlled trial at a randomisation 
rate of 1:1. 
 
The primary endpoint will be a 20% reduction in the rate of FFR <0.80 in subjects planned to 
undergo staged PCI at 3 months among those randomly assigned to ACAC therapy. That is 
a difference of 6 or more in the ACAC group who had an FFR <0.80 at onset will have a FFR 
≥0.80 at 3 months than in control group. 
 
4. 
SELECTION OF STUDY POPULATION 
 
4.1 
Inclusion Criteria 
 
The subject must meet all of the following criteria to be eligible for inclusion in the study: 
 

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1. Males and females (without childbearing potential as evidenced by hysterectomy, tubal 
ligation or at least one year post-menopause) aged 18 to 80 years, inclusive.  
 
2. Ability to provide written informed consent to participate in the study. 
 
3. Subjects with documented recent acute coronary syndrome (ACS) or evidence of 
myocardial ischemia.  
 
4. Subjects who have a culprit lesion suitable for PCI, and a non-critical lesion in another 
vessel suitable for staged PCI with an FFR of ≤0.80, for subjects undergoing diagnostic 
angiography and FFR without ad hoc PCI. Or subjects who have a single non-critical culprit 
lesion of intermediate severity with a clinically indicated FFR ≤0.80 which is suitable for staged PCI.  
 
5. No serious co-morbidities, which might interfere with the subject’s ability to enter the study. 
 
6. Able to communicate effectively with the study team and to comply with the protocol. 
 
4.2  Exclusion Criteria 
 
The subject must be excluded for any of the following reasons: 
 
1. Females that are of child bearing potential 
 
2. Subjects without a non-culprit lesion considered appropriate to plan a staged PCI.  
 
3. Clinically significant haematologic, hepatic, metabolic, renal, rheumatologic, anaphylactic 
reactions, neurological or psychiatric disease 
 
4. Clinical evidence of any other disease, which might interfere with the subject’s ability to enter 
the trial. 
 
5. Concomitant administration of medications that may interfere with treatment as assessed by 
the Investigator, including allergy to any component of the therapy. 
 
6. Concomitant administration of any medication prohibited for use during this study (e.g. 
colchicine) 
 
7.  Male subjects consuming greater than 60g alcohol per day, or female subjects consuming 
greater than 40g alcohol per day. 
 
8.    Evidence of any recent history of, or current recreational drug abuse 
 
9. Serious adverse reaction or hypersensitivity to therapeutic drugs. 
 
10. Unable and to comply with the study requirements. 
 
11. Subjects who have been involved in an experimental drug protocol within the past four weeks. 
 
A list of subjects screened but deemed ineligible will be maintained indicating 
reason(s) for exclusion. 
 
If a subject becomes pregnant during the course of the study, they will be immediately 
withdrawn and treated in the way least likely to harm both subject and foetus. 

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4.3 
Recruitment 
 
Two centre’s will participate, enrolling subjects until 60 have completed study participation 
defined as completing paired FFR assessments per protocol. Subjects meeting the diagnostic 
criteria for myocardial ischemia or a recent acute coronary syndrome whose cardiologist 
recommends angiography will be eligible. 
 
Subjects presenting to the study centre/s will be invited to participate. All eligible subjects who 
are willing to participate will be given the opportunity to ask questions, and will be informed 
about the study before signing consent. Subject characteristics will be registered on a case 
report form that contains basic demographics and clinical characteristics age, sex, medical 
history, smoking and drinking habits, concomitant medications and current symptoms. In 
addition, a physical examination will be performed by the Investigator or sub-investigators 
including height, weight and vital signs. 
 
Subjects who fail the inclusion/exclusion criteria will be informed that they are not eligible for 
inclusion into the study and will be treated by the Investigator as per standard clinical practice. 
 
 
4.4   Number of Subjects 
 
A total of 60 subjects will complete study participation. Withdrawn and delayed exclusions may 
be replaced, see Section 9.2. 
 
 
4.5   Randomisation and Randomisation Schedule 
 
For the purposes of this study, participants will be randomised at screening visit. 
 
Subjects recruited into the study who are then deemed eligible for Randomisation at 
Screening Visit will be randomised in a double-blinded 1:1 manner, either to active study 
medication or matching placebo. 
 
Randomisation will be performed centrally by CDD. Sites will need to contact CDD to 
randomise study participants. CDD will be responsible for allocation of study medication 
based on the randomisation number. Randomisation numbers will be given out to site over 
the phone and confirmed electronically via signed, emailed randomisation confirmation 
sheet. 
 
CDD is not a clinical site for the conduct of the trial so study investigators involved in any 
study participant recruitment, assessment and eventual follow-up will remain blinded to the 
medication therapy assignment. 
 
Investigators/Sub-Investigators will be instructed to contact CDD on the number below; 
 
CDD 
Research Department 
02 9713 4011 then dial ‘2’ for the Research Department 
 
4.6   Blinding Procedures 
 
 
 
In order to eliminate a placebo effect, the subject and clinical study investigators / staff will be 
blinded to the allocation of treatment in a double-blinded fashion. 
 

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Unblinded CDD staff will allocate subject numbers according to the treatment arm to which 
the subject is assigned. Medication will be dispensed by site staff as allocated by subject 
numbers provided by CDD. 
 
5. 
STUDY PRODUCT 
 
5.1  Dosage Schedule 
 
The treatment will be administered as 50mg capsules of doxycycline, 250mg capsules of 
azithromycin and 150mg of rifabutin twice daily (morning and evening). The total number of 
capsules taken is 3 capsules a day in the first week then 6 capsules a day to be taken after 
food, with plenty of fluids, until the end of dosing period. 
 
The treatment is to be on a dose escalation schedule, taken as per the following schedule: 
 
Week 1 (Day 1 to Day 7) 
 
Time 
Doxycycline 
Azithromycin 
Rifabutin 
Breakfast 
50mg 
250mg 
150mg 
Dinner 
 
 
 
 
 
Week 2 until EOT (Day 8 to Day 90) 
 
Time 
Doxycycline 
Azithromycin 
Rifabutin 
Breakfast 
50mg 
250mg 
150mg 
Dinner 
50mg 
250mg 
150mg 
 
 
5.2  Supplies and Accountability 
 
The Sponsor will be responsible for supplying the Investigators/institutions with the study drug.  
The Sponsor will not supply an Investigator/institution with the study drug until the Sponsor 
obtains all required documentation from the HREC and regulatory authorities.  The Sponsor 
will ensure timely delivery of investigational product(s) to the Investigator(s) and maintain 
records that document shipment, receipt, disposition, return, and destruction of the study drug. 
The Principal Investigator is responsible for study drug accountability, reconciliation, and 
record maintenance at his/her site. The Principal Investigator or designated, trained study 
site personnel will document all aspects of drug receipt, inventory, dispensing, return, 
reconciliation, and shipment. 
All study medication must be kept in a locked area with access restricted to designated study 
site personnel. At each visit, a supply of study medication sufficient to last until the next clinic 
visit will be dispensed (plus a small additional quantity to account for the visit window). A list 
of the exact supply of study treatment dispensed to each Subject at each visit will be included 
on the Investigational Product Accountability Log that will need to be completed at each study 
visit.  Used and unused product will be returned by the Subject to the clinic in the packaging 
in which it was provided to the Subject.  The Investigator or delegated staff will reconcile all 
study units with those recorded as being dispensed and account for any inconsistencies in 
writing in the Investigational Product Accountability Log or similar document maintained in the 
Investigator study file.  

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At the conclusion of the study, all unused medication and all medication containers will be 
returned to the Sponsor.  The Sponsor will ensure that a final report of drug accountability is 
prepared and that unused medications are appropriately destroyed. 
 
5.3  Packaging and Labeling 
 
Study medications will be packed and supplied by the Sponsor. Medication will be labelled 
with dosing instructions, the protocol number, subject number and will indicate that the 
supplies are for clinical trial use only. Study medications will be dispensed in study specific 
bottles, appropriately labeled. Packs must only be allocated to the subject whose number is 
borne on that pack.  Subjects will be asked to return all partly used packs at each clinic visit. 
Further supply will be prescribed at visit suitable for the treatment period.  
 
5.4 
Compliance 
 
Compliance will be assessed by capsule counts conducted by the Investigator or delegated 
staff at each visit. Compliance will be calculated as a percentage (%) of expected and the 
value will be entered on the appropriate page of the CRF at each study visit. Secondary ‘on 
treatment’ analyses will be performed. Participants will be deemed ‘non-compliant’ if 
compliance percentage falls below 80%, at which point, study staff are required to re-educate 
the participant on study medication dosing. 
 

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6.   PRIOR AND CONCOMITANT ILLNESSES AND 
TREATMENTS 
 
6.1 
Prior and Concomitant Illnesses 
 
Participants who have provided consent will have their files reviewed and be required to 
provide details to document any illnesses present at the time of sample collection. Illnesses 
present at the time of informed consent, will be regarded as concomitant illnesses and will be 
documented on the appropriate pages of the Case Report Form (CRF) - see Section 8. 
Adverse Events 
 
6.2 
Prior and Concomitant Treatments 
 
All treatments being taken by the subjects on entry to the study or at any time during the study 
are regarded as concomitant treatments and must be documented preferably by generic name 
on the appropriate pages of the CRF. 
 
Changes to concomitant medications should be kept to a minimum during the study. However 
they may be altered at the discretion of the investigator according to Good Clinical Practice. 
 
6.3 
Prohibited medication 
 
A list of drugs prohibited for use during the study is listed in Appendix 2. 
 
7. 
INVESTIGATIONAL PROCEDURES AND SCHEDULE 
  
 
7.1 
Description of Study Schedule 
 
7.1.1  Visit 1 Screening and Baseline  
 
The subject will be approached regarding the study and will be asked to read the Subject 
Information and Consent document, encouraged to ask any questions, which will be answered 
to best of the Investigators ability. If the subject agrees to participate then they will be asked 
to provide written informed consent. Subject will be asked to provide details of their medical 
history, a description of their current symptoms and list all current medications. Subjects will 
also be given a Diary to collect symptoms relating to coronary artery disease and this will 
remain with the participant for the duration of the study. The Diary will be reviewed at each 
visit. Blood samples will be collected for laboratory tests. Pregnancy testing will be completed 
to ensure pregnant women are not included into the study. The following tests and 
assessments will be performed: 
- 
FBC, ESR and EUC  
- 
LFT and Lipid Studies  
- 
CK-MB, high sensitivity Troponin T 
- 
High sensitivity CRP 
- 
Chlamydophila pneumoniae macrophage cultures  
- 
C. pneumoniae titer measurement 
- 
C. pneumoniae DNA detection using LAMP 

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- 
Pregnancy Testing 
- 
Physical examination  
- 
Vital Signs 
- 
Symptomatology record 
- 
ECG  
- 
Angiogram 
- 
Fractional Flow Reserve Study and pressure/flow measurements 
- 
IVUS and OCT of culprit and non-culprit arteries (sub-study) 
- 
Functional status – New York Heart Association Class 
- 
Concomitant medications/ concomitant illness record 
- 
Cardiac events record 
The Subject’s GP will be informed of the Subjects participation in the study, unless the subject 
does not consent to this disclosure. 
Subjects will be dispensed with investigational product with instruction on correct 
administration. The investigational product will be dispensed in specifically labelled bottles.  
 
7.1.2 Visit 2 (Day 30 ± 7) 
 
At this visit the subject will be asked to report on current symptoms, changes to concomitant 
medications, and adverse events. A blood sample will be collected for laboratory tests. Subject 
will undergo a complete physical examination. The following assessments will also be 
performed: 
- 
FBC, ESR and EUC  
- 
LFT and Lipid Studies  
- 
CK-MB, high sensitivity Troponin T 
- 
High sensitivity CRP 
- 
ECG 
- 
Physical examination  
- 
Vital Signs 
- 
Symptomatology record 
- 
Functional status – New York Heart Association Class 
Subjects will be required to bring their medication with them for assessment of compliance. 
 
 

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7.1.3 Visit 3 – End of Treatment (Day 90 ± 21)  
 
At this visit the Subject will be asked to report on current symptoms, changes to concomitant 
medications, and adverse events. A blood sample will be collected for laboratory tests. Subject 
will undergo a physical examination. The following assessments will also be performed: 
- 
FBC, ESR and EUC  
- 
LFT and Lipid Studies  
- 
CK-MB, high sensitivity Troponin T 
- 
High sensitivity CRP 
- 
Chlamydophila pneumoniae macrophage cultures 
- 
C. pneumoniae titer measurement  
- 
C. pneumoniae DNA detection using LAMP 
- 
Symptomatology record 
- 
Physical examination  
- 
Vital Signs 
- 
ECG  
- 
Angiogram 
- 
Fractional Flow Reserve Study and pressure/flow measurements 
- 
IVUS and OCT of culprit and non-culprit arteries (sub-study) 
- 
Functional status – New York Heart Association Class 
The Subject will be required to return all unused medication, and all used empty packaging 
for assessment of compliance. Subjects will also be required to return diaries for review and 
collection. 
7.1.4 Visit 4 Final Follow up  
 
Subjects will be asked to return a final time to the clinic at Day 180 (+21 days), where 
changes to symptoms, concomitant medications and adverse events will be recorded.  
 
This will mark the end of subject participation.                   
 
7.1.5 Phone Contact (Day 150) 
 
At this time, the participant will be contacted by phone to assess symptoms and any Adverse 
Events after discontinuation of antibiotic therapy and to check the use of concomitant 
medications.  
 
7.2 
Methods of Data Collection 
 
7.2.1 Efficacy data 
 
Response to antibiotic therapy will be assessed through a set of specified 
measurements: 

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7.2.1.1 Laboratory Studies 
 
Efficacy of combination therapy will be assessed using blood samples collected at 
each visit. The following tests will be performed: FBC, ESR, lipid studies, liver function. 
In addition the following will be performed: 
 
High Sensitivity C-Reactive protein (Hs-CRP) is a protein in the blood that increases 
in the presence of inflammation. Hs-CRP will measure the small amounts of CRP 
produced by the long-term inflammation from atherosclerosis.  
 
 
4ml of blood will be collected in an EDTA tube. This sample will then be 
transferred to the laboratory for a full blood count 
 
4ml of blood will be collected in an SST/Gel tube and transferred to the 
laboratory for liver function tests, Cholesterol, triglyceride studies and hs-CRP. 
 
4ml of blood will be collected in a lithium heparin tube. Sample will then be 
transferred to the laboratory for CK-MB, Troponin T tests and UEC testing. 
 
5ml of blood will be collected in a special ESR collection tube. This will then be 
sent to the laboratory to test the ESR 
 
2 x 4ml of blood will be collected in citrated tubes. This sample will be 
transferred to the laboratory for C. pneumoniae detection by macrophage 
culture and C. pneumoniae titer determination (Visit 1 and 3 only). 
 
3 x 4ml (i.e. 12 ml) of blood will be collected in an EDTA tube. This sample will 
be transferred to the laboratory for C. pneumoniae DNA detection by LAMP 
(Visit 1 and 3 only). 
 
The total blood drawn on at Visit 1 and Visit 3 will be approximately 40mls. The total 
blood drawn at Visit 2 will be approximately 20 ml. 
 
Blood samples will be tested by an experienced pathologist at Laverty Pathology for 
all tests excluding C. pneumoniae DNA detection by LAMP (exploratory research) and 
C.pneumoniae macrophage cultures.  
 
7.2.1.2 Symptomatology 
 
At each study visit, Subjects will be asked about their symptoms as reported during the 
Screening period and Visit 1. Changes in symptoms severity will be recorded in the source 
documentation. 
 
7.2.1.3 Other 
 
At each visit subjects will be asked to complete a Functional status – New York Heart 
Association Class questionnaire. This questionnaire will be used to assess changes in their 
quality of life. 
 
7.2.1.4 Electrocardiogram (ECG) 
 
An ECG will be performed for safety at Visit 1 and Visit 3. 
 
7.2.1.5 Fractional Flow Reserve (FFR) Study  
 
The results will assess the physiological effect of arterial stenosis.  
Fractional Flow Reserve study is a guide wire based procedure to measure changes in blood 
pressure and flow across non-critical lesions in the coronary arteries performed at the time of 
a diagnostic or interventional coronary procedures. The results will assess the degree of 
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baseline and at Visit 3. Additional measurements of coronary flow as measured with the FFR 
pressure/flow guidewire will be recorded in the culprit and non-culprit artery at the time of FFR 
measurement. 
 
7.2.1.6 Intra-coronary Imaging (IVUS and OCT) Sub-study 
 
The results will assess the anatomic extent and morphology of atherosclerosis and response 
to treatment. 
Intra-coronary imaging (IVUS and OCT) are catheter based imaging techniques allowing 
direct visualisation and characterisation of coronary plaque in vivo in addition to assessment 
of coronary arteries and stent expansion pre and post stent implantation. Indications for use 
are to determine lesion characteristics and to guide stent implantation. The results will be used 
to assess plaque volume and  morphology and response to therapy. 
 
 
 
7.2.2 Safety data 
 
7.2.2.1 Laboratory Studies 
 
A blood sample will be collected at each visit. The following blood tests will be performed: Full 
blood count, Full biochemistry as per detailed in 7.2.1.1. Additional tests may also be 
requested by the physician, but will not be part of the study unless related to adverse events. 
 
The reference ranges for normal laboratory values and current certificate of NATA 
accreditation will be obtained from the relevant laboratories before the study commences. 
 
Values outside the normal range will be noted in the CRF and those considered to be of 
clinical significance, particularly those related to the study medication, will be recorded as 
adverse events. Values outside the normal range will be monitored until they have been 
stabilised. 
 
Comparison of pre and post treatment C. pneumoniae parameters will be assessed to show 
efficacy of the ACAC combination. 
7.2.2.2 Adverse Events 
 
Adverse events will be assessed at each visit throughout the study by open general 
questioning from the Investigator or study staff and entered into the CRF. The use of other 
medications during the study will also be noted along with the reason for use in order to capture 
other potential adverse effects.  
 
8.  
ADVERSE EVENTS 
 
8.1  Definitions 
 
8.1.1 Adverse event 
 
The term adverse event (AE) covers any sign, symptom, syndrome, or illness that appears or 
worsens in a subject during the period of observation in the clinical study and that may impair 
the well being of the subject. The term also covers laboratory findings or results of other 
diagnostic procedures that are considered to be clinically relevant (e.g. that require 
unscheduled diagnostic procedures or treatment measures, or result in withdrawal from the 
study). Undesirable experiences including intercurrent events (or diseases), drug reactions 
and clinical abnormalities or clinically significant laboratory test abnormalities, which occur 
during the course of a trial, are also included. 
 

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The AE may be: 
 
 
A new illness 
 
Worsening of a sign or symptom of the condition under treatment or of a concomitant 
illness 
 
An effect of a comparator drug 
 
Unrelated to participation in the clinical study 
 
A combination of one or more of these factors 
 
Thus, no causal relationship with the study medication is implied by the use of the term 
“adverse event”. Surgical procedures themselves are not adverse events; they are therapeutic 
measures for conditions that require surgery. The condition for which the surgery is required 
may be an adverse event. Planned surgical measures permitted by the study protocol and the 
conditions leading to these measures are not adverse events. (See Appendix 4 - Definitions 
of causality and severity of adverse events). 
 
Interviews concerning AEs must be conducted with regard to objectivity. Questions must be 
phrased so that they do not, by suggestion, lead the subject into giving information, which is 
not valid. The investigator must carefully evaluate the response and comments of the subject 
in order that he or she may judge the true nature and severity of the adverse event. 
 
 
8.2.2 Serious adverse event 
 
A serious adverse event (SAE) is any AE that occurs at any dose of the study medication or 
at any time during the period of observation that: 
 
 
Results in death 
 
Is immediately life threatening 
 
Requires or prolongs hospitalisation 
 
Results in persistent or significant disability or incapacity 
 
Occurs with overdose 
 
Involves cancer 
 
Involves congenital anomaly/birth defects 
 
Is medically important 
 
Requires medical intervention to prevent permanent impairment or damage 
 
“Medically important” events are events that may not be immediately life threatening or result 
in death or hospitalisation, but may jeopardise the subject or require intervention to prevent 
one of the other outcomes listed in the definition above. Examples of such events are intensive 
treatment in an emergency room for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalisation, or development of drug dependency or drug abuse. Such 
events should be documented and reported as SAEs. 
 
Events “requiring medical intervention to prevent permanent impairment or damage” are 
events where the investigator believes that medical or surgical intervention is necessary to 
preclude permanent impairment of a body function or to prevent damage to a body structure. 
 
As there is an overlap between the terms “medically important event” and events requiring 
medical intervention to prevent permanent impairment or damage, it is left to the discretion of 
the investigator to select the more applicable of the two criteria when completing the “Serious 
adverse event form”. 
 
All AEs observed by the investigator or reported by the subject whether or not considered 
related to the test medication will be followed up by the investigator until resolution, 
stabilisation or lost to follow up. 
 

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All AEs will be reported in the adverse event forms of the CRF and assessed by the 
investigator in terms of severity and relationship to the test medication. The outcome of the 
adverse event as well as the measures taken as a result of this event will be described in the 
adverse event form of the case record form. 
 
8.2 
Period of observation 
 
AEs fall into the categories non-serious and serious (see section 8.1.2 serious adverse event). 
The period of observation for adverse events extends from the time the subject gives his 
informed consent, until he/she undergoes the final clinical examination scheduled in the study. 
All AEs unresolved at the final clinical examination will be monitored until they resolve or are 
clearly determined to be due to a subject’s stable or chronic condition, or intercurrent 
illness(es). 
 
Adverse events occurring after this period of observation are to be reported if the investigator 
feels that there is a causal relationship to the test medication. 
 
8.3  Documentation and Reporting of Adverse Events by the 
Investigator 
 
All AEs that occur after the subject has signed the informed consent document must be 
documented on the pages provided in the CRF. The adverse events must also be recorded in 
the subject’s medical records. 
 
The following approach will be taken to documentation: 
 
 
All SAEs must be documented on “Serious Adverse Event” forms. 
 
 
Non-serious AEs must be documented in the adverse event forms supplied in the CRF. 
 
 
Subjects should be encouraged to note adverse events and discuss them at their next 
visit or to report any event of concern to the investigator immediately. 
 
 
Every attempt should be made to describe the AE in terms of a diagnosis. If 
appropriate, component symptoms should also be listed below the diagnosis. If only 
non-specific signs or symptoms are present, these should be recorded as a diagnosis. 
 
 
For each event occurring after the first dose of study medication/randomisation, the 
investigator will classify whether the event is to be considered treatment emergent and 
whether there is a reasonable possibility that the event was associated with the use of 
the study medication. 
 
An AE that occurs during the study after the first dose of study medication/randomisation will 
be considered as treatment emergent if (1) it was not present at the time of the first dose of 
study medication/randomisation and is not a chronic condition that is part of the subject’s 
history, or (2) it was present at the time of the first dose of the study medication/randomisation 
or as part of the subject’s medical history, but its intensity (severity or frequency) has worsened 
after the first dose of study medication/randomisation. 
 
AEs that fulfil the criteria for seriousness (section 8.1.2 serious adverse event) have to be 
reported to the sponsor immediately (for procedure see Section 8.4 Immediate reporting by 
investigator to sponsor). 
 
AEs that do not fulfil the criteria for immediate reporting will be supplied to the sponsor in the 
same way as all other CRF pages. 
 

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All subjects who have AEs -whether considered associated with the use of the study 
medication or not-must be monitored to determine the outcome. The clinical course of the 
adverse event will be followed up according to accepted standards of medical practice- even 
after the end of the period of observation-until a satisfactory explanation is found or the 
investigator considers it medically justifiable to terminate follow-up.  Should the adverse event 
result in death, a full pathologist’s report should be supplied, if possible. 
 
All questions on the completion and supply of adverse event forms and any further forms 
issued to the investigator at a later date to clarify unresolved issues should be addressed to 
the sponsor. 
 
 
8.4  Immediate Reporting by Investigator to Sponsor 
 
Serious adverse events must be documented on “Serious adverse event” forms and supplied 
to the sponsor within 24 hours or at the latest on the following working day. The investigator 
must also inform the site monitor in all cases. The sponsor will ensure all legal reporting 
requirements are met. 
 
Serious Adverse Events should be reported to: 
Prof Thomas Borody  
CDD 
02 97134011 or 0417 733 707 
 
The initial report must be as complete as possible, including details of current illnesses and 
(serious) adverse events and assessment of the causal relationship between the event and 
the study medication. Copies of the case report form pages containing the following 
information (if not already supplied to the sponsor) must be sent with the “Serious adverse 
event” form: 
 
 
Demography 
 
Medical and surgical history 
 
Previous and concomitant medication  
 
Study medication administration record 
 
The forms documenting all non-serious adverse events that have occurred up to the time of 
occurrence of a serious adverse event, even if still incomplete, must also be sent with the 
“Serious adverse event” form. 
 
Information not available at the time of the initial report (e.g. an end date for the adverse event 
or laboratory values received after the report) must be documented on a follow-up “Serious 
adverse event” form that carries the number(s) of the initial report(s). 
 
The principal investigator at each site will be responsible for reporting SAE’s at their site. The 
principal investigator at Liverpool Hospital (lead site) will be responsible for reporting all SAE’s 
to the Human Research Ethics Committee. 
 
 
8.5 
 Data and Safety Monitoring Board 
 
The Data and Safety Monitoring Board (DSMB) will monitor participant safety, data quality and 
evaluate progress of the study. The DSMB will be composed of 3 members including a 
biostatician. They monitor the safety of the study and will advise on the conduct and the 
ongoing validity of the trial. 
Dr Ross Grant will be the nominated DSMB contact and will be responsible for communication 
between the DSMB and the Sponsor, Study Sites (and relevant personnel), Ethics committee 
and Investigators. 

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9. WITHDRAWALS AND DEFAULTERS 
Subjects may be withdrawn from study medication for the following reasons: 
 
 Determined to be necessary as per investigator, including: 
o Due to AE or SAE 
o Development of any exclusion criteria may be cause for discontinuation 
o Treatment with prohibited medications 
o Female participants fall pregnant or female partners of male participants fall 
pregnant 
o Subject lost to follow up (does not complete all Study visits and Study staff 
have failed to make contact with the subject nor arrange a successful visit for 
a period of 1 month past a scheduled Study visit). 
o If, in the investigators opinion continuation in the study would be detrimental 
to the subjects well-being 
 
 
Subjects are free to withdraw consent at any time. 
 
 
In all cases the reason for withdrawal, if given, must be recorded in the Case Report Form 
and in the subject’s medical records.  The subject must be followed up to establish whether 
the reason was an adverse event, and if so, this must be reported in accordance with the 
procedures in section 8 Adverse Events. 
 
Every effort will be made to follow up subjects who withdraw or are withdrawn from the study. 
All subjects withdrawn or who choose to withdraw consent will be asked to return to the study 
site to undergo final EOT study procedures, or as far as possible, all safety examinations 
scheduled for the final EOT visit for all subjects who taken at least one dose of the study 
drug/s. This is especially important for those subjects who withdraw due to AEs or SAEs, in 
order to allow for collection of detailed safety data in accordance with the procedures in section 
8 Adverse Events.  These subjects should be given appropriate care under medical 
supervision until the symptoms of any AE resolve, or the subject’s condition becomes stable. 
Subjects may then be contacted at the end of the study for final safety monitoring procedures. 
 
While primary analysis will be of all consenting subjects, a secondary ‘on-treatment’ analysis 
will be performed on subjects who remain compliant at the end of the 90-day endpoint. 
 
 

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10.  EMERGENCY PROCEDURES 
 
10.1  Emergency Sponsor Contact 
 
In emergency situations, the subject should phone the number listed on the subject 
information sheet. 
 
 
10.2  Emergency Treatment 
 
During and following a subject’s participation in the trial, the investigator/institution should 
ensure that adequate medical care is provided to a subject for any adverse events, including 
clinically significant laboratory values, related to the trial. The investigator/institution should 
inform the subject when medical care is needed for intercurrent illness(es) of which the 
investigator becomes aware. Any participant with potential cardiac emergency will be directed 
to the nearest hospital Emergency Room.  
 
 
11.  STATISTICAL PROCEDURES  
 
11.1 Analysis Variables 
 
Analysis of efficacy will be performed according to intention-to-treat method and include all 
subjects who received the combination antibiotic therapy. However as the primary efficacy 
analysis is of subjects with paired FFR assessments, only such subjects will be included in 
the primary analysis. All other subjects will be included in secondary analyses. Numerical data 
will be presented as mean + SD for normally distributed variables and as median with 
interquartile range for non-normally distributed data. Non-normally distributed data will be log-
transformed (e.g. CRP levels) before being used for comparisons. Significant changes in 
subjects’ arterial flow, clinical symptoms and biochemical variables over time compared with 
that baseline will be assessed using an analysis of covariance. Differences between treatment 
and control groups in the occurrence of FFR≥80 will be assessed using Fisher’s exact test. All 
tests will be 2-tailed with a 5% significance level.   
 
11.2 Interim Analysis 
 
 
 A DSMB directed interim analysis is planned when 60 paired FFR data are available. At this 
time point, the trial would declare the combination therapy as effective if the p value is less 
than 0.05. However, the trial might still continue to collect extra data to accurately characterise 
side effects as advised by the DSMB. 
 
11.3 Sample Size Justification  
 
This is a feasibility study designed to provide preliminary observations and generate 
hypothesis for future studies. The sample size of 60 subjects with paired FFR was not defined 
on the basis of a clinical endpoint hypothesis but rather to provide information about antibiotic 
combination therapy efficacy and safety. The sample size required is established by 
assessment of the minimum number of subjects needed to provide reliable and non-trivial 
results. The sample size is in the range of the intervention group in the azithromycin clinical 
trial of subjects with CAD (n=60). 
12.  ETHICAL AND LEGAL ASPECTS 
 

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12.1 Good Clinical Practice 
 
The procedure set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigator abide 
by the principles of the NIH Good Clinical Practice (GCP) guidelines of the Therapeutic Goods 
Administration (TGA) published in CPMP/ICH/135/95 July 2000 and the ethical principles laid 
down in the current revision of the Declaration of Helsinki 2004 (Appendix 5) and the NHMRC 
National Statement on Ethical Conduct in Human Research 2007. The study will also be 
carried out in keeping with local legal and regulatory requirements. 
 
12.2 Delegation of Investigator Responsibilities 
 
The investigator should ensure that all persons assisting with the trial are adequately informed 
about the protocol, the study treatments, and their trial-related duties and functions. 
 
The investigator should maintain a list of co-investigators and other appropriately qualified 
persons to whom he or she has delegated significant trial-related duties.  
 
12.3 Subject Information and Informed Consent 
 
Before being admitted to the clinical study, the subject must consent to participate after the 
nature, scope, and possible consequences of the trial have been explained in a form 
understandable to him or her. 
 
An informed consent document that includes both information about the study and the consent 
form will be prepared and given to the subject. The document must be in a language 
understandable to the subject and must specify who informed the subject. The person who 
informs the subject must be a physician. 
 
After reading the informed consent document, the subject must give consent in writing. The 
subject’s consent must be confirmed at the time of consent by the personally dated signatures 
of; the subject, person conducting the informed consent discussions, and a witness. 
 
It is recommended that the investigator inform the subjects’ primary physician (GP) about the 
subjects’ participation in the trial if the subject has a primary physician and if the subject agrees 
to the primary physician being informed.  
 
12.4 Confidentiality 
 
Only the Subject Number and Subject initials will be recorded in the Case Report Form, and 
if the Subject name appears on any other document (e.g. pathologist report), it must be 
obliterated before a copy of the document is supplied with the CRF. Study findings stored on 
a computer will be stored in accordance with local data protection laws. The subjects will be 
told that representatives of the Sponsor, HREC, or regulatory authorities may inspect their 
medical records to verify the information collected, and that all personal information made 
available for inspection will be handled in strictest confidence and in accordance with local 
data protection laws. 
 
The Investigator will maintain a confidential Subject identification list (Subject numbers with 
the corresponding Subject names) to enable records to be identified. 
 
12.5 Protocol Amendments 
 
Neither the investigator nor the sponsor will alter this study protocol without obtaining the 
written agreement of the other. Once the study has started, amendments should be made only 
in exceptional cases. The changes then become part of the study protocol.   

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12.6 Approval of the Study Protocol and Amendments 
 
Before the start of the study, the study protocol, informed consent document, and any other 
appropriate documents will be submitted to the institutional ethics committee (HREC) with a 
cover letter or a form listing the documents submitted, their dates of issue, and the site for 
which approval is sought. If applicable the documents will also be submitted to the authorities, 
in accordance with local legal requirements (CTN). 
 
Study medication can only be accessible to the investigator for study use after documentation 
on all ethical and legal requirements for starting the study has been received by the sponsor. 
This documentation must also include a list of the members of the HREC and their occupations 
and qualifications. If the HREC will not disclose the names of the committee members to the 
Sponsor, it should be asked to issue a statement confirming that the composition of the 
committee is in accordance with GCP and NHMRC guidelines. Formal approval by the HREC 
should preferably mention the study title, study code, study site, and any other documents 
reviewed. It must mention the date on which the decision was made and must be officially 
signed by a committee member.  
 
Before the first subject is enrolled in the study, all ethical and legal requirements must be met. 
The HREC and, if applicable, the authorities must be informed of all subsequent amendments, 
in accordance with local legal requirements. Amendments must be evaluated to determine 
whether formal approval must be sought and whether the informed consent document should 
also be revised. If formal HREC approval is required then the amendments must not be 
implemented until approval is granted. 
 
The investigator must keep a record of all communication with the HREC and, if applicable 
between a coordinating investigator and the HREC. This also applies to any communication 
between the investigator (or coordinating investigator, if applicable) and the authorities.  
 
12.7 Ongoing Information for HREC 
 
If required by legislation or the HREC, the investigator must submit to the HREC:  
 
 
Information on serious or unexpected adverse events as soon as possible. 
 
Periodic reports on the progress of the study. 
 
12.8 Premature Closure of the Study 
 
The sponsor or the investigator has the right to close this study at any time. As far as possible, 
this should occur after mutual consultation. The HREC must be informed, if required by 
legislation. 
 
Should the study be closed prematurely, all study materials (completed, partially completed, 
and blank case report forms, study medication, etc) must be returned to the sponsor, as if the 
study had been completed. 
 
12.9 Record Retention 
 
The following records must be retained by the investigator for a minimum of 15 years after the 
completion or termination of the study: 
 
Signed informed consent documents for all subjects 
 
Subject identification code list, screening log (if applicable), and enrolment log 
 
Record of all communications between the investigator and the HREC 
 
Composition of the HREC (or other applicable statement as described in section 12.6 
Approval of the study protocol and amendments) 

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 
Record of all communications between the investigator and sponsor  
 
List of sub investigators and other appropriately qualified persons to whom the 
investigator had delegated significant trial-related duties, together with their roles in 
the study and their signatures 
 
Copies of case record forms and of documentation of corrections for all subjects 
 
Drug accountability records 
 
Records of any body fluids or tissue samples obtained 
 
All other source documents (subject records, hospital records, laboratory records etc) 
 
Normally, these records will be held in the investigator’s archives. If the investigator is unable 
to meet this obligation, he or she must ask the sponsor for permission to make alternative 
arrangements. Details of these arrangements should be documented. 
 
12.10 Liability and Insurance 
 
The sponsor will underwrite any legal liability for injuries caused to participating persons and 
arising out of this research performed strictly in accordance with the scientific protocol as well 
as with applicable law and professional standards. 
 
12.11 Ongoing Access to Study Drug  
 
According to the Declaration of Helsinki (Revision 2008), at the conclusion of the study, every 
subject entered into the study should be assured of access to the best proven, in this case, 
therapeutic method identified by the study. As such, this study is assessing the efficacy of a 
combination therapy. If this therapy should be deemed to beneficial to the subject, the Sponsor 
will provide the subject with access to the study drug from the time at which the study has 
concluded through to either the Study drug being registered for use in Australia, the application 
for registration in Australia is rejected by the TGA, the Sponsor determines that the Study drug 
will not succeed in gaining registration, or through further studies determines that it is not the 
best proven therapy.   
 
 
13.   ADMINISTRATION 
 
13.1 Case Report Forms (CRFs) 
 
A CRF will be provided by the sponsor for each subject. 
 
All protocol-required information collected during the study must be entered by the 
investigator, or designated representative, in the case report form. Details of case report form 
completion and correction will be explained to the investigator. If the investigator authorises 
other persons to make entries in the case report form, the names, positions, signatures, and 
initials of these persons must be supplied to the sponsor. 
 
The investigator, or designated representative, should complete the case report form pages 
as soon as possible after information is collected, preferably on the same day that a study 
subject is seen for an examination, treatment, or any other study procedure. Any outstanding 
entries must be completed immediately after the final examination. An explanation should be 
given for all missing data. 
 
The completed case report form must be reviewed and signed by the investigator named in 
the study protocol or by a designated sub-investigator. 
 
The sponsor will retain the originals of all case report forms. The investigator will retain a copy 
of all completed CRF pages. 

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13.2 Monitoring 
 
 
Monitoring and auditing procedures developed by the sponsor (or delegate) will be followed, 
in order to comply with GCP guidelines. On-site checking of the case record forms for 
completeness and clarity, cross checking with source documents, and clarification of 
administrative matters will be performed. 
 
13.2.1 Study monitoring 
 
Monitoring will be done by personal visits from a representative of the sponsor (site monitor) who 
will review the case record forms and source documents. By frequent communications (letter, 
telephone and fax), the site monitor will ensure that the investigation is conducted according to 
protocol design and regulatory requirements. 
 
All unused study materials are to be returned to the sponsor after the clinical phase of the trial has 
been completed. 
 
 
13.3 Source Data Verification and On-site Audits 
 
Regulatory authorities, the HREC, and/or the sponsor’s clinical quality assurance group may 
request access to all source documents, case record forms, and other study documentation 
for on-site audit or inspection. Direct access to these documents must be guaranteed by the 
investigator, who must supply support at all times for these activities. 
 
13.4 Archiving 
 
All study documents (including source documents) will be archived for a period of 15 years 
following completion of the study (according to the requirements of GCP). The archive boxes 
must the labelled clearly to identify the study/subject/documents as well as the 15-year 
archiving requirement. 
 
The Investigator must store these in a secure, limited access area. 
 
13.5  Use of Study Findings 
 
All information concerning the product as well  any matter concerning the operation of the 
sponsor such as clinical indications for the drug, its formula, methods of manufacture and 
other scientific data relating to it, that have been provided by and are unpublished, are 
confidential and must remain the sole property of the sponsor.  The investigator will agree to 
use the information only for the purposes of carrying out this study and for no other purpose 
unless prior written permission from sponsor is obtained. 
 
The original case report forms will be stored for 15 years completed as part of the study. 
 
By signing the study protocol, the investigator agrees that the results of the study may be used 
for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals. If necessary, the authorities will be notified of the 
investigator’s name, address, qualifications, and extent of involvement. 
 
13.6 Report and Publications 
 
The sponsor will prepare the final report on the study 12-16 weeks after the close of the 
database and the close out meeting. The investigator (or co-investigator) will be required to 

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sign a statement that he/she has read the report and confirms that, to the best of his or her 
knowledge, it accurately describes the conduct and results of the study.  
 
The Final Study Report may be made available to the HREC, at the HREC’s request. The 
HREC Final Study Report will be sent to the HREC once the study has been closed. This 
document includes information on how the study was performed, number of AE’s and SAE’s 
and their resolution status. 
 
The findings of the study may be published in a scientific journal or presented at a scientific 
meeting. Before submitting the results of the study for publication or presentation, the 
investigator will allow the sponsor 30 days in which to review and comment on the manuscript. 
For any publication manuscript prepared by the sponsor, the sponsor reserves the right to 
select the investigators who will be authors and review the manuscript. The sponsor will allow 
the selected investigators 30 days for full review of the manuscript before publication.  
 
 
14. STUDY DURATION AND DATES 
 
The duration of this study is to be a period of 24months with subject recruitment proposed to 
start in Q1 2016 and ending in Q2 2018.  
15. DECLARATION OF SPONSOR AND INVESTIGATOR 
 
15.1 Declaration of Sponsor 
 
The study protocol was subject to critical review and has been approved by the appropriate 
protocol review committee of the sponsor. The information it contains is consistent with: 
 
- 
The current risk-benefit evaluation of the investigational product. 
- 
The moral, ethical, and scientific principles governing clinical research as set out in the 
Declaration of Helsinki and the principles of GCP. 
 
The investigator will be supplied with details of any significant or new findings, including 
adverse events, relating to treatment with the investigational product. 
 
Authorised Representative 
 
 
Date: ___/___/___ 
Signature: 
 
Name (block letters): 
 
 
Statistician 
 
 
Date: ___/___/___ 
Signature:                                                           
 
Name (block letters):                                                                 
 

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15.2 Declaration of Investigator 
 
I 
 
 
 
 
 
  
 
- 
have received approved product information for the combination therapy consisting of 
rifabutin, azithromycin and doxycycline. 
 
- 
have read this study protocol and agree that it contains all the information required to 
conduct the study.  I agree to conduct the study as set out in this protocol. 
 
- 
will not enrol the first subjects in the study until I have received approval from the 
appropriate HREC and until all legal requirements in have been fulfilled. 
 
- 
agree the study will be conducted in accordance with the moral, ethical, and scientific 
principles governing clinical research as set out in the Declaration of Helsinki and the 
GCP guidelines of the TGA. 
 
- 
agree to obtain, in the manner described in this study protocol, written informed consent 
or witnessed verbal informed consent to participate for all subjects enrolled in this study. 
 
- 
am aware of the requirements for the correct reporting of serious adverse events, and I 
undertake to document and to report such events as requested. 
 
- 
agree with the use of results of the study for the purposes of national and international 
registration, 
publication, 
and 
information 
for 
medical 
and 
pharmaceutical 
 
professionals. 
 
- 
agree to keep all source documents and case report forms as specified in Section 12.9 
Record retention, of this protocol. 
 
- 
will provide curriculum vitae before the study starts, which may be submitted to 
regulatory authorities. 
 
 
Investigator 
 
 
Date: ___/___/___ 
Signature:                                                             
 
 
Name (block letters):                                                                     
 
 
 

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16. REFERENCES 
1. 
Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation 1995;92:657-71. 
2. 
Hermus L, Lefrandt JD, Tio RA, Breek J-C, Zeebregts CJ. Carotid plaque formation and serum 
biomarkers. Atherosclerosis 2010;213:21-9. 
3. 
Mathur S. Epidemic of coronary heart disease and its treatment in Australia. 2002. 
4. 
Chapter 3: The Diseases: Heart, Stroke and Vascular diseases Australian Facts. 2004. 
5. 
Ridker PM, Danielson E, Fonseca F, et al. Rosuvastatin to prevent vascular events in men and 
women with elevated C-reactive protein. New England Journal of Medicine 2008;359:2195. 
6. 
Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for 
Atherosclerotic Disease. New England Journal of Medicine 2017;377:1119-31. 
7. 
Kalayoglu MV, Byrne GI. A Chlamydia pneumoniae component that induces macrophage foam cell 
formation is chlamydial lipopolysaccharide. Infection and immunity 1998;66:5067-72. 
8. 
Gupta S. Chronic infection in the aetiology of atherosclerosis—focus on Chlamydia pneumoniae. 
Atherosclerosis 1999;143:1-6. 
9. 
Blasi F, Denti F, Erba M, et al. Detection of Chlamydia pneumoniae but not Helicobacter pylori in 
atherosclerotic plaques of aortic aneurysms. Journal of Clinical Microbiology 1996;34:2766-9. 
10. 
Ieven MM, Hoymans VY. Involvement of Chlamydia pneumoniae in atherosclerosis: more evidence 
for lack of evidence. Journal of Clinical Microbiology 2005;43:19-24. 
11. 
Belland RJ, Ouellette SP, Gieffers J, Byrne GI. Chlamydia pneumoniae and atherosclerosis. Cellular 
microbiology 2004;6:117-27. 
12. 
Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding 
percutaneous coronary intervention. New England Journal of Medicine 2009;360:213-24. 
13. 
Camici PG, d'Amati G, Rimoldi O. Coronary microvascular dysfunction: mechanisms and functional 
assessment. Nature Reviews Cardiology 2014;12:48. 
14. 
Al-Obaidi FR, Fearon WF, Yong ASC. Invasive physiological indices to determine the functional 
significance of coronary stenosis. IJC Heart & Vasculature 2018;18:39-45. 
15. 
Koskinas KC, Ughi GJ, Windecker S, Tearney GJ, Räber L. Intracoronary imaging of coronary 
atherosclerosis: validation for diagnosis, prognosis and treatment. European Heart Journal 2016;37:524-35. 
16. 
van der Sijde JN, Karanasos A, van Ditzhuijzen NS, et al. Safety of optical coherence tomography in 
daily practice: a comparison with intravascular ultrasound. European heart journal cardiovascular Imaging 
2017;18:467-74. 
17. 
Shor A. Atherosclerosis: lipid infiltration or Chlamydia pneumoniae infection? Circulation 
2002;106:e135-e6. 
18. 
Jespersen CM, Als-Nielsen B, Damgaard M, et al. Randomised placebo controlled multicentre trial to 
assess short term clarithromycin for patients with stable coronary heart disease: CLARICOR trial. bmj 
2006;332:22. 
19. 
Baker WL, Couch KA. Azithromycin for the secondary prevention of coronary artery disease: A meta-
analysis. American journal of health-system pharmacy 2007;64:830-6. 
20. 
Bjerrum L, Andersen M, Hallas J. Antibiotics active against Chlamydia do not reduce the risk of 
myocardial infarction. European journal of clinical pharmacology 2006;62:43. 
21. 
Wells BJ, Mainous AG, Dickerson LM. Antibiotics for the secondary prevention of ischemic heart 
disease: a meta-analysis of randomized controlled trials. Archives of internal medicine 2004;164:2156-61. 
22. 
Stone AF, Mendall MA, Kaski J-C, et al. Effect of treatment for Chlamydia pneumoniae and 
Helicobacter pylori on markers of inflammation and cardiac events in patients with acute coronary syndromes: 
South Thames Trial of Antibiotics in Myocardial Infarction and Unstable Angina (STAMINA). Circulation 
2002;106:1219-23. 
23. 
Andraws R, Berger JS, Brown DL. Effects of antibiotic therapy on outcomes of patients with coronary 
artery disease: a meta-analysis of randomized controlled trials. Jama 2005;293:2641-7. 
24. 
Gieffers J, Füllgraf H, Jahn J, et al. Chlamydia pneumoniae infection in circulating human monocytes 
is refractory to antibiotic treatment. Circulation 2001;103:351-6. 
25. 
Gieffers J, Rupp J, Gebert A, Solbach W, Klinger M. First-choice antibiotics at subinhibitory 
concentrations induce persistence of Chlamydia pneumoniae. Antimicrobial agents and chemotherapy 
2004;48:1402-5. 
26. 
Rupp J, Pfleiderer L, Jugert C, et al. Chlamydia pneumoniae hides inside apoptotic neutrophils to 
silently infect and propagate in macrophages. PloS one 2009;4:e6020. 

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APPENDIX 1:   STUDY LABORATORY TESTS 
 
Blood Examination 
 
BIOCHEMISTRY 
 
LFTs 
 
 
Albumin 
 
 
Bilirubin 
 
 
GGT  (Gamma Glutamyl Transferase) 
 
 
ALP  
(Alkaline Phosphatase) 
 
 
ALT  
(Alanine Aminotransferase) 
 
 
AST  (Aspartate Aminotransferase) 
 
 
 
CK-MB 
 
High sensitivity Troponin T 
 
Hs-CRP 
 
  
 
Electrolytes, urea, creatinine 
 
Serum lipids  
 
 
HAEMATOLOGY  
 
Haemoglobin 
 
Red Cell Count 
 
Haematocrit 
 
MCV 
 
MCH 
 
MCHC 
 
RDW 
 
WCC 
 
Neutrophils 
 
Lymphtocytes 
 
Eosinophils 
 
Basophils 
 
NRBC 
 
Platelets 
 
ESR 
 
 
 
Chlamydophila pneumoniae macrophage cultures 
 
 
Chlamydophila pneumoniae titers 
 
Chlamydophila pneumoniae DNA detection by LAMP (exploratory) 
 
 

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APPENDIX 2 – LIST OF RESTRICTED MEDICATIONS 
 
The below list includes the trade names of restricted medications. However it cannot be assumed that 
this is a complete list. As such, all concomitant medications should be checked, regardless of their 
presence/absence on the below list.  
 
INR monitoring will be conducted on any participant taking Warfarin 
  
Closer clinical and blood-test monitoring on those with the following concomitant therapies: 
 
 
Calcium channel blockers 
 
Beta blockers 
 
Amiodarone 
 
Anti-depressants 
 
 
Statins and ezetimibe can cause abnormal liver function tests. In such patients slower initiation of 
antibiotics may be required 
 
Absolutely Contraindicated 
 
      Colchicine (Azithromycin interaction) 
 
Relatively Contraindicated  
 
 
Theophylline 
 
Terfenadine 
 
Tolterodine 
 
 
  

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APPENDIX 3:  SERIOUS ADVERSE EVENT REPORT FORM 
 
 Initial Report: 
 
 
Date   ___/___/___ 
 Follow-up Report (1): 
 
Date   ___/___/___ 
 Follow-up Report (2): 
 
Date   ___/___/___ 
 Follow-up Report (3): 
 
Date   ___/___/___ 
 
SITE INFORMATION 
Protocol 
No. 
Site 
No. 
Investigator Name 
Reporter Name 
Reporter Phone 
No. 
 
Sponsor 
 
 
 
 
 
 
 
PATIENT INFORMATION 
Patient 
No. 
Patient 
Initials 
D.O.B 
Sex 
Height 
(at time of event) 
Weight 
(at time of event) 
 
 
 
___/___/___ 
Male / Female 
cm 
kg 
EVENT 
Event 
Onset 
Date 
Resolution 
Date 
Severity of 
Event 
Relationship to Product 
Treatment 
Required 
Outcome of Event 
__/__/__ 
__/__/__ 
 
Mild 
 
Moderate 
 
Severe 
 
Definitely related 
 
Probably related 
 
Possibly related 
 
Unlikely related  
 
Not related (If cause 
known, specify    
______________  
 
Unassessable 
 
 
No 
 
Yes 
 
(If yes, 
specify in 
comments 
and con 
meds) 
 Recovered 
without 
treatment 
 Recovered with 
treatment 
 Event ongoing 
      without 
treatment 
 Event ongoing 
& controlled 
with treatment 
 Event ongoing 
& not controlled 
with treatment 
 Patient died 
Did the SAE occur during Lead-In (Pre-randomisation) Phase                  YES   /   NO 
EVENT CATEGORY (Check all that apply) 
 Fatal 
 Life Threatening 
 Required Inpatient Hospitalisation or         
Prolongation of Existing Hospitalisation 
 Resulted in Permanent or Significant Disability 
 Congenital Anomaly / Birth Defect 
 Other Significant Medical Hazard (Medically Important) 
 Necessitates medical or surgical intervention to 
preclude permanent impairment of body function / 
structure 
 Necessitates medical or surgical intervention to relieve 
unanticipated, temporary impairment of body function  
 Results in permanent impairment of a body function or 
permanent damage to a body structure 
 
 
STUDY DRUG INFORMATION 
Product Name 
Form 
Strength 
Dose 
Route 
Date of First 
Intake 
Date of Last 
Intake 

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___/___/___ 
___/___/___ 
 
 
 
 
 
___/___/___ 
___/___/___ 
 
 
 
 
 
___/___/___ 
___/___/___ 
 
 
 
 
 
 
___/___/___ 
___/___/___ 
ACTION TAKEN 
 None 
 Dose Reduced to   : _________________________  Date:   _____/_____/_____ 
 Dose Increased to : _________________________  
Date:   _____/_____/_____ 
 Drug Interrupted    : Date:   _____/_____/_____ 
 Drug Restarted      : Date:   _____/_____/_____ 
 Drug Discontinued Permanently 
 
CONCOMITANT MEDICATIONS 
(Exclude study drugs and medications used to treat this SAE) 
Medication 
Name 
Form 
Strength 
Dose 
Date Started 
 
Date Stopped 
 
Reason 
 
 
 
 
___/___/___ 
___/___/___ 
 
 
 
 
 
___/___/___ 
___/___/___ 
 
 
 
 
 
___/___/___ 
___/___/___ 
 
 
 
 
 
___/___/___ 
___/___/___ 
 
 
 
 
 
___/___/___ 
___/___/___ 
 
RELEVENT SAE LABORATORY DATA 
Test 
Date of Baseline 
Test 
Value of Baseline 
Test 
Date of Study Test 
Value of Study Test 
 
___/___/___ 
 
___/___/___ 
 
 
___/___/___ 
 
___/___/___ 
 
 
___/___/___ 
 
___/___/___ 
 
 
___/___/___ 
 
___/___/___ 
 
 
___/___/___ 
 
___/___/___ 
 
 
___/___/___ 
 
___/___/___ 
 
 
 
 

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DESCRIPTION OF EVENT: (Include significant medical history, treatment given for the SAE, test results, outcome of events) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADDITIONAL COMMENTS: 
 
 
 
 
 
 
 
 
 
 
 
PERSON COMPLETING SAE REPORT: ________________________________  
 
POSITION: _____________________________ 
 
 
SIGNATURE: _________________________________       DATE:  _____/_____/_____ 
 
 
 
 
CONFIRMED BY INVESTIGATOR: _________________________________ 
 
 
SIGNATURE: _________________________________       DATE:  _____/_____/_____ 
 

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APPENDIX 4: DEFINITIONS OF CAUSALITY AND SEVERITY OF 
ADVERSE EVENTS 
 
1. 
Criteria for determining relationship of clinical adverse events to test drugs 
a. Not Related 
This category applies to those adverse experiences that, after careful consideration, are clearly 
and incontrovertibly due to extraneous causes (disease, environment, etc.). 
b. Unlikely (must have two of the following) 
In general, this category can be considered applicable to those adverse experiences, which, after careful 
medical consideration at the time in which they are evaluated, are judged to be unrelated to the test drug. 
An adverse experience may be considered unlikely related if or when: 
 
 
i. 
It does not follow a reasonable temporal sequence from administration of the drug. 
ii. 
It could readily have been produced by the participant’s clinical state, environment or toxic 
factors, or other modes of therapy administered to the patient. 
 
iii. 
It does not follow a known or expected response pattern to the test drug. 
 
iv. 
It does not reappear or worsen when the drug is re-administered. 
 
c. Possibility (must have two of the following) 
 
This category applies to those adverse experiences which, after careful medical 
consideration at the time they are evaluated, a connection with the study medication appears 
unlikely but can not be ruled out with certainty. An adverse experience may be considered 
possibly related if or when: 
 
 
i. 
It follows a reasonable temporal sequence from administration of the drug. 
 
ii. 
It could not readily have been produced by the participant’s clinical state, environment 
or  toxic factors, or other modes of therapy administered to the patient. 
 
iii. 
It follows a known response pattern to the test drug. 
 
d. Probably (it must have three of the following) 
This category applies to adverse experiences which, after careful medical consideration at the time 
they are evaluated, are felt with a high degree of certainty to be related to the study medication. An 
adverse experience may be considered probably related if or when: 
 
 
i. 
It follows a reasonable temporal sequence from administration of the drug. 
 
ii. 
It could not readily have been produced by the participant’s clinical state, environment 
or  toxic factors, or other modes of therapy administered to the patient. 
 
iii. It disappears or decreases on cessation or reduction in dose. There are important 
 
exceptions when the adverse event does not disappear upon discontinuance of the drug, 
 
yet drug-relatedness clearly exists; eg. a) bone marrow depression, b) fixed drug 
 
eruptions, and c) tardive dyskinaesia. 
 
iv. 
It follows a known response pattern to the test drug. 
 
e.  Definitely (Must have all four of the following) 
This category applies to those adverse experiences which the investigator feels are incontrovertibly 
related to the study medication. An adverse experience may be considered definitely related if or 
when: 
 
 
i. 
It follows a reasonable temporal sequence from administration of the drug. 
 
ii. 
It could not readily have been produced by the participant’s clinical state, environment 
or toxic factors, or other modes of therapy administered to the patient. 
 
iii. It disappears or decreases on cessation or reduction in dose and recurs with re-
exposure to the drug. This is not to be construed as requiring re-exposure to the drug. 
However, a category of definitely related can only be used when recurrence is observed. 
iv. It follows a known response pattern to the test drug. 
 
 
3. Criteria for rating the severity of adverse events: 
 

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“Adverse Events”: Any adverse change or experience from the patient’s baseline (pre-treatment) 
condition which occurs during the course of a clinical study, after starting treatment, whether 
considered treatment related or not. “Treatment” includes all investigational agents administered 
during the course of the study. 
 
“Severity of adverse events”: All adverse events must be rated on a three-point scale of increasing 
severity. 
 
a. 
Mild: symptoms barely noticeable to the patient; does not influence performance or function. 
Prescription drugs not ordinarily needed for relief of symptoms but may be given because of 
the personality of the patient. 
b. Moderate: symptoms of a sufficient severity to make patient uncomfortable; performance of 
daily activities is influenced; patient is able to continue in the study; treatment for symptoms 
may be needed. 
c. 
Severe: symptoms cause severe discomfort. May be of such severity that patient can not 
continue performance of daily activities. Severity may cause cessation of treatment with study 
drugs; treatment for symptoms may be given and/or patient hospitalised. 

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APPENDIX 5 – DECLARATION OF HELSINKI 2008 
 
1 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
 
A. INTRODUCTION 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should not be applied without consideration of all other relevant paragraphs.  
2. Although the Declaration is addressed primarily to physicians, the WMA encourages 
other participants in medical research involving human subjects to adopt these principles. 
3. It is the duty of the physician to promote and safeguard the health of patients, including 
those who are involved in medical research. The physician's knowledge and conscience 
are dedicated to the fulfilment of this duty. 
4. The Declaration of Geneva of the WMA binds the physician with the words, “The health 
of my patient will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A physician shall act in the patient's best interest when providing medical 
care.” 
5. Medical progress is based on research that ultimately must include studies involving 
human subjects. Populations that are underrepresented in medical research should be 
provided appropriate access to participation in research. 
6. In medical research involving human subjects, the well-being of the individual research 
subject must take precedence over all other interests. 
7. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best current 
interventions must be evaluated continually through research for their safety, effectiveness, 
efficiency, accessibility and quality. 
8. In medical practice and in medical research, most interventions involve risks and burdens. 
DoH/Oct2008 
9. Medical research is subject to ethical standards that promote respect for all human 
subjects and protect their health and rights. Some research populations are particularly 
vulnerable and need special protection. These include those who cannot give or refuse 
consent for themselves and those who may be vulnerable to coercion or undue influence. 
10. Physicians should consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable international 
norms and standards. No national or international ethical, legal or regulatory requirement 
should reduce or eliminate any of the protections for research subjects set forth in this 
Declaration. 
 
 
 

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B. PRINCIPLES FOR ALL MEDICAL RESEARCH 
11. It is the duty of physicians who participate in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. 
12. Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, other 
relevant sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
13. Appropriate caution must be exercised in the conduct of medical research that may 
harm the environment. 
14. The design and performance of each research study involving human subjects must be 
clearly described in a research protocol. The protocol should contain a statement of the 
ethical considerations involved and should indicate how the principles in this Declaration 
have been addressed. The protocol should include information regarding funding, sponsors, 
institutional affiliations, other potential conflicts of interest, incentives for subjects and 
provisions for treating and/or compensating subjects who are harmed as a consequence of 
participation in the research study. The protocol should describe arrangements for post-
study access by study subjects to interventions identified as beneficial in the study or access 
to other appropriate care or benefits. 
15. The research protocol must be submitted for consideration, comment, guidance and 
approval to a research ethics committee before the study begins. This committee must be 
independent of the researcher, the sponsor and any other undue influence. It must take into 
consideration the laws and regulations of the country or countries in which the research is 
to be performed as well as applicable international norms and standards but these must not 
be allowed to reduce or eliminate any of the protections for research subjects set forth in 
this Declaration. The committee must have the right to monitor ongoing studies. The 
researcher must provide monitoring information to the committee, especially information 
about any serious adverse events. No change to the protocol may be made without 
consideration and approval by the committee. 
16. Medical research involving human subjects must be conducted only by individuals with 
the appropriate scientific training and qualifications. Research on patients or healthy 
DoH/Oct2008volunteers requires the supervision of a competent and appropriately qualified 
physician or other health care professional. The responsibility for the protection of research 
subjects must always rest with the physician or other health care professional and never 
the research subjects, even though they have given consent. 
17. Medical research involving a disadvantaged or vulnerable population or community is 
only justified if the research is responsive to the health needs and priorities of this population 
or community and if there is a reasonable likelihood that this population or community 
stands to benefit from the results of the research. 
18. Every medical research study involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and communities involved 
in the research in comparison with foreseeable benefits to them and to other individuals or 
communities affected by the condition under investigation. 
19. Every clinical trial must be registered in a publicly accessible database before 
recruitment of the first subject. 
20. Physicians may not participate in a research study involving human subjects unless they 
are confident that the risks involved have been adequately assessed and can be 
satisfactorily managed. Physicians must immediately stop a study when the risks are found 
to outweigh the potential benefits or when there is conclusive proof of positive and beneficial 
results. 
21. Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the inherent risks and burdens to the research subjects. 

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22. Participation by competent individuals as subjects in medical research must be 
voluntary. Although it may be appropriate to consult family members or community leaders, 
no competent individual may be enrolled in a research study unless he or she freely agrees. 
23. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information and to minimize the impact of the study on their 
physical, mental and social integrity. 
24. In medical research involving competent human subjects, each potential subject must 
be adequately informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and potential risks 
of the study and the discomfort it may entail, and any other relevant aspects of the study. 
The potential subject must be informed of the right to refuse to participate in the study or to 
withdraw consent to participate at any time without reprisal. Special attention should be 
given to the specific information needs of individual potential subjects as well as to the 
methods used to deliver the information. After ensuring that the potential subject has 
understood the information, the physician or another appropriately qualified individual must 
then seek the potential subject’s freely-given informed consent, preferably in writing. If the 
consent cannot be expressed in writing, the non-written consent must be formally 
documented and witnessed. DoH/Oct2008 
25. For medical research using identifiable human material or data, physicians must 
normally seek consent for the collection, analysis, storage and/or reuse. There may be 
situations where consent would be impossible or impractical to obtain for such research or 
would pose a threat to the validity of the research. In such situations the research may be 
done only after consideration and approval of a research ethics committee. 
26. When seeking informed consent for participation in a research study the physician 
should be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent should be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
27. For a potential research subject who is incompetent, the physician must seek informed 
consent from the legally authorized representative. These individuals must not be included 
in a research study that has no likelihood of benefit for them unless it is intended to promote 
the health of the population represented by the potential subject, the research cannot 
instead be performed with competent persons, and the research entails only minimal risk 
and minimal burden. 
28. When a potential research subject who is deemed incompetent is able to give assent to 
decisions about participation in research, the physician must seek that assent in addition to 
the consent of the legally authorized representative. The potential subject’s dissent should 
be respected. 
29. Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition that 
prevents giving informed consent is a necessary characteristic of the research population. 
In such circumstances the physician should seek informed consent from the legally 
authorized representative. If no such representative is available and if the research cannot 
be delayed, the study may proceed without informed consent provided that the specific 
reasons for involving subjects with a condition that renders them unable to give informed 
consent have been stated in the research protocol and the study has been approved by a 
research ethics committee. Consent to remain in the research should be obtained as soon 
as possible from the subject or a legally authorized representative. 
30. Authors, editors and publishers all have ethical obligations with regard to the publication 
of the results of research. Authors have a duty to make publicly available the results of their 
research on human subjects and are accountable for the completeness and accuracy of 
their reports. They should adhere to accepted guidelines for ethical reporting. Negative and 
inconclusive as well as positive results should be published or otherwise made publicly 
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declared in the publication. Reports of research not in accordance with the principles of this 
Declaration should not be accepted for publication. DoH/Oct2008 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
31. The physician may combine medical research with medical care only to the extent that 
the research is justified by its potential preventive, diagnostic or therapeutic value and if the 
physician has good reason to believe that participation in the research study will not 
adversely affect the health of the patients who serve as research subjects. 
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best current proven intervention, except in the following circumstances: 
The use of placebo, or no treatment, is acceptable in studies where no current proven 
intervention exists; or 
Where for compelling and scientifically sound methodological reasons the use of 
placebo is necessary to determine the efficacy or safety of an intervention and the patients 
who receive placebo or no treatment will not be subject to any risk of serious or irreversible 
harm. Extreme care must be taken to avoid abuse of this option. 
33. At the conclusion of the study, patients entered into the study are entitled to be informed 
about the outcome of the study and to share any benefits that result from it, for example, 
access to interventions identified as beneficial in the study or to other appropriate care or 
benefits. 
34. The physician must fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never interfere with the patient-physician relationship.  
35. In the treatment of a patient, where proven interventions do not exist or have been 
ineffective, the physician, after seeking expert advice, with informed consent from the 
patient or a legally authorized representative, may use an unproven intervention if in the 
physician's judgement it offers hope of saving life, re-establishing health or alleviating 
suffering. Where possible, this intervention should be made the object of research, designed 
to evaluate its safety and efficacy. In all cases, new information should be recorded and, 
where appropriate, made publicly available.