Phase II Randomised, Double Blind, Placebo Controlled Trial of Neoadjuvant Artesunate in Stage II/III Colorectal Cancer
Phase: PHASE2
Conditions: Stage II/III Colon Cancer, Bowel Cancer
Sponsor: Metanoic Health Ltd.

 
 
Phase II Randomised, Double Blind, Placebo Controlled Trial of 
Neoadjuvant Artesunate in Stage II/III Colorectal Cancer (NeoART- 
M trial) 
 
Protocol ID: 2023-MHL-001 
Publicly available Trial Registration Number ID: NCT02633098 
Protocol Version: 6.0 Date 4 October 2024 
 
CHIEF INVESTIGATOR (CI): 
Professor Sanjeev Krishna MA, MBChB, DPhil, FRCP, ScD, FMedSci 
St George’s ,University of London and Centre for Affordable Diagnostics and Therapeutics 
30 City Road, London 
England EC1Y 2AB 
United Kingdom 
Mobile:  
Email: skrishna@cadt.org.uk 
 
SPONSOR: 
Metanoic Health Limited 
36 Clarkes Avenue 
Worcester Park 
Surrey KT4 8PZ 
England 
United Kingdom 
Email: clinicaltrials@metanoichealth.com 
 
SPONSOR REPRESENTATIVE:  
Name: Dr Isaac John 
Mobile:  
Email: Isaac.John@metanoichealth.com 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Information in this protocol is confidential and should not be disclosed, other than to those directly involved in the execution or the 
ethical/regulatory review of the study, without written authorisation from Centre for Affordable Diagnostic and Therapeutics and its 
affiliates. 
 

                  
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Signature Page and Statement  
 
The Chief Investigator (CI) and the Sponsor representative have discussed this protocol version. The 
investigators agree to perform the investigations and to abide by this protocol except in the case of a medical 
emergency or where departures from the protocol are mutually agreed in writing.  
 
The investigators agree to conduct the trial in compliance with the approved protocol, Malaysian Good Clinical 
Practice and National Pharmaceutical Regulatory Agency (NPRA) Regulations  for Clinical Trial Import License, 
the Malaysian Data Protection Act, local governance policy, the Sponsor’s Standard Operating Procedure 
(SOPs), and other regulatory requirements as amended.  
 
This protocol has been written in accordance with the Sponsor’s procedure and is intended for use at 
Malaysian sites only.  
  
Chief Investigator  
 
Professor Sanjeev Krishna  
MA, MBChB, DPhil, FRCP, ScD, FMedSci  
St George’s, University of London and Centre 
for Affordable Diagnostics and Therapeutics 
30 City Road, London 
England EC1Y 2AB 
United Kingdom 
Signature 
Date 
 
 
4 October 2024 
Sponsor Representative  
Dr Isaac John 
Metanoic Health Limited  
36 Clarkes Avenue 
Worcester Park 
Surrey  
United Kingdom 
 
Signature 
  
 
Date 
 
4 October 2024 
 
Acknowledgements and Protocol contributories  
Professor Sanjeev Krishna and Professor Devinder Kumar (St George’s, University of London) conceived the 
study; Professor Krishna, Professor Kumar, Professor Thomas Efferth (University of Mainz), Professor Peter 
Kremsner (University Hospital Tübingen), Dr Yolanda Augustin (St George’s, University of London), Debbie 
Rolfe (St George’s, University of London), and Nia Al-Samarrai (St George’s Hospital) assisted with trial design. 
Dr Irina Chis Ster (St George’s, University of London) provided statistical expertise in clinical trial design and is 
conducting the statistical analysis. All authors contributed to refinement of the study protocol and approved 
the final manuscript.  
  
 
 
 
 
 
 

                  
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Contents 
1. List of abbreviations ........................................................................................................................ 7 
2. Roles and Responsibilities ............................................................................................................ 10 
3. Study Synopsis ............................................................................................................................. 13 
4. Primary Objective.......................................................................................................................... 16 
4.1 Primary endpoint ........................................................................................................... 16 
5. Secondary Objectives ................................................................................................................... 16 
5.1 Secondary end points ..................................................................................................... 16 
6. Background ................................................................................................................................... 16 
6.1 Study disease ................................................................................................................. 16 
6.2 Investigational Medicinal Product (IMP) ........................................................................... 17 
6.3 Experimental lab work examining the anti-cancer effects of artemisinins. ........................... 18 
6.4 Artemisinins display effects on the cell cycle. .................................................................... 18 
6.5 Artemisinins induce apoptosis in cancer cells. ................................................................... 19 
6.6 Artemisinins display anti-angiogenic effects ..................................................................... 20 
6.7  Artemisinins block tissue invasion and metastasis ............................................................ 20 
6.8 Clinical evidence of anti-tumour effects of artesunate ....................................................... 21 
6.9 Summary ....................................................................................................................... 22 
6.10 Other treatments ......................................................................................................... 22 
6.11 Study Rationale and risk/benefit analysis ........................................................................ 22 
6.12 Assessment & management of potential risk .................................................................. 22 
7. Trial design ................................................................................................................................... 23 
7.1 Overall Design ................................................................................................................ 23 
7.2 Schematic design of trial: Stage II/III Colorectal cancer planned for curative surgery ............ 25 
8. IMP Dosage regimen and rationale .............................................................................................. 26 
8.1 Source of IMPs including placebo .................................................................................... 27 
8.2 Accountability procedures for the IMP(s) ......................................................................... 28 
8.3 Assessment of compliance .............................................................................................. 28 

                  
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8.4 Post-trial IMP arrangements ........................................................................................... 29 
8.5 Name and description of each non-IMP (NIMP) ................................................................ 29 
8.6 Concomitant treatment .................................................................................................. 29 
9. 
Participant Selection criteria ...................................................................................................... 29 
9.1 
Inclusion criteria ....................................................................................................... 29 
9.2   Exclusion criteria .......................................................................................................... 30 
10. Subject/Patient Recruitment process .......................................................................................... 30 
10.1 Participant Recruitment ................................................................................................ 30 
11. Study procedures ........................................................................................................................ 31 
11.1 Informed consent ......................................................................................................... 31 
11.2 Randomisation procedure ............................................................................................. 32 
11.3 Prescribing & Dispensing of IMP .................................................................................... 32 
11.4 Emergency unblinding .................................................................................................. 33 
11.5 Overdose of Trial medication ......................................................................................... 33 
11.6 Discontinuation/withdrawal of participants and stopping rules ........................................ 34 
11.6.1 Discontinuing/withdrawal of participants ............................................................................... 34 
11.6.2 List of criteria for premature discontinuation of the study ........................................................ 34 
11.7 Participant transfers ..................................................................................................... 35 
11.8 Lost to Follow up .......................................................................................................... 35 
Definition of the End of Trial ................................................................................................. 35 
12. Study Assessments .................................................................................................................... 35 
12.1 Screening assessments ................................................................................................. 35 
12.2 Baseline assessments .................................................................................................... 35 
12.3 Treatment procedure ................................................................................................... 36 
12.5 Methods ...................................................................................................................... 38 
12.5.1 Samples ............................................................................................................................... 38 
12.6  
Radiology or any other procedure(s) ....................................................................... 39 
13. Translational research / Pharmacodynamic Studies ................................................................... 39 

                  
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14. Pharmacovigilance ..................................................................................................................... 39 
14.1  Definitions .................................................................................................................. 39 
14.2 Investigator responsibilities relating to safety reporting ................................................... 40 
14.3 Development Safety Update Reports (DSURs) ................................................................. 42 
14.4 Annual Progress/Safety Reports (APRs) .......................................................................... 42 
14.5 Pregnancy .................................................................................................................... 42 
14.6 Reporting Urgent Safety Measures ................................................................................. 42 
14.7 Notification of Serious Breaches of GCP and/or the protocol ............................................ 43 
15. Data management and quality assurance .................................................................................. 43 
15.1 Confidentiality ............................................................................................................. 43 
15.2 Data collection tool ...................................................................................................... 43 
15.3 Incidental findings ........................................................................................................ 44 
15.4 Data handling and analysis ............................................................................................ 44 
16. Archiving arrangements .............................................................................................................. 44 
17. Statistical design ......................................................................................................................... 44 
17.1 Statistical input in trial design ........................................................................................ 44 
17.2 
Endpoints ................................................................................................................. 45 
17.2.1 
 Primary endpoints ...................................................................................................... 45 
17.2.2 
 Secondary endpoints .................................................................................................. 45 
17.3 Sample size and recruitment ......................................................................................... 45 
17.3.1 Sample size calculation .......................................................................................................... 45 
17.3.2 Planned recruitment rate ...................................................................................................... 48 
17.3.3 Statistical analysis plan .......................................................................................................... 48 
17.4 Randomisation ............................................................................................................. 50 
17.5 Interim analysis ............................................................................................................ 51 
17.6 Other statistical considerations ..................................................................................... 51 
18. Committees involved in the trial .................................................................................................. 51 
19. Direct access to source data ....................................................................................................... 52 

                  
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20. Site approval and ongoing regulatory compliance ...................................................................... 52 
21. Monitoring plan for the trial ......................................................................................................... 52 
22. Finance ....................................................................................................................................... 53 
23. Insurance and Indemnity............................................................................................................. 53 
24. Intellectual Properties and development policy ........................................................................... 53 
25. Publication Policy ........................................................................................................................ 54 
25.1 Before the official completion of the Trial ....................................................................... 54 
25.2 Up to 180 days after the official completion of the Trial ................................................... 54 
25.3 Beyond 180 days after the official completion of the Trial ................................................ 55 
26. Statement of compliance ............................................................................................................ 55 
27. List of Protocol appendices ......................................................................................................... 55 
28. References ................................................................................................................................. 56 
8.6 Concomitant treatment .................................................................................................. 66 
12.2 Baseline assessments .................................................................................................... 66 
At sites participating in the biomarker sub-study, a pre-treatment blood sample will be taken for study 
molecular analyses. ............................................................................................................. 66 
17.3.3 Statistical analysis plan .......................................................................................................... 67 
 
 
 

                  
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1. List of abbreviations 
AE                                                    Adverse Event 
AR 
Adverse Reaction 
ATM/ATR 
Ataxia telangiectasia mutated/Ataxia telangiectasia and Rad3-related protein 
ATP 
Adenosine triphosphate 
AUC 
Area under the curve 
BMI 
Body Mass Index 
CA 
Competent Authority 
CADT 
Centre for Affordable Diagnostics and Therapeutics 
Cape-OX 
Capecitabine-Oxaliplatin 
CEA 
Carcinoembryonic Antigen 
CI 
Chief Investigator 
Chk1/Chk2 
Checkpoint kinase 1/Checkpoint kinase 2 
Cip/Kip 
CDK interacting protein/Kinase inhibitory protein 
CD31 
Cluster of Differentiation 31 
CRC 
Colorectal Cancer 
CRC 
Clinical Research Centre 
CRF 
Case Report Form 
CRM 
Clinical Research Malaysia 
CT 
Computed tomography 
CTA 
Clinical Trial Authorisation 
CTC 
Common Toxicity Criteria 
CTIMP 
Clinical Trial of Investigational Medicinal Product 
DHA 
Dihydroartemisinin 
 
DNA 
Deoxyribonucleic acid 
DDSB 
DNA double–strand breaks 
DDR 
DNA damage response 
DMC 
Data Monitoring Committee 
DSUR 
Development Safety Update Report 
EGFR 
Epidermal Growth Factor Receptor 
eGFR 
Estimated Glomerular Filtration Rate 
EUCTD 
European Clinical Trials Directive 
EudraCT 
European Clinical Trials Database 
JePEM 
Jabatan Etika Penyelidikan Manusia USM 
FAK 
Focal Adhesion Kinase 
FDT 
First Definitive Treatment 
5FU 
Fluorouracil 
FOLFIRI 
Fluorouracil-Irinotecan  
FOLFOX 
Fluorouracil-Oxaliplatin 
GCP 
Good Clinical Practice 
GCSF 
Granulocyte colony-stimulating factor 
GFR 
Glomerular Filtration Rate 
g/l 
grams per litre 
GP 
General Practitioner 
Hb 
Haemoglobin 

                  
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HIF-1α 
Hypoxia induced factor - 1α 
HTA 
Human Tissue Authority 
IB                                           
Investigator Brochure 
ICF 
Informed Consent Form 
ID 
Identification 
IIT 
Investigator Initiated Trial 
IMP 
Investigational Medicinal Product 
IP 
Investigational Product 
IP  
Intellectual Property 
ISF 
Investigator Site File 
ISRCTN 
International Standard Randomised Controlled Trial Number 
ITT 
Intention to treat 
KG 
Kilogram 
KRAS 
Kirsten rat sarcoma viral oncogene homolog 
LFT 
Liver Function Test 
MA                                         
Marketing Authorisation 
MAPK 
Mitogen-activated protein kinase 
MG 
Milligram 
ML 
Millilitre 
MMPs 
Metalloproteinases 
MMR 
Mismatch Repair 
MoU 
Memorandum of Understanding 
MOH 
Ministry of Health 
MOHE 
Ministry of Higher Education 
MRI 
Magnetic Resonance Imaging 
MS                                                   Member State 
NCAM 
Neural cell adhesion molecule 
NCI 
National Cancer Institute 
NF-kB 
Nuclear factor kappa-light-chain-enhancer of activated B cells 
NHS 
National Health Service  
NIMP 
Non- Investigational Medicinal Product 
NoK 
Next of Kin 
NPRA 
National Pharmaceutical Regulatory Agency 
OD 
Once daily  
PBMC 
Peripheral blood mononuclear cell 
PDGF 
Platelet-derived growth factor 
PFS 
Progression free Survival 
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
Plts 
Platelets  
PO 
Oral administration 
pRb 
Retinoblastoma protein 
QA                                                   Quality Assurance 
QC 
Quality Control 
QOL 
Quality of Life 
QP 
Qualified Person  
R&D  
Research & Development   

                  
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RCT 
Randomised Control Trial 
REC 
Research Ethics Committee 
ROS 
Reactive Oxygen Species 
RSI 
Reference Safety Information 
SAR 
Serious Adverse Reaction 
SAE 
Serious Adverse Event 
SDV 
Source Document Verification 
SGUL 
St George’s, University of London 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure  
SSAR 
Suspected Serious Adverse Reaction 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
UM 
University of Malaya 
TF 
Transferrin 
TIMP 
Tissue inhibitors of metalloproteinase 
TMF 
Trial Master File 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
TTP 
Time to progression 
ULN 
Upper limit of normal 
VEGF 
Vascular endothelial growth factor 
WCC 
White Cell Count 
WHO 
World Health Organisation 
 
 

                  
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2. Roles and Responsibilities 
Chief Investigator (CI): 
 
Professor Sanjeev Krishna, MA, MBChB, DPhil FRCP,    
 
 
ScD, FMedSci  
St George’s ,University of London and Centre for Affordable Diagnostics 
and Therapeutics, University of Malaya 
30 City Road, London 
EC1Y 2AB England  
United Kingdom. 
Mobile 
Email: skrishna@cadt.org.uk 
 
 
Co- Principal Investigator (PI): 
Dr Yolanda Augustin 
St George’s, University of London and Centre for Affordable Diagnostics 
and Therapeutics 
30 City Road, London 
England EC1Y 2AB 
United Kingdom 
Mobile: 
Email: yaugustin@cadt.org.uk 
 
 
Dr Mohana Raj a/l Thanapal 
Hospital Kuala Lumpur  
Jalan Pahang 50586 
Kuala Lumpur  
Mobile:  
Email:  
 
 
 
Dr Eng Jie Yi 
Hospital Umum Sarawak 
Jalan Hospital  
93586 Kuching 
Sarawak 
Mobile:  
Email:  
 
 
Dr Nil Amri B Mohamed Kamil 
Hospital Sultanah Bahiyah,  
Km6, Jalan Langgar,  
05460 Alor Setar, Kedah 
Mobile:  
Email:  
 
 
Dr Soo Hoo Hwoei Fen  
Hospital Pulau Pinang  
Jalan Residensi, 10990 Georgetown 

                  
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Pulau Pinang  
Mobile:  
Email:  
 
 
Dr Mohd Razali Bin Ibrahim 
Hospital Sungai Buloh  
Jalan Hospital  
47000 Sungai Buloh 
Mobile:  
Email:  
 
Dr Mohd Syafferi Bin Masood 
Hospital Sungai Buloh  
Jalan Hospital  
47000 Sungai Buloh 
Mobile 
Email:  
 
Dr Ruben Gregory Xavier 
Pusat Perubatan Universiti Malaya 
Lembah Pantai,59100 Kuala Lumpur 
Email: rubengregory@ummc.edu.my 
 
 
NeoART Clinical Trial  
                        Dr Nafeesa Mat Ali 
Co-ordinator:  
St George’s, University of London and Centre for Affordable 
 
Diagnostics and Therapeutics  
 
 
  
 
 
 
 
         30 City Road, London 
 
 
 
 
         England EC1Y 2AB  
 
 
 
 
         United Kingdom 
 
 
 
 
         Mobile: + 
 
 
 
 
         Email: nmatali@cadt.org.uk 
 
Independent Statistician: 
        Professor Bertrand Lell 
 
 
 
 
        Centre de Recherches Médicales Lambaréné (CERMEL)     
 
 
 
 
        Gabon 
 
 
 
 
        Email: Bertrand.lell@cermel.org 
 
 
 
 
 
 
 
Surgical Oncology Trial Advisor:          Professor Davinder Kumar, MBBS, PhD, FRCS 
 
 
 
 
 
 
        Mobile:  
 
 
 
   
        Email: dkumar@sgul.ac.uk 
 
Lead Research Pharmacist: 
        Tai Yi Wern 
 
        Pharmacy Main Store, 
 
        First Floor, Menara Utama, 
 
        UMMC, Lembah Pantai, 59100 KL, Malaysia. 
 
        Mobile: + 60 (0)7949 2831 
 
        Email: ywtai@ummc.edu.my 

                  
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NeoART Study team  
emergency number: 
 
        +60 (0) 17 2152964  
 
 
Trial Management Group (TMG): 
Membership will consist of personnel involved in daily    operational 
issues in the management of the trial and will act upon 
advice/recommendations received by the sponsor and/or the Data 
Monitoring Committee. 
 
Membership:  Professor Sanjeev Krishna, Dr Yolanda Augustin, Dr 
Nafeesa Mat Ali, Professor Devinder Kumar, Sponsor’s Metanoic 
Health Limited representative. 
 
Trial Steering Committee (TSC):  
Membership will consist of personnel directly involved in the trial 
and/or independent individuals. The TSC will concentrate on the 
progress of the trial in relation to protocol compliance and review of 
any participant safety considerations including the review of any 
recommendations made by the Data Monitoring Committee if 
relevant to the trial and to advise the Sponsor of any decisions. 
 
Membership: 
Chair – Mr Clive Whitehouse  
Independent expert – Professor Vikram Mathews 
Co-Investigator – Mr Nirooshan Rajendran, Professor Thi 
Thirumalaisamy P Velavan 
Lay persons – Mr Duncan McNair, Mr Clive Whitehouse 
 
Data Monitoring Committee (DMC): 
 
 An independent committee established by the Sponsor to    
 
 assess at intervals the progress of the clinical trial, the safety   
 data and the critical efficacy end points and to 
recommend the Trial Steering Committee whether to continue, 
modify or stop the trial.              
 
Membership;   Professor Jack Cuzick, Professor Ajit Lalvani, Dr Pan 
Pantziarka 
 
 
                  
 
 
 
 
 
 
 
 
 

                  
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3. Study Synopsis 
Brief Title 
NeoART - M Trial 
Official title:  
Phase II Randomised, Double Blind, Placebo Controlled Trial of 
Neoadjuvant Artesunate in Stage II/III Colorectal Cancer  
Brief Summary 
This is a Phase II randomized, double-blind, placebo-controlled trial of 
neoadjuvant artesunate given orally as a dose of 200 mg once a day for 14 days 
to patients with histologically confirmed Stage II/III colorectal cancer (CRC) 
awaiting surgical treatment with curative intent. 
Sponsor reference 
number: 
2023-MHL-001 
Public database Trial  
identifier number 
Clinicaltrials.gov NCT02633098 
Study type & Phase 
Phase II Clinical Trial of an Investigational Medicinal Product (CTIMP) 
Study Design 
Prospective, randomised, double blind, placebo controlled 
Study Population 
Patients with colorectal cancer suitable for surgical resection 
Condition 
Stage II/III colorectal cancer 
Study Group/cohort (s) 
Patients with Stage II/III colorectal cancer planned for curative surgery 
  
Inclusion criteria :  
 
1.   Aged 18 or over 
 
2.   Histologically proven single primary site colorectal 
 adenocarcinoma or high grade dysplasia plus unequivocal 
 radiological evidence of invasive cancer 
 
3.   Stage II/III colorectal cancer planned for surgical resection and no clinical 
indication for neoadjuvant preoperative chemotherapy/chemoradiation 
therapy 
 
4.   WHO performance status 0,1 or 2 
 
5.   Adequate full blood count:  
   White Cell Count (WCC) >3.0 x 109 /l;  
   Platelets >100 x 109/l;  
   Haemoglobin (Hb)  >80g/L 
 
6.   Adequate renal function :  

                  
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      Glomerular Filtration Rate >30ml/min by Cockcroft-Gault     
       formula  
 
7.   Adequate hepatobiliary function :  
      Total bilirubin < 3 x Upper limit normal 
 
8.   Female participants of child bearing potential must have a   
      negative pregnancy test < 72 hours prior to initiating study     
      intervention and agree to avoid pregnancy using adequate,   
      medically approved contraceptive precautions for up to 6   
      weeks after the last dose of study treatment intervention 
 
9.   Male participants with a partner of childbearing potential   
      must agree to use adequate, medically approved  
      contraceptive precautions during and for up to 6 weeks  
      after the last dose of the study treatment intervention 
 
10. Patient able and willing to provide written, informed    
      consent for the study 
 
Exclusion criteria: 
 
1. Contraindication to the use of artesunate due to hypersensitivity 
 
2. Pregnancy or lactation 
 
3. Male or female participants unwilling to use an effective method of birth 
control (either hormonal in the form of the contraceptive pill or barrier 
method of birth control accompanied by the use of a proprietary 
spermicidal foam/gel or film); or agreement of true abstinence from time 
consent is signed until 6 weeks after the last dose of study treatment 
intervention (i.e. withdrawal, calendar, ovulation, symptothermal and post 
ovulation methods are not considered acceptable methods)  
 
4. History of immunosuppression  
 
5. History of hearing or balance problems 
  
6. Weight < 52 kg or > 110 kg 
 
7. Other planned intervention, apart from standard of care 
 
8. Any other malignant disease diagnosis within the preceding 2   
 years with the exception of non-melanomatous skin cancer  
 and carcinoma in situ  
 
9.  Lactose intolerance 
Target number of 
participants: 
200 patients in total  
The study will be run in 3 countries with the following recruitment targets: 
 

                  
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1.NeoART  -  Malaysia: 120 patients 
2. NeoART - UK:  34 patients 
3. NeoART -Vietnam: 46 patients 
Criteria for evaluation: 
Primary outcome measure :  
 
The primary outcome measure is recurrence free survival 2 years after surgery. 
 
Secondary outcome measure(s) :  
 
• 
Recurrence free survival at 5 years 
• 
Overall survival at 2 and 5 years 
• 
Colon cancer specific death at 2 and 5 years 
• 
Artesunate drug related toxicity 
• 
Adverse events 
• 
Pathological assessment of tumour regression (involvement of lymph 
nodes ; serosa ; resection margin) 
• 
Quality of life (assessed using validated EuroQol EQ-5D, EORTC QLQ C-
30 and EORTC QLQ CR29 quality of life tools) 
• 
Surgical morbidity/mortality 
• 
Predictive value of tumour biomarkers in terms of predicting response 
to artesunate therapy 
• 
Biomarker and molecular profiling studies  
Sources of funding: 
Funded by the Malaysian Federal Government, Selangor State Government, 
charitable and philanthropic donations provided financial support for the 
study. 
 
Start date: 
Open to recruitment in Malaysia: Q4 2024 
Anticipated primary 
recruitment completion 
date: 
Q4 2026 
Sponsor 
 Metanoic Health Limited 
Contact names 
 
Chief Investigator 
Professor Sanjeev Krishna 
Mobile: +44 (0) 7931901724 
Email: skrishna@cadt.org.uk 
 
Sponsor Representative: 
Name: Dr Isaac John 
Phone: +44 (0) 7798566612 
Email: Isaac.john@metanoichealth.com 
 
Team NeoART Emergency number: +60 (0) 172152964 
Email: clinicaltrials@metanoichealth.com 

                  
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4. Primary Objective 
The primary objective of the study is to determine if neoadjuvant oral artesunate improves progression free 
survival at 2 years in Stage II/III colorectal cancer compared to standard treatment with surgery alone +/- 
adjuvant post-operative chemotherapy where indicated.  
 
The primary outcome measure for the comparison of the artesunate versus placebo group is recurrence free 
survival 2 years after surgery. 
5. Secondary Objectives 
• 
To assess the impact of neoadjuvant artesunate on recurrence free survival at 5 years post 
randomisation 
• 
To assess the impact of neoadjuvant oral artesunate on overall survival at 2 and 5 years post-
randomisation 
• 
To assess the tolerability of neoadjuvant artesunate 
• 
To assess the impact of artesunate treatment on patient quality of life 
• 
To assess the nature and frequency of surgical complications following neoadjuvant artesunate 
treatment 
• 
To assess the prognostic and predictive value of tumour biomarkers 
• 
To conduct biomarker and molecular profiling studies 
 
• 
Recurrence free survival at 5 years 
• 
Overall survival at 2 and 5 years 
• 
Colon cancer specific death at 2 and 5 years 
• 
Artesunate drug related toxicity 
• 
Adverse events 
• 
Pathological assessment of tumour regression (involvement of lymph nodes ; serosa ; resection 
margin) 
• 
Patient Quality of Life (assessed using validated EuroQol EQ-5D, EORTC QLQ C-30, EORTC QLQ C-29 
quality of life tools) 
• 
Surgical morbidity/mortality 
• 
Predictive value of tumour biomarkers in terms of predicting response to artesunate therapy 
• 
Biomarker and molecular profiling studies 
6. Background 
Colorectal cancer is the third most common cancer worldwide and represents a significant health care burden 
with an incidence of one million new cases per year (Ferlay et al. 2012). Each day in the UK, 110 new colorectal 
cancer cases are diagnosed, with over 50 % of new cases presenting with locally advanced disease and older 
patients being particularly at risk of death (UK CR., 2014). Current standard multimodality treatment with 
surgery, chemotherapy and radiotherapy has not thus far increased 5 year overall survival beyond 60%. 

                  
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Cancer development in humans is a complex multistep process defined by 8 key hallmarks: sustaining 
proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, 
inducing angiogenesis, activating invasion and metastasis, reprogramming energy metabolism and evading 
immune destruction (Hanahan&Weinberg., 2011).  
 
The Quasar study and meta-analysis have shown that postoperative chemotherapy improves survival in Stage 
III colorectal cancer and some Stage II colorectal cancers with negative prognostic features (QUASAR., 2007; 
Price et al., 2013). However for a significant number of patients the current treatment paradigm of surgery 
followed by adjuvant chemotherapy fails to eradicate locoregional disease and distant micrometastases, 
resulting in disease recurrence. Current adjuvant therapy in colorectal cancer includes combination 
chemotherapy with intravenous 5-fluorouracil or oral capecitabine in combination with oxalipatin (FOLFOX or 
Cape-OX) (Price et al., 2013). In the metastatic colorectal cancer setting, current treatment paradigms include 
5-FU based chemotherapy regimens combined with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) alongside 
biologically targeted agents such as the humanised monoclonal anti-vascular endothelial growth factor (VEGF) 
antibody bevacizumab and epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab 
(Price et al., 2013). These regimens however carry significant toxicity profiles and remain unaffordable for the 
majority of patients in developing countries. 
 
Neoadjuvant pre-operative chemotherapy has been shown to be more effective in a number of other cancer 
types supporting the theory that optimal neoadjuvant systemic therapy at the earliest opportunity may be 
more effective at eradicating distant metastases compared to adjuvant therapy delivered following the delay 
and immunological stress of surgery. Colorectal cancer metastases have a short doubling time (Tanaka et al., 
2004 ; Finlay et al., 1988) and it has been postulated that micrometastatic tumour growth may be further 
accelerated in the early post operative period by enhanced growth factor activity (Zeamari et al., 2004 ; Fahmy 
et al., 2003 ; Schelfhout et al., 2002). Neoadjuvant therapy also confers the potential advantage of primary 
tumour shrinkage, thereby reducing the risk of incomplete surgical excision and tumour shedding 
contaminating the surgical field during surgery (Nelson et al., 2001). This may have particular relevance for 
transcoeliac spread with peritoneal metastases found in up to 50% of patients with locoregional relapse 
(Assehorn et al., 1999). Neoadjuvant preoperative therapy in colorectal cancer started within days of 
diagnostic and staging investigations provides an unique treatment paradigm that could potentially eradicate 
micrometastases not managed with current standard treatment regimes. Indeed, neoadjuvant combination 
chemotherapy +/- targeted anti-EGFR monoclonal antibody therapy with panitumumab forms the basis of the 
current FOxTROT trial (FoxTROT Collaborative Group., 2012). As previously mentioned, these regimens are, 
however, often associated with significant side effects and result in a delay in surgery whilst patients recover. 
A well tolerated, affordable, novel anticancer agent that could be given to patients whilst they wait for surgery, 
without causing a surgical delay due to treatment related toxicity, would therefore have a significant clinical 
impact on patient care. 
 
Artesunate 
 
Artemisinins are a family of sesquiterpene trioxane anti-malarial agents derived from Sweet wormwood 
(Artemisia annua L) that have been used in traditional Chinese medicine for centuries to treat fevers.  
Artesunate, artemether and arteether are derivatives of artemisinin that are converted into their active 
metabolite dihydroartemisinin (DHA). Artesunate is approved for the treatment of uncomplicated and 
multidrug-resistant malaria and is on the WHO list of Essential Medicines (WHO., 2015). Artesunate has a 
hemisuccinate group which confers substantial water-solubility and high oral bioavailability and therefore a 
convenient oral route of administration. Artesunate has a good safety and tolerability profile, having been 
used to treat tens of millions of adults and children globally (Hien et al., 1994 ; Kremsner et al., 2004). It has a 
renal mode of excretion and is rapidly eliminated with a short metabolic half life of hours (WHOPAR., 2011).  

                  
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Several reviews have examined the evidence for the anti-cancer effects of artemisinins in detail (Ho et al., 
2014 ; Krishna et al., 2008). Studies of artemisinins in in vitro experiments and animal models have 
demonstrated broad anti-cancer activity including pro-apoptotic, anti-proliferative, anti-angiogenesis and 
anti-metastatic effects (Efferth et al., 2001,2007 ; Anfonsso et al., 2006 ; Krishna et al., 2008). Artesunate has 
demonstrated cytotoxic effects against a number of cancer cell lines including colon, breast, leukaemia, 
melanoma, central nervous system, ovarian, prostate and renal cancer (Efferth et al., 2001, 2003). The active 
metabolite of artemisinin, dihydroartemisinin (DHA), has also displayed antineoplastic effects on breast, 
glioma, colon, lung, ovarian and pancreatic cancer cell lines (Singh & Lai., 2001 ; Kim et al., 2006 ; Lu et al., 
2011 ; Mu et al., 2007 ; Chen et al., 2009 ; Hooft van Huijsduijnen., 2013).  
 
The exact underlying mechanisms remain to be elucidated but include actions on cell cycle proteins that 
control transit through cell cycle G1 phase restriction, induction of apoptosis, inhibition of NF-kB, 
antioangiogenic and antimetastatic effects. Iron-mediated endoperoxide bridge cleavage and the formation 
of toxic free radicals are thought to be key mechanisms underlying the anti-cancer effects of artesunate 
(Efferth et al., 2003, 2004). Cancer cells are highly proliferative, requiring a heavy iron load which acts as a 
cofactor in the synthesis of deoxyriboses prior to cell division (Daniels et al., 2012). Artemisinins induce cellular 
damage via the formation of reactive oxygen species (ROS) such as hydroxyl and superoxide anion radicals. 
When free iron is available, artemisinins are converted into a highly potent alkylating radical, capable of 
inducing direct oxidative damage in cancer cells (Efferth et al., 2003, 2004). Cancer cells frequently 
overexpress the transferrin (TF) receptor. Increased antitumor activity has been observed in human liver 
hepatocellular carcinoma and lung adenocarcinoma cell lines with increased TF receptor adducts (Yang et al., 
2014). Artemisinin–transferrin conjugates have been shown to possess higher anti-cancer efficacy than 
artemisinins alone (Lai et al., 2009 ; Nakase et al., 2008, 2009). For example, a DHA–transferrin conjugate has 
demonstrated at least 280 times more potent anti-cancer activity in breast cancer cells compared to normal 
breast cells (Xie et al., 2009).  
 
Artesunate has also been shown to induce oncosis in renal cancer cell lines (Jong et al., 2015). Increased levels 
of calpain-1 and calpain-2 expression and decreased levels of α-tubulin expression were exhibited in cell lines 
treated with artesunate. Calpains are a family of calcium-dependent cysteine proteases that exert proteolytic 
cleavage on a number of cellular substrates, including cytoskeletal proteins. In oncosis, ion pumps are affected 
by adenosine triphosphate (ATP) depletion, leading to the collapse of mitochondrial potential resulting in 
cytomembrane destruction and the accumulation of reactive oxygen species (ROS). Downregulation of cyclin 
D1, c-MYC, survivin, c-Met, EGFR, Src, FAK and α-tubulin expression were also observed. 
 
Berdelle et al. (2011) showed that artesunate induced oxidative deoxyribonucleic acid (DNA) damage, 
sustained DNA double-strand breaks (DDSB) and activated Ataxia telangiectasia mutated/Ataxia telangiectasia 
and Rad-3 related protein (ATM/ATR) damage response in glioblastoma cell lines. Artesunate was shown to 
be a powerful inducer of oxidative DNA damage, which was dose dependent and paralleled by cell death via 
apoptosis and necrosis. Artesunate was also shown to provoke a DNA damage response (DDR) with 
phosphorylation of ATM/ATR, Chk1 and Chk2 proteins. Wang et al. (2015) showed that artesunate induced 
oxidative stress, DNA double-strand breaks (DSB), downregulated RAD51 foci and homologous recombination 
repair (HRR), thereby impairing DSB repair in ovarian cancer cell lines. 
 
Cell growth and repair require progression through the cell cycle which is controlled by a series of cyclins and 
cyclin-dependent kinases. Inhibitors of cell division include the cip/kip family of inhibitory proteins such as 
p16, p21, p27 and p57. Recent studies have shown that artemisinins are capable of inducing cell cycle arrest 
via a number of pathways. Artesunate  was shown to markedly impede the growth of colon carcinoma, 

                  
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leukemia, small cell lung carcinoma and glioma cell lines by inducing cell cycle arrest at G2/M phase 
(Steinbruck et al., 2010) and inducing G1 cell cycle arrest in human breast cancer cell and nasopharyngeal 
cancer cell lines (Tin et al., 2012). Artesunate induced cell cycle arrest at the G2/M phase and induced oncosis-
like cell death in renal cancer cell lines (Jong et al., 2015). Decreased levels of cyclin B, cyclin D1 and 
transription factor E2F1 were also observed. 
 
In human nasopharyngeal cancer cells, artemisinin upregulated p16 and p27 and suppressed the level of cyclin 
D1, cyclin E, CDK2, CDK4 and CDK6 (Wu et al., 2011). Artemisinins have been shown to induce G1 cell cycle 
arrest by deactivating the retinoblastoma protein (pRb), a mediator of cell cycle progression and disrupt 
transcription of the cyclin CDK4 promoter in prostate cancer lines (Willoughby et al., 2009). DHA was also 
found to inhibit cell cycle progression from G0/G1 into S phase in pancreatic cell lines via reduction of CDK2, 
CDK4 and CDK6, cyclin E and NF-κB. Levels of the p27 inhibitory protein were amplified (Chen et al., 2010). 
 
Liu et al. (2010) showed that artesunate caused dose dependent decreases in cell numbers in colorectal, breast 
and lung cancer cell lines via cytotoxic and cytostatic mechanisms. Artesunate was found to alter proteins that 
regulate G1 transit. Levels of CDK4 and cyclin proteins were reduced in a dose dependent manner along with 
concomitant reductions in pRb protein. Levels of the cyclin-dependent kinase p21 inhibitory protein were 
increased. Artesunate induced cytotoxicity was enhanced by a recovery phase which was associated with an 
easing of the G2 blockade and a concomitant increase in the sub-G1 (apoptotic) cell phase in all 3 cell lines.  
 
Artesunate has been shown to induce radiosensitivity in cervical cancer cell lines by inducing apoptosis and 
G2/M cell cycle arrest (Luo et al., 2014). Radiosensitisation with artesunate has also been shown in 
glioblastoma cell lines by diminishing expression of the anti-apoptotic protein survivin (Reichert et al., 2012) 
and lung cancer cell lines by increasing nitrous oxide production and associated signal transduction pathways, 
to induce cell cycle arrest in G2/M phase (Zhao et al., 2011). 
 
Apoptosis (programmed cell death) is maintained by a complex balance between a family of pro-apoptotic 
proteins (BAX, BAK, BAD, Bid) and anti-apoptotic proteins (Bcl-2 and Bcl-xl) (Hanahan&Weinberg., 2011). 
When cells detect DNA damage, tumour suppressor protein TP53 is upregulated, leading to increased levels 
of pro-apoptotic proteins and cytochrome c (caspase activator) leading to programmed cell death. 
Artemisinins have been shown to activate BAX induction of cytochrome c in human colon cancer cell lines 
resulting in apoptosis (Riganti et al., 2009). Similar effects have been seen in human lung adenocarcinoma (Lu 
et al., 2009) and prostate cancer cell lines (Nakase et al., 2009). Artesunate has been shown to induce 
apoptosis in leukemic T cells and breast cancer cell lines via iron dependent ROS formation resulting in 
cytochrome c release and cleavage of procaspases-2, 3, 8 and 9 (Efferth et al., 2007; Hamacher- Brady et al., 
2011).  
 
Lu et al. (2015) showed that dihydroartemisinin (DHA) induced apoptosis is associated with inhibition of 
sarco/endoplasmic reticulum calcium ATPase activity in colorectal cancer. Artesunate was found to inhibit 
proliferation, enhance apoptosis and arrest the cell cycle at G0/G1. Intracellular calcium concentrations were 
also significantly increased after artesunate treatment. The expression of CAAT/enhancer binding protein 
homologous protein (CHOP) in a DHA-treated colorectal cancer cell line was upregulated, as was the 
expression of pro-apoptotic protein Bax with a reduction in levels of anti-apoptotic protein Bcl-2. An increase 
in Bid accompanied increased activation of caspase-3 in cancer cells exposed to DHA. 
 
Li et al. (2007) showed that artesunate suppressed proliferation and promoted apoptosis of colorectal cancer 
cells in a dose-dependent manner. Immunohistochemical staining showed membranous translocation of 
regulator protein beta-catenin and inhibition of unrestricted activation of the Wnt/beta-catenin pathway. In 
vivo studies showed that artesunate significantly slowed the growth of colorectal human tumor xenografts. 

                  
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Bioluminescent imaging showed that artesunate decreased the physiological activity of tumor xenografts and 
delayed the development of liver metastases.  
 
Yang et al. (2014) showed that artesunate induced apoptotic cell death in cervical and hepatocellular cancer 
cell lines. Artesunate accumulated in lysosomes and activated lysosomal function via promotion of lysosomal 
V-ATPase assembly. Lysosomes function upstream of mitochondria in the production of reactive oxygen 
species (ROS). Lysosomal iron is required for lysosomal activation. Artesunate treatment induced 
mitochondrial ROS production. Artesunate-induced cell death was mediated by release of iron in the 
lysosomes, which resulted from the lysosomal degradation of ferritin, an iron storage protein, and is 
postulated to be one mechanism through which artesunate may have a cytotoxic effect on cancer cells. 
 
Du et al. (2010) showed dose dependent pancreatic tumour regression in xenograft models treated with 
artesunate. Artesunate treated cells showed loss of mitochondrial membrane potential, undergoing caspase-
independent and non-apoptotic cell death in the presence of reactive oxygen species (ROS). Artesunate has 
also been shown to induce dose-dependent DNA damage and apoptosis in embryonal rhabdomyosarcoma cell 
lines via the production of ROS and induction of the p38 mitogen-activated protein kinase (MAPK) pathway 
(Beccafico et al., 2015).  
 
Angiogenesis plays a vital role in cancer cell growth and development. Isolated tumor cells without an 
adequate nutrition and oxygen supply display a growth restriction of about 1–2 mm3. Cancer cells require pro-
angiogenic stimuli such as metalloproteinase (MMP) and vascular endothelial growth factor (VEGF) and a 
reduction in anti-angiogenic factors such thrombospondin and tissue inhibitor of metalloproteinase (TIMP) to 
maintain a viable blood supply required for growth (Hanahan & Weinberg., 2011). Under hypoxic conditions, 
hypoxia induced factor (HIF-1α) and nuclear factor-κB (NF-κB) are activated resulting in transcription of VEGF 
and angiogenesis.  Artemisinins were shown to reduce the levels of HIF-1α and VEGF in mouse embryonic 
stem cells (Wartenberg et al., 2003). In a mouse lung carcinoma model, administration of artemisinin resulted 
in a reduction in VEFG-C and lymphangiogenesis (Wang et al., 2008).  Artesunate also suppressed levels of 
VEGF and KDR/flk-1 resulting in reduced tumor growth in BALB/c nude mice implanted with human ovarian 
cancer cells (Chen et al., 2004), in Kaposi's sarcoma (KS-IMM) xenograft mice  (Dell'Eva et al., 2004)  and in a 
rat glioma model (Wu et al., 2009). Artesunate was also shown to exert anti-angiogenic effects on renal cancer 
cells in vitro in a dose-dependent manner (Jong et al., 2015). Following treatment with artesunate, renal cell 
tumours in subcutaneous xenografts models showed decreased levels of proliferation marker Ki-67 and 
reductions in mean microvessel density compared to controls. 
 
A key hallmark of cancer cells is their ability to detach from the primary tumour, degrade the extracellular 
matrix and metastasise through the bloodstream (Hanahan& Weinberg., 2011). Metalloproteinases (MMPs) 
play a critical role in tumour migration, invasion and metastases via degradation of the extracellular matrix. E-
cadherin is an important cell adhesion molecule. One study in human melanoma cells, showed that artemisinin 
was able to reduce MMP2 levels thereby blocking cell migration (Buommino et al., 2009). In human pancreatic 
and ovarian cancer cells lines, DHA suppressed the levels of MMP2, inhibiting NF-κB and metastases (Wang et 
al., 2011 ; Wu et al., 2012). Similarly, artesunate was shown to abrogate MMPs and NF-κB activity, thereby 
blocking metastases in non-small cell lung cancer lines. Artemisinins downregulated the levels of MMP2 and 
TIMP-2 whilst up-regulating E-cadherin in hepatocarcinoma cells lines (Weifeng et al., 2011). Artesunate has 
been shown to upregulate the expression of adhesion molecules integrin β1 and neural cell adhesion molecule 
(NCAM) in embryonal rhabdomyosarcoma cells, thereby reducing migration and invasion (Beccafico et al., 
2015).  
 

                  
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The Wnt/beta-catenin cell signalling pathway has been identified as a critical pathway in colorectal 
carcinogenesis (MacDonald et al., 2009 ; Clevers et al., 2006). Artesunate has been shown to inhibit the 
hyperactive Wnt/beta-catenin pathway in colorectal cancer cell lines, thereby attenuating cancer cell growth 
(Li et al., 2008). The anticancer effects of artesunate on three colorectal cancer cell lines were compared and 
the relationship between drug sensitivity and malignant tumour phenotype analysed. In poorly-differentiated 
colorectal cancer cell line – CLY, beta-catenin accumulation and loss of E-cadherin was seen in the nucleus; in 
moderately-differentiated Lovo cells these two proteins accumulated in the cytoplasm; and in well-
differentiated HT-29 cells beta-catenin and E-cadherin localized to the cell membrane. In vitro and in vivo, 
poorly- or moderately-differentiated CLY and Lovo cells were more susceptible to artesunate treatment than 
well-differentiated HT-29. The response of CLY and Lovo to artesunate were associated with membranous 
translocation of beta-catenin and increased expression of E-cadherin, which indicated the inhibition of the 
hyperactive Wnt/β-catenin signaling pathway and the reversion of the epithelial to mesenchymal transition, 
respectively. Artesunate has also been shown to induce apoptosis via inhibition of the Wnt/β-catenin pathway 
in myelodysplastic syndrome (MDS) cells (Xu et al., 2015). 
 
A number of case reports have reported antitumour effects of artesunate in small groups of patients. One 
case study in a patient with laryngeal squamous cell carcinoma described a 70% reduction in tumor size after 
two months of artesunate treatment (Singh & Verma., 2002). Another case study reported a slowing of disease 
progression in a pituitary macroadenoma patient treated with artemether for 12 months (Singh & Panwar., 
2006). Artesunate was also found to control tumor growth and improve survival in metastatic uveal melanoma 
(Berger et al., 2005). One patient with stage IV uveal melanoma experienced objective regression of splenic 
and lung metastases following the addition of artesunate to dacarbazine and remained alive 47 months after 
first diagnosis. An open label pilot study of dihydroartemisinin in 10 patients with advanced cervical cancer 
reported that treatment was well tolerated and improved patient symptoms (Jansen et al., 2011). A 
randomized controlled trial of artesunate in metastatic non small cell lung cancer randomised 60 patients to 
a control arm treated with doublet chemotherapy [intravenous vinorelbine (25mg/m2) on Day 1 and Day 8 
and intravenous cisplatin (25mg/m2) from Day 2-Day 4] and 60 patients treated with the same chemotherapy 
regime in addition to artesunate 120mg IV once daily from Day 1-Day 8 (Zhang et al., 2008). No statistically 
significant differences were seen in terms of the 1-year survival rate between the two treatment arms, 
although the disease control rate of the artesunate intervention group (88.2%) was significantly higher than 
that of the control group (72.7%) (P<0.05), and the artesunate arm’s median time to progression (TTP) was 
significantly longer than that of the control arm (24 weeks vs 20 weeks) (P<0.05). No significant difference was 
found in toxicity between the two groups, including that of myelosuppression and gastrointestinal symptoms 
(P>0.05). A pharmaokinetic study of oral artesunate in 23 patients with metastatic breast cancer was also 
recently published (Ericcson et al., 2014). Survival data were not reported. 
 
The first randomized placebo controlled double blind pilot study of artesunate in colorectal cancer randomized 
23 patients with resectable colorectal cancer to receive either 14 daily doses of artesunate or placebo (Krishna 
et al., 2015). During a median follow up time of 42 months, 1 patient in the artesunate group developed 
recurrent colorectal cancer compared to 6 patients in the placebo group.  Six patients receiving artesunate 
and 4 patients receiving placebo had measurable Carcinoma Embryonic Antigen (CEA) levels. Three patients 
in the placebo group had a rise in their CEA on rechecking their levels after the trial intervention whereas no 
patients in the artesunate group experienced a rise in their CEA levels (p=0.03). In one patient receiving 
artesunate there was a 75 % reduction in circulating CEA level after 2 weeks of artesunate treatment alone. 
Patients in the artesunate arm showed a high probability of a reduction in the ki67 proliferation index marker 
on tumour immunohistochemical analysis compared to those in the placebo arm. Artesunate was generally 
well tolerated apart from 2 cases of Grade 3 neutropenia and anaemia with one of the cases undergoing a 
spontaneous recovery of neutrophils and the other requiring granulocyte colony stimulating factor (GCSF). 
Both patients received a blood transfusion and went on to have surgery with no further complications. 

                  
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Artesunate is a safe and effective antimalarial with evidence of anticancer properties across a range of cancer 
cell lines. Results from our pilot feasibility study in colorectal cancer patients showed that artesunate was safe 
and well tolerated (Krishna et al., 2015). These findings provided the basis for a Phase II clinical trial 
investigating the effects of neoadjuvant artesunate on progression free survival and overall survival (NeoART).  
 
No other agents or treatments will be used in this study. 
 
Neoadjuvant pre-operative chemotherapy is effective in a number of other cancer types supporting the theory 
that optimal neoadjuvant systemic therapy at the earliest opportunity may be more effective at eradicating 
distant metastases compared to adjuvant therapy delivered following the delay and immunological stress of 
surgery. Colorectal cancer metastases have a short doubling time (Tanaka et al., 2004 ; Finlay et al., 1988) and 
it has been postulated that micrometastatic tumour growth may be further accelerated in the early post 
operative period by enhanced growth factor activity (Zeamari et al., 2004 ; Fahmy et al., 2003 ; Schelfhout et 
al., 2002). Neoadjuvant therapy also confers the potential advantage of primary tumour shrinkage, thereby 
reducing the risk of incomplete surgical excision and tumour shedding contaminating the surgical field during 
surgery (Nelson et al., 2001). This may have particular relevance for transcoeliac spread with peritoneal 
metastases found in up to 50% of patients with locoregional relapse (Assersohn et al., 1999). Neoadjuvant 
preoperative therapy in colorectal cancer started within days of diagnostic and staging investigations provides 
an unique treatment paradigm that could potentially eradicate micrometastases not managed with current 
standard treatment regimes. 
 
Indeed, neoadjuvant combination chemotherapy with or wothout targeted anti- EGFR monoclonal antibody 
therapy with panitumumab forms the basis of the current FOxTROT trial (FOxTROT Collaborative Group., 
2012). As previously mentioned however these regimens are associated with significant toxicities and surgery 
is often delayed whilst patients recover from these effects. These treatments are also expensive and remain 
economically out of reach for the majority of patients in developing countries.  
 
There remains an urgent need to improve survival outcomes in patients with colorectal cancer globally using 
affordable interventions where possible. Artesunate has a good safety and tolerability profile, having been 
used to treat tens of millions of malaria patients globally. It is also relatively affordable at around £0.70 per 
daily dose. If neoadjuvant treatment with artesunate is found to reduce the risk of cancer recurrence and 
improve survival in operable colorectal cancer, this would be a practice- changing observation and would 
significantly improve care for millions of colorectal cancer patients worldwide. 
 
Participants who develop CTCAE v5.0, Grade 3 or 4 serious adverse effects related to artesunate (or placebo) 
will be withdrawn from the study treatment but will continue in the study to enable an intention to treat 
analysis. The main possible risks associated with artesunate in this phase II trial are neutropenia and 
haemolytic anaemia. Patients should be monitored closely for these potential side effects and sites should 
take appropriate clinical action if such adverse events occur.  
 
Defination of aanemie is  a disorder characterized by a reduction in the amount of haemoglobin in 100 ml of 
blood. Signs and symptoms of anaemia may include pallor of the skin and mucous membranes, shortness of 

                  
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breath, palpitations of the heart, soft systolic murmurs, lethargy, and fatigability.Patients developing anaemia 
as defines by CTCAE 5.0  
 
• 
Grade 3  anaemia: Hgb <8.0 g/dL; <4.9 mmol/L;<80 g/L; transfusion indicated 
• 
Grade 4  anaemia: Life-threatening consequences; urgent intervention indicated 
 
The treatment for anaemia is blood transfusion.  
 
Definition of neutropenia: A disorder characterized by an ANC <1000/mm3 and a single temperature of >38.3 
degrees C (101 degrees F) or a sustained temperature of >=38 degrees C (100.4 degrees F) for more than one 
hour. Patients developing neutropenia as defines by CTCAE 5.0  
 
• 
Grade 3 neutropenia : ANC <1000/mm3 with a single temperature of >38.3 degree C (101 degrees F) 
or a sustained temperature of >=38 degrees C (100.4. degrees F) for more than one hour 
• 
Grade 4  neutropenia: Life-threatening consequences; urgent intervention indicated 
 
Treatment for neutropenia is GCSF.  
 
There will be a 24 hour emergency card provided to each participant when they receive their IMP dispensed 
from pharmacy. The 24 hour emergency card will contain the contact details of the local PI and site team in 
addition to a NeoART-M 24 hour emergency telephone number. 
 
The IMP will be supplied double-blinded and IMP allocation will be performed by each site pharmacy or clinical 
resarch centre in accordance with the randomisation list provided by the sponsor’s representative at the start 
of the study. In the case of a medical emergency each Pharmacy or CRC will have the ability to unblind 
treatment. 
 
The participating sites all have appropriate experience and knowledge of the target patient population. All 
team members will have demonstrated experience in clinical research and Good Clinical Practice (GCP). 
 
The study is categorised  ‘Somewhat higher than the risk of standard medical care’. This would therefore 
require that IMP storage and accountability. The CI and the CI delegate will construct a Trial Master File and 
ensure that all essential trial documents are stored safely and securely. The trial will be subject to monitoring 
in accordance with the Sponsor risk-based monitoring plan. The purpose of the monitoring is to ensure the 
safety, rights and well being of the trial participants are upheld and that any risk to the trial data is minimised. 
7. Trial design 
This study is a Phase II, randomised, double blind, placebo controlled, multi-centre trial. We aim to recruit 200 
patients presenting with stage II/III colorectal cancer.. Patients who consent to enter the study will receive the 
trial intervention for 2 weeks prior to their planned surgery and then be followed up for 5 years following 
surgery.  
 
A master randomisation list generated by the Sponsor representative was made available at the start of the 
study. The master randomisation list is further divided into blocks of 20 and provided to each study site with 
the IMP deliveries. The Research Pharmacy or CRC at each site will retain the randomisation list upon receipt 
in their Pharmacy Site File. Upon receipt of a NeoART prescription the next sequential allocation will indicate 
whether to dispense active artesunate or matched placebo tablets to a particular participant.  At the time of 

                  
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dispensing the tear off label identifying the product will be removed by the Research Pharmacy or CRC and 
added to the accountability log. This will ensure that the investigators and study participants remain blinded 
to the treatment allocation. In exceptional circumstances, when knowledge of the investigational drug is 
essential for medical treatment of the patient, treatment allocation can be unmasked by pharmacy or CRC  
centres by a study coordinator that is not involved in the study directly . 
 
The Sponsor retain a copy of the master randomisation list in their respective study files. 
 
 
 
 
 
 
 
 
 
 

                  
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  Patient screening, consent, treatment allocation 
 
  
 
 
 
 
              
 
     Artesunate 200mg PO OD 14 days or Placebo PO OD 14 days 
 
 
 
             Midpoint telephone review 
 
 
 
                        End of treatment telephone review 
                                       
                                               
 
  
 
 
                    Safety blood test check prior to Surgery  
           (Day 14/Day 15) 
 
                Radical Surgery 
                                                                   
 
                                        
       
                 Blood test Check 
 
 
 
                             Post-Surgical Review 
 
 
                     
                                             Clinical follow up every 6 months for 5 years
  
Day 0 
 
 
 
 
Day 1 
 
 
 
           
 
 
Day 7 
 
 
 
 
 
Day 14 
 
 
 
 
 
Day 15 
 
 
 
 
 
 
 
 
Day 28 
 
 
 
 
 
Day 42 
 
 
  
 
 
Month 
6-60 

 
 
8. IMP Dosage regimen and rationale 
The dose of artesunate for the study will be 200 mg per oral (PO) once daily (OD) for fourteen days. There are 
no data on the most appropriate dose of artesunate in cancer in humans. This dose has been chosen by a 
consensus among medical experts experienced with using artesunate for the treatment of malaria and 
following published results from a pilot feasibility and safety study of neodajuvant oral artesunate in patients 
with colorectal cancer (Krishna et al. 2015). 
 
The daily dose of artesunate used in combination treatments to treat uncomplicated Plasmodium falciparum 
malaria is 4 mg/kg, given over three days. When given as monotherapy for uncomplicated falciparum malaria 
the total dose is approximately 20 mg/kg, over seven to ten days. For curative courses in severe malaria, the 
total doses of artesunate (parenteral and oral combined) can reach 24 mg/kg. The daily dose of artesunate for 
a patient in this study will be between 2 mg/kg and 4 mg/kg, depending on the weight of the participant 
(ranging between 52-110 kg). At daily doses of 6 mg/kg the dose limiting side effect of artesunate is 
neutropenia. The study products do not contain porcine but contains produced from bovine that is safe for 
human consumption. 
 
Metabolite  
Artesunate is extensively hydrolysed by plasma esterases and possibly CYP2A6. Its main metabolite, DHA is 
metabolised through glucuronidation (WHOPAR., 2011).  
Elimination  
The plasma half-life of artesunate is 3-29 minutes whilst its active metabolite DHA has a plasma half-life of 
40 to 95 minutes (WHOPAR., 2011).  
If vomiting occurs during the course of treatment and the tablet is visible in vomit, the dose should not be 
retaken. The occurrence and frequency of any vomiting during the reporting period must be noted in the 
adverse events log and CRF. 
The effect of food  
The effect of food consumption with artesunate has been studied. When healthy volunteers consumed 
artesunate fixed dose combinations with a high fat meal, the Cmax and AUC (0-t) of artesunate decreased by 
66% and 13% respectively, compared to fasting. The Cmax and AUC (0-t) of the active metabolite 
dihydroartemisinin (DHA) decreased by 48% and 5% respectively with a high-fat meal, compared to fasting 
(WHOPAR., 2011). Patients should take the study medication after a light meal. 
Packaging and storage conditions 
 
Study medication will be provided in bottles. One patient bottle will provide 28 tablets – sufficient for the 
duration of the study. The product labelling will be fully compliant with both Appendix E: Labelling 
Requirements of the Rules and guidance for Malaysian-Guideline-for-Application-of-CTIL-and-CTX-7.1-Edition 
and the protocol submitted and authorised by the NPRA.  

 
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Drug interactions with artesunate 
 
There are no reports of negative drug interactions with artesunate to date. 
 
Adverse events associated with artesunate 
 
Artesunate is a safe drug that has been taken by millions of patients worldwide. In data taken from 
studies of malaria, serious side-effects are extremely rare.  
 
The Summary of Product Characteristics for Artesunate provided to sites lists the potential side 
effects. 
 
The reference safety information document provided to sites lists the adverse events considered by 
the Sponsor as being ‘expected’. 
 
Pregnancy 
 
Artesunate is teratogenic in animal models and is contraindicated in the first trimester of pregnancy 
in humans. Pregnant women with malaria nevertheless are exposed to artesunate when no 
alternatives are available for treatment and studies published to date do not indicate an increased 
risk of teratogenicity. Pregnant women will not be recruited and participants will be required to use 
effective methods of medical contraception during the study. Women of child bearing age will be 
required to undergo a pregnancy test within 72 hours prior to commencing the study and must 
consent to adequate contraceptive methods from the time of consent and for up to 6 weeks following 
the end of treatment. Male participants with a partner of childbearing potential must agree to use 
adequate, medically approved contraceptive precautions from the time study consent is signed till up 
to 6 weeks after the last dose of study treatment intervention.Methods of contraception that are 
acceptable for the trial include the following:  
 
The implant, the coil and male or female sterilisation will be acceptable for the trial. The injection and 
most forms of hormonal contraception will also be deemed acceptable for the trial if used in 
combination with condoms or other barrier methods. However, condoms alone won’t be sufficient 
during the study.  
 
IMPs and non-IMPs used in the trial  
 
Patients entered into the study will be randomised to receive artesunate 200 mg (administered as 2 x 
100mg tablets) or identical matching placebo once a day orally for 14 days. 
 
Dosage modifications 
 
No dosage modifications will be undertaken. Any Grade 3/4 reaction (according to Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0) which occurs in any patient and is 
deemed related to the IMP or placebo by the treating investigator will result in that patient’s trial 
treatment being discontinued. 
 
Bulk artesunate 100 mg and matching placebo tablets are manufactured by HCM- Medical 

 
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according to Good Manufacturing Practice (GMP). The matching placebo tablets contain lactose 
monohydrate, microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silica and a 
magnesium stearate blend. 
Artesunate and placebo tablets are packaged into bottles each containing 28 tablets of either 
artesunate or placebo. Package labelling was performed under controlled conditions to ensure no 
cross contamination. The bottles have a removable label affixed. The removable label will allow 
identification of each bottle to facilitate correct treatment allocation in accordance with the 
randomisation list held in the pharmacy or clinical research centre departments. The pharmacy 
department or research centre will remove the labels during the dispensing process and affix all of the 
labels to the IMP accountability records. 
The named Qualified Person (QP) will issue a QP release certificate. The IMP  will be delivered, 
accompanied by the QP batch release certificate.  
Shipment of the IMP will be under temperature-controlled conditions and the recipient pharmacy 
department at each site will be required to confirm by return of a completed delivery note as 
instructed that correct shipment conditions have been maintained. A copy of the QP release will be 
provided to each site to file in the Pharmacy Site File (PSF). 
Full IMP accountability will be maintained at all participating site pharmacy departments. 
Temperature records are to be maintained with daily minimum/maximum readings via a 
calibrated/certificated thermometer. The records will be available for monitoring visit purposes and 
either a copy of those records or a signed statement of compliance will be placed in the PSF following 
the end of IMP treatment phase. 
The IMP – artesunate/placebo 100 mg tablets must be stored below 25°C. 
 
Each participating site’s pharmacy department will be responsible for maintaining and updating the 
IMP Accountability Log, filed in the pharmacy site file. All used/unused IMP(s) will be returned to the 
site pharmacy. If research pharmacy is not available at the study site, a qualitfied study coordinator 
that is not part of the investigator’s team can perform this task. 
 
IMP(s) destruction will be conducted, following verification by the Clinical Trials Monitor and 
agreement by the Sponsor, in accordance with local pharmacy practice. Destruction records will be 
maintained and filed in the site pharmacy site file.  
 
An assessment of medication compliance will be made by the principal investigator or delegated 
research team, member on Day 7 and at the end of the treatment course based on verbal answers 
given to direct questioning and a count of untaken medication on Day 15. These data will be entered 
into the Case Report Form.  
 
Following completion of the patient’s IMP treatment period any unused medication will be returned 
to the site Pharmacy department for the IMP accountability log to be updated.  Patients who take the 
study drug for < 8 days in the 14 day treatment period will be considered ‘non-compliant’. All patients 
will continue to be followed up according to the study protocol regardless of compliance.  
 

 
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This is a neoadjuvant study. There will be no further IMP supplied to participants following colorectal 
surgery. 
 
No NIMPs used. 
 
There are no reports of negative drug interactions with artesunate to date. Concomitant medication 
details will be collected at baseline and any changes recorded at subsequent study visits. 
 
We will document adjuvant treatment following surgery such as chemotherapy and aspirin therapy. 
We will include this in our final data analysis in order to account for any confounding results that could 
arise as a result of adjuvant therapy. If patients develop Grade 3 neutropenia or more (according to 
the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0) Definition of neutropenia: 
A disorder characterized by an ANC <1000/mm3 and a single temperature of >38.3 degrees C (101 
degrees F) or a sustained temperature of >=38 degrees C (100.4 degrees F) for more than one hour. 
Grade 3 neutropenia : ANC <1000/mm3 with a single temperature of >38.3 degree C (101 degrees F) 
or a sustained temperature of >=38 degrees C (100.4. degrees F) for more than one hour. They should 
be managed with granulocyte colony stimulating factor (GCSF) supplied via routine hospital pharmacy 
in accordance with local policy and prescribing practice. 
9. Participant Selection criteria 
There will be no exceptions (waivers) to eligibility criteria prior to participant inclusion into the study. 
Any questions raised about eligibility should be addressed prior to entering the participant. 
 
The eligibility criteria have been carefully considered and are standard to ensure both the safety of 
the participants and that the trial results can be appropriately used to make future treatment 
decisions for other patients with similar disease or medical condition. It is therefore vital exceptions 
are not made to the following detailed selection criteria.  
 
Deviations from the eligibility criteria are considered to be protocol violations and may be reported 
to the NPRA as a serious breach. 
 
All participants that are screened for inclusion into the study must be entered onto the screening log 
and will be assigned a sequential number. Participants will be considered eligible for enrolment into 
this trial if they fulfil all of the inclusion criteria and none of the exclusion criteria as defined below.  
 
Eligible participants will be entered onto the Subject ID log and assigned a Trial specific Identification 
number in a pre-agreed format in accordance with Site identifier and next sequential numerical value 
e.g. SG001.  
 
Each site will be provided with a unique site identifier communicated via the Sponsor. 
 
Eligibility Criteria   
 
 

 
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1. Aged 18 or over 
2. Histologically proven single primary site colorectal adenocarcinoma or high grade dysplasia 
plus unequivocal radiological evidence of invasive cancer 
3. Stage II/III colorectal cancer planned for surgical resection and no clinical indication for 
neoadjuvant preoperative chemotherapy/chemoradiation therapy 
4. WHO performance status 0,1 or 2 
5. Adequate full blood count: White Cell Count (WCC) >3.0 x 109 /l; Platelets >100 x 109/l; 
Haemoglobin (Hb)  >80g/L 
6. Adequate renal function : Glomerular Filtration Rate >30ml/min by Cockcroft-Gault formula. 
7. Adequate hepatobiliary function : Total bilirubin < 3 x Upper limit norm 
8. Female participants of child bearing potential must have a negative pregnancy test <72 hours 
prior to initiating study intervention and agree to avoid pregnancy using adequate, medically 
approved contraceptive precautions for up to 6 weeks after the last dose of study treatment 
interventions.  
9. Male participants with a partner of childbearing potential must agree to use adequate, 
medically approved contraceptive precautions during and for up to 6 weeks after the last dose 
of the study treatment intervention.  
10. Patient able and willing to provide writen, informed consent for the study.  
 
1. Contraindication to use of artesunate due to hypersensitivity 
2. Pregnancy or lactation 
3. Male or female participants unwilling to use an effective method of birth control (either 
hormonal in the form of the contraceptive pill or barrier method of birth control accompanied 
by the use of a proprietary spermicidal foam/gel or film) ; or agreement of true abstinence 
from time consent is signed until 6 weeks after the last dose of study treatment intervention 
(i.e. withdrawal, calendar, ovulation, symptothermal and post ovulation are not acceptable 
methods) 
4. History of hearing or balance problems 
5. History of immunosuppression  
6. Patient weight < 52 kg or > 110 kg  
7. Other planned intervention, apart from standard of care 
8. Any other malignant disease diagnosis within the preceding 2 years with the exception of non-
melanomatous skin cancer and carcinoma in situ 
9. Lactose intolerance 
10. Subject/Patient Recruitment process 
 
Participant recruitment at any site will only commence once evidence of the following are in place in 
the Sponsor site file. 
 
1. Relevant ethics committee approval, and NPRA 
2. Delegation of Duties and Sponsorship Agreement signed by the CI 
3. Final sponsorship (following evidence of Pharmacy green light) issued by the Sponsor 
representative.  

 
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All sites participating in the trial will also be asked to provide a copy of the signed Clinical Trial Site 
Agreement (CTSA) and Confirmation of Capacity and Capability. 
 
Once the trial initiation procedure is completed the Sponsor will issue the ‘Open to recruitment’ letter. 
All participants who wish to enter the study will be fully screened and consented by the Principal 
Investigator, or one of the qualified clinicians involved in the study as Clinical Co-investigator.  
 
NeoART aims to randomise 200 participants worldwide with 120 patients in Malaysia. We aim to 
recruit 8-12 participants to the study per month to meet our recruitment target over 24 months. Our 
Phase I pilot trial (Krishna et al., 2015) was the first trial to investigate neoadjuvant artesunate for 
colorectal cancer and demonstrated the feasibility, practicability, and safety of this novel approach. 
 
Each patient will receive a minimum of RM150 reimbursement for their transportation cost at each 
additional visit. 
 
11. Study procedures 
It is essential that all trial personnel/staff undertaking the informed consent process have signed the 
Delegation of Responsibilities Log to ensure that the person has been delegated the responsibility by 
the study CI/PI. All personnel taking informed consent must be GCP trained. Refer to sponsor’s SOP 
‘TMF Maintainence’.  
 
Informed consent from the participant must be obtained following explanation of the aims, methods, 
anticipated benefits and potential hazards of the trial and before any protocol-specific procedures are 
performed. If a potential participant is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the informed 
consent form to the participant and must allow for questions. Thereafter, both the participant and 
the witness must sign (or mark in the case of illiteracy) the informed consent form to attest that 
informed consent was freely given and understood. Where appropriate, written translation will be 
provided in addition to professional verbal translation. 
 
The only procedures permitted in advance of written informed consent are those that would be 
performed on all participants in the same situation as routine clinical practice.  
 
The Investigator or designee will explain that the participants are under no obligation to enter the trial 
and that they can withdraw at any time during the trial, without having to give a reason. 
 
A copy of the signed Informed Consent Form (ICF) along with a copy of the most recent approved 
Patient Information Sheet (PIS) will be given to the study participant.  An original signed and dated 
consent form will be retained in the ISF and a copy will be placed in the medical notes. If new safety 
information results in significant changes to the risk–benefit assessment, the consent form will be 
reviewed and updated if necessary. All participants, including those already treated, will be informed 
of the new information, given a copy of the revised patient information sheet and will be asked to re-
consent if they choose to continue in the study. This process must also be recorded and documented 
as above. 
 

 
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Participants recruited to the study will be randomised to receive either artesunate or placebo 1:1. 
Randomisation will be by a computer-generated code. An unblinded randomisation list will be 
provided to each participating site and held in Pharmacy or held by a study coordinator that is not 
directly involved in the study. Following completion of the study the participant treatment allocation 
list held in the site Pharmacy files will be anonymised prior to collection by the Clinical Trials Monitor. 
The anonymised lists will be handed over to the statistician to facilitate data analysis.  
 
All patients will be given a study specific 24 hrs emergency contact card immediately after being 
randomised. The card includes details of the Trial: Study title, details of IMP, patient trial number, 
CI/PI’s contact details along with out of hours contact details in case of emergency.  
 
The Sponsor will construct a protocol specific Clinical Trial Procedure which will detail participant 
management in relation to IMP dosing and pharmacy dispensing procedures. The Sponsor will also 
provide a study specific prescription template to be used for the study. All IMP prescriptions presented 
to pharmacy must be on the Sponsor approved template and be signed and dated by an approved 
prescriber. The prescriber must have been signed off by the CI /PI on the Staff delegation of duties log 
for that task. A sample signature of all delegated prescribers must be provided for the Pharmacy Site 
File prior to receipt of the 1st trial prescription. Upon site initiation completed delegation logs will be 
copied by the Sponsor Clinical Trials Monitor and filed in the Pharmacy/Institute Site File. Prescriptions 
received by a non-approved prescriber will not be acceptable and will cause the participant 
unnecessary delays. 
 
Upon receipt of a valid prescription the Research Pharmacy staff or study coordinator who is not part 
of the investigator’s team will assign the next available IMP allocation either artesunate or placebo as 
indicated on the randomisation list. A single supply of IMP in a bottle of 28 tablets of 100 mg 
artesunate/placebo tablets will be made, sufficient to cover the duration of the trial. The label of the 
IMP will contain instructions to the trial participant of the date to commence artesunate/placebo 
dosing calculated as 15 days prior to the day of surgery. The surgery date will be annotated on the 
NeoART prescription by the prescriber. The peel-off/tear-off labels on the outside of the IMP bottle 
will be removed and affixed to the IMP accountability forms held in the pharmacy site file.  
 
The treatment allocation should not be revealed to the investigator team nor the participant. The 
Patient Trial Number and Site ID should be completed on each label. The label must follow the 
Appendix E: Labelling Requirements of the Rules and guidance for Malaysian-Guideline-for-
Application-of-CTIL-and-CTX-7.1-Edition and have the following details completed :- Patient initials, 
Patient Trial Number, date of dispensing and the start date – calculated as 15 days prior to day of 
surgery as indicated on the prescription to facilitate a 14 day of course of treatment. 
 
A pharmacy dispensing label may also be affixed to the bottle in accordance with local hospital policy 
but must not obscure the approved bottle label. IMP accountability records must be completed for 
each participant indicating date of dispensation, Participant Trial ID, treatment start date – dispenser 
and checker. Tear off/ removable labels must be affixed to this accountability record. The IMP will be 
provided to the participant together with a 24 hour emergency contact card and instructions to 
request the return of the IMP medication to pharmacy.  
 
The IMP accountability logs will be checked for the presence of the tear off/peel off label for each 
participant by the Clinical Monitor.  

 
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Each study site will have the capabilities of revealing patient treatment allocation in case of 
emergency. In the case where there is a need for emergency unblinding, follow the local SOP. The 
investigators  will remain blinded. An SOP on local policy for unblinding must be file in the local ISFand 
PSF. Unneccessary unblinding should be avoided. 
 
All code break requests must be directed via the local PI who can contact their local assigned personel 
to reveal treatment allocation. A file note and NeoART code break form documenting clearly the 
reason for code break must be completed and sent to the Sponsor within 24 hours (or on the next 
working day if a weekend or bank holiday). 
 
The delegated personel will; 
 
Complete a NeoART-M code-break record form with the details supplied by the NeoART-M study team 
member.  
 
Cross reference the NeoART-M dispensing record labels with the Participant Trial ID provided to 
determine artesunate or placebo treatment.  
 
The treatment reveal should be communicated to the originator of the request only. Do not reveal 
treatment allocation to the NeoART-M Sponsor Emergency Out of hours cover. 
 
Add details to the NeoART-M code break form –email completed NeoART-M code break form to the 
Sponsor within 24 hours.  
 
File the original copy in the Pharmacy site file code break section.  
 
Annotate against participants IMP accountability record – code broken- initial and date. 
 
Site team will need to be informed the following working day to facilitate completion of a Serious 
Adverse Event Form and reporting timelines must be followed. Refer to protocol section 14.2 
 
Certain serious adverse events such as a trial patient developing anaphylaxis, a serious heart 
arrhythmia or neutropenic sepsis may require emergency unblinding. The participant should be 
managed accordingly and full medical support provided as necessary.   
 
 
In the event of an overdose of trial medication the patient should attend the Accident and Emergency 
(A&E) and be urgently reviewed by a member of the research team during working hours or the oncall 
Medical Officer. A thorough medical history and events leading to the overdose should be 
documented as well as a complete physical examination including blood pressure monitoring. Blood 
tests should be performed including full blood count, urea and electrolytes and liver function tests. 
There is no antidote or documented role for gastric lavage. The overdose should be documented in 
the participants medical notes and CRF.The Adverse Event log and the SAE reporting form should be 
completed. The completed SAE form should be emailed  to the Sponsor in accordance with protocol 
section 14.2. 
 

 
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11.6.1 Discontinuing/withdrawal of participants 
In consenting to the trial, participants are consenting to trial treatments, trial follow up and data 
collection. However, an individual participant may stop treatment early or be stopped early for any 
one of the following reasons : 
 
• 
Unacceptable treatment toxicity or an monitoring 
• 
Investigator decides that it is in the best interests of the patient to terminate his/her 
participation in the study 
• 
Poor patient compliance and/or major protocol deviation 
• 
Intercurrent illness that prevents further protocol treatment 
 
Withdrawal of consent from the participant 
 
As participation in the trial is entirely voluntary, the participant may choose to discontinue treatment 
at any time without penalties or loss of benefits to which they may be entitled. Although not obliged 
to give a reason for discontinuing their trial treatment/study participation a reasonable effort should 
be made to establish this reason, whilst remaining fully respectful of the participant’s rights.  
Participants who discontinue protocol treatment, for any of the above reasons, should remain in the 
trial for the purpose of follow up and data analysis. 
 
Temporary discontinuations of study medication are not permitted. If a patient decides to discontinue 
treatment then the patient’s decision should be documented on the Subject Tracking log, CRF and the 
IMP returned to the study site Pharmacy. Participants should continue to be followed up as closely as 
possible to the follow-up schedule defined in the protocol, providing they are willing. However if the 
participant confirms they do not wish to participate in the scheduled follow up data collection visits 
then data that has already been collected should be kept and analysed according to the ITT principle 
for all participants who stop follow up early. Patients withdrawn from the study will continue to be 
followed up according to the study protocol to the scheduled date of study completion, or to recovery 
or stabilisation of a followed-up AE, whichever comes last. Routine medical and surgical care of 
withdrawn participants will continue as planned. The investigator will make every effort to contact 
the participant in the case of non attendance to a planned review appointment. Participants who stop 
the trial follow up early will not be replaced. 
 
 
11.6.2 List of criteria for premature discontinuation of the study 
The study may be discontinued prematurely by the Sponsor, the DMC or the Chief Investigator if: 
 
• 
As a result of the interim analysis or any other event during the study there is significant doubt 
based on statistical evaluation as to the risk/benefit ratio 
• 
The aim of the study has become outdated or is no longer of interest 
• 
There is a serious breach by the investigator of a fundamental obligation under this 
agreement, including but not limited to breach of the Study Protocol, breach of the applicable 
laws and regulations or breach of the ICH guidelines for Good Clinical Practice 
 
In all cases the relevant ethics committee, NPRA and CRM will be informed in accordance with 
statutory guidance. 
 

 
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If a participant moves from the area making continued follow up at their consenting centre 
inappropriate, every effort should be made for them to be followed up at another Sponsor approved 
trial centre. Written consent should be taken at the new centre and then a copy of the participant’s 
CRF should be provided to the new centre. for the participant remains with the original consenting 
centre until the new consent process is complete.  
 
For all participants that qualify for randomisation, information in relation to their Next of Kin (NoK) 
and registered GP details will be confirmed as correct and current in the patient medical records to 
facilitate ease of contact throughout the study and data collection period. Following a missed 
scheduled visit, effort to contact the participant and/or Next of Kin on up to 3 occasions over a 7-10 
day period should be made. Each occasion will be documented in the medical notes and on the 
Telephone log . If following 3 attempts contact has failed via the participant/ NoK then participant 
status will need to be confirmed via the GP. 
 
The end of the trial will be defined as the last participant to have completed follow up at 5 years (last 
patient last visit) or to have died 5 years following surgery. The relevant ethics committee and the 
NPRA will be notified of the end of the trial within 90 days of its planned completion or within 15 days 
if the study is terminated early in accordance with. 
12. Study Assessments 
Each study related visit and any interventions, tests or procedures will be documented in the 
participant medical notes and clearly marked as relative to their NeoART-M participation 
 
For potential participants who appear to meet the criteria for study participation, the Investigator will 
provide the patient information sheet and answer any questions to allow the patient to make an 
informed decision regarding study participation. Investigators will be expected to maintain the 
Screening Log of all potential participants. This Log will include limited information about the potential 
participant.  
 
If informed consent is given, the Investigator will conduct a full screening evaluation to ensure that 
the patient satisfies all inclusion and exclusion criteria. Site research staff must record Patient 
screening activities on Screening Log. A patient who gives written informed consent and who satisfies 
all the inclusion and exclusion criteria may enrol in the study, be added to the Subject ID log and 
proceed to randomisation. 
 
Note that assessments conducted as standard of care do not require informed consent and may be 
provided as screening data if conducted within the acceptable timeframe prior to registration. 
Assessments required at baseline are detailed in section 12.2. 
 

 
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All participants who consent to enter the study and fulfill all of the eligibility criteria will be entered 
onto the Subject ID log and be assigned a unique subject ID and undergo a review at the 1st study visit 
prior to randomisation and commencing the artesunate/placebo treatment course. A full medical and 
concomitant medication history will be taken. Staging investigations will be reviewed and vital signs 
and baseline blood samples will be performed. Baseline blood tests will include FBC, urea and 
electrolytes, liver function tests (LFT), and carcinoembryonic antigen (CEA). A pre-treatment blood 
sample will be taken for study molecular analyses. Patients will be asked to complete EORTC validated 
quality of life questionnaires (EuroQol EQ-5D, EORTC QLQ C-30, QLQ-CR29). Potential female 
participants of child bearing age must have a negative pregnancy test.  
 
[Refer to Appendix 2 for a summary chart of study assessments] 
 
Participants entered into the study will be randomised 1:1 to receive artesunate 200 mg or matched 
placebo once a day orally for 14 days to commence 15 days prior to day of scheduled surgery. The 
artesunate/placebo packs dispensed to the participant will provide clear instructions on when to 
start taking the IMP and when to stop. 
 
Study medication will be started fifteen days before the scheduled surgery with the final dose taken 
on Day 14 (the day before surgery). 
Day 7 of study medication (telephone assessment) 
Medical History 
Concomitant medication and patient self reported adverse events 
QOL –questionnaires – EuroQol EQ-5D, EORTC QLQ C-30, QLQ-CR29 
 
Day 14 of study medication/Pre-operative admission assessment 
Medical history 
Concomitant medication and patient self reported adverse events  
QOL –questionnaires – EuroQol EQ-5D, EORTC QLQ C-30, QLQ-CR29 
 
Day 15 Surgery 
Blood tests – FBC, Kidney and liver function tests, CEA tumour marker 
Post treatment serum sample for study molecular analyses, these blood tests will be done on either 
day 14 or 15.  
Safety blood tests (FBC, U&E, LFT) must be available prior to patients having surgery to exclude risk of 
neutropenia and deranged biochemistry. 
Post surgery/in-patient stay/or at a relevant time point in the case of cancellation of surgery 
Patient self-reported adverse events. 
 
Day 28 
Blood test – FBC  
 
Day 42 (Routine follow up 4 weeks post surgery) 
Medical history 
Blood tests – FBC, Kidney and liver function tests, CEA tumour marker 
 
6 month follow up visit post surgery 
Medical history 
Blood tests – CEA tumour marker 
 

 
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12 month follow up visit post surgery 
Medical history 
Blood tests – CEA tumour marker 
Colonoscopy 
CT scan chest, abdomen and pelvis 
 
18 month follow up visit post surgery 
Medical history 
Blood tests – CEA tumour marker 
 
24 month follow up visit post surgery 
Medical history 
Blood tests – CEA tumour marker 
CT scan chest, abdomen and pelvis 
 
30 month follow up visit post surgery 
Medical history 
Blood tests – CEA tumour marker 
 
36 month follow up visit post surgery 
Medical history 
Blood tests – CEA tumour marker 
 
42 month follow up visit post surgery 
Medical history 
Blood tests – CEA tumour marker 
 
48 month follow up visit post surgery 
Medical history 
Blood tests – CEA tumour marker 
 
54 month follow up visit post surgery 
Medical history 
Blood tests – CEA tumour marker 
 
60 month follow up visit post surgery 
Medical history 
Blood tests – CEA tumour marker 
CT scan chest, abdomen and pelvis 
 
At the end of 5 years follow up patients with no evidence of disease recurrence will be discharged 
back to the care of their GP. All patients with disease recurrence will have their management discussed 
at the Colorectal Multidisciplinary meeting (if available). 
 
For pragmatic trial management, the following visit windows are permitted : 
Day 1 and Day 7 -/+3 days of the study review date. Any baseline blood tests within 1 week of starting 
the study treatment are acceptable.  
 
The Day 28 review may be performed within 7 days of the set date. 
 
The Day 42 review may be performed within 2 weeks of the set date. 

 
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The 6 to 60 month follow up visits post surgery may be performed +/- 6 weeks of the set date.  
 
If for any reason study follow up visits defer from the scheduled study time scales (for example the 12 
month follow up visit is scheduled before the timeframe window  due to a rising CEA or post adjuvant 
chemotherapy) this will be  at the managing clinicians discretion. However a minor Deviation 
Reporting Form should be completed to document the reason for the deviation and reported 
according to SOP.  
 
12.5.1 Samples 
12.5.1.1 Obtaining, labelling, storing  
 
Following informed consent, blood samples will be collected into vacutainer systems or similar tubes 
(usually 2 x 10 ml EDTA vacutainers) on D1 and D14/D15 of the study. The collected blood should be 
centrifuged, processed and stored at -80ºC according to the NeoART- trial: Blood sample collection, 
processing and storage SOP . NB. The Sponsor representative should be notified in instances where 
the storage freezer temperature deviation from -80 ºC by more than +/-10 º C  
 
These samples will be used for genomic and proteomic analysis. Blood samples will be suitably stored 
in the pathology department of each site till required for batch analysis. When requested for batch 
analysis at various recruitment time points throughout the study, blood samples will be transferred 
for centralised study sample storage under the Human Tissue Authority License/ Permit to Import or 
Export of Human Tissues or Part Thereof Health Office/District Health Office (BLESS) 
 
The Sponsor ‘Record of retained body fluids log’ will be maintained throughout the study at each site 
to track all participant blood and Tumour samples accountability and location. These completed logs 
should be made available upon request at study monitoring visits. 
 
Tumour samples will be derived from tumour biopsies performed during colonoscopy and surgical 
samples following surgery. Any excess tumour tisue left over after the tissue sample has been 
processed for routine diagnostic purposes will be utilised. Formalin fixed, paraffin embedded blocks 
will be prepared and stored in the pathology department of each site till requested for batch analysis. 
All tissue samples will be transferred for centralised study sample storage under the Human Tissue 
Authority License/ Permit to Import or Export of Human Tissues or Part There of Health Office/District 
Health Office (BLESS).  
 
Each sample will be coded with the unique participant study ID to maintain confidentiality. The date 
of collection will also be recorded on study sample log and the relevant CRF completed. The samples 
will be stored indefinitely, with patient consent. However patients have the right to have the samples 
destroyed by contacting the Chief Investigator who will then arrange for the samples to be 
confidentially destroyed. Tumour samples will be analysed to identify tumour markers predictive of 
response to artesunate and elucidate potential mechanisms of action. Samples will be sent for further 
molecular analyses to the  labs of other collaborators involved in the NeoART project collaboration in 
accordance with the NeoART-M Material Transfer Agreement (MTA). 
 
Patient treatment allocation blinding will be maintained throughout the trial including during the sub-
study biomarker/mechanism of action analysis. An independent lab researcher will de-link the patient 
sample from the trial patient ID and allocate the sample a separate random study sample lab number. 
Once the serum and tissue samples have been processed, the exploratory molecular endpoint results 

 
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will be entered into a lab results excel spreadsheet. The sponsor will then be provided with the de-
linked study sample lab number and they will notify the independent lab researcher of the study arm 
allocation for each de-linked study sample. 
12.5.1.2 Transporting samples   
 
An approved specialised courier will transfer the samples at the appropriate temperature  
(e.g. -80ºC for specimens stored at -80 ºC) with in-transit monitoring and transport labelling of 
specimens. Arrangements for confirmation of receipt will be clearly outlined and logged on. A copy of 
this will be kept within the Trial Master File. 
12.5.1.3 Laboratory procedures 
 
The CI or the CI delegate will ensure that any laboratory that is used for the trial is adequate for “the 
foreseen duration of the trial to conduct the trial properly and safely” (ICH GCP 4.2.3 and ICH GCP 
5.184b). The CI or the CI delegate will ensure that the laboratory the study will use has been verified 
and is compliant with accreditation standards and that all necessary contracts for the contracted 
activities have been finalised. The CI or the CI delegate will ensure that any laboratory used for 
research purposes sets up and maintains a study specific Laboratory Site File that contains a current 
approved version of the protocol. Access to the laboratory files will be provided to the Sponsor trial 
monitor. ct s 
Samples will be stored and shipped to any external labs involved in the NeoART project collaboration 
according to the agreed NeoART Material Transfer Agreement (MTA). Each sample will be coded with 
the participants Trial ID to maintain confidentiality. The date of shipping of the samples will be 
recorded on the Sample Collection Log.  
Patients will have a routine baseline CT Chest/Abdomen/Pelvis as part of their staging investigations 
prior to entering the study. Following surgery they will have a routine restaging CT Chest/Abdo/Pelvis 
at 1 year, 2 year and 5 year follow up visits to exclude disease recurrence as per routine clinical follow 
up. 
13. Translational research / Pharmacodynamic Studies 
For instructions on processing and storage of study bloods, tissue samples please refer to 
the study lab manual.  
 
 
14. Pharmacovigilance 
Adverse Event (AE) — Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment.  

 
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An adverse event (AE) can therefore be any unfavourable and unintended sign (e.g. an abnormal 
laboratory finding), symptom or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. Pre-existing conditions should only be 
reported as an adverse event if the condition worsens by at least 1 CTCAE grade. As the IMP has a 
short half-life, we would expect drug clearance within 24 hours of stopping the IMP.  
 
As part of pharmacovigilance, adverse event data will be collected from the day 1 of IMP dose until 4 
weeks following the end of the IMP 14 day treatment schedule. This coincides with the D42 post 
surgical review. 
 
 
Adverse Reaction (AR) — All noxious and unintended responses to a medicinal product related to any 
dose should be considered adverse drug reactions.  
 
Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) — any untoward medical occurrence 
that at any dose:  
 
• 
Results in death,  
• 
Is life-threatening,  
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation,  
• 
Results in persistent or significant disability/incapacity or  
• 
Is a congenital anomaly/birth defect.  
 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalisation but may jeopardise the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should also 
usually be considered “serious”.  
 
Suspected Unexpected Serious Adverse Reaction (SUSAR) — an Adverse Reaction which is classed in 
nature as both serious and unexpected 
 
An ‘Unexpected Adverse Reaction’ is when both the nature and severity of the event is not consistent 
with the reference safety information available for the IMP in question. 
 
 
All Adverse Events whether serious or not will be recorded in the hospital notes in the first instance.  
A record will also be kept in the participant’s CRF and the Sponsor’s AE Log.  In the event of a mildly 
deranged blood test or clinical observation of no clinical significance to the patient (for example a 
mildly elevated liver function test or a mildly elevated blood pressure reading in a participant with 
known hypertension taking prescribed antihypertensive medication), the local PI will be informed and 
will sign and date the participants CRF. However it will not be necessary to complete an AE CRF or the 
Sponsor’s AE Log for these minor events. 
SAEs and SARs must be notified to the sponsor as soon as the investigator becomes aware of the event 
(within 24 hours). Refer to sponsor’s SOP and ensure the completed SAE report form is sent to the 
sponsor via E-mail.  

 
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The sponsor will inform the National Pharmaceutical Regulatory Agency (NPRA) and relevant ethics 
committee of SAE and SUSARs as soon as possible, but no later than 7 calendar days after first 
knowledge by the sponsor that a case qualifies. Any additional information will be reported within 8 
additional calendar days. This report must include an assessment of the importance and implication 
of the findings, including relevant previous experience with the same or similar medicinal products. 
Follow-up information should be actively sought and follow-up reports should be submitted to the 
NPRA when it becomes available.  
Causality Assessment — All cases judged by either the reporting health care professional or the 
sponsor as having a reasonable suspected causal relationship to the medicinal product qualify as 
ARs.  
Definitely — there is clear evidence to suggest a causal relationship, and other possible contributing 
factors can be ruled out. 
Probably — there is evidence to suggest a causal relationship and the influence of other factors is 
unlikely. 
Possibly — there is some evidence to suggest a causal relationship (e.g. the event occurred within 
a reasonable time after administration of the trial medication). However, the influence of other 
factors may have contributed to the event (i.e. the patient’s clinical condition, other concomitant 
events). 
Unlikely — there is little evidence to suggest there is a causal relationship (e.g. the event did not 
occur within a reasonable time after administration of the trial medication). There is another 
reasonable explanation for the event (e.g. the participant’s clinical condition, or other 
concomitant treatments). 
Unrelated — there is no evidence of any causal relationship. 
Not Assessable — Note if this description is used the sponsor will assume the event is related to 
the IMP until follow up information is received from the investigator to confirm a definitive 
causality assessment. 
Any SUSAR assessed as related to the IMP will need to be reported to the Sponsor irrespective of how 
long after IMP administration the reaction has occurred. 
 
Expectedness should be based solely on the available RSI for the IMP and will be described using 
following categories : 
 
Expected — an AE that is classed in nature as serious and which is consistent with the information 
about the IMP listed in the RSI or clearly defined in this protocol. 
Unexpected — an AE that is classed in nature as serious and which is not consistent with the 
information about the IMP listed in the RSI. 
The completed AE Log will be sent to Sponsor upon request and/or every 2 months.  
 

 
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The Chief Investigator (CI) will respond to any SAE queries raised by the Sponsor as soon as possible. 
Follow up reports must continually be completed within acceptable timeframes and sent to the 
sponsor as detailed above until the reportable event is considered resolved. 
 
Notification of deaths 
 
All deaths will be reported to the Sponsor irrespective of whether the death is related to disease 
progression, the IMP or an unrelated event.  
 
The CI or the CI delegate will prepare the DSUR, using the Sponsor’s template and in accordance with 
the Sponsor’s DSUR SOP. It will be reviewed by the Sponsor and when necessary be referred to an 
independent committee (i.e. Research Governance Safety Sub Committee). The CI or the CI delegate 
will provide to the relevant ethics committee and the Sponsor will provide to NPRA the prepared DSUR 
annually within the defined reporting timelines. 
 
The CI or the CI delegate will prepare the APR in accordance with SOP. Following review by the 
Sponsor, the CI or the CI delegate  will  send to the relevant ethics committee to the reviewed report. 
The APR is due for submission annually within 30 days of the anniversary date on which the favourable 
opinion was given by the Ethics committee, until the trial is declared ended.  
 
The limited data available on exposure during pregnancy does not indicate any adverse effects of 
artesunate on the health of the foetus/newborn child. However, there is inadequate information for 
determining the foetal risk of artesunate treatment during pregnancy. Data from preclinical embryo 
foetal development studies in rats and rabbits showed a low incidence of cardiovascular malformation 
and syndrome of skeletal defects at doses close to embryolethal doses starting at around 6mg/kg/day. 
The dose used in our study of artesunate 200 mg will be below this threshold. In the event that 
pregnancy occurs whilst on the study drug, the pregnancy will be recorded in both the participant 
notes and CRF, the Sponsor and DMC will be notified. The female participant/pregnant partner of a 
male participant will be urgently reviewed by the research team and obstetric specialist and 
emergency un-blinding of the trial arm will be undertaken as per protocol section 11.4. If the 
participant is found to be receiving artesunate, the female participant or pregnant partner of a male 
participant will be followed up closely on a fortnightly basis together with an Obstetric Specialist and 
Foetal Medicine Specialist. The pregnancy will be monitored closely for any intrauterine 
abnormalities. Following successful delivery the newborn child will be monitored for up to 12 months 
together with a Paediatrician to ensure no adverse developmental effects have occurred. 
 
The Sponsor and Investigators may take appropriate urgent safety measures in order to protect the 
participants against any immediate hazard to their health or safety. The CI must telephone the NPRA 
to discuss the circumstances leading to the decision and the proposed measures to be taken. No later 
than 3 days following the conversation the CI must give written notice to the NPRA of that 
conversation and agreed actions. The Sponsor must also receive a copy of this communication to 
facilitate oversight of participating PI and participating site notification of imposed safety measures. 
A formal Substantial Amendment will be required for preparation and submission to the relevant 

 
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ethics committee/NMRR and NPRA at the earliest opportunity. Refer to sponsor SOP Management of 
Amendments  for guidance. 
 
 
Any Study Deviations or Violations will be documented using Sponsor’s Protocol Deviation form, and 
entered onto the Sponsor’s log. Potential Serious Breaches and Urgent Safety Measures will be 
reported according to SOP. 
 
A “serious breach” is a breach which is likely to effect to a significant degree : 
 
(a) The safety or physical or mental integrity of the participants of the trial; or 
(b) The scientific value of the trial 
 
The CI or the CI delegate will notify the Sponsor immediately of any case where there exists a possible 
occurrence of a serious breach. 
15. Data management and quality assurance 
All data will be handled in accordance with the Data Protection Act. The Case Report Forms (CRFs) will 
not bear the participant’s name or other directly identifiable data. The participant’s trial Identification 
Number (ID) only will be used for identification. The Sponsor Subject ID log can be used to cross 
reference participant’s identifiable information. 
 
Case Report Forms will be designed by the CI and the CI delegate and the final version will be approved 
by the Sponsor.  
 
It is the Investigator’s responsibility to ensure the accuracy of all data entered and recorded in the 
CRFs. The Staff Delegation of Responsibilities Log will identify all trial personnel responsible for data 
collection, entry, handling and managing the database.  Basic demographic and clinical information 
will be gathered at the time of the initial interview and by review of the medical notes if needed. The 
following information will be recorded for all subjects in the CRF : 
 
• 
Demographic details: Date of enrolment, age, gender, ethnicity 
• 
Clinical data: symptomatology, risk factors for development of CRC, weight, height, vital 
signs 
• 
Findings at endoscopy 
• 
Imaging: findings of ultrasound, CT and/or MRI (performed as clinically indicated) 
• 
Disease staging: TNM staging prior to surgery and definitive histological staging (TNM, 
Duke’s stage) 
• 
Histology: routine histological grading, apoptosis count and specialist assays (see below) 
• 
Concomitant medication: a full record of all non-study drugs taken will be kept 
• 
Study-drug treatment: compliance with study medication, all adverse events, serious or 
otherwise 
• 
Validated Quality of Life Tool (EORTC QLQ C-30, EuroQol EQ-5D, QLQ-CR29) 

 
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The following blood sample analysis will be performed: 
 
• 
Baseline - FBC, urea and electrolytes, LFTs, CEA, pre-treatment serum sample for study 
molecular analyses  
• 
Day 14/15 of treatment - FBC, urea and electrolytes, LFTs, CEA, post-treatment serum 
sample for study molecular analyses 
• 
Day 28 - FBC 
• 
Day 42 (4 weeks post-surgery) - FBC, urea and electrolytes, LFT, CEA 
• 
6 monthly visits for 5 years following surgery - CEA 
• 
Serum plasma samples will be taken at baseline (Day 1) and end of treatment (Day 14), 
processed and stored at -80°C (+/- 10°C) for future analyses 
• 
Any other blood or clinical sample at any time if deemed necessary by the investigators in 
case of a suspected adverse event 
 
All laboratory analysis should be reviewed by the PI and where results reported are not within the 
normal range the PI must clearly annotate ‘Not clinically Significant’ or ‘Clinically significant’ and sign 
and date the results. The relevant results should be carefully transcribed to the Case Report Forms. 
 
In order to ensure completeness of data collected, participants will be contacted by the research team 
(telephone call/email) in the event of missing data such as patient quality of life questionnaires. 
 
Incidental findings arising during the study will be discussed with the medical and research team 
involved in the patients care. The medical and research team will always act in the patient’s best 
interest and take appropriate clinical action in accordance with good clinical practice. 
 
Data will be stored in anonymised form in a password-protected database. We will use a 44 
Randomize44 study database storage programme. Study documentation will be stored for fifteen 
years after the completion of the study. Quality Control will be applied at each stage of data handling 
to ensure that all data are reliable and are processed correctly. Study data is destroyed after period 
of storage. 
16. Archiving arrangements 
The trial essential documents (e.g. TMF) along with the trial database will be archived in accordance 
with the sponsor SOP. The agreed archiving period for this trial will be defined within the Delegation 
of Duties Sponsorship Agreement. 
17. Statistical design 
Dr Irina Chis Ster – Senior Lecturer in Biostatistics, provided statistical expertise in clinical trial design 
and statistical planning. Professor Bertrand Lell will conduct the statistical analyses and data  
interpretation as data is now being combined from 2 studies implementing the same protocol 

 
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(NeoART-UK and NeoART-Vietnam). Professor Bertrand Lell is also providing the statistical expertise 
and support for NeoART-Vietnam. 
 
17.2.1  Primary endpoints 
 
The primary endpoint for the main comparison between the artesunate treatment and placebo arms 
will be persistent disease or disease recurrence, two years following surgery. All analyses will be made 
on an intention to treat basis, although per protocol analyses will also be reported. Statistical 
significance will be assumed at the 5% level unless otherwise indicated.  
17.2.2  Secondary endpoints  
Secondary endpoints will include: 
• 
Overall survival at 2 and 5 years 
• 
Recurrence free survival at 5 years 
• 
Colon cancer specific death at 2 and 5 years 
• 
Artesunate drug related toxicity 
• 
Adverse events 
• 
Pathological assessment of tumour regression (involvement of lymph nodes; serosa; 
resection margin) 
• 
Quality of life (EuroQol EQ-5D, EORTC QLQ C-30, EORTC QLQ-CR29) 
• 
Surgical morbidity/mortality 
• 
Predictive value of tumour biomarkers in terms of predicting response to artesunate therapy 
• 
Biomarker and molecular profiling studies  
 
 17.3.1 Sample size calculation 
We performed our sample size calculation largely based on inferences drawn from our pilot Phase I 
study (Krishna et al., 2015). The input assumes that the analysis would be conducted using a univariate 
Cox proportional hazard survival model from the time of surgery to the first disease recurrence with 
one binary covariate representing treatment groups (artesunate or placebo). We calculated that a 
minimum sample size of 168 patients is necessary to test a hazard ratio (HR) of 0.56 for the 
intervention versus placebo. This value is within the confidence intervals estimated in our phase I 
study (Krishna et al., 2015) and somewhat between the point estimate in the worse case scenario 
inference in the paper and a value of 0.7 commonly circulated in oncology clinical trials. For this Phase 
II study, we set the power at 0.8 and accepted a type one error of 0.1 for a one-sided test.  
1) The null nypothesis H0: HR=0.56 (equivalent ≤) 
2) The alternative hypothesis H1: HR>0.56 
These settings would result in a sample size of 168 patients. Inflating this sample size by 15-20% to 
allow for loss at follow-up would result in approximately 194-202 patients. We believe that 200 
patients therefor represents a feasible and achievable target given our time and financial constraints. 
The rationale and sensitivity analyses for these calculations are outlined below. The general setting 
is that of a survival analysis where the event is defined as the first disease recurrence after surgery.  
 

 
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A cohort of Stage II/III colorectal cancer patients undergoing surgery will be randomised as per 
recruitment to receive the artesunate intervention or placebo. Patients will be followed-up for 5 years 
following surgery. The minimum sample size to test a hazard ratio (HR) of 0.56 for the intervention vs. 
placebo group is based on: 
 
Calculation framework: 
 
1. The minimum sample size calculation has been calculated as for a univariate Cox proportional 
hazard survival model with one binary covariate representing treatment groups (artesunate 
or placebo).  
2. The necessary number of events are calculated as  
            D = (Z1−α + Z1−β)
2 [P × (1 −P) × (log(HR))
2]
−1
 
Where P represents the proportion of the sample assigned to the treatment group (0.5 
corresponding to a 1:1 treatment assignment in our setting) and the HR is the estimated hazard ratio 
of the event (disease recurrence) for the treatment group vs. placebo. The values of the inverse of 
the standard normal cumulative distribution function are 
 𝑍1−𝛼= 1.28 for one sided α=0.1 and 𝑍1−𝛽= 0.842 for β=0.20 (equivalent to 80% power). 
 
3. Hence, the minimum total number needed for the trial is calculated as 
                                          N = D × (100/32) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Graph 1: Study sample size- a sensitivity analysis to various settings for hazard ratios and type one 
error for one-sided test. 
 
0
50
100
150
200
250
300
350
400
450
500
550
600
.3
.35
.4
.45
.5
.55
.6
.65
.7
Hazard ratio (Artesunate vs. Placebo)
Events
One sided 0.15
Events
One sided 0.10
Events
One sided 0.05
Power=0.8

 
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Total number 
participants 
One sided level of 
significance 
HR 
Number of events 
53 
.15 
.4 
17 
56 
.15 
.41 
18 
59 
.15 
.42 
19 
62 
.15 
.43 
20 
66 
.15 
.44 
22 
70 
.15 
.45 
23 
74 
.15 
.46 
24 
78 
.15 
.47 
25 
82 
.15 
.48 
27 
87 
.15 
.49 
28 
92 
.15 
.5 
30 
104 
.15 
.52 
34 
117 
.15 
.54 
38 
132 
.15 
.56 
43 
149 
.15 
.58 
48 
169 
.15 
.6 
55 
193 
.15 
.62 
62 
222 
.15 
.64 
72 
256 
.15 
.66 
82 
297 
.15 
.68 
96 
347 
.15 
.7 
112 
 
 
 
 
68 
.1 
.4 
22 
71 
.1 
.41 
23 
75 
.1 
.42 
24 
80 
.1 
.43 
26 
84 
.1 
.44 
27 
89 
.1 
.45 
29 
94 
.1 
.46 
31 
99 
.1 
.47 
32 
105 
.1 
.48 
34 
111 
.1 
.49 
36 
118 
.1 
.5 
38 
132 
.1 
.52 
43 
149 
.1 
.54 
48 
168 
.1 
.56 
54 
190 
.1 
.58 
61 
216 
.1 
.6 
70 
247 
.1 
.62 
80 
283 
.1 
.64 
91 
327 
.1 
.66 
105 
379 
.1 
.68 
122 
443 
.1 
.7 
142 
 
 
 
 
93 
.05 
.4 
30 
98 
.05 
.41 
32 
103 
.05 
.42 
33 
109 
.05 
.43 
35 
115 
.05 
.44 
37 
122 
.05 
.45 
40 
129 
.05 
.46 
42 
136 
.05 
.47 
44 
144 
.05 
.48 
47 
152 
.05 
.49 
49 
161 
.05 
.5 
52 
181 
.05 
.52 
58 
204 
.05 
.54 
66 
230 
.05 
.56 
74 
261 
.05 
.58 
84 
297 
.05 
.6 
96 
339 
.05 
.62 
109 
389 
.05 
.64 
125 
448 
.05 
.66 
144 
520 
.05 
.68 
167 

 
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608 
.05 
.7 
195 
 
Table 2: Details sensitivity analyses to various settings for hazard ratio values. Power is set at 0.8. 
 
The minimum sample size has been calculated within the same general circumstances and similar 
outcome (disease recurrence) as the pilot study. Namely, the calculations are initially based on the HR 
of treatment group versus placebo group values ranging from 0.15-0.31 as obtained in our pilot study 
(assuming a 1:1 randomization). The overall ratio of events (disease recurrence) was 0.32 (7/22). 
However, given the small sample size of the pilot study, we have extended our sensitivity analysis up 
to the value of 0.56 for the hazard ratio and the corresponding sample size to 200 patients (see graph 
1 and table 2). May we add that, under the assumption that the intervention is not worse, the numbers 
would also be valid for a setting in which one-sided alpha level of significance is set at 0.15 and HR = 
0.6 and for one sided alpha level of significance of 0.05 and HR = 0.5 – with power held at 0.8. 
 
17.3.2 Planned recruitment rate 
NeoART aims to randomize 200 participants in total. We have faced challenges meeting our 
recruitment target in. We have therefore discussed these issues with the DMC and TSC in the UK and 
a decision has been made to combine the data from the UK with a mirror study in Vietnam (NeoART-
Vietnam) and Malaysia (NeoART-Malaysia). Although different study populations, these are mirror 
studies in terms of trial protocol, study procedures and Investigational Medicinal Product source. The 
target recruitment in the UK will now be 34, Vietnam will be 46 and Malaysia will be 120 patients and 
a target trial recruitment of 200 patients. 
 
In Malaysia, 5 Ministry Of Health, Universiti Malaya are ready to open the trial. We aim to recruit 8-
12 participants to the study per month in each sites in Malaysia over 24 months.  
 
17.3.3 Statistical analysis plan 
The event of interest (failure defined as cancer recurrence from a survival analysis perspective) is 
defined as the first recurrence of the disease after the patients’ treatment allocation and surgery. 
Patients will be followed-up for 2 years; if the event of interest does not occur the patient will be 
considered (right) censored. The general assumption for time-to-event (survival analysis) is that the 
censoring is non-informative, i.e. it is independent of the event process. The Cox proportional hazard 
(PH) model would be applied to investigate the hazard ratio of disease recurrence for the artesunate 
group versus placebo group. The semi-parametric technique allows no assumption to be made on the 
baseline hazard; nevertheless proportionality of the hazards in the two arms should hold. The latter 
assumption can be tested on the basis of Shoenfeld residuals after fitting the model to the data. 
 
We discussed an interim analysis in December 2021 with the DMC and TSC. At this time point 78 
patients will have reached the primary end point (recurrence free survival 2 years after surgery). This 
analysis will be performed by an independent trial statistician familiar with both trials (Prof Bertrand 
Lell) and a report presented to the DMC and TSC members for review and recommendations 
thereafter. 
17.3.3.1 Summary of baseline data and flow of patients 
 
Details of the number of patients eligible for the trial, the number of patients consenting and the 
number randomised along with a breakdown for each group of the numbers of participants assigned, 
receiving the intended treatment, completing the study protocol, and analysed for the primary 
outcome will be clearly documented. This information will be displayed as a flow diagram 
(http://www.consort-statement.org/). 
 

 
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The analyses will be performed in STATA (StataCorp. 2014. Stata Statistical Software: Release 14. 
College Station, TX: StataCorp LP.) and/or (R: A language and environment for statistical computing. R 
Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, URL http://www.R-
project.org/). GraphPad (Prism) or other comparable statistical package.  
 
Descriptive statistics, preliminary analysis and graphics will be used to understand the data structure, 
the nature of the variables and the appropriateness of the subsequent tests and analyses. Data will 
be summarized as mean, standard deviation and range if normally distributed. If the data are skewed 
then additional statistics such as median and inter-quartile ranges will be used to correctly describe 
the selected sample in the population. Parametric or non-parametric tests will be used as appropriate 
to ensure/verify that the two groups do not differ statistically with respect to any aspects but the 
intervention.  
 
Three safety interim analyses are planned as the trial data collection proceeds, approximately after 
10%, 50% and 75% of patients have completed their day 28 assessments.  
 
The appropriate statistical framework for the analysis of the primary outcome is that of a survival 
analysis. Patients will be followed-up up to 2 years; if the event of interest does not occur within this 
time frame, the patient is considered (right) censored. The general assumption is that the censoring 
is independent of the event process. The Cox proportional hazard (PH) model would be applied to 
investigate the hazard ratio of disease reccurrence for the artesunate group vs. placebo group. The 
semi-parametric technique allows no assumption to be made on the baseline hazard; nevertheless 
proportionality of the hazards in the two arms should hold. The latter assumption can be tested on 
the basis of Shoenfeld residuals after fitting the model to the data.  
 
The inference is expressed in survival type metrics: i.e. proportion of individuals surviving recurrence 
beyond 1 year, 2 years and median time to recurrence in each group. Predictions (survival prognostics) 
will refer to the colon cancer population within our data range. 
 
Missing data (attrition) will be assessed and sensitivity analysis will be employed upon the 
particularities exhibited by the data, i.e. missing data pattern and whether the missing information is 
associated with the main outcome. This will include data analysis under a ‘missing at random 
assumption’ and imputation methods tailored to interval censored data will also be applied.     
 
Both a frequentist and Bayesian framework for statistical inference are envisaged. The uncertainty 
will be expressed in terms of 95% confidence intervals (CI) or 95% credible intervals (CrI) for their 
corresponding estimates. The frequentist statistical significance would be deemed at the 0.05 (5%) 
level. 
 17.3.3.2 
Primary endpoint analysis 
 
Additional exploratory analyses will be undertaken of the potential impact of tumour biomarkers on 
treatment efficacy and prognosis. The analyses of these outcomes will be decided upon depending on 
data structure and nature, i.e. whether to use one measurement or multiple measurements per 
individual. Appropriate multilevel approaches will be implemented in case of the later. Suitable 
variable transformations will be applied if required by modelling assumptions. Missing data patterns 
will also be evaluated and appropriate methodologies and sensitivity analyses will be used to assess 
the results sensitivity compared to the statistical assumptions.   
17.3.3.3 
Secondary endpoint analysis 
 
Overall survival 

 
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Overall survival and cancer specific survival analyses at 2 and 5 years will be treated in the same 
manner as progression free survival analysis. 
 
Pathological Response/assessment of tumour regression 
 
Pathological tumour response will be assessed for all patients and comparisons examined using the 
chi-squared test with 95% confidence intervals expressed for response rates. 
 
Toxicity assessments 
 
The proportion of patients experiencing grade 3 or 4 toxicity will be compared between the two 
treatment arms using the chi-squared test. When cell frequencies are less than 5, Fisher’s exact test 
will be used. The chi-squared test for trend will also be used to compare all toxicity scores. 
 
Locoregional failure 
 
Patterns of locoregional failure will be reported descriptively. 
 
Quality of life  
 
The functional and symptomatic scales of the EORTC quality of life questionnaires (EuroQol EQ-5D, 
EORTC QLQ C-30, EORTC QLQ-CR29)  will be examined by calculating the differences in measurements 
from baseline. The standard EORTC recommended methods will be used to calculate function and 
symptomatic scores. The nature of the variable which quantifies this EORTC score will be investigated 
and summary statistics will be presented for values at baseline and post treatment. A multivariable 
regression type analysis will be conducted with post-treatment scores and pre- treatment (baseline) 
scores as an outcome and groups defined by the interventions as explanatory variables. Additional 
explanatory variables such as age, gender, disease stage may also be included. Missing data will be 
investigated in a similar fashion as previously described. 
 
Surgical morbidity/mortality 
 
The proportion of patients experiencing an adverse event in relation to surgical morbidity/mortality 
will be compared between the two treatment arms using the chi-squared test. When cell frequencies 
are less than 5, Fisher’s exact test will be used. The chi-squared test for trend will also be used to 
compare rates of adverse events. Length of hospital stay will be reported as a mean. 
 
Molecular biomarkers 
 
Predictive value of tumour biomarkers in terms of predicting response to artesunate therapy and 
molecular profiling studies will be evaluated. Where appropriate, paired analyses will be performed 
to evaluate the effect of known prognostic factors or potential prognostic factors on outcomes 
observed. 
Patients recruited to the study will be randomised to receive either artesunate or placebo in equal 
proportions. Randomisation lists will be generated for each site by computer-generated code, 
supplied by the study Sponsor’s representative to the Clinical Trials Pharmacist or a study coordinator 
who is not part of the investigator’s team only. The code will only be broken in exceptional 

 
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circumstances, when knowledge of the investigational drug is essential for medical treatment of the 
patient. 
 
An interim analysis reviewing feasibility and tolerability will be performed once 10%, 50% and 75% of 
patients have completed their day 42 assessments. Upon data collection availability, further refined 
analysis may be possible using advanced multistate modelling methodologies (Schmoor et al 2013).  
 
We have discussed an interim analysis in December 2021 with the DMC and TSC. At this time point 78 
patients will have reached the primary end point (recurrence free survival 2 years after surgery). This 
analysis will be performed by an independent trial statistician familiar with both trials (Prof Bertrand 
Lell) and a report presented to the DMC and TSC members for review and recommendations 
thereafter. 
 
 
It is possible that the general Cox proportional hazard model assumption, i.e. proportional hazard may 
not hold. Parametric survival analyses may then be required, such as accelerated time failure (AFT) 
models. Whereas a proportional hazards model assumes that the effect of a covariate is to multiply 
the hazard by some constant, an AFT model assumes that the effect of a covariate is to accelerate or 
decelerate the life course of a disease by some constant. However, this is especially appealing in a 
technical context where the 'disease' is a result of some mechanical process with a known sequence 
of intermediary stages and more appropriate in case of fast dynamic diseases. It may also be possible 
that it is more appropriate to assume that the failure rate is proportional to a power of time – in which 
case a Weibull type distribution may be a more accurate description of the process. However, all these 
statements are speculative as they depend on the patterns in the data which are impossible to 
accurately predict at this stage. 
18. Committees involved in the trial  
Appropriate oversight mechanisms will be put in place for the trial.  
 
1. Trial Management Group (TMG) – will include those individuals responsible for the day-to-day 
management of the trial, such as the CI, statistician, trial manager, research nurse, data manager, 
Clinical Trial Monitor/Sponsor representative. The role of the group is to monitor all aspects of the 
conduct and progress of the trial, ensure that the protocol is adhered to and take appropriate action 
to safeguard participants and the quality of the trial itself. Decisions about continuation or termination 
of the trial or substantial amendments to the protocol will be the responsibility of the Trial 
Management  Group as informed by the TSC and DMC. 
 
2. Trial Steering Committee (TSC) - provides overall supervision of the trial and ensures that it is being 
conducted in accordance with the principles of GCP and the relevant regulations. The Trial Steering 
Committee should agree the trial protocol and any protocol amendments and provide advice to the 
Investigators on all aspects of the trial. A Trial Steering Committee may have members who are 
independent of the Investigators, in particular an independent chairperson. The TSC will discharge its 
saftey assessment of the study to the DMC. The TSC will advise the Sponsor directly of any decision 
regarding any change to study status in accordance with the NeoART TSC Charter.  
 

 
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3. Data Monitoring Committee (DMC) - will meet to review the interim analysis results and to assess 
whether there are any safety issues that should be brought to the attention of the TSC. The Data 
Monitoring Committee should be independent of both the Investigators and the funder/Sponsor and 
should be the only body that has access to unblinded data. The DMC will operate in accordance with 
the NeoART DMC Charter. 
 
All formally constituted trial groups/committees will be provided with a charter that sets out group 
composition, quorum requirements, responsibilities, structure of meetings, processes for decision 
making and reaching consensus. 
19. Direct access to source data 
The Investigator(s)/institution(s) will permit trial-related monitoring, audits, relevant ethics 
committee review, and regulatory inspection(s), providing direct access to source data/documents. 
Trial participants are informed of this during the informed consent discussion. Participants will 
consent to provide access to their medical notes. 
20. Site approval and ongoing regulatory compliance 
Before any site can enroll patients into the trial, the Sponsor will be in possession of ethics approval. 
The site will have a fully executed Clinical Site Agreement and have received the Open to Recruitment 
letter issued by the Sponsor. The site must conduct the trial in compliance with the protocol as agreed 
by the Sponsor and, by the regulatory authorities as appropriate and which was given a favourable 
opinion by the relevant ethics committee and NMRR.  
 
The Chief Investigator will be provided (via the Sponsor) with file indexes i.e. TMF index and ISF index 
for use with SOP of ‘Preparation and Maintenance of the TMF’. The CI will be responsible for the 
maintenance of the TMF and will delegate the responsibility of ISF file maintenance to the PI at each 
participating site. 
 
It is the responsibility of the PI at each site to ensure that all subsequent amendments gain the 
necessary approvals. Refer to SOP of ‘Management of Amendments’. This does not affect the 
individual clinician’s responsibility to take immediate action if thought necessary to protect the health 
and interest of individual patients (see section 14.6 for details of reporting procedures/requirements). 
 
Within 90 days after the end of the trial, the CI and Sponsor will ensure that the relevant ethics 
committee and the National Pharmaceutical Regulatory Authority are notified that the trial has 
finished.  If the trial is terminated prematurely, those reports will be made within 15 days after the 
end of the trial. Refer to SOP ‘End of study declaration’. 
 
The CI will supply an End of Study report of the clinical trial to the NPRA and relevant ethics committee 
within one year after the end of the trial. The Sponsor can provide the End of study Report template. 
21. Monitoring plan for the trial 
The CI will be requested to complete the Risk Assessment Questionnaire and forward to the Sponsor 
to facilitate appropriate costing and Sponsorship in Principle to be issued prior to NMRR application. 
The trial will be monitored according to the risk based monitoring plan agreed by the Sponsor and CI. 
The governance team will determine the initial project risk assessment and justify change as the study 

 
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progresses. The PI at each collaborating site in addition to site monitoring visits will required to 
complete self-monitoring form(s) and must return the forms to the Sponsor for review and action. 
Failure for any PI to comply with requests for on behalf of the Sponsor may be escalated in accordance 
with SOP Escalation Procedure ; the site may also be selected for a GCP audit.  
 
It is the Sponsor’s Clinical Research Associate’ s (CRA) responsibility to ensure that any findings 
identified in any monitoring report are actioned appropriately and in a timely manner and that any 
violations of GCP or the protocol will be reported to the CI and Sponsor. Any serious breach will be 
handled according to SOP Serious Breach Reporting. 
 
Any urgent safety measures at either the CI or a PI site must be reported by that site, as per NPRA 
Regulations. The CI and/or the CI delegate will be provided with a copy of the study monitoring plan 
during the Trial Initiation monitoring visit. 
22. Finance 
Funded by the Malaysian Federal Government, Selangor State Government, charitable and 
philanthropic donations provided financial support for the study.  
23. Insurance and Indemnity 
Metanoic Health Limited as the study Sponsor holds insurance to cover participants for injury 
caused by their participation in the clinical trial. Participants may be able to claim compensation if 
they can prove that sponsor has been negligent. This includes negligence in the writing of the protocol, 
or selection of trial resources.  
 
Where the trial is conducted in a hospital, the hospital has a duty of care to participants. Metanoic 
Health Limited will not accept liability for any breach in the hospital’s duty of care, or any negligence 
on the part of hospital employees.  Hospitals selected to participate in this clinical trial shall provide 
clinical negligence insurance cover for harm caused by their employees and a copy of the relevant 
insurance policy or summary shall be provided to Metanoic Health Limited ,upon request. 
 
Participants may be able to claim compensation for injury caused by participation in this Trial without 
the need to prove negligence on the part of sponsor or another party.  
 
If a participant indicates that they wish to make a claim for compensation, this needs to be brought 
to the attention of Metanoic Health Limited immediately. Failure to alert Metanoic Health Limited 
without delay and to comply with requests for information by the sponsor or any designated Agents 
may lead to a lack of insurance cover for the incident.   
24. Intellectual Properties and development policy  
Unless otherwise specified in agreements, the following guidelines shall apply : All Intellectual 
Property Rights and Know How (IP) related to the Protocol and the Trial are and shall remain the 
property of the Sponsor excluding :  
 
1) pre-existing IP related to clinical procedures of any Hospital. 
2) pre-existing IP related to analytical procedures of any external laboratory. 
 

 
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All contributors shall assign their rights in relation to all Intellectual Property Rights and in all Know 
How, not excluded above, to the Sponsor and at the request and expense of the Sponsor, shall execute 
all such documents and do all such other acts as the Sponsor may reasonably require in order to vest 
fully and effectively all such Intellectual Property Rights and Know How in the Sponsor or its nominee.  
 
All contributors shall promptly disclose to the Sponsor any Know How generated pursuant to this 
Protocol and not excluded above and undertake treat such Know How as confidential information 
jointly owned it and the Sponsor. 
 
Nothing in this section shall be construed so as to prevent or hinder the medical professional team 
from using Know How gained during the performance of the Trial in the furtherance of its normal 
business activities, to the extent such use does not result in the disclosure or misuse of Confidential 
Information or the infringement of any Intellectual Property Right of the Sponsor.  
 
Transfer of ownership of Intellectual Property and Know How from Sponsor will be arranged through 
the principal funding and coordinating agency in Malaysia (based on funding for the study coming 
from the Malaysian Federal Government and Selangor State Government). 
25. Publication Policy 
Publication: “Any activity that discloses, outside of the circle of trial investigators, any final or interim 
data or results of the Trial, or any details of the Trial methodology that have not been made public by 
the Sponsor including, for example, presentations at symposia, national or regional professional 
meetings, publications in journals, theses or dissertations.” 
 
All scientific contributors to the Trial have a responsibility to ensure that results of scientific interest 
arising from Trial are appropriately published and disseminated. The Sponsor has a firm commitment 
to publish the results of the Trial in a transparent and unbiased manner without consideration for 
commercial objectives.  
 
To maximise the impact and scientific validity of the Trial, data shall be consolidated over the duration 
of the trial, reviewed internally among all investigators and not be submitted for publication 
prematurely. Lead in any publications arising from the Trial shall lie with the Chief Investigator in the 
first instance, in discussion with Sponsor.  
 
All publications associated with this trial will be discussed with the Sponsor but duties regarding 
publication will be delegated to the Chief Investigator. Any disputes regarding authorship will be 
discussed and settled by the Trial Steering Committee. Exempt from this requirement are student 
theses that can be submitted for confidential evaluation but are subject to embargo for a period not 
shorter than the anticipated remaining duration of the trial.      
 
• 
During this period the Chief Investigator shall liaise with all investigators and strive to 
consolidate data and results and submit a manuscript for peer-review with a view to 
publication in a reputable academic journal or similar outlet as the Main Publication. 
 

 
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• 
The Chief Investigator and Surgical Oncology Trial Adviser shall be senior and 
corresponding/co-corresponding authors of the Main Publication.  
 
• 
Insofar as compatible with the policies of the publication outlet and good academic practice, 
the other Investigators shall be listed according to contributions and/or under a Trial title such 
as Neo-ART.  
 
• 
Providers of analytical or technical services shall be acknowledged, but will only be listed as 
co-authors if their services were provided in a non-routine manner as part of a scientific 
collaboration.  
 
• 
Members of the Steering Group will be acknowledged as co-authors. 
 
• 
Members of the DMC will be acknowledged in publications . If there are disagreements about 
the substance, content, style, conclusions, or author list of the Main Publication, the Chief 
Investigator and Surgical Oncology Trial Adviser  shall arbitrate and ask the Steering Group to 
assist.     
 
After the Main Publication or after 180 days from Trial end date any Investigator or group of 
investigators may prepare further publications.  In order to ensure that the Sponsor will be able to 
make comments and suggestions where pertinent, material for public dissemination will be submitted 
to the Sponsor for review at least thirty (30) days prior to submission for publication, public 
dissemination, or review by a publication committee. In exceptional circumstances this should be 
expedited. Sponsor’s reasonable comments shall be reflected. All publications related to the Trial shall 
credit the Chief and Surgical Oncology Trial Adviser as co-authors where this would be in accordance 
with normal academic practice and shall acknowledge the Sponsor and the Funders.    
26. Statement of compliance 
The trial will be conducted in compliance with the protocol, Sponsor’s Standard Operating Procedures 
(SOPs), GCP and the applicable regulatory requirement(s). 
 
The study conduct shall comply with all relevant laws of Malaysia in which the study site is located 
including but not limited to, the Human Rights Act 1998,  Personal Data Protection Act 2010 (PDPA) 
of Act 709., the Human Medicines Regulations 2012, the Medicines for Human Use (Clinical Trial) 
Regulations 2004, and with all relevant guidance relating to medicines and clinical studies from time 
to time in force including, but not limited to, the ICH GCP, the World Medical Association Declaration 
of Helsinki entitled 'Ethical Principles for Medical Research Involving Human Subjects' (2008 Version). 
This study will be conducted in compliance with the protocol approved by the relevant ethical 
committee and according to GCP standards and NPRA. No deviation from the protocol will be 
implemented without the prior review and approval of the Sponsor except where it may be necessary 
to eliminate an immediate hazard to a research participant.  In such case, the deviation will be 
reported to the Sponsor and relevant ethical committee as soon as possible. 
27. List of Protocol appendices 
Appendix 1 
Protocol Amendment/Revision History  

 
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Appendix 2 
Summary chart of study assessments 
Appendix 3  
Quality of Life Questionnaires  
 
EuroQol EQ-5D, EORTC QLQ C-30, EORTC QLQ CR29 
Appendix 4 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 
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artemisinin on growth inhibition of nasopharyngeal carcinoma cells. J Cell Biochem 2011;112:1938–
1948. 
 
Wu B., Hu K., Li S., Zhu J., Gu L., Shen H. Dihydroartiminisin inhibits the growth and metastasis of 
epithelial ovarian cancer. Oncol Reports 2012;27:101–108. 
 
Xie W., Yang L., Zeng PH  X., Cai JY. Effect of 4-(12-dihydroartemisininoxy) benzoic acid hydrazide 
transferrin tagged drug on human breast cancer cells. Chin J Anal Chem 2009;37: 671–675. 
 
Xu N., Zhou X., Wang S., Xu LL., Zhou HS., Liu XL. Artesunate Induces SKM-1 Cells Apoptosis by 
Inhibiting Hyperactive β-catenin Signaling Pathway. Int J Med Sci. 34 
; 12(6):524-9.  
 
Yang Y., Zhang X., Wang X., Zhao X., Ren T., Wang F., Yu B. Enhanced delivery of artemisinin and its 
analogues to cancer cells by their adducts with human serum transferrin. Int J Pharm 2014;467(1-
2):113-22. 
 
Yang ND., Tan SH., Ng S., Shi Y., Zhou J., Tan KS., Wong WS., Shen HM. Artesunate induces cell death 
in human cancer cells via enhancing lysosomal function and lysosomal degradation of ferritin. J Biol 
Chem. 2014;289(48):33425-41. 
 
Zeamari S., Roos E., Stewart FA.Tumour seeding in peritoneal wound sites in relation to growth-factor 
expression in early granulation tissue. Eur J Cancer. 2004;40(9):1431-40.  
 
Zhang Z., Yu S., Miao L., Huang X., Zhang X., Zhu Y., et al. Artesunate combined with vinorelbine plus 
cisplatin in treatment of advanced non-small cell lung cancer: a randomized controlled trial. J Chin 
Integr Med. 2008;6:134. 
Zhao Y., Jiang W., Li B., Yao Q., Dong J., Cen Y., Pan X., Li J., Zheng J., Pang X., et al. Artesunate enhances 
radiosensitivity of human non-small cell lung cancer A549 cells via increasing no production to induce 
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Zoller T., Junghanss T., Kapaun A., Gjorup I., Richter J., Hugo-Persson M., Mørch K., Foroutan B., 
Suttorp N., Yürek S., Flick H. Intravenous artesunate for severe malaria in travelers.Europe Emerging 
Infect Dis. 2011;17:771-777.  
 
Appendix 1. Protocol amendment /Revision History 
 

 
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NeoART-M Version 6.0 4 October 2024 
 
Protocol 
Version and 
Date 
Amended text 
Section details and change  
Version 2.0 
6 January 
2023 
Title: Changed the short name of the study from NeoART Trial to NeoART-M trial 
Version 2.0 
6 January 
2023 
Front page: Added protocol ID: 2023-MHL-001 
Changed protocol version and date 
Changed Chief Investigator's email address to skrishna@cadt.org.uk 
Changed of sponsor to Metanoic Health Limited 
Changed of sponsor representative to Dr Isaac John 
Version 2.0 
6 January 
2023 
Signature page and statement 
- Changed sponsor representative  
Version 2.0 
6 January 
2023 
 2. Roles and Responsibilities 
- Added Co-Principal Investigator  
- Added Lead Research Pharmacists 
Version 2.0 
6 January 
2023 
3. Study Synopsis 
-Anticipated primary recruitment completion date: 31stJuly 2025 
Sponsor: Metanoic Health Limited 
Version 2.0 
6 January 
2023 
8. IMP Dosage regimen and rationale 
- 'The study product does not contain porcine, bovine or animal components.' 
- Methods of contraception that are acceptable for the trial include the following:  
The implant, the coil and male or female sterilisation will be acceptable for the trial. The 
injection and most forms of hormonal contraception will also be deemed acceptable for 
the trial if used in combination with condoms or other barrier methods. However, 
condoms alone won’t be sufficient during the study. 
Version 2.0 
6 January 
2023 
11.3 Prescribing & Dispensing of IMP 
 'The label must follow the Appendix E: Labelling Requirements of the Rules and 
guidance for Malaysian-Guideline-for-Application-of-CTIL-and-CTX-7.1-Edition and 
Version 2.0 
6 January 
2023 
11.4 Emergency unblinding 
- Each study site will have the capabilities of revealing patient treatment allocation in 
case of emergency. In the case where there 
Version 2.0 
6 January 
2023 
12.5.1.1 Obtaining, labelling, storing  
 Permit to Import or Export of Human Tissues or Part Thereof Health Office/District 
Health Office (BLESS) to  
Version 2.0 
6 January 
2023 
13. Translational research / Pharmacodynamic Studies 

 
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NeoART-M Version 6.0 4 October 2024 
 
For instructions on processing and storage of study bloods, tissue samples please refer 
to the study lab manual. 
Version 2.0 
6 January 
2023 
17.3.2 Planned recruitment rate 
.The target recruitment in the UK will now be 40 to 50, Vietnam will be 40 to 50 and 
Malaysia will be 120 patients and a target trial recruitment of 200 patients in total by 
31/07/2025. 
We aim to recruit 8-12 participants to the study per month in each site in Malaysia to 
meet our recruitment target by 31st July 2025. 
Version 2.0 
6 January 
2023 
22. Finance 
The study will be funded through Centre for Affordable Diagnostics and Therapeutics 
Version 2.0 
6 January 
2023 
23. Insurance and Indemnity 
Added Metanoic Health Limited holds insurance to cover participants  
Version 2.0 
6 January 
2023 
Added Intellectual Properties  
Version 3.0 
11 July 2023 
12.5.1.1 Obtaining, labelling, storing  
A new ethics approval will be obtained from University Malaya Medical Centre 
Medical Research Committee (UMMC-MREC) should we need to use the transferred 
samples for any further exploratory analysis. 
Version 4.0 
10 May 
2024 
Changed email to sponsor: clinicaltrials@metanoichealth.com 
Version 4.0 
10 May 
2024 
Removed Co-PI  
 
Associate Professor Khong Tak Loon  and Dr Norfadhlina Binti Abdul Satar 
and replaced with  
Dr David Lee Dai Wee 
Pusat Perubatan Universiti Malaya 
Lembah Pantai,59100 Kuala Lumpur 
Email: daiwee@ummc.edu.my 
 
Dr Ruben Gregory Xavier 
Pusat Perubatan Universiti Malaya 
Lembah Pantai,59100 Kuala Lumpur 
Email: rubengregory@ummc.edu.my 

 
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NeoART-M Version 6.0 4 October 2024 
 
 
Removed  
Dr Wong Pak Kai as Co-PI from USM. 
Version 4.0 
10 May 
2024 
Study Synopsis 
Changed funding through Centre for Affordable Diagnostics and Therapeutics to Funded 
by the Malaysian government, Selangor State Government, charitable and philanthropic 
donations provided finaleencial support for the study.  
 
Changed Start date from 'August 2023' to 'Open to recruitment in Malaysia: Q22024'  
Changed Anticipated primary recruitment completion date from '31st July 2025' to 'Q4 
2025' 
Changed email clinicaltrials@metanoichealth.com to contact details 
Version 4.0 
10 May 
2024 
8. IMP Dosage regimen and rationale 
Packaging and storage conditions 
Changed One patient box will provide 28 tablets – sufficient for the duration of the 
study to 
One patient bottle will provide 28 tablets – sufficient for the duration of the study.  
Version 4.0 
10 May 
2024 
10. Subject/Patient Recruitment process 
'NeoART aims to randomise 200 participants worldwide with 120 patients in Malaysia. 
We aim to recruit 8-12 participants to the study per month to meet our recruitment 
target over 24 months. Our Phase I pilot trial (Krishna et al., 2015) was the first trial to 
investigate neoadjuvant artesunate for colorectal cancer and demonstrated the 
feasibility, practicability, and safety of this novel approach.' 
 

 
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NeoART-M Version 6.0 4 October 2024 
 
Version 4.0 
6 January 
2024 
17.3.2 Planned recruitment rate 
Changed 'NeoART aims to randomize 200 participants in total. Due to the COVID19 
pandemic, the clinical trial has been on hold, and we have faced challenges meeting our 
recruitment target. We have therefore discussed these issues with the DMC and TSC 
and a decision has been made to combine the data from the UK with a mirror study in 
Vietnam (NeoART-Vietnam) and Malaysia (NeoART-Malaysia). Although different study 
populations, these are mirror studies in terms of trial protocol, study procedures and 
Investigational Medicinal Product source. The target recruitment in the UK will now be 
40 to 50, Vietnam will be 40 to 50 and Malaysia will be 120 patients and a target trial 
recruitment of 200 patients in total by 31/07/2025.Principal Investigators at the 5 
National Health Service sites throughout the UK are ready to re-open 
the trial and committed to recruiting to the study. In Vietnam, 2 large teaching hospitals 
will run the  study (108 Military Central Hospital and the National Cancer Hospital which 
is under Ministry of Health). In Malaysia, 5 Ministry Of Health, University Malaya and 
University Science Malaysia are ready to open the trial. We aim to recruit 8-12 
participants to the study per month in each sites in Malaysia to meet our recruitment 
target by 31st July 2025' to  
 
'NeoART aims to randomize 200 participants in total. Due to the COVID-19 pandemic, 
the clinical trial has been on hold, and we have faced challenges meeting our 
recruitment target. We have therefore discussed these issues with the DMC and TSC 
and a decision has been made to combine the data from the UK with a mirror study in 
Vietnam (NeoART-Vietnam) and Malaysia (NeoART-Malaysia). Although different study 
populations, these are mirror studies in terms of trial protocol, study procedures and 
Investigational Medicinal Product source. The target recruitment in the UK will now be 
34, Vietnam will be 46 and Malaysia will be 120 patients and a target trial recruitment of 
200 patients. 
 
In Malaysia, 5 Ministry Of Health, University Malaya are ready to open the trial. We aim 
to recruit 8-12 participants to the study per month in each sites in Malaysia over 24 
months.'  
Version 4.0 
10 May 
2024 
22. Finance 
Funded by the Malaysian Federal Government, Selangor State Government, charitable 
and philanthropic donations provided financial support for the study.  
Version 4.0 
10 May 
2024 
24. Intellectual Properties and development policy  
 
Added 'Transfer of ownership of Intellectual Property and Know How from Sponsor will 
be arranged through the principal funding and coordinating agency in Malaysia (based 
on funding for the study coming from the Malaysian Federal Government and Selangor 
State Government).' 
Version 5.0 
31 July 2024 
8. IMP Dosage regimen and rationale 
We have removed bovine or animal components fromt the statement . 
 
The study product does not contain porcine, bovine or animal components. 
 
 

 
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NeoART-M Version 6.0 4 October 2024 
 
Version 5.0 
31 July 2024 
Added 6.12 Assessment & management of potential risk 
Participants who develop CTCAE v5.0, Grade 3 or 4 serious adverse effects related to 
artesunate (or placebo) will be withdrawn from the study treatment but will continue in 
the study to enable an intention to treat analysis. The main possible risks associated 
with artesunate in this phase II trial are neutropenia and haemolytic anaemia. Patients 
should be monitored closely for these potential side effects and sites should take 
appropriate clinical action if such adverse events occur.  
Definition of anaemia is a disorder characterized by a reduction in the amount of 
hemoglobin in 100 ml of blood. Signs and symptoms of anaemia may include pallor of 
the skin and mucous membranes, shortness of breath, palpitations of the heart, soft 
systolic murmurs, lethargy, and fatigability. Patients developing neutropenia as defines 
by CTCAE 5.0  
 
• 
Grade 3  anaemia: Hgb <8.0 g/dL; <4.9 mmol/L;<80 g/L; transfusion indicated 
• 
Grade 4  anaemia: Life-threatening consequences; urgent intervention indicated 
 
The treatment for anaemia is blood transfusion. 
 
Definition of neutropenia: A disorder characterized by an ANC <1000/mm3 and a single 
temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of >=38 
degrees C (100.4 degrees F) for more than one hour. Patients developing neutropenia as 
defines by CTCAE 5.0  
 
• 
Grade 3 neutropenia : ANC <1000/mm3 with a single temperature of >38.3 
degree C (101 degrees F) or a sustained temperature of >=38 degrees C (100.4. 
degrees F) for more than one hour 
• 
Grade 4  neutropenia: Life-threatening consequences; urgent intervention 
indicated 
 
Treatment for : GCSF for neutropenia 
 
Version 5.0 
31 July 2024 
Added Definition of neutropenia: A disorder characterized by an ANC <1000/mm3 and a 
single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of 
>=38 degrees C (100.4 degrees F) for more than one hour. Grade 3 neutropenia : ANC 
<1000/mm3 with a single temperature of >38.3 degree C (101 degrees F) or a sustained 
temperature of >=38 degrees C (100.4. degrees F) for more than one hour. 
 
Version 5.0 
31 July 2024 
Removed  
Day 15 Surgery 
Blood tests – FBC, Kidney and liver function tests, CEA tumour marker 
Post treatment serum sample for study molecular analyses (at sites participating in 
biomarker substudy) – these blood tests will be done on either day 14 or 15.  
 

 
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NeoART-M Version 6.0 4 October 2024 
 
Version 5.0 
31 July 2024 
17.3.2 Planned recruitment rate 
Changed ''NeoART aims to randomize 200 participants in total. Due to the COVID19 
pandemic, the clinical trial has been on hold, and we have faced challenges meeting our 
recruitment target. We have therefore discussed these issues with the DMC and TSC 
and a decision has been made to combine the data from the UK with a mirror study in 
Vietnam (NeoART-Vietnam) and Malaysia (NeoART-Malaysia). Although different study 
populations, these are mirror studies in terms of trial protocol, study procedures and 
Investigational Medicinal Product source. The target recruitment in the UK will now be 
40 to 50, Vietnam will be 40 to 50 and Malaysia will be 120 patients and a target trial 
recruitment of 200 patients in total by 31/07/2025.Principal Investigators at the 5 
National Health Service sites throughout the UK are ready to re-open 
the trial and committed to recruiting to the study. In Vietnam, 2 large teaching hospitals 
will run the  study (108 Military Central Hospital and the National Cancer Hospital which 
is under Ministry of Health). In Malaysia, 5 Ministry Of Health, University Malaya and 
University Science Malaysia are ready to open the trial. We aim to recruit 8-12 
participants to the study per month in each sites in Malaysia to meet our recruitment 
target by 31st July 2025' to  
 
NeoART aims to randomize 200 participants in total. We have faced challenges meeting 
our recruitment target in. We have therefore discussed these issues with the DMC and 
TSC in the UK and a decision has been made to combine the data from the UK with a 
mirror study in Vietnam (NeoART-Vietnam) and Malaysia (NeoART-Malaysia). Although 
different study populations, these are mirror studies in terms of trial protocol, study 
procedures and Investigational Medicinal Product source. The target recruitment in the 
UK will now be 34, Vietnam will be 46 and Malaysia will be 120 patients and a target 
trial recruitment of 200 patients. 
Version 5.0 
31 July 2024 
15.2 Data collection tool. 
Removed (if participating in biomarker sub study) 
•Baseline - FBC, urea and electrolytes, LFTs, CEA, pre-treatment serum sample for study 
molecular analyses (if participating in biomarker sub study) 
• 
Day 14/15 of treatment - FBC, urea and electrolytes, LFTs, CEA, post-treatment 
serum sample for study molecular analyses (if participating in biomarker sub study) 
 
Version 5.0 
31 July 2024 
17.3.3 Statistical analysis plan 
Change 
Due to the COVID-19 pandemic, we have discussed an interim analysis in December 2021 
with the DMC and TSC. At this time point 78 patients will have reached the primary end 
point (recurrence free survival 2 years after surgery). This analysis will be performed by 
an independent trial statistician familiar with both trials (Prof Bertrand Lell) and a report 
presented to the DMC and TSC members for review and recommendations thereafter to  
 
We have discussed an interim analysis in December 2021 with the DMC and TSC. At this 
time point 78 patients will have reached the primary end point (recurrence free survival 
2 years after surgery). This analysis will be performed by an independent trial statistician 
familiar with both trials (Prof Bertrand Lell) and a report presented to the DMC and TSC 
members for review and recommendations thereafter. 
Version 5.0 
31 July 2024 17.5 Interim analysis 

 
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NeoART-M Version 6.0 4 October 2024 
 
Changed 'Due to the COVID-19 pandemic, we have discussed an interim analysis in 
December 2021 with the DMC and TSC. At this time point 78 patients will have reached 
the primary end point (recurrence free survival 2 years after surgery). This analysis will 
be performed by an independent trial statistician familiar with both trials (Prof Bertrand 
Lell) and a report presented to the DMC and TSC members for review and 
recommendations thereafter. to  
We have discussed an interim analysis in December 2021 with the DMC and TSC. At this 
time point 78 patients will have reached the primary end point (recurrence free survival 
2 years after surgery). This analysis will be performed by an independent trial statistician 
familiar with both trials (Prof Bertrand Lell) and a report presented to the DMC and TSC 
members for review and recommendations thereafter. 
Version 6.0 
4 October 
2024 
Added The study products do not contain porcine but contains produced from bovine 
that is safe for human consumption. 

                                                     
 
 
 
 
 
 
 
 
 
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NeoART-M Version 6.0 4 October 2024 
 
Appendix 2. Summary chart of study assessments 
 
 

                                                     
 
 
 
 
 
 
 
 
 
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NeoART-M Version 6.0 4 October 2024 
 
Appendix 3. QOL Tools (EuroQol EQ-5D, EORTC QLQ C-30 and EORTC QLQ CR29)  
 
Appendix 4. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0