Phase II Single Arm, Open Label Study of Artesunate for the Treatment of Human Papilloma Virus Positive High Grade Cervical Intraepithelial Neoplasia (CIN2/3)
Phase: PHASE2
Conditions: CIN 2/3
Sponsor: Metanoic Health Ltd.

 
 
Phase II Single Arm, Open Label Study of Artesunate for 
the Treatment of Human Papilloma Virus positive High 
Grade Cervical Intraepithelial Neoplasia (CIN2/3)  
  
 
Protocol ID: 2023-MHL-002 
NMR ID: NMRR ID-24-01779-UWV 
Protocol Version: Version 5.0 Date 13 November 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 
2 Leman St, London,E1 8FA  
United Kingdom 
Mobile: Email: skrishna@cadt.org.uk 
 
SPONSOR:   
Metanoic Health Limited  
36 Clarkes Avenue 
Worcester Park 
Surrey  
United Kingdom 
Mobile: +44 (0)7798566612 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 Metanoic 
Health Limited. 

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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 (GCP) and National Pharmaceutical Regulatory Authority (NPRA)  Regulations 
for Clinical Trial Import License (CTIL), the Malaysian Data Protection Act, local governance policy, 
the Sponsor’s SOPs, and other regulatory requirements as stipulated.   
 
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 
 
13 November 
2024 
Sponsor Representative  
Dr Isaac John 
Metanoic Health Limited  
36 Clarkes Avenue 
Worcester Park 
Surrey  
United Kingdom 
 
Signature 
  
 
Date 
 
13 November 
2024 
 
Acknowledgements and Protocol contributories  
This protocol was developed at the European Organisation for Research and Treatment of Cancer 
(EORTC)- European Society for Medical Oncology (ESMO)- American Association for Cancer Research 
(AACR) Workshop on Methods in Clinical Cancer Research in June 2022 by Dr Yolanda Augustin in 
collaboration with Professor Sanjeev Krishna. 
 
 
 
 
 
 

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Table of Contents 
Signature Page and Statement ............................................................................................................ 2 
List of abbreviations: ............................................................................................................................ 5 
Roles and Responsibilities .................................................................................................................... 7 
Protocol Summary................................................................................................................................ 9 
1.1. 
Study objectives ................................................................................................................. 14 
1.1.1 Primary objective ........................................................................................................... 14 
1.1.2 Secondary objectives ..................................................................................................... 14 
1.2 
Outcome measures ............................................................................................................ 14 
1.2.1 Primary outcome measure ............................................................................................... 14 
1.2.2 Secondary outcome measures .......................................................................................... 14 
2. 
Background and Introduction .................................................................................................... 15 
2.1 
Background Disease Information ....................................................................................... 15 
2.2 
Background Therapeutic Information ................................................................................ 16 
3. 
Trial Design ................................................................................................................................. 21 
4. 
Patient Selection Criteria ........................................................................................................... 21 
4.1 Inclusion criteria ....................................................................................................................... 21 
4.2 Exclusion criteria ...................................................................................................................... 22 
4.3 Subject Recruitment Process ................................................................................................... 22 
5. 
Study Interventions and Concomitant Therapy ......................................................................... 22 
5.1 
Drug information ................................................................................................................ 22 
5.1.1 Drug Administration ....................................................................................................... 22 
5.1.2   Premedication ................................................................................................................. 22 
5.1.3   Patient Monitoring .......................................................................................................... 23 
5.1.4 Treatment duration........................................................................................................ 23 
5.1.5 Dose and schedule modifications .................................................................................. 23 
5.1.6 Packaging and storage conditions ................................................................................. 23 
5.1.7 Pregnancy ....................................................................................................................... 23 
5.1.8 Adverse events associated with artesunate .................................................................. 23 
5.1.9 Source of IMP ................................................................................................................. 24 
5.1.10 
Accountability procedures for the IMP ...................................................................... 24 
5.2 
Concomitant therapy ......................................................................................................... 24 
5.3 
Withdrawal criteria ............................................................................................................ 25 
5.4 
Assessment of compliance ................................................................................................. 26 
5.5 
Overdose of Trial medication ............................................................................................. 26 
5.6 
List of criteria for premature discontinuation of the study ............................................... 26 
5.7 
Lost to Follow up ................................................................................................................ 27 

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5.8 
End-of-Study Definition ..................................................................................................... 27 
6. 
Clinical Evaluation, Laboratory Tests, Follow-Up ....................................................................... 27 
6.1 
Before treatment start ....................................................................................................... 27 
6.2 
During treatment ............................................................................................................... 27 
6.3 
After the end of treatment (Follow-up) ............................................................................. 28 
6.4 
Summary table ................................................................................................................... 29 
7. 
Pharmacovigilance ..................................................................................................................... 30 
7.1 
Safety/Toxicity ................................................................................................................... 30 
7.2 
Reference Safety Information ............................................................................................ 30 
7.3 
Serious adverse events ...................................................................................................... 30 
7.4 
Investigator responsibilities relating to safety reporting .................................................. 31 
7.5 
Development Safety Update Reports (DSURs) .................................................................. 33 
7.6 
Annual Progress Reports (APRs) ........................................................................................ 33 
7.7 
Pregnancy ........................................................................................................................... 33 
8. 
Translational Research / Pharmacodynamic Studies ................................................................. 33 
9. 
Data Collection Tool ................................................................................................................... 34 
9.1 
Incidental findings .............................................................................................................. 34 
9.2 
Data handling and analysis ................................................................................................ 34 
10. Statistical Considerations ........................................................................................................... 34 
10.1 
Statistical design ................................................................................................................ 34 
10.1.1 
Interim analyses / Decision rules ............................................................................... 35 
10.1.2 
Accrual and Duration of Study ................................................................................... 35 
10.2 
Statistical Analysis .............................................................................................................. 35 
10.2.1 
Analysis populations .................................................................................................. 35 
10.2.2 
Patient disposition, data recording and display ........................................................ 35 
10.2.3 
Safety ......................................................................................................................... 36 
10.2.4 
Study outcome measures .......................................................................................... 36 
11. Committees Involved In The Trial .............................................................................................. 37 
12. Direct Access To Source Data ..................................................................................................... 38 
13. Site Approval And Ongoing Regulatory Compliance ................................................................. 38 
14. Monitoring Plan For The Trial .................................................................................................... 38 
15. Finance ....................................................................................................................................... 39 
16. Insurance And Indemnity ........................................................................................................... 39 
17. Intellectual Property and Development Policy .......................................................................... 39 
18. Publication Policy ....................................................................................................................... 40 
18.1 
Before the official completion of the Trial ......................................................................... 40 
18.2 
Up to 180 days after the official completion of the Trial .................................................. 40 

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18.3 
Beyond 180 days after the official completion of the Trial ............................................... 41 
19. Statement Of Compliance .......................................................................................................... 41 
20. List of Protocol Appendices ....................................................................................................... 41 
21.References .................................................................................................................................... 42 
 
List of abbreviations: 
AE 
 
Adverse Event 
AUC 
 
Area under the curve 
CA 
 
Competent Authority 
CADT  
Centre for Affordable Diagnostics and Therapeutics 
CI 
 
Chief Investigator 
CIC 
 
Clinical Investigation Centre  
Chk1/Chk2 
Checkpoint kinase 1/Checkpoint kinase 2 
Cip/Kip 
CDK interacting protein/Kinase inhibitory protein 
CD31  
Cluster of Differentiation 31 
CRF 
 
Case Report Form 
CT 
 
Computed tomography 
CTA 
 
Clinical Trial Authorisation 
CTCAE  
Common Terminology Criteria for Adverse Events   
CTC 
 
Common Toxicity Criteria 
CTIL 
 
Clinical Trial Import License 
DHA 
 
Dihydroartemisinin 
 
DNA 
 
Deoxyribonucleic acid 
DDSB  
DNA double–strand breaks 
DMC  
Data Monitoring Committee 
DSUR  
Development Safety Update Report 
EGFR  
Epidermal Growth Factor Receptor 
eGFR  
Estimated Glomerular Filtration Rate 
EORTC              European Organisation for Research and Treatment of Cancer   
GCP 
 
Good Clinical Practice 
GCSF  
Granulocyte colony-stimulating factor 
GFR 
 
Glomerular Filtration Rate 
GMP   
Good Manufacturing Practice 
g/l 
 
grams per litre 
Hb 
 
Haemoglobin 
HIF-1α  
Hypoxia induced factor - 1α 
HPV 
 
Human Papilloma Virus 
IB           
Investigator Brochure 
ICF 
 
Informed Consent Form 
ID 
 
Identification 
IMP 
 
Investigational Medicinal Product 
IIT 
 
Investigator Initiated Trial 
IP  
 
Intellectual Property 
ISF 
 
Investigator Site File 
ISRCTN  
International Standard Randomised Controlled Trial Number 

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ITT 
 
Intention to treat 
KG 
 
Kilogram 
LFT 
 
Liver Function Test 
MG 
 
Miligram 
ML 
 
Mililitre 
MMPs  
Metalloproteinases 
MOH  
Ministry of Health 
NCAM  
Neural cell adhesion molecule 
NF-kB  
Nuclear factor kappa-light-chain-enhancer of activated B cells 
NMRR  
National Medical Research Register 
NPRA  
National Pharmaceutical Regulatory Agency 
NoK 
 
Next of Kin 
OD 
 
Once daily  
PBMC  
Peripheral blood mononuclear cell 
PI 
 
Principal Investigator 
PIS 
 
Participant Information Sheet 
Plts 
 
Platelets  
PO 
 
Oral administration 
QC 
 
Quality Control 
QOL 
 
Quality of Life 
QP 
 
Qualified Person  
R&D   
Research & Development   
REC 
 
Research Ethics Committee 
ROS 
 
Reactive Oxygen Species 
RSI 
 
Reference Safety Information 
SAR 
 
Serious Adverse Reaction 
SAE 
 
Serious Adverse Event 
SDV 
 
Source Document Verification 
SmPC  
Summary of Product Characteristics 
SOP 
 
Standard Operating Procedure  
SSAR  
Suspected Serious Adverse Reaction 
SUSAR  
Suspected Unexpected Serious Adverse Reaction  
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 
UM 
 
University of Malaya 
UMMC  
University Malaya Medical Centre 
VEGF  
Vascular endothelial growth factor 
WCC 
 
White Cell Count 
WHO  
World Health Organisation 
 
 
 

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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  
2 Leman St, London,E1 8FA United Kingdom 
Mobile:  
Email: skrishna@cadt.org.uk 
 
 
Co-Principal Investigators (PI):        
 
 
 
 
 
Dr Yolanda Augustin 
St George’s, University of London and Centre for Affordable 
Diagnostics and Therapeutics        
 
2 Leman St, London,E1 8FA United Kingdom          
 
Mobile:  
        
 
 
 
         
Email: yaugustin@cadt.org.uk 
 
         Professor Woo Yin Ling 
          
 
 
 
Department of Obstetrics & Gynaecology 
         Faculty of Medicine, University of Malaya 
         Lembah Pantai,59100 
         Kuala Lumpur, Malaysia 
         Email: ylwoo@ummc.edu.my 
 
         Professor Rozita Malik 
          
 
 
 
Department of Oncology, 
         Faculty of Medicine, University of Malaya 
         Lembah Pantai,59100 
         Kuala Lumpur, Malaysia. 
         Email: rozita@ummc.edu.my 
 
Dr Yong Chee Meng 
Hospital Ampang 
Jalan Mewah Utara, 
Taman Pandan Mewah, 
68000 Ampang, Selangor,  
Malaysia 
Mobile:  
Email:  
 
Dr Jamil bin Omar 
Institut Kanser Negara 
4, Jalan P7, Presint 7, 62250 Putrajaya,  
Wilayah Persekutuan, 
Malaysia 

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Mobile:  
Email:  
 
Dr Kanddy Loo Chin Yee 
     
 
 
 
              Hospital Umum Sarawak  
   
 
 
 
              Jalan Hospital, 93586 Kuching,  
Sarawak, Malaysia 
Mobile:  
                            
Email:  
 
             Dr Vicknesh Visvalingam 
 
Hospital Selayang 
Selayang - Kepong Hwy,  
68100 Batu Caves, Selangor, Malaysia 
Mobile:  
Email:  
 
NeoART Clinical Trial Co-ordinator:  Dr Nafeesa Mat Ali 
 
   St George’s, University of London and Centre for Affordable   
and Diagnostics and Therapeutics          
   2 Leman St, London,E1 8FA United Kingdom    
   Mobile:  
   Email: nmatali@cadt.org.uk 
                                     
Pathology Laboratory: 
   Dr Razmin binti Ghazali 
 Pathology Department , 
 Hospital Kuala Lumpur, 
 Jalan Pahang,  
 Kuala Lumpur 50586 
 Wilayah Persekutuan 
 Mobile:  
 Email:  
 
 
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 
 
        
NeoART Study team  
emergency number:  
    +60 (0) 172152964 
 
   
 
 
 

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Protocol Summary 
 
Trial number 
and full title 
 
Phase II Single Arm, Open Label Study of Artesunate for the Treatment of Human Papilloma 
Virus positive High Grade Cervical Intraepithelial Neoplasia (CIN2/3)  
 
Protocol 
number 
2023-MHL-002 
 
Rationale 
 
Artesunate belongs to the artemisinin 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 a variety of ailments including fever, inflammation 
and haemorrhage. Artesunate is approved for the treatment of uncomplicated, severe and 
multidrug-resistant malaria, is on the WHO list of Essential Medicines with an excellent 
safety profile and is affordable at USD1 per daily dose.  
 
Several comprehensive reviews have examined the evidence for the anti-cancer effects of 
artemisinins. Pre-clinical studies of artemisinins in cell line and animal models have 
demonstrated broad anti-cancer activity including pro-apoptotic, anti-proliferative, anti-
angiogenesis and anti-metastatic effects. A Phase I dose-escalation study of artesunate 
vaginal inserts in biopsy-confirmed CIN 2/3 in 28 patients showed that treatment was safe 
and well tolerated with histologic regression observed in 19/28 (67.9%) subjects and HPV 
viral clearance in 9/19 subjects (47.4%) (Trimble et al., 2020). In patients who did not 
experience histological regression, no viral clearance was seen.  
NeoART-CIN is a Phase II clinical study evaluating the safety and effectiveness of oral 
artesunate in patients with CIN2/3, to investigate if a course of treatment with oral 
artesunate can lead to regression of  pre-cancerous changes in the cervix and prevent the 
development and progression of invasive cancer. Findings from this study will increase our 
understanding of the effects of artesunate on CIN2/3 and, if confirmatory, inform future 
clinical studies. 
Objective(s) 
+ Endpoint(s) 
 
Overall objective: To determine the feasibility, safety and preliminary anti-proliferation 
activity of oral artesunate in Human Papilloma Virus positive (HPV +ve) High Grade Cervical 
Intraepithelial Neoplasia (CIN2/3).  
 
Primary Objective  
Primary Endpoints  
To determine the effect of artesunate  
on histologic regression of CIN2/3   
 
Histological regression of CIN2/3 on colposcopy  
and biopsy at Day 90 
Secondary Objective  
Secondary Endpoints  
To determine the effect of artesunate on  
HPV DNA viral clearance  
HPV DNA viral clearance at Day 90 
To determine the effect of artesunate  
on the vaginome and gut microbiome 
Comparison of vaginome and gut microbiome at  
Day 0, Day 64 and Day 90 
To determine the effects of artesunate  
on patient safety   
Serious Adverse Event at 90 days using  
Common Toxicity Criteria (CTCAE V5.0)  
To determine the effects of artesunate  
on patient Quality of Life  
 
Quality of life using the  
European Quality of Life–5 Dimensions (EQ-5D) quality 
of life tool  
 
Study design 
Phase II open label single arm study    

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Number of 
patients 
(statistical 
design) 
 
A maximum of 28  participants will be enrolled to receive the study intervention.  
The primary end point is histological regression of CIN2/3 on colposcopy and biopsy at Day 
90. Significance level and power: The procedure described above tests the null hypothesis 
that the response rate is 20 % versus alternating hypotheses that the response rate is 50 %.  
The significance level (i.e., the probability of rejecting H0 when it is true) is α=0.1 and the 
power (i.e., 1-beta, the probability of deciding the regimen is active) is 90%  when true 
response rate is 50 %.  At the significance level of 0.05, with an equivalence limit of 0.15, a 
sample size of 24 is required to achieve 90% power when the response rate for the historical 
control is 0.2 and response rate for the treatment is 0.5. Inflating this sample size by 20% to 
allow for loss at follow-up would result in a sample size of approximately 28 patients.  
 
Trial 
population 
Main inclusion criteria 
• Aged 18 or over   
• Histologically proven HPV positive cervical CIN2/3   
• WHO performance status 0-2  
• Adequate full blood count:   
o White Cell Count (WCC) >3.0 x 109 /l;   
o Platelets >100 x 109/l;     
o Haemoglobin (Hb)  >80g/L  
• Adequate renal function:   
o Glomerular Filtration Rate >30ml/min  
• Adequate hepatobiliary function:    
o  Total bilirubin < 3 x Upper limit normal  
• 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 
• Patient able and willing to provide written, informed consent for the study 
Main exclusion criteria 
• Contraindication to the use of artesunate due to hypersensitivity 
• Pregnancy or lactation 
• Weight < 52 kg 
• History of previous CIN 
• Immunocompromised patients 
Treatment 
 
 
Study Intervention:  
Patients with HPV positive CIN2/3 will receive 3 cycles of oral artesunate 200mg OD prior to 
standard of care therapeutic large loop excision of transformation zone (LLETZ). Each 21 day 
treatment cycle will comprise oral artesunate 200mg OD for 14 days followed by a 7 day 
treatment break.  
  
Reference 
Treatment 
 
Not applicable. 
Statistical 
analyses 
Patients’ demographics, baseline characteristics, prior and concomitant medications, 
treatment exposure, protocol compliance and study withdrawals will be summarized in the 
intent-to-treat population. For categorical variables, frequency tables (with %) will be 
presented with descriptive listings of details specified in text fields, where appropriate. 

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Continuous variables will be reported using median, range and interquartile range. 
 
Primary outcome measure(s) 
• 
Histological regression of CIN2/3 on colposcopy and biopsy at Day 90 will be defined 
as histologic regression to CIN1 or less. This will be described as a response 
percentage. 
 
Secondary outcome measure (s) 
 
• 
HPV DNA viral clearance at Day 90  
Viral clearance will be defined as absence of HPV genotoype(s) that were detected 
at baseline and described as a response percentage. 
• 
Vaginome and gut microbiome at Day 1, Day64 and Day 90 
Changes in vaginome and gut microbiome will be compared between Day 0, Day 64 
and Day 90. 
 
• 
Serious Adverse Events at Day 90 using Common Toxicity Criteria (CTCAE V5.0)  
Safety assessment will be based on patients who received at least one dose of IMP. 
Tolerability assessment will be based on the percentage of subjects that complete 
the designated dosing regimen.  
• 
Patient quality of life will analysed using the European Quality of Life–5 Dimensions 
(EQ-5D) quality of life analysis tool. 
Translational 
research 
Study Assessments:  
 
Patients will have study bloods samples for translational research collected on Day 1, Day 
14, Day 64 and Day 90 of the study. HPV DNA will be tested on vaginal sampling Day 1, Day 
64 and Day 90 of the study. Vaginome and microbiome samples will be collected on Day 1, 
Day 64 and Day 90. A laboratory manual has been prepared separate to this protocol. 
 
Quality of Life 
European Quality of Life–5 Dimensions (EQ-5D-5L) quality of life tool will be completed on 
Day 1, Day 7, Day 14, Day 22, Day 43, Day 64 and Day 90 of the study. 
  
Benefit-risk 
analysis 
Cervical cancer represents significant morbidity and mortality globally, particularly in Low 
and Middle Income Countries (LMICs). The current standard of care in women with pre-
cancerous high grade CIN2/3 are surgical or ablative treatments. Although these treatments 
are generally safe, there remains a small risk of complications such as infection, bleeding, 
perforation, and cervical stenosis with the most severe late complication being an increased 
risk of preterm birth and obstetric complications. Following surgical resection, the risk of 
recurrence with uninvolved margins may range from 8-23% ((Nagai et al., 2000 ; Serati et 
al., 2012 ; Fan et al., 2018 ; Verguts et al., 2006). For many women, travel costs, time off 
work and childcare considerations represent significant barriers to engaging with cervical 
cancer screening, treatment and follow up. There is an urgent need to develop affordable 
therapeutics at point-of-need to manage the burden of global oncology. A safe, effective, 
affordable and convenient oral treatment that results in regression of CIN2/3 and clears 
HPV infection would represent a significant development in the management of this 
condition. 

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Trial-specific risks and burdens include additional diagnostic, therapeutic and monitoring 
procedures to ensure safety, tolerability and preliminary antiproliferative effects in this 
patient population. Patients may not derive any direct benefit from participating in this 
study. However they will contribute to our scientific and clinical understanding of the 
potential antiproliferative effects of artesunate in CIN2/3 as we research better treatments 
for this condition. 
 
 
 
 
 
 
 
 
 

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Phase II single arm open label study of oral artesunate in Human Papilloma Virus positive  
High Grade Cervical Intraepithelial Neoplasia (CIN2/3) 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 
Artesunate 200mg 
OD 14 days, 7 day 
break
Cycle 2 
Artesunate 200mg 
OD 14 days, 7 day 
break
Cycle 3 
Artesunate 200mg 
OD 14 days, 7 day 
break
Treatment Cycle 2: Artesunate once daily for 14 days followed 
by 7 day treatment break  
Treatment Cycle 1: Artesunate once daily for 14 days followed 
by 7 day treatment break  
Patient screening and consent                  
Procedures: 
- Safety blood test 
- Study blood test 
- HPV DNA test 
- Pregnancy test 
- Vaginome & gut microbiome 
samples 
- Colposcopy 
- QOL 
Day 0 
 
 
 
Day 1 
 
 
 
 
Day 7  
 
 
 
Day 14 
 
 
 
 
Day 22 
 
 
 
Day 36 
 
 
 
Day 43 
 
 
 
 
Day 57 
 
 
 
Day 64 
 
 
 
Day 90
Procedures: 
- Safety blood test 
- Study blood test  
- QOL 
Colposcopy, cervical biopsy & LLETZ 
Procedures 
-Safety Blood test 
-Study Blood test 
-Vaginome &  gut 
microbiome sample 
-HPV DNA Test 
-QOL 
D1 
 
 
   D22                                  D43                                     D64                            D90 
Colposcopy + 
cervical 
biopsy & 
LLETZ 
Telephone review : QOL & Self-reported adverse events 
Clinical Review 
Procedures: 
- Safety blood test 
- Speculum examination  
- QOL 
Telephone review : Self-reported adverse events 
Treatment Cycle 3: Artesunate once daily for 14 days followed 
by 7 day treatment break  
Telephone review : Self-reported adverse events 
Clinical Review 
Procedures: 
- Safety blood test 
- Study blood test 
- Speculum examination  
- QOL 
Procedures 
-Safety Blood test 
-Study Blood test 
-Speculum examination with 
Vaginome & -HPV DNA Test 
- Gut microbiome sample 
-QOL 

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1. Objectives and outcome measures of the study 
1.1. 
Study objectives 
 
Primary Objective  
Primary Endpoints  
To determine the effect of artesunate on 
histologic regression of CIN2/3   
 
Histological regression of CIN2/3 on colposcopy  
and biopsy at Day 90 
Secondary Objective  
Secondary Endpoints  
To determine the effect of artesunate on 
HPV DNA viral clearance  
 
HPV DNA viral clearance at Day 90 
To determine the effect of artesunate on 
the vaginome and gut microbiome 
Vaginome and gut microbiome at Day 0, Day 64 and 
Day 90 
To determine the effects of artesunate on 
patient safety   
Serious Adverse Events at 90 days using  
Common Toxicity Criteria (CTCAE V5.0)  
To determine the effects of artesunate on 
patient Quality of Life  
 
Patient quality of life using the European Quality of 
Life–5 Dimensions (EQ-5D) quality of life tool Day 1, 
Day 7, Day 14, Day 22, Day 43, Day 64 and Day 90. 
 
1.1.1 Primary objective   
• To determine the effect of artesunate on histologic regression of CIN2/3. 
1.1.2 Secondary objectives 
• To determine the effect of artesunate on HPV DNA viral clearance. 
• To determine patient safety and tolerability of artesunate. 
• To determine the effects of artesunate on patient Quality of Life. 
1.2 Outcome measures 
1.2.1 Primary outcome measure  
• Histological regression of CIN2/3 on colposcopy and biopsy at Day 90.  
- 
Histological regression will be defined as histologic regression to CIN1 or less. 
1.2.2 Secondary outcome measures 
• HPV DNA viral clearance at Day 90. 
- 
Viral clearance will be defined as absence of HPV genotoype (s) detected at 
baseline.  
• Vaginome and gut microbiome at Day 1, Day 64 and Day 90. 
- 
Changes in vaginome and gut microbiome will be compared between Day 1, Day 64 
and Day 90. 
• Serious Adverse Events at Day 90 using Common Toxicity Criteria (CTCAE V5.0). 
- 
Safety assessment will be based on patients who received at least one dose of IMP.  
• Tolerability assessment will be based on the percentage of subjects that complete the 
designated dosing regime.  

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• Patient quality of life using the European Quality of Life–5 Dimensions (EQ-5D) quality of 
life tool Day 1, Day 7, Day 14, Day 22, Day 43, Day 64 and Day 90. 
2. Background and Introduction 
2.1 Background Disease Information 
Cervical cancer is the 4th most common form of cancer in women globally (Sung et al., 2020). It is a 
significant cause of morbidity and mortality with over half a million new cases and over 300,000 
deaths per year despite being preventable and curable if detected early and managed effectively. 
Low and Middle Income Countries (LMICs) are disproportionately affected with 80% of cases and 
90% of cervical cancer related deaths occurring in low resource settings. There is an urgent need to 
develop affordable therapeutics to manage this burden of global oncology. For many women, travel 
costs, time off work and childcare considerations represent significant barriers to engaging with 
cervical cancer screening, treatment and follow up (McPherson et al., 2020 ; Majid et al., 2019). 
 
The World Health Organisation (WHO) cervical cancer elimination strategy has set a target to 
eliminate cervical cancer as a public health problem (target incidence <4/100,000 population) (WHO 
2020).  To be on track to achieve this by the end of the century, draft targets are that 90% of girls 
should be vaccinated against HPV by the age of 15 years, 70% of all women aged 30 to 49 years 
should have at least 2 high precision screening tests 10 years apart and 90% of screen positive 
women, as well as 90% of women with cancer, should receive treatment by 2030. Countries are 
called to meet the 90-70-90 targets by 2030 in order to work towards cervical cancer elimination. It 
is estimated that over 62 millions deaths due to cervical cancer could be prevented in the next 100 
years through the implementation of this strategy alongside HPV vaccination.  
Whilst survival rates from colorectal, breast, prostate, cervical and lung cancer are improving in high 
income countries (HICs) due to a combination of early detection and more effective treatments, 
cancer death rates in LMICs are unfortunately increasing. This is in part because many lifesaving 
cancer treatments remain unaffordable for patients in LMICs where cancer remains a neglected 
disease. Novel drug development takes on average 10-15 years to go from bench to clinic at an 
average cost of USD1 billion. Repurposing of 'old' drugs for new indications can shorten this pathway 
substantially with significant cost savings (Nosengo 2016 ; Bertolini et al., 2015).  
 
In Malaysia, cervical cancer is the fourth leading cause of cancer related morbidity and mortality 
amongst women  with an annual incidence of 1700 in 2018 (MyScan 2018). At present, only around 
25% of women participate in regular cervical screening and many patients present with advanced 
disease with 5 year overall survival around 52 % (MyScan 2018). There is an urgent need for 
effective, safe and affordable treatments to improve survival. 
 
Chronic infections are a major contributor to the development of around 20% of certain cancers 
(Plummer et al., 2016). Some pathogenic agents disrupt signaling that controls proliferation and cell 
growth, exert effects on immune-modulation and cause persistent inflammation that can lead to 
cancer. The majority of cervical cancers are caused by persistent infection with high-risk oncogenic 
types of Human Papillomavirus (HPV) (Walboomers et al., 1999). There are over 100 types of HPV, 
of which 14 are classified as high-risk oncotypes (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 
66, and 68) (WHO 2021 ; Sanjose et al., 2010). Two HPV types (16 and 18) cause 70% of cervical 

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cancers and pre-cancerous cervical lesions. HPV is also responsible for a significant proportion of 
vaginal, vulval, anal and oropharyngeal cancers (Roden et al. 2018 ; Otter et al., 2019) 
The prevention of cervical cancer requires vaccination against the most oncogenic types of HPV (at 
least types 16 and 18) for pre-adolescents and screening of adult women to enable detection and 
treatment of pre-cancerous abnormalities. Infection with HPV is ubiquitous and in the majority of 
cases is resolved by the host within 1- 2 years (Schiffman et al., 2007 ; Maucort-Boulch et al., 2010). 
However, in around 10-20% of women, for reasons that remain unclear, persistent infection results 
in chronic inflammation, which can then progress to pre-cancerous lesions and cancer. High-risk 
HPV infections leading to cervical cancer require the production of both HPV E6 and E7 oncoproteins 
(Pal et al., 2020). Sustained expression of the viral E6 and E7 oncogenes are required to drive the 
transformation and growth of cancerous lesions. 
The average time from initial HPV infection to the development of invasive CIN is 10-30 years (Fan 
et al., 2016 ; Rodriguez et al., 2010 ; WHO 2020). Although estimates vary, around 20–40% of CIN2-
3 will undergo spontaneous regression with around 30% of high-grade dysplasia (CIN2-3) 
progressing to cancer (Verguts et al., 2006). At present, the standards of care in women with CIN2-
3 are surgical or ablative treatments (WHO 2020). Although these treatments are generally safe, 
there remains a small risk of complications such as infection, bleeding, perforation, and cervical 
stenosis with the most severe late complication being an increased risk of preterm birth and 
obstetric complications (Heinonen et al., 2013). Following surgical resection, the risk of recurrence 
with uninvolved margins may range from 8-23% (Nagai et al., 2000 ; Serati et al., 2012 ; Fan et al., 
2018 ; Verguts et al., 2006). 
Whilst the WHO Cervical Cancer Elimination strategy is resulting in an increase in cervical screening 
in many LMICs, diagnostic follow up and treatment pathways also requiring strengthening. A safe, 
effective, affordable and convenient oral treatment that results in regression of CIN2/3 and clears 
HPV infection would represent a significant development in the management of this condition. 
2.2 Background Therapeutic Information 
Artesunate is derived from a plant called Sweet Wormwood (Artemisia annua L. / ’Qing Hao’), which 
has been used for more than two thousand years in traditional Chinese medicine to treat a variety 
of ailments (Augustin et al., 2020 ; Krishna et al., 2008). Pre-clinical studies of artemisinins in cell 
line and animal models have demonstrated broad anti-cancer activity including pro-apoptotic, anti-
proliferative, anti-angiogenesis and anti-metastatic effects (Augustin et al., 2020; Krishna et al., 
2014 ; Ho et al., 2014).  
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).  
 
The dose of artesunate for the study will be 200 mg per oral (PO) once daily (OD) for fourteen days 
per treatment cycle. 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 

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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. 
 
Artesunate Chemical Structure  
 
Figure 1: Chemical structure of Artesunate 
The molecular formula: C19 H28 O8 
The relative molecular mass: 384.43 
Chemical Name: [3R-(3R*)]-  Butanedioic acid mono (Decahydro-10-methoxy-3,6,9-trimethyl-3,12-epoxy-
12H-pyrano[4,3-j]-1,2-benzodioxepin-10-yl) ester. 
Chemical Abstracts Service (CAS) registry number: 88495-63-0 
 
Metabolite  
Artesunate is extensively hydrolysed by plasma esterases and possibly CYP2A6. Its main metabolite, 
dihydroartemisinin (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). Artesunate has a renal mode of excretion. 
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. 
Pre-clinical models examining the anti-cancer effects of artemisinins 
O
C
H3
O
O
O
CH3
CH3
O
OH
O
O

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Carcinogenesis in humans is a complex process and 8 key hallmarks have been well described 
(Hanahan & Weinberg, 2011). These include sustained proliferative signaling, evasion of cell death 
and growth suppression, induction of angiogenesis, invasion and metastasis, reprogramming energy 
metabolism and evasion of immune destruction (Hanahan & Weinberg, 2011). In the last three 
decades, artemisinins have shown potent and broad anticancer properties in a range of cell lines 
and animal models, supporting the hypothesis that artemisinins have the potential to be developed 
as an effective anti-cancer therapy (Fig 2). Several comprehensive reviews have examined the 
evidence for the anti-cancer effects of artemisinins (Efferth, 2017a; Ho et al., 2014; Krishna et al., 
2008). Multiple potential mechanisms of action include anti-proliferative effects through cell-cycle 
disruption, reactive oxygen species(ROS) -induced DNA damage, induction of apoptosis, anti-
angiogenesis, immunomodulation and induced radiosensitivity. 
 
 
 
Fig. 2. Artemisinins: multiple modes of action against cancer CDK2/4/6; Cyclin dependent kinase 2/4/6:mTOR; mammalian target of 
rapamycin: EGFR;epidermal growth factor: HIF---1α; Hypoxia Inducible Factor 1 alpha:VEGF; Vascular endothelial growth factor: KDR/flk---1;kinase 
insert domain receptor MMP2; Matrix Metallopeptidase 2: TIMP---2; Tissue inhibitor of metalloproteinases 2: NCAM; Neural Cell Adhesion 
Molecule: IL---6;interleukin---6: IL---1β; Interleukin---1β: TNF---α; Tumour necrosis factor---α: TGF---β1; Transforming growth factor beta 1: NF---κB; 
nuclear factor kappa---light---chain--- enhancer of activated B cells: MIP---2; Macrophage Inflammatory Protein 2: PGE2; Prostaglandin E2: NO;Nitric 
Oxide. (Reproduced from Augustin et al. 2020) 
 
The active metabolite of artemisinin, dihydroartemisinin (DHA), has also displayed antineoplastic 
effects on cervical, breast, glioma, colon, lung, ovarian and pancreatic cancer cell lines (Disbrow et 
al., 2005 ; Singh & Lai., 2001 ; Kim et al., 2006 ; Lu et al., 2011 ; Mu et al., 2007 ; Chen et al., 2009 ; 
Hooft van Huijsduijnen., 2013).  
 
Artesunate has been shown to promiscuously target multiple critical biological pathways and over 
300 specific artesunate targets using a chemical proteomics approach with artemisinin-based 
activity probes (Wang et al., 2017). Cellular functions associated with these target proteins include 
growth and proliferation, cell death and survival, protein synthesis, fatty acid metabolism, cellular 
movement, free radical scavenging and energy metabolism. Pleiotropic alkylation targets in 
different cell lines raise questions about which ones are key to anticancer effects of artemisinins, 
and which ones may be bystanders to the main anticancer pathways. In depth mechanism of action 
studies in various cancer models are needed to better understand the nature of specific molecular 
targets in different cellular environments. 

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The exact underlying mechanism of artesunate anti-proliferative effects 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 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). 
Disbrow et al (2005) found that dihydroartemisinin (DHA) and artesunate displayed strong cytotoxic 
effects on HPV-immortalized and transformed cervical cells in vitro, inducing apoptosis through 
activation of the mitochondrial caspase pathway. Apoptosis appeared to be independent of p53 
activation and did not appear to be the result of drug-induced reductions in viral oncogene 
expression.  
Inflammatory cytokines such as Interleukin-6 (IL-6), Interleukin-1β (IL-1β),Nuclear factor kappa B 
(NF-κB). Nitric Oxide (NO) and Tumour Necrosis Factor alpha (TNFα) are key regulators of cancer 
development (Fishbein et al., 2020). Chronic inflammation in a key characteristic of carcinogenesis 
and inflammation in the tumour microenvironment leads to the release of pro-inflammatory 
cytokines and triggers oxidative stress, DNA damage and uncontrolled cell proliferation (Fishbein et 
al., 2020; Kay et al., 2019). Artesunate has shown to be a potent inhibitor of IL-6, NO, TNF- α and  NF-
κB in other disease models of inflammation and sepsis  (Sordi et al., 2017 ; Khan et al., 2018; Liu et 
al., 2018; Wan & Li, 2017; Zhao et al., 2017). 
 
Clinical evidence of antiproliferative activity in CIN2/3 and cervical squamous cell cancer 
In a Phase I dose-escalation study of artesunate vaginal inserts in biopsy confirmed CIN 2/3 in 28 
patients showed that treatment was safe and well tolerated with histological regression observed 
in 19/28 (68%) subjects and HPV viral clearance in 9/19 subjects (47%) (Trimble et al., 2020). 
Twenty-eight patients received 1, 2, or 3 five-day treatment cycles at study weeks 0, 2, and 4, 
respectively, prior to a planned, standard-of-care resection at study week 15. The mean time to 
regression was shorter in subjects who received 2 or 3 treatment cycles (12.9 weeks, n = 10) 
compared to the group that received one treatment cycle only (20.4 weeks, n = 9). In patients 
undergoing histological regression, 9 of the 19 (47.4%) subjects also underwent clearance of HPV 

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genotypes detected at baseline. In 3 of the 9 subjects, viral clearance was documented concurrently 
with histological regression whilst in 6 subjects, histological regression preceded viral clearance 
(range 8 - 35 weeks). Time to viral clearance was longer in  subjects treated with one cycle (mean 
27.5 weeks, n = 9) compared to those who had received either 2 or 3 treatment cycles (mean 16.5 
weeks, n = 10). No subjects underwent viral clearance prior to histological regression. Viral clearance 
did not occur in any subject who had persistent CIN2/3 at the end of the study. Of note, all residual 
CIN2/3 lesions were limited to the endocervical glandular compartment, not involving the 
ectocervix. The authors concluded that intravaginal artesunate pessaries were likely to exert their 
effects through topical contact that may not penetrate the endocervical compartment (Trimble et 
al., 2020). This provides further rational for testing an oral, systemic formulation in our study. 
In a separate Phase I study, oral and intravenous artesunate were safe when systemically 
administered and displayed cytotoxic effects on human solid tumours including HPV positive 
tumours (Deeken et al.,2018).  A small open label pilot study of dihydroartemisinin (the major active 
metabolite of artesunate) in 10 patients with advanced  cervical cancer reported a reduction in Ki67 
proliferation, p53,  EGFR and CD31 and symptomatic benefit (Jansen et al., 2011).   

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3. Trial Design 
This is a Phase II single arm, open label study of artesunate to determine the feasibility, safety and 
preliminary anti-proliferation activity of oral artesunate in HPV +ve High Grade Cervical 
Intraepithelial Neoplasia (CIN2/3).  Patients with HPV positive CIN2/3 will receive 3 cycles of oral 
artesunate 200mg OD prior to standard of care therapeutic large loop excision transformation zone 
(LLETZ). Each 21 day treatment cycle will comprise oral artesunate 200mg OD for 14 days followed 
by a 7 day treatment break. Patients will be followed up clinically after each cycle of treatment till 
standard of care large loop excision transformation zone (LLETZ)  at 90 days. Colposcopy and cervical 
biopsy to assess histological regression will be performed at 90 days. A cervical sample to test for 
HPV DNA clearance will also be collected. A vaginal swab will also be collected for vaginome analysis 
and a faecal sample collected for microbiome analysis. 
4. Patient 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 Sponsor 
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 Sponsors 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. PPUM001.  
4.1 Inclusion criteria 
• Aged 18 or over   
• Histologically proven HPV positive cervical CIN2/3   
• WHO performance status 0-2  
• Adequate full blood count:   
• White Cell Count (WCC) >3.0 x 109 /l;   
• Platelets >100 x 109/l;     
• Haemoglobin (Hb)  >80g/L  
• Adequate renal function:   
• Glomerular Filtration Rate >30ml/min  
• Adequate hepatobiliary function:    
• Total bilirubin < 3 x Upper limit normal  

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• 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 
• Patient able and willing to provide written, informed consent for the study 
4.2 Exclusion criteria 
• Contraindication to the use of artesunate due to hypersensitivity 
• Pregnancy or lactation 
• Weight < 52 kg  
• History of previous CIN  
• Immunocompromised patients 
4.3 Subject Recruitment Process 
Participant recruitment at any site will only commence once evidence of the following are in place 
in the Sponsor site file. 
 
• Relevant ethics committee and NPRA approval 
• Delegation of Duties and Sponsorship Agreement  signed by the CI 
• Final sponsorship (following evidence of Pharmacy green light) issued by the Sponsor 
representative 
 
All sites participating in the trial will also be asked to provide a copy of the signed Clinical Trial 
Agreement (CTA) 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-CIN aims to recruit participants over 24 months with 3 months follow-up. We aim to recruit 
2-3 participants to the study per month to meet our recruitment target.  
5. Study Interventions and Concomitant Therapy 
5.1 Drug information 
5.1.1 Drug Administration 
Patients with HPV positive CIN2/3 will receive 3 cycles of oral artesunate 200mg OD prior to 
therapeutic large loop excision transformation zone (LLETZ). Each treatment cycle comprises 21 
days, with oral artesunate 200mg OD given for 14 days followed by a 7 day treatment break.   
5.1.2   Premedication  
No premedication is required.   

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5.1.3   Patient Monitoring  
Baseline temperature, blood pressure, heart rate, oxygen saturations and electrocardiogram will be 
recorded prior to commencing the IMP.  Baseline temperature, blood pressure, heart rate, oxygen 
saturations will be repeated at each study visit whilst on IMP or as requested by the PI as clinically 
indicated.  
5.1.4 Treatment duration  
Patients with HPV positive CIN2/3 will receive 3 cycles of oral artesunate 200mg OD prior to 
therapeutic large loop excision transformation zone (LLETZ). A treatment cycle comprises 21 days, 
with oral artesunate 200mg OD given for 14 days followed by a 7 day treatment break.   
5.1.5 Dose and schedule 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 by the treating investigator will result in that patient’s trial treatment 
being discontinued. If patients develop Grade 3 neutropenia or more (according to the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0) they should be managed with 
granulocyte colony stimulating factor (GCSF) supplied via routine hospital pharmacy in accordance 
with local policy and prescribing practice.  The study drug will be stopped and they will continue to 
be monitored until their full blood count recovers. They will not be recommenced on the study drug 
but will continue to be followed up within the trial. 
5.1.6 Packaging and storage conditions 
Study medication will be provided in bottles. One bottle will provide 28 tablets – sufficient for the 
duration of 1 cycle of treatment. 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.  
5.1.7 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 IMP treatment.  
5.1.8 Adverse events associated with artesunate 
Artesunate has a good safety profile and  has been taken by millions of patients worldwide for 
malaria. In data taken from studies of malaria, serious side-effects are extremely rare. However the 
average treatment duration of artesunate in malaria is 3-5 days. In our Phase II study, the treatment 
duration of 14 days for 3 cycles represents a prolonged duration of treatment compared to 
conventional treatment for malaria and therefore requires close pharmacovigilance. 
 
The Summary of Product Characteristics for Artesunate provided to sites lists the potential side 

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effects. The reference safety information document provided to sites lists the adverse events 
considered by the Sponsor as being ‘expected’. 
5.1.9 Source of IMP  
Bulk artesunate 100 mg tablets are manufactured by HCM- Medical under license according to Good 
Manufacturing Practice (GMP).  
Artesunate is packaged into bottles containing 28 tablets. Package labelling was performed under 
controlled conditions to ensure no cross contamination. HCM- Medical performed the controlled 
labelling operation. 
 
Each botttle has a label affixed in accordance with Appendix E: Labelling Requirements of the Rules 
and guidance for Malaysian-Guideline-for-Application-of-CTIL-and-CTX-7.1-Edition  
The named Qualified Person (QP) at HCM- Medical will issue a QP release certificate. The full IMP 
batch will be delivered, accompanied by the QP batch release certificate to the study sites. 
Upon instruction from the Sponsor, HCM-Medical will arrange an appropriate delivery to each 
participating trial site of sufficient artesunate. Shipment 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 or Clinical 
Research centres. 
The IMP artesunate 100 mg tablets must be stored below 25°C. 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 Pharmacy Site File (PSF) following the end of IMP 
treatment phase. 
5.1.10  Accountability procedures for the IMP 
Each participating site’s pharmacy department or research centre 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 a research pharmacist is not available at the study 
site, a qualified 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 PSF.  
5.2 Concomitant therapy 
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. The CI will 
monitor the international literature for drug interactions and report any emerging data to the study 
sponsor and as part of the annual Development Safety Update Report (DSUR). The study protocol 
and concomitant medication allowed on study will be updated accordingly. 

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If patients develop Grade 3 neutropenia or more (according to the Common Terminology Criteria 
for Adverse Events (CTCAE) Version 5.0) they should be managed with granulocyte colony 
stimulating factor (GCSF) supplied via routine hospital pharmacy in accordance with local policy and 
prescribing practice.  
5.3 Withdrawal criteria 
Patients may discontinue study treatment or withdraw their consent to participate in the study at 
any time without prejudice. 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 adverse event 
• 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 or research centre. 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 Adverse Events 
(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. 
 
Participants who develop CTCAE v5.0 Grade 3 or 4 serious adverse effects related to artesunate will 
be withdrawn from the study treatment but will continue in the study to enable an intention to 
treat analysis.  
 
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-CIN 24 hour emergency telephone number. 

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All PIs and research team members will 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 Chief Investigator (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. 
5.4 Assessment of compliance 
If vomiting occurs during the course of treatment, the dose should not be retaken on the same day. 
The occurrence and frequency of any vomiting during the reporting period must be noted in the 
adverse events log and CRF. Each treatment cycle will comprise artesunate 200mg once a day for 
14 days followed by a 7 day break. Patients will receive 3 cycles of treatment. At each treatment 
cycle, an assessment of medication compliance will be made by the principal investigator or 
delegated research team member on Day 7, Day 14, Day 22, Day 43 and Day 64 based on verbal 
answers given to direct questioning. This 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 or research centre for the IMP accountability log to be updated.  Patients 
who take the study drug for < 8 days in a 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.  
5.5 Overdose of Trial medication 
In the event of an overdose of trial medication the patient should attend the Accident and 
Emergency and be urgently reviewed by a member of the research team during working hours or 
the on-call 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 Serious 
Adverse Events (SAE) reporting form  should be completed. The completed SAE form should be 
emailed to the Sponsor in accordance with the protocol. 
5.6 List of criteria for premature discontinuation of the study 
The study may be discontinued prematurely by the Sponsor, the Data Monitoring Committe(DMC) 
or the Chief Investigator (CI) 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 
 

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In all cases the relevant ethics committee and NPRA will be informed in accordance with statutory 
guidance. 
5.7 Lost to Follow up 
For all participants that consent and are enrolled in the trial, information in relation to their Next of 
Kin (NoK) 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.  
5.8 End-of-Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study. The 
last study visit is at Day 90, when patient attends for colposcopy and standard of care LLETZ. A 
participant is considered to have completed the study if the participant has completed all periods 
of the study including the last visit as shown in the Schedule of Assessment. 
6. Clinical Evaluation, Laboratory Tests, Follow-Up 
6.1 Before treatment start 
The following information will be recorded for all subjects up to 7 days prior to starting study 
treatment on D1(-7 days): 
 
• 
Demographic details: Date of consent, enrolment, age, ethnicity, HPV vaccination status 
• 
Clinical data: symptomatology, weight, height, vital signs 
• 
Colposcopy findings (within 28 days of study commencement) 
• 
Histology: routine histological grading (within 28 days of study commencement) 
• 
HPV DNA oncotyping (within 28 days of study commencement) 
• 
Concomitant medication: all non-study drugs taken will be recorded 
 
D1 of study 
 
• 
Baseline safety blood tests full blood count (FBC), Urea and Elelctrolytes (U&E), Liver 
Function Tests (LFTs) will be conducted at D1  
• 
Baseline study blood tests (plasma, Peripheral Blood Mononuclear Cell (PBMC)) will be 
collected at D1 
• 
Vaginome and gut microbiome samples will be collected at D1 
• 
Quality of Life Tool (European Quality of Life–5 Dimensions (EQ-5D)) 
 
6.2 During treatment 
D7, D14, D22, D36, D43, D57 
 
• 
Telephone consultation on D7, D36, D57 
• 
Clinical Assessment on D14, D22, D43 
• 
Speculum examination on D22,D43 
• 
Concomitant medication on D14, D22, D43 

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• 
Patient self reported adverse events  
• 
Safety blood test – FBC, U&E, LFT on D14, D22, D43, 
• 
Study blood tests (plasma & PBMC) on D14 
• 
Quality of Life Tool (European Quality of Life–5 Dimensions (EQ-5D)) D7, D14, D22, D43 
 
6.3 After the end of treatment (Follow-up) 
Following the end of IMP treatment x 3 cycles, patients will undergo the following: 
 
Day 64 (+ 3 days) 
• 
Clinical Review  
• 
Speculum examination 
• 
Safety blood test – FBC, U&E, LFT 
• 
Study blood tests (plasma & PBMC) 
• 
HPV DNA oncotyping 
• 
Vaginome and gut microbiome samples  
• 
Quality of Life Tool (European Quality of Life–5 Dimensions (EQ-5D)) 
 
Day 90 (+ 14 days) 
• 
Clinical Assessment 
• 
Safety blood test – FBC, U&E, LFT 
• 
Study blood test (plasma & PBMC) 
• 
Colposcopy & endocervical biopsy 
• 
HPV DNA oncotyping 
• 
Vaginome and gut microbiome sampling 
• 
Large Loop Excision Transformation Zone 
• 
Quality of Life Tool (European Quality of Life–5 Dimensions (EQ-5D))  
 
 
 
 

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6.4 Summary table 
 
 
Study Procedures 
  
Screening 
prior to  
study entry 
D1  
Clinical review 
prior 
to start of 
medication 
D7 
Telephone 
consultation 
D14 
Clinical 
Review 
 
D22 
Clinical 
Review 
D36 
Telephone 
consultation 
D43 
Clinical 
Review 
 
 
D57 
Telephone 
consultation 
D64 
(+3 days) 
Clinical 
Review 
D90 
(+14 
days) 
Clinical 
Review 
Consent 
X 
 
 
 
 
 
 
 
 
 
Medical History  
X 
X 
 
X 
X 
 
X 
 
X 
X 
Clinical Examination 
X 
X 
 
 
X 
 
X 
 
X 
X 
Telephone consultation review 
 
 
X 
 
 
X 
 
X 
 
 
Toxicity Assessment 
X 
X 
X 
 
X 
 
X 
X 
Concomitant medication check 
  
X 
X 
X 
X 
 
X 
 
X 
 
Patient self-reported events 
(diary card) 
 
 
 
X 
X 
X 
 
X 
 
X 
X 
Vital signs  
X 
 
X 
X 
 
X 
 
X 
X 
Pregnancy Test  
X 
 
 
 
 
 
Study medication check 
 
 
 
X 
 
 
X 
 
X 
 
Safety Blood Test  (FBC/renal/  
liver profile)  
X 
 
X 
X 
 
X 
 
X 
X 
Study Blood test 
X 
 
X 
 
 
 
X 
X 
Speculum examination 
 
 
 
 
X 
 
X 
 
X 
 
Colposcopy examination + Cervical 
Biopsy 
 
X 
 
 
 
 
 
 
 
X 
HPV Test 
 
X 
 
 
 
 
 
 
X 
X 
Vaginome + gut microbiome sample 
 
X 
 
 
 
 
 
 
X 
X 
Large Loop Excision Transformation 
Zone (LETTZ) 
 
 
 
 
 
 
 
 
 
X 
QOL Tools (EuroQol EQ-5D) 
 
X 
X 
X 
X 
 
X 
 
X 
X 

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7. Pharmacovigilance 
7.1 Safety/Toxicity 
All adverse events will be recorded; the investigator will assess whether those events are drug 
related (reasonable possibility, no reasonable possibility) and this assessment will be recorded in 
the database for all adverse events. This study will use the Common Terminology Criteria for 
Adverse Events (CTCAE V5.0) for adverse event reporting. 
 
The AE monitoring period will commence on Day 1 of the study (start of IMP) till Day 90 of the study. 
Adverse events will be assessed by the worst grade and per CTCAE term from first dose until 30 days 
after last dose of study treatment. 
7.2 Reference Safety Information 
A NeoART-CIN Reference Safety Information document based upon the Summary Product 
Characteristics for artesunate (WHOPAR., 2017) forms the Reference Safety Information for this 
study. Section 4.8 of the Summary Product Characteristics for artesunate (WHOPAR., 2017) lists the 
following potential side effects. The adverse events are listed by body system, organ class and 
absolute frequency. They are generally not based on adequately sized randomized controlled trials 
but on published literature data generated mostly during post-approval use. When frequency 
estimates are available they are defined as follows: very common (≥1/10), common (≥1/100, <1/10), 
uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (< 1/10,000).  
 
Very Common 
Common 
Uncommon 
Rare 
Blood and lymphatic disorders 
 
 
Neutropenia 
Low reticulocyte count 
 
Cardiac disorders 
 
 
Bradycardia 
 
Gastrointestinal disorders 
 
 
Mild GI disturbances 
 
Hepato-biliary disorders 
 
 
Elevated liver enzymes 
 
General disorders 
 
 
 
Hypersensitivity 
(allergic 
reactions) 
 
7.3 Serious adverse events 
Serious adverse events or adverse drug ractions are defined by the Malaysian Guideline for Safety 
Reporting of Investigational Products and Malaysian Guideline for Good Clinical Practice, 3rd 
Edition, Item 1.56. 
 
SERIOUS ADVERSE EVENTS SHOULD BE IMMEDIATELY REPORTED ACCORDING TO THE 
PROCEDURE DETAILED IN THIS PROTOCOL. 
 
 

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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.  
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 
30 days following the end of the IMP treatment schedule.  
 
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. 
 
7.4 Investigator responsibilities relating to safety reporting 
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.  

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SAEs or serious adverse reactiosn (SAR)s must be notified to the sponsor as soon as the investigator 
becomes aware of the event (within 24 hours). Refer to SOP and ensure the completed SAE report 
form is sent to the sponsor via E-mail.  
 
The sponsor will notify all SUSARs to the NPRA  electronically and the relevant ethics committee.  
 
The sponsor will inform the NPRA and relevant ethics committee of  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 NPCB when it becomes available.  
  
Serious, unexpected ADRs that are not fatal or life-threatening must be notified to the NPCB as soon 
as possible but no later than 15 calendar days after first knowledge by the sponsor that the case 
meets the minimum criteria for expedited reporting. Follow-up information should be actively 
sought and follow-up reports should be submitted to the NPCB 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 
ADRs.  
 
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. 
 
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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.  
 
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 time-frames 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.  
7.5 Development Safety Update Reports (DSURs) 
The CI or the CI delegate will prepare the DSUR, using the Sponsor’s template and in accordance 
with the Sponsor’s 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 NPCB the prepared 
DSUR annually within the defined reporting timelines. 
7.6 Annual Progress Reports (APRs) 
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 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 
7.7 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 IMP treatment.  
8. Translational Research / Pharmacodynamic Studies 
 
For instructions on processing and storage of study bloods, vaginome and gut microbiome samples 
please refer to the study lab manual.  

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9. Data Collection Tool  
 
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 The Staff Delegation of Responsibilities Log is 
completed and all data entered and recorded in the CRFs are accurate. The Staff Delegation of 
Responsibilities Log will identify all trial personnel responsible for data collection, entry, handling 
and managing the trial Redcap 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.  
 
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/letter) in the event of missing data such as patient quality of life 
questionnaires. 
9.1 Incidental findings  
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. 
9.2 Data handling and analysis 
Data will be stored in anonymised form in a password-protected database. We will use a customised 
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.  
 
10. Statistical Considerations 
10.1 Statistical design 
Sample size 
 
This is a Phase II open label, single arm study to investigate the activity of oral artesunate in patients 
with high grade intraepithelial neoplasia CIN2/3 prior to treatment with large loop excision  

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transformation zone (LLETZ). The primary end point is histological regression of CIN2/3 on 
colposcopy and biopsy at Day 90.  
 
Significance level and power: The procedure described above tests the null hypothesis that the 
response rate is 20 % versus alternating hypotheses that the response rate is 50 %.  The significance 
level (i.e., the probability of rejecting H0 when it is true) is α=0.1 and the power (i.e., 1-beta, the 
probability of deciding the regimen is active) is 90%  when true response rate is 50 %.   
 
At the significance level of 0.05, with an equivalence limit of 0.15, a sample size of 24 is required to 
achieve 90% power when the response rate for the historical control is 0.2 and response rate for 
the treatment is 0.5. 
 
Inflating this sample size by 20% to allow for loss at follow-up would result in approximately 28 
patients. We believe that 28 patients represents a feasible and achievable target given our time and 
financial considerations. 
10.1.1 Interim analyses / Decision rules 
An interim analysis reviewing feasibility and tolerability will be performed once 10% (n = 3) and 
50% (n = 14) of patients have completed their day 90 assessments. No early conclusions will be 
drawn. 
10.1.2 Accrual and Duration of Study 
The estimated accrual for this study is 3 patients a month. Thus, patient accrual is expected to be 
completed within 24 months. An additional 6 months is required to allow the response data to 
mature.  
10.2 Statistical Analysis  
The study outcome measures are listed in chapter 2. The methods used to evaluate them are 
detailed in this section. The statistical analysis will be performed using SAS® and Graphpad software. 
10.2.1 Analysis populations 
 Intention-to-treat population: All patients will analysed according treatment allocation. 
 Per protocol population: All patients who meet the eligibility criteria and have started their 
allocated treatment (at least 8 out of 14 doses in cycle 1 of their treatment plan). 
Safety population: All patients who have started protocol treatment (e.g., at least one dose of the 
study drug). 
10.2.2 Patient disposition, data recording and display 
Patients’ demographics, baseline characteristics, prior and concomitant medications, treatment 
exposure, protocol compliance and study withdrawals will be summarized in the intent-to-treat 
population. For categorical variables, frequency tables (with %) will be presented with descriptive 
listings of details specified in text fields, when appropriate. Continuous variables will be reported 
using median, range and interquartile range. 
 

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A CONSORT diagram will be used to document the flow of patients through the various stages of 
the study. The number of patients included in the various analysis populations will be presented in 
a table and reasons for exclusions will be detailed in listings. 
10.2.3 Safety 
Safety analyses will be performed on the safety population. Patients will be analysed according to 
the treatment actually started, regardless of duration or compliance with treatment. 
Periods 
• “Baseline” is defined as the period from before study entry to first day of protocol treatment 
administration. For patients who never started treatment, the baseline period is assumed to 
end on the day of enrolment.  
• "On treatment " is defined as the time on study after baseline (i.e., starting on the first day of 
protocol treatment administration) to and including 30 days after the day of last protocol 
treatment administration. 
• "Follow-up period" is defined as the period that follows the on-treatment period until the end 
of the follow up. For patients who never started treatment, the follow-up period is assumed to 
start on the day of enrolment.  
10.2.3.1 
Safety analyses 
Tables on AEs will report  
• all AEs irrespective of their relationship to treatment 
• the AEs related to the treatment (excluding those declared not reasonably possibly related to 
the treatment, but including those with relationship not assessable). 
The worst grade of the AEs per patient and per CTCAE term over each period will be tabulated by 
treatment arm.  The percentage of patients on each treatment arm presenting severe treatment-
related AE (grade ≥ 3), of patients reported to have died of toxicity and that of patients who stopped 
treatment due to toxicity will also be calculated and the 95% confidence interval will be presented.  
 
For the reporting of SAEs:  
• the study safety overview table will list the number of reported SAE terms, SAR terms and 
SUSAR terms per treatment arm and the number of reported death and toxic death cases;  
• line listings of SAEs and of SARs will be provided;  
• the number of SAEs and SARs per System Organ Class and Preferred Term will be tabulated 
10.2.4 Study outcome measures  
Primary outcome measure(s) 
• 
Histological regression of CIN2/3 on colposcopy and biopsy at Day 90 will be defined as 
histologic regression to CIN1 or less. This will be described as a response percentage. 
Secondary outcome measures 
• 
HPV DNA viral clearance at Day 90  
Viral clearance will be defined as absence of HPV genotoype (s) detected at baseline and 
described as a response percentage. 

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• 
Vaginome and gut microbiome at Day 0, Day 64 and Day 90 
Changes in vaginome and gut microbiome will be compared between Day 0 and Day 90. 
 
• 
Serious Adverse Events at Day 90 using Common Toxicity Criteria (CTCAE V5.0)  
Safety assessment will be based on patients who received at least one dose of IMP. 
Tolerability assessment will be based on the percentage of subjects that complete the 
designated dosing regimen.  
• 
Patient quality of life using the European Quality of Life–5 Dimensions (EQ-5D) quality of 
life tool D7, D14, D22, D43, D64, D90. 
 
Toxicity assessments 
 
The proportion of patients experiencing grade 3 or 4 toxicity will be assessed using CTCAE V5.0. 
 
Quality of life  
 
The functional and symptomatic quality of life questionnaires (EuroQol EQ-5D) will be examined by 
calculating the differences in measurements from baseline. The standard EuroQol EQ-5D 
recommended methods will be used to calculate function and symptomatic scores. The nature of 
the variable which quantifies this score will be investigated and summary statistics will be presented 
for values at baseline and post treatment.  
 
Exploratory outcome measures  
 
Vaginome and gut microbiome 
 
Exploratory analyses will be conducted on patient vaginome and microbiome analysis comparing 
Day 1 with Day 90. 
11. 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 
 
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 safety assessment of the study to the DMC. The TSC will advise the Sponsor directly of 

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any decision regarding any change to study status in accordance with the NeoART-CIN TSC 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. 
12. 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.  
13. Site Approval And Ongoing Regulatory Compliance 
Before any site can enrol patients into the trial, the Sponsor will be in possession of the relevant 
ethics committee approval. The site will have a fully executed Clinical Trial 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 
registration with National Medical Research Registration (NMRR).   
 
The Chief Investigator will be provided (via the Sponsor) with file indexes Trial Master File (TMF)  
index and Investigator Site File (ISF) index for use with SOP ‘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. 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. 
 
Within 90 days after the end of the trial, the CI and Sponsor will ensure that the relevant ethics 
committee and the NPRA are notified that the trial has finished.  If the trial is ended 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 will provide the End of study 
Report template. 
14. Monitoring Plan For The Trial 
The CI will be requested to complete the Feasibility Questionnaire and forward to the Sponsor to 
facilitate appropriatecosting and Sponsorship in Principle to be issued prior to the relevant ethics 
application and NMRR registration. The trial will be monitored according to the risk based 
monitoring plan agreed by the Sponsor and CI. The investigator’s team  determine the initial project 
risk assessment and justify change as the study progresses. The PI at each collaborating site in 
addition to site monitoring visits will be 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 

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on behalf of the Sponsor may be escalated in accordance with  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  Serious Breach Reporting. 
 
Any urgent safety measures at either the CI or a PI site must be reported by that site, as per 
Malaysian Regulations. The CI and/or the CI delegate will be provided with a copy of the study 
monitoring plan during the Site Initiation Visit (SIV).  
15. Finance 
The Malaysian Federal Government, Selangor State Government, charitable and philanthropic 
donations provided financial support for the study. 
16. Insurance And Indemnity 
Metanoic Health Limited, United Kingdom 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 participating sites have 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 Metanoic Health Limited 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 parties 
may lead to a lack of insurance cover for the incident.   
17. Intellectual Property 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 participating hospital. 
2) pre-existing IP related to analytical procedures of any external laboratory. 
 
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 

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NeoART-CIN Version 5.0 13 November 2024 
 
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 such Know How as confidential information jointly 
owned between 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).  
18. 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 (CI) in the first instance, in discussion with Sponsor.  
 
18.1 Before the official completion of the Trial 
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.      
18.2 Up to 180 days after the official completion of the Trial  
During this period the Chief Investigator (CI) 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.  
 
Insofar as compatible with the policies of the publication outlet and good academic practice, the 

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other Investigators shall be listed according to contributions and/or under a Trial title such as 
NeoART-CIN.  
 
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. 
18.3 Beyond 180 days after the official completion of the Trial  
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.   
19. 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 the EU if directly applicable or of direct 
effect and all relevant laws and statutes of the Malaysian country in which the study site is located 
including but not limited to, the Human Rights Act 1998, the Data Protection Act 1998, 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, and 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 ethics 
committee  and according to GCP standards, and Malaysia Clinical Trials Regulations. No major 
deviations 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 the relevant ethics 
committee  as soon as possible. 
 
20. List of Protocol Appendices 
Appendix 1 
Protocol Amendment/Revision History  
Appendix 2 
Summary chart of study assessments 
Appendix 3  
Quality of Life Questionnaire EuroQol EQ-5D-5L 
Appendix 4 
 
             Common Terminology Criteria for Adverse Events (CTCAE V5.0)  
 

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21.References 
 
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cancer pandemic through drug repurposing. Pharmacol Ther. 2020 Dec;216:107706. doi: 
10.1016/j.pharmthera.2020.107706. Epub 2020 Oct 16. PMID: 33075360; PMCID: PMC7564301. 
 
Bertolini F, Sukhatme V, Bouche G. Drug repurposing in oncology—patient and health systems 
opportunities. Nat Rev Clin Oncol 12, 732–742 (2015). https://doi.org/10.1038/nrclinonc.2015.169 
 
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: 
GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA 
Cancer J Clin. 2018;68(6):394-424.  
 
Deeken JF, Wang H, Hartley M, Cheema AK, Smaglo B, Hwang JJ, He AR, Weiner LM, Marshall JL, 
Giaccone G, Liu S, Luecht J, Spiegel JY, Pishvaian MJ. A phase I study of intravenous artesunate in 
patients with advanced solid tumor malignancies. Cancer Chemother Pharmacol. 2018 
Mar;81(3):587-596. doi: 10.1007/s00280-018-3533-8. Epub 2018 Feb 1. PMID: 29392450. 
 
Disbrow GL, Baege AC, Kierpiec KA, Yuan H, Centeno JA, Thibodeaux CA, Hartmann D, Schlegel R. 
Dihydroartemisinin is cytotoxic to papillomavirus-expressing epithelial cells in vitro and in vivo. 
Cancer Res. 2005 Dec 1;65(23):10854-61. doi: 10.1158/0008-5472.CAN-05-1216. PMID: 16322232. 
 
Efferth T. From ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapy. 
Semin Cancer Biol. 2017 Oct;46:65-83. doi: 10.1016/j.semcancer.2017.02.009. Epub 2017 Feb 28. 
PMID: 28254675. 
 
Fan A, Wang C, Han C, Wang Y, Xue F, Zhang L. Factors affecting residual/recurrent cervical 
intraepithelial neoplasia after cervical conization with negative margins. J Med Virol. 2018 
Sep;90(9):1541-1548. doi: 10.1002/jmv.25208. Epub 2018 May 25. PMID: 29704442. 
 
Fishbein A, Hammock BD, Serhan CN, Panigrahy D. Carcinogenesis: Failure of resolution of 
inflammation? Pharmacol Ther. 2021 Feb;218:107670. doi:10.1016/j.pharmthera.2020.107670. 
Epub 2020 Sep 3. PMID: 32891711; PMCID: PMC7470770. 
Global strategy to accelerate the elimination of cervical cancer as a public health problem. 
Geneva: World Health Organization; 2020. Licence: CC BY-NC-SA 3.0 IGO. 
https://www.who.int/initiatives/cervical-cancer-elimination-initiative 
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-
74. doi: 10.1016/j.cell.2011.02.013. PMID: 21376230. 
 
Heinonen A, Gissler M, Riska A, Paavonen J, Tapper AM, Jakobsson M. Loop electrosurgical 
excision procedure and the risk for preterm delivery. Obstet Gynecol. 2013 May;121(5):1063-
1068. doi: 10.1097/AOG.0b013e31828caa31. PMID: 23635744. 

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Human papillomavirus (HPV) and cervical cancer. World Health 
Organization. https://www.who.int/news-room/fact-sheets/detail/human-papillomavirus-(hpv)-
and-cervical-cancer. Accessed August 10, 2021.  
Ho WE, Peh HY, Chan TK, Wong WS. Artemisinins: pharmacological actions beyond anti-malarial. 
Pharmacol Ther. 2014 Apr;142(1):126-39. doi: 10.1016/j.pharmthera.2013.12.001. Epub 2013 Dec 
6. PMID: 24316259. 
 
Jansen FH, Adoubi I, J C KC, DE Cnodder T, Jansen N, Tschulakow A, Efferth T. First study of oral 
Artenimol-R in advanced cervical cancer: clinical benefit, tolerability and tumor markers. 
Anticancer Res. 2011 Dec;31(12):4417-22. PMID: 22199309. 
 
Kay J, Thadhani E, Samson L, Engelward B. Inflammation-induced DNA damage, mutations and 
cancer. DNA Repair (Amst). 2019 Nov;83:102673. doi: 10.1016/j.dnarep.2019.102673. Epub 2019 
Jul 25. PMID: 31387777; PMCID: PMC6801086. 
 
Krishna S, Bustamante L, Haynes RK, Staines HM. Artemisinins: their growing importance in 
medicine. Trends Pharmacol Sci. 2008 Oct;29(10):520-7. doi: 10.1016/j.tips.2008.07.004. Epub 
2008 Aug 25. PMID: 18752857; PMCID: PMC2758403. 
 
Liu Z, Zhang J, Li S, Jiang J. Artesunate Inhibits Renal Ischemia Reperfusion-Stimulated Lung 
Inflammation in Rats by Activating HO-1 Pathway. Inflammation. 2018 Feb;41(1):114-121. doi: 
10.1007/s10753-017-0669-3. PMID: 28921399. 
 
Majid U, Kandasamy S, Farrah K, Vanstone M. Women's preferences and experiences of cervical 
cancer screening in rural and remote areas: a systematic review and qualitative meta-synthesis. 
Rural Remote Health. 2019 Oct;19(4):5190. doi: 10.22605/RRH5190. Epub 2019 Oct 23. PMID: 
31640391. 
 
Maucort-Boulch D, Plummer M, Castle PE, Demuth F, Safaeian M, Wheeler CM, et al. Predictors of 
human papillomavirus persistence among women with equivocal or mildly abnormal cytology. Int J 
Cancer. (2010) 126:684–91. 10.1002/ijc.24752  
 
McPherson GS, Fairbairn-Dunlop P, Payne D. Overcoming Barriers to Cervical Screening Among 
Pacific Women: A Narrative Review. Health Equity. 2019 Feb 14;3(1):22-29. doi: 
10.1089/heq.2018.0076. PMID: 30783634; PMCID: PMC6379043. 
National Cancer Registry, National Cancer Institute, Ministry of Health Malaysia (2018). Malaysian 
Study on Cancer Survival (MySCan).  
Nagai Y, Maehama T, Asato T, Kanazawa K. Persistence of human papillomavirus infection after 
therapeutic conization for CIN 3: is it an alarm for disease recurrence? Gynecol Oncol. 2000 
Nov;79(2):294-9. doi: 10.1006/gyno.2000.5952. PMID: 11063660. 
 
Nosengo N. Can you teach old drugs new tricks? Nature. 2016 Jun 16;534(7607):314-6. doi:  
10.1038/534314a. 
 
Otter S, Whitaker S, Chatterjee J, Stewart A. The Human Papillomavirus as a Common Pathogen in 
Oropharyngeal, Anal and Cervical Cancers. Clin Oncol (R Coll Radiol). 2019;31(2):81-90. 

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Pal A, Kundu R. Human Papillomavirus E6 and E7: The Cervical Cancer Hallmarks and Targets for 
Therapy. Front Microbiol. 2020;10:3116. Published 2020 Jan 21. doi:10.3389/fmicb.2019.03116 
 
Plummer M, de Martel C, Vignat J, Ferlay J, Bray F, Franceschi S. Global burden of cancers 
attributable to infections in 2012: a synthetic analysis. Lancet Glob Health. 2016 Sep;4(9):e609-16. 
doi: 10.1016/S2214-109X(16)30143-7. Epub 2016 Jul 25. PMID: 27470177. 
 
Rodríguez AC, Schiffman M, Herrero R, et al. Longitudinal study of human papillomavirus 
persistence and cervical intraepithelial neoplasia grade 2/3: critical role of duration of infection. J 
Natl Cancer Inst. 2010;102(5):315-324. doi:10.1093/jnci/djq001 
 
Roden RBS, Stern PL. Opportunities and challenges for human papillomavirus vaccination in 
cancer. Nat Rev Cancer. 2018;18(4):240-54. 
Sanjose S, et al. Human papillomavirus genotype attribution in invasive cervical cancer: a 
retrospective cross-sectional worldwide study. Lancet Oncol. 2010 Nov;11(11):1048-56. doi: 
10.1016/S1470-2045(10)70230-8. 
Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and 
cervical cancer. Lancet. (2007) 370:890–907. 10.1016/S0140-6736(07)61416-0  
 
Serati M, Siesto G, Carollo S, Formenti G, Riva C, Cromi A, Ghezzi F. Risk factors for cervical 
intraepithelial neoplasia recurrence after conization: a 10-year study. Eur J Obstet Gynecol Reprod 
Biol. 2012 Nov;165(1):86-90. doi: 10.1016/j.ejogrb.2012.06.026. Epub 2012 Jul 6. PMID: 22771223. 
 
Sordi R, Nandra KK, Chiazza F, Johnson FL, Cabrera CP, Torrance HD, Yamada N, Patel NS, Barnes 
MR, Brohi K, Collino M, Thiemermann C. Artesunate Protects Against the Organ Injury and 
Dysfunction Induced by Severe Hemorrhage and Resuscitation. Ann Surg. 2017 Feb;265(2):408-
417. doi: 10.1097/SLA.0000000000001664. PMID: 28059970. 
 
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer 
Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 
Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4. 
PMID: 33538338. 
 
Trimble CL, Levinson K, Maldonado L, Donovan MJ, Clark KT, Fu J, Shay ME, Sauter ME, Sanders SA, 
Frantz PS, Plesa M. A first-in-human proof-of-concept trial of intravaginal artesunate to treat 
cervical intraepithelial neoplasia 2/3 (CIN2/3). Gynecol Oncol. 2020 Apr;157(1):188-194. doi: 
10.1016/j.ygyno.2019.12.035. Epub 2020 Jan 28. PMID: 32005582. 
 
Verguts J, Bronselaer B, Donders G, Arbyn M, Van Eldere J, Drijkoningen M, Poppe W. Prediction of 
recurrence after treatment for high-grade cervical intraepithelial neoplasia: the role of human 
papillomavirus testing and age at conisation. BJOG. 2006 Nov;113(11):1303-7. doi: 10.1111/j.1471-
0528.2006.01063.x. Epub 2006 Sep 15. PMID: 16978225. 
 
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Expression and Inducing Nrf2 Activation. Inflammation. 2017 Jun;40(3):798-805. doi: 10.1007/s10753-017-
0524-6. PMID: 28315999. 
 
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Appendix 1. Protocol amendment /Revision History  
  
Protocol Version and Date  
 
Amended text  
Section details and change   
 
Version 2.0 16 January 
2023 
Replaced HPV +ve in the Protocol title  with Human Papilloma Virus 
positive replaced on page 1 
Added  Protocol ID: 2023 - MHL- 002 
Added NMRR number: RSCH ID-22-04943-NW0 
Added Protocol Version: Version 2.0 Date 16 January 2023 
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 
Mobile: +44 (0)7931901724 
Email: skrishna@cadt.org.uk 
Added  
SPONSOR:   
Metanoic Health Limited  
36 Clarkes Avenue 
Worcester Park 
Surrey  
United Kingdom 
Mobile: +44 (0)7798566612 
Email: info@metanoichealth.com 
SPONSOR REPRESENTATIVE:  
Name: Dr Isaac John 
Mobile: +44 (0) 7798566612 
Email: Isaac.John@metanoichealth.com 
Removed  
SPONSOR’S PROJECT NUMBER: 02.0154 
<INSERT> ETHICS COMMITTEE ID: <INSERT> 
NMRR NUMBER: RSCH ID-22-04943-NW0 
PROTOCOL VERSION: 1.0 Dated 12 December 2022 

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NeoART-CIN Version 5.0 13 November 2024 
 
SPONSOR: Centre For Affordable Diagnostics And Therapeutics 
SPONSOR REPRESENTATIVE: 
Name: Dr Yolanda Augustin 
Phone: +447894319056 
Email: yaugustin@cadt.org.uk 
Protocol identification number / code / Registration n° (if applicable) 
Study Coordinator: Dr Nafeesa Mat Ali 
Phone: +44 7872101116 
e-mail: nmatali@cadt.org.uk 
Version 2.0 16 January 
2023 
Removed 
This protocol was developed at the EORTC-ESMO-AACR Workshop on 
Methods in Clinical on page 2 
Cancer Research. 
Removed Chief Investigator and Co-Investigator list on page 2 
Replaced with Signature Page and Statement on page 2 
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 (GCP) and National 
Pharmaceutical Regulatory Authority (NPRA)  Regulations for Clinical 
Trial Import License (CTIL), the Malaysian Data Protection Act, local 
governance policy, the Sponsor’s SOPs, and other regulatory 
requirements as stipulated.   
This protocol has been written in accordance with the Sponsor’s 
procedure and is intended for use at Malaysian sites only.  
Replaced with Acknowledgements and Protocol contributories 
Version 2.0 16 January 
2023 
Added Roles and Responsibility on Page 9-11  
Version 2.0 16 January 
2023 
Added Protocol summary 
Study Assessments:  
Patients will have study bloods samples for translational research 
collected on Day 1, Day 14, Day 64 and Day 90 of the study. HPV DNA 
will be tested on vaginal sampling Day 1, Day 64 and Day 90 of the 
study. Vaginome and microbiome samples will be collected on Day 1 
and Day 90. A laboratory manual has been prepared separate to this 
protocol. 

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European Quality of Life–5 Dimensions (EQ-5D-5L) quality of life tool 
will be completed on Day 1, Day 7, Day 14, Day 22, Day 43, Day 64 and 
Day 90 of the study. 
Version 2.0 16 January 
2023 
Amended Schematic design of trial 
Version 2.0 16 January 
2023 
Added In a separate Phase I study, oral and intravenous artesunate 
were safe when systemically administered and displayed cytotoxic 
effects on human solid tumours including HPV positive tumours 
(Deeken et al.,2018).   
A small open label pilot study of dihydroartemisinin (the major active 
metabolite of artesunate) in 10 patients with advanced  cervical cancer 
reported a reduction in Ki67 proliferation, p53,  EGFR and CD31 and 
symptomatic benefit (Jansen et al., 2011) on page 23 
Version 2.0 16 January 
2023 
Added This is a Phase II single arm, open label study of artesunate to 
determine the feasibility, safety and preliminary anti-proliferation 
activity of oral artesunate in HPV +ve High Grade Cervical Intraepithelial 
Neoplasia (CIN2/3).  Patients with HPV positive CIN2/3 will receive 3 
cycles of oral artesunate 200mg OD prior to standard of care therapeutic 
large loop excision transformation zone (LLETZ). Each 21 day treatment 
cycle will comprise oral artesunate 200mg OD for 14 days followed by a 
7 day treatment break. Patients will be followed up clinically after each 
cycle of treatment till standard of care large loop excision transformation 
zone (LLETZ)  at 90 days. Colposcopy and cervical biopsy to assess 
histological regression will be performed at 90 days. A cervical sample to 
test for HPV DNA clearance will also be collected. A vaginal swab will also 
be collected for vaginome analysis, and a faecal sample collected for 
microbiome analysis on page 23 3. Trial design 
Version 2.0 16 January 
2023 
Replaced Pamoja BV with HCM-Medical in  5.1.9 
Source of IMP  
Version 2.0 16 January 
2023 
Added The CI will monitor the international literature for drug 
interactions and report any emerging data to the study sponsor and as 
part of the annual Development Safety Update Report (DSUR). The 
study protocol and concomitant medication allowed on study will be 
updated accordingly to 5.2 Concomitant theraphy 
Version 2.0 16 January 
2023 
Removed D14 from 6.2 During treatment D7, D14, D22, D43 
• Speculum examination on D22,D43 
Added D7 to  
• Patient self reported adverse events on D7,D14, D22, D43 
Added plasma & PBMC 
• Study blood tests (plasma & PBMC) on D14 
Added D22  

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• Quality of Life Tool (European Quality of Life–5 Dimensions 
(EQ-5D)) D7, D14, D22, D43 
Added Study blood tests (plasma & PBMC) and Quality of Life Tool 
(European Quality of Life–5 Dimensions (EQ-5D)) D64 to 6.3 After the 
end of treatment (Follow-up) and  
Following the end of IMP treatment x 3 cycles, patients will undergo the 
following: 
Added Quality of Life Tool (European Quality of Life–5 Dimensions (EQ-
5D)) to Day 90 (+ 14 days) 
Version 2.0 16 January 
2023 
Amended 6.4 Summary table 
Version 3.0 6 January 
2024 
Front page 
Changed version to 3.0 and  Date 6 January 2024 
Changes Sponsor's email clinicaltrials@metanoichealth.com 
Version 3.0 6 January 
2024 
Signature Page and Statement  
Added signature and date 6 January 2024 
Version 3.0 6 January 
2024 
Protocol synopsis  
Amended  
Protocol number 
2023-MHL-002 
Version 3.0 6 January 
2024 
Removed  
            Professor Adeeba Kamarulzaman 
            Department of Medicine 
            Faculty of Medicine, University of Malaya 
            Lembah Pantai,59100 
            Kuala Lumpur, Malaysia. 
            Email: adeeba@ummc.edu.my 
Dr Zatul Akmar binti Ahmad 
Hospital UiTM 
KS359 Pintu Utama UiTM, 42300,  
Selangor, Malaysia, 
Mobile: +60 (0)193839020 
Email: drzatul@gmail.com 
Version 3.0 6 January 
2024 
Schematic design trial 
Removed Day 14, 22, 43 and 64 
Version 3.0 6 January 
2024 
4.3 Subject Recruitment Process 
Changed 'NeoART-CIN aims to recruit participants between 1st of 
August 2023 -31st of July 2024. We aim to recruit 2-3 participants to the 
study per month to meet our recruitment target' to  
NeoART-CIN aims to recruit participants over 12-18 months. We aim to
recruit 2-3 participants to the study per month to meet our recruitment
target.  
Version 3.0 6 January 
2024 
15. Finance  
Added 'The Malaysian Federal Government' 
Version 3.0 6 January 
2024 
17. Intellectual Properties and Development Policy 
Added 

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NeoART-CIN Version 5.0 13 November 2024 
 
'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 3.0 6 January 
2024 
Added Appendix 1. Protocol amendment /Revision History  
Version 4.0 1 May 2024 Added 
1.2.2 Secondary outcome measures 
Vaginome and gut microbiome at Day 1, Day 64 and Day 90. 
Changes in vaginome and gut microbiome will be compared between 
Day 1, Day 64 and Day 90. 
6.3 
Added Vaginome and gut microbiome samples will be collected at D64 
Version 4.0 1 May 2024 Changed 1 June 2024 to 'NeoART-CIN aims to recruit participants over 
24 months with 3 months follow-up. We aim to recruit 2-3 participants 
to the study per month to meet our recruitment target.' 
Version 5.0 
13 November 2024 
Changed Schematic drawing to add telephone review on D36 and D57 
Version 5.0 
13 November 2024 
Added telephone review on D36 and D57, removed D7, D4, D22 and  
D43 from patient self-reported adverse event. 
Updated the 6.2 Summary Table  
Version 5.0 
13 November 2024 
Removed  
Dr Nik Ahmad Nik Abdullah 
Hospital Raja Perempuan Zainab II  
Bandar Kota Bharu,  
15586 Kota Bharu, Kelantan,  
Malaysia 
Mobile: +60 (0)13-9336161 
Email: nikahmadkb@me.com