Clinical trial NCT03654729
Conditions: Colorectal Cancer Chemotherapy-induced Peripheral Neuropathy
Keywords: Metastatic Colorectal Cancer Metastatic Colorectal Cancer Oxaliplatin induced CIPN CIPN Oxaliplatin
Sponsor: Egetis Therapeutics
Start date: 2018-11-07; Completion date: 2020-08-31
Enrollment: 291 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluates the investigational drug PledOx in the prevention of chronic chemotherapy induced peripheral neuropathy (CIPN) induced by the drug oxaliplatin.

Detailed description:
Oxaliplatin, in combination with 5-fluorouracil plus folinate (or capecitabine), has increased survival in stage III colorectal cancer and prolonged life in stage IV patients, but its use is compromised because of severe toxicity. Chemotherapy-induced peripheral neuropathy (CIPN) is the most problematic dose-limiting toxicity of oxaliplatin. No treatments have been clinically proven to prevent CIPN. There is a body of evidence that CIPN is caused by cellular oxidative stress. Clinical and preclinical data suggest that the manganese chelate and superoxide dismutase mimetic mangafodipir (MnDPDP) and calmangafodipir (\[Ca0.8,Mn0.2\]Na3DPDP) are efficacious inhibitors of CIPN and other conditions caused by cellular oxidative stress, without interfering negatively with the tumoricidal activity of chemotherapy.

This is a Phase 3, multicenter, double-blind, placebo-controlled study to establish the efficacious dose of PledOx in prevention of chronic CIPN induced by oxaliplatin.

Patients with metastatic colorectal cancer (mCRC), who are indicated for first-line modified FOLFOX6 (mFOLFOX6) chemotherapy for at least 3 months, without any pre-planned treatment breaks, will be randomized in a 1:1:1 ratio, stratified by region (Asia, non-Asia) and PK sub-study (yes, no), to one of three treatment arms:

* Arm A: PledOx (2 µmol/kg) + mFOLFOX6 chemotherapy
* Arm B: PledOx (5 µmol/kg) + mFOLFOX6 chemotherapy
* Arm C: Placebo + mFOLFOX6 chemotherapy

Before March 2nd., 2020, the Investigational Medicinal Product, (IMP; i.e. PledOx or placebo) was administered by an intravenous infusion on the first day of each chemotherapy (mFOLFOX6) cycle. IMP was not to be administered if mFOLFOX6 was not given to the patient.

If a patient later discontinues oxaliplatin, treatment with 5-FU/folinate may be continued.

The addition of an appropriate biologic therapy (bevacizumab, panitumumab, cetuximab) will be left to the discretion of the Investigator.

As of March 2nd., all patients have to stop IMP but may continue mFOLFOX 6

Arms: arm 1: Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. arm 2: Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. arm 3: Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy.
Interventions: intervention 1: Calmangafodipir (2 µmol/kg) intervention 2: Calmangafodipir (5 µmol/kg) intervention 3: Placebo
Intervention descriptions: intervention 1: Solution in 20 mL single dose glass vials intervention 2: Solution in 20 mL single dose glass vials intervention 3: Solution in 20 mL single dose glass vials

Protocol documents:
Prot_000.pdf: 
Protocol Number: PP06489 (POLAR-A) 
Page 1 of 109 
15 May 2020 
Version 8.0 
 
 
  
CONFIDENTIAL 
PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
CONFIDENTIAL 
CLINICAL STUDY PROTOCOL 
STUDY TITLE: 
A Phase 3, double-blind, multicenter, placebo-controlled study 
of PledOx used on top of modified FOLFOX6 (5-FU/FA and 
Oxaliplatin) to prevent chemotherapy induced peripheral 
neuropathy (CIPN) in the adjuvant treatment of patients with 
Stage III or high-risk Stage II colorectal cancer 
SHORT TITLE: 
Preventive treatment of OxaLiplatin induced peripherAl 
neuRopathy in Adjuvant colorectal cancer (POLAR-A) 
PROTOCOL NUMBER: 
PP06489 
EUDRACT NUMBER: 
2017‐004707‐43 
IND NUMBER: 
Not applicable 
STUDY DRUG: 
PledOx 
SPONSOR: 
 PledPharma AB 
Solasia Pharma K.K. 
Grev Turegatan 11c 
4F Sumitomo Fudosan 
SE 114 46 
Shiba-Koen Tower, 
Stockholm 
2-11-1, Shiba-koen, Minato-ku, 
Sweden 
Tokyo 105-0011, Japan 
 
(Co-sponsor in Asia) 
CO-ORDINATING 
INVESTIGATORS: 
Camilla Qvortrup, MD, PhD 
The Finsen Center – Rigshospitalet, Department of Oncology  
Blegdamsvej 9 
Copenhagen, DK-2100 
Denmark 
 
Kei Muro MD 
Director and Chief Department of Clinical Oncology Outpatient 
Treatment Center, Aichi Cancer Center Hospital,  
1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi 464-8681, 
Japan 
VERSION TABLE 
Final Version 1.0 
14 Dec 2017 
Final Version 2.0 
25 Jan 2018 
Final Version 3.0 
20 Feb 2018 
Final Version 4.0, incorporating Protocol Amendment 1 
20 Jun 2018 
Final Version 5.0, incorporating Protocol Amendment 2 
27 Sep 2018 
Final Version 6.0, incorporating Protocol Amendment 3 
12 Jul 2019 
Final Version 7.0, incorporating Protocol Amendment 4 
09 Jan 2020 
Final Version 8.0, incorporating Protocol Amendment 5 
15 May 2020 
 


Protocol Number: PP06489 (POLAR-A) 
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CONFIDENTIAL 
PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
STATEMENT OF CONFIDENTIALITY 
The information contained in this protocol is confidential and is intended for the use of clinical Investigators. It is 
the property of PledPharma AB, or its subsidiaries and should not be copied by or distributed to persons not involved 
in the clinical investigation, unless such persons are bound by a confidentiality agreement with PledPharma AB, or 
its subsidiaries.  


Prt>lo~ol Number. 1'1'06489 (POLAR-A) 
15 May 2020 
SIGNATURE PAGE 
Pngc 3 of 109 
Vcrsi.)11 8.0 
Thi\ s1udy protocol wa~ s11bjcc1,d lo critical 1 ·vie,~. The mfo1 mauon ii contains is consistenl wilh the current 
risk/benefit evaluHIJOn of the investigational pt duct as well as wi1h 1hc moral, ethical and ~cicntific principles 
governing clinical research as set out in the Deel ra1io11 of Helsinki and the Inte111ational Council for Hannonisation 
(!CH) guidclin~s on Good Clinical Practict: (GC ). 
This protocol is approved by. 
CE:O & President 
N1ckl~s We~terholm 
PledPharma AB 
Chief Mrdical Officer 
Stefan CaJlsson 
PledPhmma AB 
CEO & President 
Yoshihiro Arai 
Solasia Pharma K.K. (Co-sponsor in Asia) 
Principal Biostatisticinn 
i\ nders Persson 
Binom,al Sweden AB 
Coordinnting Investigator 
Camilla Qvon11Jp, MD, PhD 
The Finsen Center Rig5hospitale1, 
Denmark 
Coordinating Investigator 
Kei Muro, MD 
Aichi Cancer Center Hospital, Japan 
Signature 
Signature 
Signa1ure 
Signature 
C' NFIDENTl,\L 
Pl ·rll'honna AB 
T/111 prvl()('O( J.11J bet n Wnllfn III WC<H'tlanre ll'ith cmrl'nl /( H-GCP g111de/111cs 
Ji. /lA<.,_'j , ~1.0 
Date 
Date 
Date 


Protocol Number: PP06489 (POLAR-A) 
15 May 2020 
SIGNATURE PAGE 
Page 3 of 109 
Version 8.0 
This study protocol was subjected to critical review. The information it contains is consistent with the current 
risk/benefit evaluation of the investigational product as well as with the moral, ethical and scientific principles 
governing clinical research as set out in the Declaration of Helsinki and the International Council for Harmonisation 
(ICH) guidelines on Good Clinical Practice (GCP). 
This protocol is approved by: 
CEO & President 
Nicklas Westerholm 
PledPhanna AB 
Chief Medical Officer 
Stefan Carlsson 
PledPharma AB 
CEO & President 
Yoshihiro Arai 
Solasia Pharma K.K. (Co-sponsor in Asia) 
Principal Biostatistician 
Anders Persson 
Binomial Sweden AB 
Coordinating Investigator 
Camilla Qvortrup, MD, PhD 
The Finsen Center - Rigshospitalet, 
Denmark 
Coordinating Investigator 
Kei Muro,MD 
Aichi Cancer Center Hospital, Japan 
Signature 
Signature 
Signature 
Signature 
G---~"~ 
Signature 
CONFIDENTIAL 
PledPhanna AB 
Date 
Date 
Date 
Date 
Zo-os- 2-0 
Date 
Date 
This protocol has been wriuen in accordance with current ICH-GCP guidelines 


Protocol Number: PP06489 (POLAR-A) 
15 May 2020 
SIGNATURE PAGE 
Page 3 of 109 
Version 8.0 
This study protocol was subjected to critical review. The information it contains is consistent with the current 
risk/benefit evaluation of the investigational product as well as with the moral, ethical and scientific principles 
governing clinical research as set out in the Declaration of Helsinki and the International Council for Harmonisation 
(ICH) guidelines on Good Clinical Practice (GCP). 
This protocol is approved by: 
CEO & President 
Nicklas Westerholm 
PledPharma AB 
Chief Medical Officer 
Stefan Carlsson 
PledPharma AB 
CEO & President 
Y oshihiro Arai 
Solasia Pharma K.K. (Co-sponsor in Asia) 
Principal Biostatistician 
Anders Persson 
Binomial Sweden AB 
Coordinating Investigator 
Camilla Qvortrup, MD, PhD 
The Finsen Center - Rigshospitalet, 
Denmark 
Coordinating Investigator 
KeiMuro,MD 
Aichi Cancer Center Hospital, Japan 
Signature 
Signature 
Signature 
Signature 
Signature 
0--~ 
Signature 
CONHDENTIAL 
PledPharrna AB 
This protocol ltos been written in occordance with current ICH-GCP guidelines 
Date 
Date 
Date 
Date 
Date 
~H~r .J-.o)/b 
2 Date 


Protocol Number: PP06489 (POLAR-A) 
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CONFIDENTIAL 
PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
CONTACT NAMES 
SPONSOR: 
Chief Medical Officer 
Stefan Carlsson 
PledPharma AB 
Grev Turegatan 11c 
SE 114 46 Stockholm 
Sweden 
Tel: +46 709 641 009 
 
Principal Biostatistician 
Anders Persson  
Binomial Sweden AB  
Magasinsgatan 8C 
434 37 Kungsbacka  
Sweden  
Tel: +46 707 867 666 
CO-SPONSOR IN 
ASIA 
CEO & President 
Yoshihiro Arai 
Solasia Pharma K.K. 
4F Sumitomo Fudosan, Shiba-Koen Tower 
2-11-1, Shiba-koen, Minato-ku 
Tokyo 105-0011 
Japan 
Tel: +81 3 5843 8048 
CONTRACT 
RESEARCH 
ORGANISATION: 
Global Project Manager 
Yuliia Gorban 
Covance 
Covance Poland 
Ul. Wspólna 47/49  
00-684 Warszawa  
Tel: +48 697000197 
CO-ORDINATING INVESTIGATORS: 
Camilla Qvortrup, MD, PhD 
The Finsen Center – Rigshospitalet 
Department of Oncology 
Blegdamsvej 9, Copenhagen, DK-2100 
Denmark 
Tel.: +45 35 455 909 
Kei Muro, MD 
Director and Chief Department of Clinical 
Oncology Outpatient Treatment Center,  
Aichi Cancer Center Hospital 
1-1 Kanokoden, Chikusa,  
Nagoya, Aichi 464-8681  
Japan 
Tel.: +81 52 762 6111 
SERIOUS ADVERSE EVENT CONTACT DETAILS: 
Covance Pharmacovigilance 
Email: GlobalSAEinbox@covance.com 
Fax: Europe 00 800 529 34043 
Fax: Taiwan (886) 800 529 34043 
Fax: South Korea: (82) 002 800 529 34043 
Fax: Hong Kong: (852) 001 800 529 34043 
Fax: Japan: IDC: (81) 0061010 800-529-34043 
 
    KDDI: (81) 001010 800-529-34043 
 
    NTT: (81) 0033010 800-529-34043 


Protocol Number: PP06489 (POLAR-A) 
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PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
This Protocol has been written in accordance with current ICH-GCP guidelines. 


Protocol Number: PP06489 (POLAR-A) 
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This protocol has been written in accordance with current ICH-GCP guidelines  
TABLE OF CONTENTS 
SIGNATURE PAGE 
3 
CONTACT NAMES 
4 
TABLE OF CONTENTS 
6 
1. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
9 
2. 
PROTOCOL SYNOPSIS 
11 
3. 
BACKGROUND INFORMATION 
21 
3.1 
COLORECTAL CANCER 
21 
3.2 
PERIPHERAL NEUROPATHY INDUCED BY OXALIPLATIN 
21 
3.3 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL PRODUCT(S) 
22 
3.4 
NON-CLINICAL FINDINGS 
23 
3.5 
CLINICAL FINDINGS 
24 
3.6 
POTENTIAL RISKS AND BENEFITS 
26 
3.7 
TREATMENT 
27 
3.8 
CONDUCT OF STUDY 
27 
3.9 
POPULATION 
28 
4. 
STUDY OBJECTIVES AND PURPOSE 
29 
4.1 
OBJECTIVES 
29 
4.1.1 
Primary Objective 
29 
4.1.2 
Secondary Objectives 
29 
4.1.3 
Exploratory Objectives 
29 
4.2 
RATIONALE 
29 
5. 
INVESTIGATIONAL PLAN 
31 
5.1 
ENDPOINTS 
31 
5.1.1 
Primary Endpoint 
31 
5.1.2 
Secondary Endpoints 
31 
5.1.3 
Exploratory Endpoints 
31 
5.2 
OVERALL STUDY DESIGN AND PLAN 
32 
5.2.1 
Study Procedures 
34 
5.3 
RANDOMIZATION AND BLINDING 
39 
5.3.1 
Randomization 
39 
5.3.2 
Blinding 
40 
5.4 
STUDY TREATMENTS 
40 
5.4.1 
Identity of Investigational Medicinal Product 
40 
5.4.2 
Packaging 
40 
5.4.3 
Labelling 
40 
5.4.4 
Storage 
40 
5.4.5 
Destruction of IMP 
41 
5.4.6 
Background Therapy 
41 
5.5 
DURATION OF STUDY PARTICIPATION 
41 
5.6 
DISCONTINUATION CRITERIA 
41 
5.7 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
41 
5.8 
CODE BREAKS 
42 
5.9 
SOURCE DATA 
42 


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5.10 
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF CONTROL GROUPS 
42 
6. 
SELECTION AND WITHDRAWAL OF PATIENTS 
44 
6.1 
PATIENT INCLUSION CRITERIA 
44 
6.2 
PATIENT EXCLUSION CRITERIA 
44 
6.3 
PATIENT WITHDRAWAL CRITERIA 
45 
6.3.1 
Removal of Patients from Therapy or Assessment 
45 
6.3.2 
Pregnancy 
46 
6.4 
PREMATURE TERMINATION OF STUDY IN A STUDY CENTER 
47 
6.5 
TERMINATION OF STUDY 
48 
6.6 
FURTHER TREATMENT AFTER THE END OF THE TREATMENT PHASE 
48 
7. 
TREATMENT OF PATIENTS 
49 
7.1 
TREATMENTS ADMINISTERED 
49 
7.1.1 
Investigational Product 
49 
7.1.2 
Control Product 
49 
7.1.3 
Background Therapy 
49 
7.2 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUPS 
49 
7.3 
SELECTION OF DOSES IN THE STUDY 
49 
7.4 
SELECTION AND TIMING OF DOSE FOR EACH PATIENT 
50 
7.4.1 
PledOx/Placebo Administration 
50 
7.4.2 
Chemotherapy (mFOLFOX6) Administration 
51 
7.5 
DOSE ADJUSTMENT CRITERIA 
52 
7.5.1 
Treatment Requirements and Delays 
52 
7.5.2 
Chemotherapy Related Adverse Events and Dose Modification 
53 
7.6 
CONCOMITANT MEDICATION 
55 
7.7 
ASSESSMENT OF COMPLIANCE 
55 
8. 
ASSESSMENT OF EFFICACY 
57 
8.1 
EFFICACY PARAMETERS 
57 
8.1.1 
Primary Efficacy Variable 
57 
8.1.2 
Secondary Efficacy Variables 
57 
9. 
ASSESSMENT OF SAFETY 
60 
9.1 
SAFETY PARAMETERS 
60 
9.1.1 
Adverse Events 
60 
9.1.2 
Laboratory Evaluation 
65 
9.1.3 
Other Study Specific Parameters 
67 
9.2 
APPROPRIATENESS OF MEASUREMENTS 
69 
10. 
STATISTICS 
71 
10.1 
STATISTICAL METHODS 
71 
10.1.1 
Analysis Populations 
71 
10.1.2 
General Considerations 
71 
10.1.3 
Statistical Hypothesis 
72 
10.1.4 
Primary Efficacy Endpoint Analysis 
72 
10.1.5 
Secondary Endpoint Analyses 
72 
10.1.6 
Extent of Exposure 
73 
10.1.7 
Safety Analysis 
73 


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10.1.8 
Interim Analysis 
74 
10.2 
SAMPLE SIZE 
74 
10.3 
LEVEL OF SIGNIFICANCE 
74 
10.4 
CRITERIA FOR THE TERMINATION OF THE STUDY 
75 
10.5 
PROCEDURE FOR ACCOUNTING FOR MISSING, UNUSED AND SPURIOUS DATA 
75 
10.6 
DEVIATIONS FROM THE ORIGINAL STATISTICAL PLAN 
75 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
76 
11.1 
SOURCE DATA 
76 
11.2 
SOURCE DOCUMENTS 
76 
11.3 
DIRECT ACCESS 
76 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
77 
12.1 
QUALITY CONTROL 
77 
12.2 
QUALITY ASSURANCE 
77 
12.2.1 
Inspection 
77 
12.2.2 
Audit 
77 
13. 
ETHICS 
78 
13.1 
ETHICAL CONDUCT OF THE STUDY 
78 
13.2 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE APPROVAL 
78 
13.3 
INFORMED CONSENT 
78 
13.4 
MODIFICATION OF PROTOCOL 
79 
14. 
DATA HANDLING AND RECORD KEEPING 
80 
14.1 
COMPLETION OF ELECTRONIC CASE REPORT FORMS 
80 
14.2 
ARCHIVING 
80 
15. 
FINANCING AND INSURANCE 
81 
16. 
PUBLICATION POLICY 
82 
17. 
COVANCE SPECIFIC ADMINISTRATIVE PROCEDURES 
83 
17.1 
STUDY PERSONNEL 
83 
17.2 
STUDY MONITORING 
83 
17.2.1 
Review of Case Report Forms 
83 
17.3 
PRE-STUDY DOCUMENTATION REQUIREMENTS 
83 
18. 
REFERENCES 
84 
19. 
APPENDICES 
88 
 
 


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1. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
5-FU 
5-fluorouracil 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase  
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
β-HCG 
β-human choriongonadotropin 
CEA 
Carcinoembryonic antigen 
CI 
Confidence interval 
CIPN 
Chemotherapy induced peripheral neuropathy 
(m)CRC 
(metastatic) Colorectal cancer 
(N)CS  
(Not) Clinically significant 
CSR 
Clinical study report 
CT 
Computer tomography 
DFS 
Disease free survival 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EOS 
End of study 
EOT 
End of treatment 
EQ-5D-5L 
EuroQol – 5 Dimensions – 5 Levels 
FDA 
Food and Drug Administration 
FA 
Folinic acid 
FAS 
Full analysis set 
FACT/GOG-NTX-13 
Functional Assessment of Cancer Therapy/Gynecologic Oncology 
Group-Neurotoxicity-13-item subscale 
FSH 
Follicle stimulating hormone 
GCP 
Good clinical practice 
G-CSF 
Granulocyte-colony stimulating factor 
IB 
Investigator’s brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
IRB 
Institutional review board 


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i.v. 
Intravenous 
mFOLFOX6 
Modified FA + 5-FU + oxaliplatin chemotherapy regimen 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mn 
Manganese 
MnDPDP 
Mangafodipir 
MnSOD 
Manganese superoxide dismutase 
MRI 
Magnetic resonance imaging 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NOAEL 
No-observed-adverse-effect-level 
NRS 
Numerical rating scale 
OR 
Odds ratio 
PPS 
Per protocol set 
QA 
Quality assurance 
QoL 
Quality of life 
RBC 
Red blood cell (count) 
SADR 
Serious adverse drug reaction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SmPC 
Summary of Product Characteristics 
SOP 
Standard operating procedure 
SSC 
Study Steering Committee 
ULN 
Upper limit of normal 
WBC 
White blood cell (count) 
WOCBP 
Women of child-bearing potential 


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This protocol has been written in accordance with current ICH-GCP guidelines  
2. PROTOCOL SYNOPSIS 
Title (Full) 
A Phase 3, double-blind, multicenter, placebo-controlled study of 
PledOx used on top of modified FOLFOX6 (5-FU/FA and 
Oxaliplatin) to prevent chemotherapy induced peripheral neuropathy 
(CIPN) in the adjuvant treatment of patients with Stage III or high-risk 
Stage II colorectal cancer 
Title (Short) 
Preventive treatment of OxaLiplatin induced peripherAl neuRopathy 
in Adjuvant colorectal cancer (POLAR-A) 
Protocol Number 
PP06489 
IND Number 
Not applicable 
EudraCT Number 
2017‐004707‐43 
Investigational Product 
PledOx 
Co-ordinating 
Investigator: 
Camilla Qvortrup, MD, PhD 
The Finsen Center – Rigshospitalet, Department of Oncology 
Blegdamsvej 9 
Copenhagen, DK-2100 
Denmark 
 
Kei Muro, MD 
Director and Chief Department of Clinical Oncology Outpatient 
Treatment Center, Aichi Cancer Center Hospital 
1-1 Kanokoden, Chikusa,  
Nagoya, Aichi 464-8681  
Japan 
Number of Sites and 
Countries 
Approximately 95 centers in Europe and Asia  
Phase 
Phase 3 
Indication 
Prevention of chemotherapy induced peripheral neuropathy (CIPN) 
Study Design 
This is a Phase 3, multicenter, double-blind, placebo-controlled study 
with PledOx for prevention of chronic CIPN induced by oxaliplatin in 
patients with Stage III or high-risk Stage II colorectal cancer (CRC).  
Patients with CRC, who are indicated for adjuvant modified 
FOLFOX6 (mFOLFOX6) chemotherapy for up to 6 months, will be 
randomized in a 1:1 ratio to 1 of 2 treatment arms: 
• Arm A: PledOx (5 µmol/kg) + mFOLFOX6 chemotherapy  
• Arm B: Placebo + mFOLFOX6 chemotherapy 
Before March 2nd., 2020, the investigational medicinal product (IMP; 
i.e. PledOx or placebo) was administered by an intravenous (i.v.) 
infusion on the first day of each chemotherapy cycle. IMP was not to 
be administered if mFOLFOX6 was not given to the patient. 
If a patient discontinues oxaliplatin, treatment with 5-FU/folinate may 
be continued. 


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This protocol has been written in accordance with current ICH-GCP guidelines  
As of March 2nd., all patients have to stop IMP but may continue 
mFOLFOX6.  
Primary Objective 
To compare PledOx (5 µmol/kg) vs placebo with respect to the 
proportion of patients with moderate or severe chronic CIPN. 
Secondary Objectives 
To compare PledOx vs placebo regarding the following: 
Efficacy 
• The proportion of patients with mild, moderate or severe chronic 
CIPN 
• The sensitivity to touching cold items 
• The cumulative dose of oxaliplatin during chemotherapy 
• The vibration sensitivity on the lateral malleolus 
• The worst pain in hands or feet 
• The functional impairment (in the non-dominant hand) 
• The sustained efficacy on prevention of CIPN during long-term 
follow-up 
Safety 
• Disease free survival (DFS) 
• Safety and tolerability 
Exploratory Objectives 
To compare PledOx vs placebo regarding the following: 
• Chronic CIPN by supporting analysis using the full 
FACT/GOG-NTX-13 
• The cumulative dose of 5-FU during chemotherapy 
• For both oxaliplatin and 5-FU: Dose intensity, number of cycles, 
dose reductions, reason(s) for dose reductions, patients with dose 
delays, and length of dose delays 
• The functional impairment (in the non-dominant hand) during 
long-term follow-up 
• The worst pain in hands or feet during long-term follow-up. 
• Quality of life (QoL)/health status 
• Health economic impact 
Study Duration 
Enrolment period: 16 months 
First patient in: October 2018 
Last patient in: March 2nd., 2020 
Treatment Phase: at least 12 weeks (3 months) up to 24 weeks 
(6 months) 
Follow-up Phase: 24 months after first dose of IMP 
Total study duration (from first dose of IMP to the End of Study): 
24 months 
A data cut-off implementation date is estimated by 30 September 
2020. 
Principal Selection 
Criteria 
Inclusion criteria 
1. 
Signed informed consent form before any study related 
assessments and willing to follow all study procedures. 
2. 
Male or female aged ≥18 years. 


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3. 
Pathologically confirmed adenocarcinoma of the colon or rectum 
including: Stage III carcinoma (any T N1,2 M0) or Stage II 
carcinoma (T3,4 N0 M0). 
4. 
The patient has undergone curative (R0) surgical resection 
performed within 12 weeks prior to randomization  
5. 
The patient has a postsurgical carcinoembryonic antigen (CEA) 
level ≤1.5 x upper limit of normal (ULN, in current smokers, 
CEA level ≤2.0 x ULN is allowed). 
6. 
No prior anti-cancer therapy for CRC except radiotherapy or 
concomitant chemo-radiotherapy using a fluoropyrimidine alone 
for locoregional rectal cancer. 
7. 
Patient indicated for up to 6 months of oxaliplatin-based 
chemotherapy and without pathological findings of a neurologic 
exam performed prior to oxaliplatin treatment according to local 
practice.  
8. 
Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 or 1. 
9. 
Adequate hematological parameters: hemoglobin ≥100 g/L, 
absolute neutrophil count ≥1.5 x 109/L, platelets ≥100 x 109/L. 
10. Adequate renal function: creatinine clearance >50 cc/min using 
the Cockcroft and Gault formula or measured. 
11. Adequate hepatic function: total bilirubin ≤1.5 x ULN (except in 
the case of known Gilbert’s syndrome); aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT) 
≤3 x ULN. 
12. Baseline blood manganese (Mn) level <2.0 x ULN. 
13. For patients with a history of diabetes mellitus, HbA1c ≤7%. 
14. Negative pregnancy test for women of child-bearing potential 
(WOCBP). 
15. For men and WOCBP, use of adequate contraception (oral 
contraceptives, intrauterine device or surgically sterile) while on 
study drug and for at least 6 months after completion of study 
therapy. 
Exclusion criteria 
1. 
Any evidence of metastatic disease.  
2. 
Any unresolved toxicity by National Cancer Institute-Common 
Terminology Criteria for Adverse Events Version (NCI-CTCAE) 
v.4.03 >Grade 1 from previous anti-cancer therapy (including 
radiotherapy), except alopecia. 
3. 
Any grade of neuropathy from any cause. 
4. 
Any evidence of severe or uncontrolled systemic diseases 
(e.g., unstable or uncompensated respiratory, cardiac, unresolved 
bowel obstruction, hepatic or renal disease). 
5. 
Chronic infection or uncontrolled serious illness causing 
immunodeficiency. Patients with known history of chronic 
hepatitis B can be enrolled if they are asymptomatic and an acute 
and active HBV infection can be excluded. 
6. 
Any history of seizures 
7. 
A surgical incision that is not healed. 
8. 
Known hypersensitivity to any of the components of 
mFOLFOX6 and, if applicable, therapies to be used in 


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PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
conjunction with the chemotherapy regimen or any of the 
excipients of these products. 
9. 
History of other malignancies (except for adequately treated 
basal or squamous cell carcinoma or carcinoma in situ) within 
5 years, unless the patient has been disease free for that other 
malignancy for at least 2 years. 
10. Known dihydropyrimidine dehydrogenase deficiency. 
11. Pre-existing neurodegenerative disease (e.g., Parkinson’s, 
Alzheimer’s, Huntington’s) or neuromuscular disorder 
(e.g., multiple sclerosis, amyotrophic lateral sclerosis, polio, 
hereditary neuromuscular disease). 
12. Major psychiatric disorder (major depression, psychosis), alcohol 
and/or drug abuse. 
13. Patients with a history of second or third degree atrioventricular 
block or a family heredity. 
14. A history of a genetic or familial neuropathy. 
15. Treatment with any investigational drug within 30 days prior to 
randomization. 
16. Pregnancy, lactation or reluctance to using contraception.  
17. Any other condition that, in the opinion of the Investigator, 
places the patient at undue risk. 
18. Previous exposure to mangafodipir or calmangafodipir. 
19. Welders, mine workers or other workers in occupations (current 
or past) where high Mn exposure is likely. 
Study Drug  
 
 
Formulation, dosage, 
 
administration 
PledOx (calmangafodipir, 50 mM i.v. solution) given as a single dose 
infused over approximately 10 minutes, 15 minutes prior to each 
mFOLFOX6 cycle. 
PledOx 5 μmol/kg i.v. dosed every 2 weeks and administered with 
mFOLFOX6 (Arm A).   
Reference Therapy  
 
 
Formulation, dosage, 
 
administration 
Placebo (0.9% NaCl), given as a single dose infused over 
approximately 10 minutes, 15 minutes prior to each mFOLFOX6 cycle 
(Arm B). 
Background Anti-tumor 
Therapy (Chemotherapy) 
 
 
Formulation, dosage, 
 
administration 
mFOLFOX6 (calcium-folinate or calcium-levofolinate, 5-FU and 
oxaliplatin) will be administered in 2-week cycles (Arms A and B) 
according to approved Summary of Product Characteristics. 
Visit Schedule 
There will be 2 types of study visits. 
Before March 2nd., 2020, at Treatment Visits, the patient received 
IMP on the first day of each mFOLFOX6 cycle. As of March 2nd, 
2020, treatment visits will be done for patients receiving mFOLFOX6 
on the first day of each cycle, without IMP, until Cycle 12.  
Assessment Visits will be performed every 3 months from the first 
dose of IMP, for up to 12 months, thereafter every 6 months, for up to 
24 months.  


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This protocol has been written in accordance with current ICH-GCP guidelines  
For further details see the Schedule of Assessments at the end of the 
synopsis and in Appendix 1. 
Criteria for Evaluation 
Primary Endpoint 
• Proportion of patients (with moderate or severe chronic CIPN) 
scoring 3 or 4 in at least 1 of the first 4 items of the 
FACT/GOG-NTX-13 (i.e., FACT/GOG-NTX-4), targeting 
numbness, tingling or discomfort in hands and/or feet, 9 months 
after the first dose of IMP (i.e. PledOx or placebo administered on 
Day 1, Cycle 1 of mFOLFOX6 chemotherapy). 
Secondary Endpoints 
Efficacy 
• Proportion of patients (with mild, moderate or severe chronic 
CIPN) scoring 2, 3, or 4, in at least 1 of the first 4 items of the 
FACT/GOG-NTX-13 (i.e. FACT/GOG-NTX-4), targeting 
numbness, tingling or discomfort in hands and/or feet, 9 months 
after the first dose of IMP 
• Mean change from baseline in sensitivity to touching cold items on 
Day 2, Cycle 4 of mFOLFOX6 chemotherapy, as assessed by the 
Cold Sensitivity questionnaire 
• Mean cumulative dose of oxaliplatin administered per patient 
during mFOLFOX6 chemotherapy, 9 months after the first dose of 
IMP 
• Mean change from baseline in vibration sense, on the lateral 
malleolus (left and right), using a graduated tuning fork, at 
9 months after the first dose of IMP 
• Mean change from baseline in worst pain in hands or feet in the 
past week, using a numerical rating scale (NRS), at 9 months after 
the first dose of IMP 
• Mean change from baseline in the time to complete the grooved 
Pegboard with the non-dominant hand, at 9 months after the first 
dose of IMP 
• Proportion of patients scoring 3 or 4 in at least 1 of the first 4 items 
of the FACT/GOG-NTX-13 (i.e. FACT/GOG-NTX-4), targeting 
numbness, tingling or discomfort in hands and/or feet, 12, 18, and 
24 months after the first dose of IMP 
Safety 
• DFS at 12 and 24 months 
• Safety and tolerability as assessed by adverse events (AEs), 
laboratory variables and vital signs 
• Proportion of patients with PledOx toxicities in addition to 
chemotherapy-related toxicities graded using the NCI-CTCAE 
v4.03 
Exploratory Endpoints 
• Proportion of patients with any CIPN scoring 1, 2, 3 or 4, in any of 
the first 4 items of the FACT/GOG-NTX-13 (i.e. 
FACT/GOG-NTX-4), targeting numbness, tingling or discomfort 
in hands and/or feet, at all other timepoints after the first dose of 
IMP 


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This protocol has been written in accordance with current ICH-GCP guidelines  
• Mean score of the first 4 items of the FACT/GOG-NTX-13 
(i.e. FACT/GOG-NTX-4), at 9 months after the first dose of IMP 
• Mean score of the 13 items of the FACT/GOG-NTX-13, at 
9 months after the first dose of IMP 
• Mean cumulative dose of 5-FU administered per patient during 
mFOLFOX6 chemotherapy, 9 months after the first dose of IMP 
• For both oxaliplatin and 5-FU: Dose intensity, mean number of 
cycles per patient, proportion of patients with any dose reduction, 
reason(s) for dose reductions, proportion of patients with any dose 
delay, and mean duration of dose delay 
• Mean health index and mean visual analogue scale (VAS) score, 
using the EQ-5D-5L, at 9, 12, 18, and 24 months after the first 
dose of IMP 
• Mean health index, using the FACT/GOG, at 9, 12, 18, and 
24 months after the first dose of IMP 
• Mean time to complete the grooved Pegboard, with the 
non-dominant hand, at 12, 18, and 24 months after the first dose of 
IMP 
• Mean change from baseline in worst pain in hands or feet in the 
past week, using a NRS, at 12, 18, and 24 months after the first 
dose of IMP 
• The proportion of patients with a 2-point, 3-point and 4-point 
increase in worst pain in hands or feet in the past week, using a 
NRS, at 9, 12, 18, and 24 months after the first dose of IMP 
• Health economic impact, measured by the combined impact of 
medical resource utilization (hospitalizations, outpatient visits, 
medical procedures and medical use), patient impact (AEs, fall 
accidents, functional loss) and indirect societal costs (loss of 
ability to work) at 6, 12, 18 and 24 months after the first dose of 
IMP 
An independent Data Safety Monitoring Board (DSMB) will monitor 
accumulating safety, efficacy and other types of data throughout the 
study. 
Study Populations 
Four analysis populations will be defined: 
• All patients randomized will be included in the All Randomized 
Patients population, according to their randomized treatment 
• The intention to treat principle is used to define the primary 
analysis population, the Full Analysis Set (FAS), which will 
consist of all randomized patients who receive at least 1 dose of 
IMP 
• The Per Protocol Set is defined as a subset of the FAS constituted 
by patients who: (a) meet all inclusion/exclusion criteria liable to 
affect the efficacy assessment, and (b) do not present any major 
protocol deviations 
• The Safety Analysis Set will consist of all patients included in the 
study and treated with at least 1 dose of IMP 
Statistical Methods  
Following the premature study hold, the power of the study has been 
affected as a results of the premature stop of IMP dosing in individual 
patients.  
For that reason the statistical analyses will be done on the combined 


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This protocol has been written in accordance with current ICH-GCP guidelines  
dataset of the POLAR-A and POLAR-M study, with data from 
POLAR-A and POLAR-M cohorts being evaluated as separate strata. 
For the details of the combined and stratified analyses, please refer to 
the SAP. 
Below the Statistical Methods can be found as originally described. 
The primary endpoint will be analyzed only once when patients have 
completed and reached 12 months. Analysis of primary endpoint, 
major secondary endpoints and current safety data will be performed 
after all patients have completed treatment and reached 12 and 
24 months after first dose of IMP. In addition, survival data will be 
analyzed after 24 months. Final evaluation and analysis of study data 
will be performed after all patients have completed the study. 
The active arm will be statistically tested against placebo. For the test 
the statistical hypothesis is:  
H0: PledOx treatment arm is equal to placebo with respect to the 
primary efficacy endpoint. 
H1: PledOx treatment arm is not equal to placebo with respect to the 
primary efficacy endpoint. 
For the primary endpoint, the Cochran-Mantel-Haenszel test will test 
the following two-sided hypothesis:  
H0: Ψ=1 versus H1: Ψ≠1 
where Ψ defines the common odds ratio (OR) of PledOx to placebo 
across all strata. An OR<1 favors the PledOx group. 
The overall type I family-wise error rate for testing the primary and 
the main secondary efficacy endpoints will be controlled at the 0.05 
significance level using a multiple comparison procedure. All 
hypothesis tests will be two-sided. 
The primary endpoint will be presented descriptively (n, %) together 
with its corresponding 95% confidence interval (CI) based on the 
Wilson-score method and will be presented for both treatment groups. 
The Cochran-Mantel-Haenszel test will be performed as an analysis 
using the baseline score of FACT/GOG (2 levels), treatment and 
region. 
The OR, 95% CI and p-value using the Cochran-Mantel-Haenszel test 
for the difference in event rates between the 2 treatment groups will be 
presented. The results from the Cochran-Mantel-Haenszel test are 
considered the primary analysis results using the FAS. 
Other secondary endpoints will be using two-sided hypothesis testing 
and details will be presented in the Statistical Analysis Plan. All tests 
will be two-sided and a pre-defined hierarchical family wise test order 
will be used to control the 0.05 type-I error rate. 
Sample Size 
Assumptions with regards to the revised samples size following the 
premature hold of the study are described in the final SAP. 
With 112 patients per group, the POLAR-A study has 91% power to 
detect a reduction (improvement) from 40% to 20% (OR = 0.375) in 
the primary endpoint using two-sided test controlled at the 0.05 type-I 
error rate. To account for 20% dropout in the study, in total 280 
patients (140 patients per arm) will be randomized. 


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This protocol has been written in accordance with current ICH-GCP guidelines  
Sample size assumptions will be monitored in a blinded fashion as part 
of the regular monitoring of the study. In case there are indications 
these are not met; a re-estimation of the sample size may occur. 
 


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This protocol has been written in accordance with current ICH-GCP guidelines  
Schedule of Assessments (short version) 
 
EOT13
D 14 of last 
cycle +/- 3 days
Visits in Month
M3
M611 M9 M12 M18
M24
Visit in Days per Cycle
D-28 D-14 D-7
D0
D1C1D1C2D1C3D1C4D1C5D1C6D1C7
D1C8D1C9D1C10D1C11D1C12
D14C12
EOS
Visits in Weeks
W-4
W-1
not a 
visit
W0
W2
W4
W6
W8 W10 W12
W14 W16 W18
W20
W22
W24
Informed Consent
x
Demography, Prior Medication (including D-30 medication)
x
Medical History
x
Screening ECG (QTc)
x
Inclusion/Exclusion Criteria, Randomization6
x
CT/MRI scan and Disease assessment1
x
x
x
Disease Free Survival
x
x
x
x
x
x
CarcinoEmbryonic Ag (CEA)
x
x
x
x
Vital signs (T°, pulse rate, BP) and weight (except after EOT)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Pregnancy test (serum)2
x
results
x
x
x
x
x
x
x
Hematology3
x
results
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Biochemistry4
x
results
x
x
x
x
x
x
x
Manganese blood sample5
x
results
x
x
x
x 
ECOG Performance Status
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Grooved PEG-board & Vibration Sensitivity Testing
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
FACT/GOG-NTX-137
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Pain Numeric Rating Scale (NRS)7
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
QoL (EQ-5D-5L)7 
x
x
x
x
x
x
x
x
x
x
x
Cold Sensitivity Diary (pre-dose, post dose of D1 + D2 and D3)
x
x
x
x
PledOx/Placebo Infusion (before mFOLFOX)8
x
x
x
x
x
x
x
x
x
x
x
x
Physical examination
x
x
x
x
x
x
x
x
Brain MRI and Blood Mn incl. neurological exam 10
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
Concomitant Medication9 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse Events9 
x
x
x
x
x
x
x
x
x
x
x
x
x
Health Economics Impact12
x
x
x
x
x
POLAR-A
+/- 2 days
SELECTION PHASE
TREATMENT PHASE 
FOLLOW-UP PHASE14
 +/- 1 week


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CONFIDENTIAL 
PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
AE = adverse event; BP = blood pressure; CEA = Carcinoembryonic antigen; CT = computed tomography; D = day; DFS = disease free survival; ECG = electrocardiogram; ECOG = Eastern 
Cooperative Oncology Group; EoS = end of study; EoT = end of treatment; FACT/GOG-NTX-13 = Functional Assessment of Cancer Therapy/Gynecologic Oncology 
Group-Neurotoxicity-13-item subscale; M = month; Mn = manganese; MRI = magnetic resonance imaging; NRS = numeric rating scale; QoL = quality of life; T = temperature; W = week 
1 
CT-scan or MRI, but the same assessment should be performed throughout the study for each patient. For screening, results from a scan performed within 42 days prior to surgery or after 
surgery are allowed. Tumors will be analyzed and records will be evaluated locally. 
2 
WOCBP must give a negative serum pregnancy test at screening and then every 4 weeks while patient is on IMP treatment 
3 
Hematology (every Treatment Visit): WBC count differential, ANC, RBC count, platelet count, and hemoglobin. Analyzed by a local hospital laboratory. 
4 
Biochemistry (every 4 weeks or every 2nd Treatment Visit): ALP, total bilirubin, ALT, AST, serum creatinine, and albumin. Analyzed by a local hospital laboratory. 
5 
Blood Mn (full blood): Collected at Day -28 Visit, Treatment Visit 4, 8, 12 and EOT. A patient can be enrolled without the result of Mn level analysis before the randomization, but the 
result should be confirmed prior to Cycle 1 Day 1. Mn samples will also be taken whenever Parkinson-like symptoms occur. Analyzed by a central laboratory. 
As of March 2nd., 2020, no more Blood Mn samples will be taken with the exception for patients with Parkison-like symptoms. 
6 
Randomization (within 3 days prior to Cycle 1 Day 1)– this is not a patient visit. This is the moment when the Investigator will confirm that a patient complies with all inclusion/exclusion 
criteria and the patient will be randomized into a treatment arm using the electronic randomization system within the eCRF. The Investigator will then request the unblinded pharmacist/designee 
to prepare the study treatment according to the randomization schedule available only to the unblinded hospital staff. 
7 
Questionnaire to be completed by the patient in the hospital.  
During the COVID-19 pandemic, remote data collection via either phone call or mailing of paper copies of rating scales for completion at home may be implemented. 
8 
IMP (PledOx or placebo) will be administered before the background chemotherapy (mFOLFOX6). Study treatment will be stopped in case of mFOLFOX6 treatment discontinuation, 
disease progression, intolerable toxicity or withdrawal of consent. 
As of March 2nd., 2020, the IMP administration is stopped in ongoing patients and no new patients are included in the study.  
9 
All AEs including SAEs and concomitant medications will be collected up to 30 days after the last administration of IMP. AEs will be followed until resolution. 
As of March 2nd., 2020, all AEs including SAEs and concomitant medications will be collected up to 30 days after the EOT visit and followed until resolution.  
10 In patients who develop Parkinson-like symptoms, a neurological examination and a brain MRI will be performed and an additional blood Mn sample will be analyzed. A brain MRI should 
also be performed if elevated Mn is found during the scheduled Mn samples.  
11 If the patient continues with the study treatment until Treatment Visit 12 (Week 22), the relevant Treatment Visit or the End of Treatment Visit will be combined with the Assessment visit at 
Month 6. The Assessment visit at Month 6 will be performed as a separate visit only if a patient stops study treatment prior to Treatment Visit 12 (Week 22).  
As of March 2nd., 2020, if the patient continues with mFOLFOX6 without IMP until Treatment Visit 12 (Week 22), the relevant Treatment Visit or the End of Treatment Visit will be 
combined with the Assessment Visit at Month 6. The Assessment Visit at Month 6 will be performed as a separate visit only if a patient stops mFOLFOX6 prior to Treatment Visit 12 
(Week 22) 
12 The Health Economic Impact Questionnaire will be completed by the Investigator or well-trained site staff. During the COVID-19 pandemic the Health Economic Impact Questionnaire can 
be done via phone or by mailing paper copies for completion at home if a site visit is not possible and. 
13 At time of estimated data cut-off date by 30 September 2020, all patients who are still in the Treatment Phase have an EOT visit on Day 14 ± 3 days of the last cycle with mFOLFOX6 before 
the data cut-off date. 
14 During the COVID-19 pandemic, a visit window of ± 6 weeks is allowed during the Follow-up Phase. 
 


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This protocol has been written in accordance with current ICH-GCP guidelines  
3. BACKGROUND INFORMATION 
3.1 COLORECTAL CANCER 
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and is the third leading 
cause of cancer death (Siegel et al. 2017). Fundamentally CRC is a genetically and clinically 
heterogeneous disease. The evolving understanding of the molecular aberrations 
(e.g., microsatellite instability) and clinical factors (e.g., right-sided or left-sided localization 
of the primary tumor) is hoped to impact the therapeutic paradigm of the future 
(Boisen et al. 2013; Brule et al. 2015; Guinney et al. 2015; Moretto et al. 2016; 
Dienstmann et al. 2017; Tejpar et al. 2017).  
Fortunately, approximately 80% of the patients present with resectable disease that can be 
potentially cured with appropriate therapy. Adjuvant chemotherapy for Stage III CRC is now 
widely accepted as it decreases the relapse rate and improves disease free survival (DFS) 
compared to surgery alone. The benefit of adjuvant chemotherapy in Stage II is more limited 
and remains controversial, and, if used, it is generally reserved for tumors with high-risk 
features (McCleary et al. 2017). 
3.2 PERIPHERAL NEUROPATHY INDUCED BY OXALIPLATIN 
Oxaliplatin, a third-generation cisplatin analogue, is approved in combination with infusional 
5-FU/FA (5-fluorouracil/folinic acid; FOLFOX) for the treatment of metastatic as well as 
adjuvant as CRC (Alcindor et al. 2011). Despite its success, a number of key safety issues place 
limitations on the potential efficacy of this agent, particularly neurotoxicity.  
Oxaliplatin induces 2 distinct forms of chemotherapy-induced peripheral neuropathy (CIPN) 
that are thought to arise by different mechanisms (Weickhardt et al. 2011). The first is a very 
common and pathognomonic acute syndrome (Wilson et al. 2002) that is transient and appears 
during, or shortly after, exposure to oxaliplatin, and a dose-limiting chronic sensory 
neurotoxicity that is cumulative (Sereno et al. 2014).  
Acute peripheral neuropathy is observed in >90% of patients exposed to FOLFOX-4 
(Andre et al. 2004). It consists of sensory symptoms in the fingertips and toes in a “stocking 
and glove” distribution, which are classically triggered by exposure to cold. Perioral numbness, 
jaw spasms and muscle cramps can also be seen. Although acute symptoms can be disturbing 
for patients, this symptom complex is transient and usually (Lehky et al. 2004; 
Wilson et al. 2002) but not always (Pachman et al. 2015) reversible. The pathogenesis of acute 
oxaliplatin-induced neuropathy is thought to be due to a disturbance of axonal sodium channels 
by the oxalate salt of oxaliplatin (Adelsberger 2000; Gamelin et al. 2007). 
By contrast, oxaliplatin-induced chronic neurotoxicity is related to the cumulative dose of 
oxaliplatin administered over time and is not cold-triggered, and the pathogenesis is similar to 
the neuropathy caused by other platins (Weickhardt et al. 2011; Zimmerman et al. 2016, and 
references therein). It can be dose-limiting, and the symptoms may last for years and severely 
impact quality of life (QoL) (Driessen et al. 2012; Tofthagen et al. 2012). Symptoms include 
numbness and tingling, affects hands and feet, and includes burning and shooting pain 
symptoms. Sensory impairment of peripheral neural function can lead to impairment of 
activities of daily living, such as writing and buttoning. Physiologic and pathologic studies 
reveal chronic morphologic damage and reduced sensory conduction velocity. These changes 


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This protocol has been written in accordance with current ICH-GCP guidelines  
become apparent at greater cumulative doses of oxaliplatin, particularly above a cumulative 
dose of 410 mg/m2 (Loprinzi et al. 2014, and references therein). The symptoms may continue 
to worsen at higher doses. Specifically, the incidence of severe adverse events (AEs) is 
approximately 15% after a cumulative dose of 780 to 850 mg/m2 and 50% after a cumulative 
dose of 1170 mg/m2. Also, in what is referred to as the “coasting” phenomenon,” in 10-15% of 
patients the symptoms of peripheral sensory neurotoxicity emerge or worsen a period after the 
completion of oxaliplatin therapy (Andre et al. 2004; Loprinzi et al. 2014).  
The pathogenesis of chronic neurotoxicity may be due to mitochondrial dysfunction and 
deficient adenosine triphosphate production (Bennett et al. 2014, and references therein). 
Abnormally vacuolated mitochondria in peripheral nerve sensory axons can be seen in 
preclinical models after oxaliplatin exposure and induction of painful peripheral neuropathy 
(Zheng 2011). Axonal excitability studies also demonstrate ongoing and progressive changes 
in peripheral nerve function (Zheng et al. 2011). A preventative and therapeutic role for 
antioxidants has been demonstrated in some studies (Cascinu et al. 2002; Lin et al. 2006). After 
oxaliplatin induced painful neuropathy, peripheral nerves also contain significantly elevated 
levels of nitrated manganese superoxide dismutase (MnSOD), a key mitochondrion-specific 
antioxidant enzyme. As a result, MnSOD activity is greatly reduced. Treatment with a 
superoxide 
dismutase 
mimetic 
prevents 
and 
reverses 
both 
acute 
and 
chronic 
oxaliplatin-induced neuropathies as well as the mitochondrial deficit. The most compelling 
demonstration in clinic so far has been with the use of a MnSOD mimetic, mangafodipir 
(Coriat et al. 2014) and calmangafodipir (Glimelius et al. 2017). 
Taken together, despite some studies demonstrating amelioration of oxaliplatin-induced CIPN, 
it is generally accepted that no pharmacologic agent has shown definitively to prevent CIPN 
(Pachman et al. 2014). Although duloxetine, a nonopioid, has been shown to be effective in the 
amelioration of neuropathic pain, to date the clinical experience has not validated the data from 
the trial (Hershman et al. 2014; Loprinzi et al. 2014; Majithia et al. 2016).  
In the absence of effective pharmacologic interventions, a number of trials have examined the 
duration of oxaliplatin exposure and stop-and-go strategies in the metastatic setting in an 
attempt to reduce the incidence or severity of CIPN (Tournigand et al. 2006; 
Maindrault-Goebel et al. 2007).  
This strategy has also been evaluated in the adjuvant setting, and the most recent and complete 
development was the data from the IDEA collaboration (Shi et al. 2017), which described the 
combined experience from 6 large adjuvant trials and 12,834 patients. The trial evaluated the 
concept that 3 months of oxaliplatin-based chemotherapy is non-inferior to 6 months of therapy 
with regard to DFS but advantageous with regard to CIPN. The trial failed to meet its primary 
endpoint of demonstrating non-inferiority for the 3-month duration of therapy. However, 
additional analyses revealed 3 months of adjuvant chemotherapy with capecitabine and 
oxaliplatin-based regimen was noninferior to 6 months for patients with high-risk Stage II or 
Stage III colon or rectal cancer, but this secondary finding was not noted with FOLFOX. 
Therefore, although there may be clinical strategies to manage CIPN, overall CIPN remains an 
unmet medical need particularly with regard to any pharmacologic therapy. 
3.3 NAME AND DESCRIPTION OF THE INVESTIGATIONAL PRODUCT(S) 
PledOx® 


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PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
Details of PledOx mechanism of action, preclinical and available clinical data are described in 
the Investigator Brochure. 
PledOx (calmangafodipir; Ca4Mn(DPDP)5) mimics the activity of the MnSOD, and thereby 
helps to degrade reactive oxygen species and allows cells to survive oxidative stress. PledOx 
is a stabilized version of mangafodipir (MnDPDP), which was approved by the Food and Drug 
Administration (FDA) and European Health Authorities in 1997 for use in patients as a contrast 
agent for magnetic resonance imaging (MRI) of the liver and pancreas. Experience with 
mangafodipir as a contrast agent from more than 240,000 patients reveals a good safety and 
tolerability profile after a single administration. Mangafodipir marketing was later 
discontinued for commercial reasons (Karlsson et al. 2015). 
PledOx is a potentially more potent and safer form of mangafodipir. It has shown promising 
activities 
in 
model 
systems 
in 
preventing 
oxaliplatin-induced 
adverse 
effects 
(Karlsson et al. 2012). Mn2+ is dissociated from the complexed drug after administration of 
both mangafodipir and PledOx. Although Mn2+ is considered essential, chronic exposure to 
Mn2+ could cause Parkinson like symptoms resulting from its accumulation in the brain 
(Guilarte 2010). In PledOx, 4 of 5 of the Mn2+ ions present in mangafodipir are replaced by 
more readily displaceable calcium (Ca2+) ions, which stabilize the release of Mn2+ after 
administration resulting in a doubling of the renal excretion of fodipir bound Mn2+ 
(Karlsson et al. 2012). As an improved version of mangafodipir, PledOx is considered to have 
a lower risk due to the lesser amounts of free Mn2+. In addition, at equivalent Mn2+ doses, 
PledOx was at least 10 times more potent than mangafodipir (Karlsson et al. 2012). 
3.4 NON-CLINICAL FINDINGS 
Results from pharmacology studies show that calmangafodipir protects BALB/c mice against 
the myelosuppressive effects of oxaliplatin and that the analogue mangafodipir effectively 
prevents the onset of locomotor and sensory disturbances as well as neuromuscular 
hyperexcitability in C57Bl/6 mice treated with oxaliplatin. Importantly, calmangafodipir does 
not interfere negatively with the antitumor activity of oxaliplatin; on the contrary, preclinical 
data suggest that it increases the antitumor efficacy in immune competent mice which might 
be an inherent property of DPDP or its dephosphorylated counterparts.  
The general toxicity program with calmangafodipir consists of pilot repeat dose studies of 
28 days duration in rats and dogs and clinical trial enabling 13-week studies in the same species 
as well as a 6 months study in rats and a 9 months study in dogs. The 28-day and 13-weeks 
studies used a dosage regimen of three injections per week rather than the once fortnightly 
regimen used in humans.  The 6 and 9 months studies used the clinical regimen of once every 
fortnight. 
Overall, the rat 13-week study revealed no toxicities of significant clinical concern in spite of 
single dose levels of calmangafodipir being up to 12-fold higher than the highest proposed 
clinical dose (5 µmol/kg) and 72-fold higher based on a fortnightly dose both calculated on a 
mg/m2 basis. Calmangafodipir-related findings were restricted to apparent weight reductions 
of the testes and epididymides in high dose animals and lower pituitary weights in all male 
treated animals and in high dose females. The good tolerability observed in the 13-week study 
was confirmed in the 6 months study where the no-observed-adverse-effect-level (NOAEL) 
was the highest dose investigated; 1440 µmol/kg (1066.6 mg/kg body weight). This NOAEL 
is 46-fold the clinical dose on a mg/m2 basis. Exposure measurement in terms of whole blood 


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PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
Mn levels as well as Cmax and AUC0-inf PLED give additional reassurance of good tolerability 
relative to the corresponding clinical exposures.    
The dog 13-week study also did not reveal any toxicities of significant clinical concern in spite 
of single dose levels of calmangafodipir being 34-fold higher than the highest clinical dose 
(5 μmol/kg) on a mg/m2 basis and 204-fold the cumulative dose over the clinical dosing interval 
of 14 days. The treatment could possibly have affected estrus cycling but owing to the low age 
of the animals the relationship of this to the treatment is uncertain. One high dose 
calmangafodipir animal showed testicular tubular atrophy. In addition to this, all animals 
showed various injections site reactions with a possibly higher incidence of hemorrhage in 
treated animals than in the controls, a finding of questionable clinical relevance in view of the 
absence of any calmangafodipir related injection site reactions in the 9 months dog study. This 
study showed vomiting and salivation in high dose animals of both sexes, lowered food 
consumption in high dose males and one early sacrifice of a high dose male owing to poor 
clinical condition. The NOAEL was the mid high dose, a dose being 33-fold higher than the 
clinical dose on a mg/m2 basis. Results from exposure measurement (whole blood Mn levels 
as well as Cmax and AUC0-inf PLED) relative to that in man, provide reassurance of good 
tolerability of calmangafodipir in the dog. 
Fertility studies in male rats and embryofetal development studies in rats and rabbits have been 
conducted with mangafodipir. Skeletal malformations were observed in the embryofetal 
development study in rats at the lowest dose investigated and embryofetal toxicity was 
observed in rabbits. Identical effects were seen after administration of equimolar MnCl2. It is 
the Sponsor’s opinion that mangafodipir and calmangafodipir should have a similar 
reproduction toxicity liability.  
Calmangafodipir was investigated for in vitro genotoxicity using the Ames Salmonella Assay 
and a micronucleus assay in human lymphocytes. No mutagenic activity was recorded. In the 
in vitro micronucleus assay with an extended 24 + 24 hour treatment at a cytotoxic dose 
(reduction in replication index of 66%), a weak induction of micronuclei was observed. The 
effect observed at such a high cytotoxic concentration is of questionable biological relevance. 
When the clastogenic activity of calmangafodipir was examined in a rat bone marrow 
micronucleus study in rats, no such activity was observed when after the administration of up 
to 2000 mg/kg (the regulatory maximum dose) on two consecutive days and bone marrow 
sampling 24 hours after the last dose. 
3.5 CLINICAL FINDINGS 
Oxaliplatin causes disabling acute and chronic peripheral neuropathy. We explored the 
preventive effects of calmangafodipir, mimicking the mitochondrial enzyme Mn superoxide 
dismutase, thereby protecting cells from oxidative stress, in a placebo-controlled, 
double-blinded randomized Phase 2 study (ClinicalTrials.gov, NCT01619423) in patients with 
metastatic colorectal cancer (mCRC). 
mCRC patients treated with mFOLFOX6 (FA 200 mg/m2, 5-FU bolus 400 mg/m2, oxaliplatin 
85 mg/m2 and 5-FU 2400 mg/m2 continuous infusion for 46 hours) every fortnight for 8 cycles 
in first or second line were eligible. Calmangafodipir was given in a Phase 1 dose-finding 
(Part 1) and in a Phase 2 placebo-controlled part of the study (Part 2 and 3), as a 5 minutes 
infusion, 10 minutes prior to oxaliplatin. Neurotoxicity was evaluated by the physician using 
the Oxaliplatin Sanofi Specific Scale and by the patient using the cold allodynia test (Ventzel 


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PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
cylinder [Ventzel et al. 2016]) and the Leonard scale (oxaliplatin-associated neuropathy 
questionnaire, OANQ [Leonard et al. 2005]).  
Eleven patients were included in Phase 1 without any detectable toxicity to calmangafodipir. 
In the Phase 2 study, 173 patients were randomized to placebo (n=60), calmangafodipir 
2 µmol/kg (n=57) and calmangafodipir 5 µmol/kg (n=45, (part 2b) initially 10 µmol/kg, n=11 
(part 2a). Calmangafodipir-treated patients (all 3 doses pooled) had less physician graded 
neurotoxicity (odds ratio [OR] (90% confidence interval [CI] one-sided upper level) 0.615 
(1.159), p=0.158), less problems with cold allodynia and fewer sensory symptoms in the 
Leonard scale during treatment and during follow-up 3 and 6 months after last dose. Response 
rate, progression-free and overall survival did not differ among groups. 
Calmangafodipir at a dose of 5 µmol/kg appears to prevent the development of 
oxaliplatin-induced acute and delayed CIPN without apparent influence on tumor outcomes. 
SUNCIST a randomized, double-blind, placebo-controlled, ascending (2, 5 and 10 µmol/kg vs 
placebo, sequential enrolling cohort, single-dose study in healthy Japanese and Caucasian men, 
age 20 to 55 years, inclusive. 48 participants (24 Japanese and 24 Caucasian) were studied in 
two groups of three sequentially enrolling dose cohorts. Group 1 consisted of three cohorts of 
8 Japanese subjects each, and Group 2 consisted of 3 cohorts of 8 Caucasian subjects each. 
Calmangafodipir at doses up to 10 µmoL/kg was safe and well tolerated. Calmangafodipir 
exposure (AUC0-last and Cmax) was comparable for the Japanese and Caucasian subjects. 
AUC0-last and Cmax increased proportionately with increasing dose. 
In the adjuvant setting, the multicenter, international MOSAIC study was the first of several 
large trials to demonstrate a definitive role for oxaliplatin in the adjuvant setting 
(Andre et al. 2004, Andre et al. 2009). The study compared oxalipatin in combination with 
5-FU/FA (FOLFOX-4) with the same 5-FU/FA regimen alone in 2446 patients with Stage II 
and III CRC (40% of the patients had Stage II and 60% had Stage III disease). The combination 
of oxaliplatin with 5-FU/FA was associated with statistically significant advantages over 
5-FU/FA alone in terms of 3-year (72.2% versus 65.3%) and 4-year (69.7% versus 61%) 
survival rates in Stage III disease, but not in Stage II disease (3 years: 87.0% versus 84.3%; 4 
years: 85.1% versus 81.3%). In a final analysis, the 6-year survival rates in patients with Stage 
III disease were 72.9% for FOLFOX-4 and 68.3% for 5-FU/FA alone (hazard ratio [HR] 
= 0.80). Among patients with stage II disease, no difference was observed between treatment 
groups in terms of 6-year survival rate (86.8%, HR = 1.00). However, the safety analysis 
demonstrated a number of toxicities that were significantly increased with the addition of 
oxaliplatin, including Grade 3 and 4 neutropenia (41% versus 4.7%), diarrhea (10.8% versus 
6.6%), and allergic reactions (2.9% versus 0.2%). Paresthesia as a component of peripheral 
neuropathy was observed in 92% of patients in the FOLFOX-4 arm and in 15.6% of patients 
in the 5-FU/FA arm, while the frequencies of Grade 3 events in these arms were 12.4% and 
0.2%, respectively. 
Based on the results of this and subsequent large trials, FOLFOX or its variants containing 
oxaliplatin can be considered standard for the adjuvant therapy of patients with potentially 
curatively resected Stage III CRC. Moreover, 2- or 3-year DFS has also been shown to be 
highly predictive of overall survival at 5 and 6 years in Stage III patients (Sargent et al. 2011). 
Although not definitive, these data may not necessarily apply to selected high-risk Stage II 
patients; nevertheless, in many settings oxaliplatin is utilized for these patients. 


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PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
3.6 POTENTIAL RISKS AND BENEFITS 
Oxaliplatin-induced neuropathy is a serious condition with patients experiencing loss of QoL 
and the possibility of long-term neuropathic disabilities. Due to oxaliplatin-induced 
neuropathy, chemotherapy treatment may have to be reduced, postponed, or completely 
discontinued. This can lead to suboptimal treatment results and decreased survival in patients. 
There are currently no existing/available therapies for the prevention of oxaliplatin-induced 
neuropathy. Calcium and magnesium infusions and neuromodulatory agents have been used 
and tested for prevention, however these agents have not proven to be sufficiently effective to 
become standard preventative agents for acute and chronic neuropathy. 
The clinical evidence from the PLIANT (randomized controlled, Phase 2 study in patients with 
advanced or mCRC, n=173) provides evidence that PledOx can prevent CIPN during and after 
treatment with a commonly used oxaliplatin combination for patients with mCRC. 
PledOx has demonstrated substantial improvement on clinically significant endpoints of 
neuropathy. Most notably, patients receiving PledOx were less likely to experience a Grade 2 
or higher AE related to oxaliplatin-induced neuropathy in the PLIANT study. In addition, 
PledOx was shown to decrease patients’ hypersensitivity to cold. 
Overall, PledOx was very well tolerated. The frequency and severity of AEs for patients treated 
with PledOx was similar to patients treated with placebo. Additionally, the incidence of serious 
AEs (SAEs) was similar between the PledOx and placebo treated groups. There was only 
1 SAE related to PledOx (hypersensitivity reaction with the 10 µmol/kg dose).  
In conclusion, the CIPN effects are sufficiently strong and the lack of any indications of a tumor 
protective effect reassuring, motivating initiation of this Phase 3 study. 
There are currently 2 ongoing studies with the study drug PledOx, this study and another study 
POLAR-M (adjuvant CRC setting). In the POLAR-A and POLAR-M studies, up to 
19 December 2019, 125 SAEs were reported in patients treated with IMP. 
One patient in the POLAR-M study had a hyperkalemia, which was considered ‘Possibly 
Related’ to the IMP by the Investigator. 
Three patients in the POLAR-A program have been reported having had anaphylactoid 
reactions or allergic infusion reactions: 
• One patient had an anaphylactoid reaction to the IMP during infusion. The IMP was 
probably the causative factor of the event. 
• Two patients in the POLAR-A study had allergic infusion reactions/hypersensitivity; 
1 patient had 2 events, both deemed ‘Probably Related’ by the Investigator, and the 
other patient’s event was deemed as ‘Possibly Related’. 
As reported in these 3 patients, hypersensitivity reactions (urticaria and other possible allergic 
phenomena) or anaphylactoid reactions may occur, rarely. Familiarity with the practice and 
technique of resuscitation and treatment of anaphylaxis is essential. Appropriate medicinal 
products and instruments should be readily available (Roselló et al. 2017). 
Two patients who were treated with the IMP have been reported seizures. One patient in the 
POLAR-A study had a ‘tonic clonic seizure’ of unknown origin with a fatal outcome, which 
was considered ‘Possibly Related’ to the IMP. The other patient, in the POLAR-M Study, had 
a seizure that was reported 2 days after IMP infusion. The event was considered to be unrelated 
to the IMP. 


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CONFIDENTIAL 
PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
In a previous study sponsored by Pled Pharma, ‘The PP100-01 for Overdose of Paracetamol 
Trial (POP Trial)’, a female subject suffered from epilepsy and experienced 2 seizures, 2 days 
after treatment with N-Acetyl Cysteine and calmangafodipir after an overdose with 
paracetamol (acetoaminophen). The subject had missed 2 doses of anti-epileptic drug 
treatment, which was considered to be the causative factor of the seizures.The risk of 
Mn toxicity is low, precautions that further minimizes the risk that this will happen in 
individual patients are described in the protocol. They are among others that patients that 
develop Parkinson’s-like symptoms, will be evaluated for elevated blood Mn levels. 
 
On March 2nd., 2020, PledPharma and Solasia decided to put dosing and recruitment of 
patients in the POLAR-A study globally on hold, which was communicated to the study sites 
via a Dear Dr Letter dated March 2nd., 2020 and confirmed in a second DDL dated 
April 8th., 2020. 
This decision followed a clinical hold of the POLAR-M study in the US issued by the FDA 
on January 22nd., 2020, and a similar request to stop recruitment and dosing of patients in the 
POLAR-A and POLAR-M studies in France made by the French Authority, ANSM. 
Finally the Independent Data and Safety Monitoring Board (DSMB), following their review 
of unblinded safety data during their meeting in February and March 2020, recommended to 
stop both trials due to an accumulation of allergic reactions in the studies.  
At that time 591 patients out of the planned 700 patients had been randomized, and 
420 patients had completed more than 6 cycles of study drug treatment while 250 patients 
had completed more than 9 cycles. 
In order to allow for the benefit-risk analysis to be based on as many patients as possible 
reaching their 9 month visit, PledPharma and Solasia in their DDLs have requested to make 
all necessary efforts collecting key efficacy and safety data in the POLAR studies up to the 
estimated data cut-off date by 30 September 2020. 
The estimated data cut-off date by 30 September 2020 was selected so all patients eligible for 
6 cycles of treatment with study drug have completed the 9-month data collection of the 
primary endpoint.  
 
Finally, due to the COVID-19 situation and site/country restrictions, on April 2nd.,2020, a 
recommendation was made to allow remote data collection according to local requirements. 
In order to follow up and maintain patient safety and collect study-related data, the physical 
site visit of the patient may be replaced by a phone call or by mailing of paper copies of 
questionnaires for completion at the home of the patient. 
3.7 TREATMENT 
To date, approximately 420 patients with CRC have received repetitive dosing with PledOx. 
3.8 CONDUCT OF STUDY 
This clinical study will be conducted in compliance to this Protocol, the guidelines of the World 
Medical Association Declaration of Helsinki, International Council for Harmonisation (ICH) 
Good Clinical Practice (GCP), designated standard operating procedures (SOPs), and with 
local laws and regulations relevant to the use of new therapeutic agents in the country of 
conduct. 


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CONFIDENTIAL 
PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
3.9 POPULATION 
The target population for this study is patients with pathologically confirmed CRC including 
Stage III carcinoma (any T N1,2 M0) or Stage II carcinoma (T3,4 N0 M0). Patient must have 
undergone curative surgical treatment, generally within 12 weeks prior to randomization. 
Approximately 280 patients will be enrolled. The planned population of 280 patients will be 
enrolled at approximately 95 study centers.  
There will be no additional patients included in order to compensate for withdrawals. 


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PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
4. STUDY OBJECTIVES AND PURPOSE 
4.1 OBJECTIVES 
4.1.1 Primary Objective 
• To compare PledOx (5 µmol/kg) vs placebo with respect to the proportion of patients 
with moderate or severe chronic CIPN 
4.1.2 Secondary Objectives 
To compare PledOx vs placebo regarding the following: 
Efficacy 
• The proportion of patients with mild, moderate or severe chronic CIPN 
• The sensitivity to touching cold items 
• The cumulative dose of oxaliplatin during chemotherapy 
• The vibration sensitivity on the lateral malleolus 
• The worst pain in hands or feet 
• The functional impairment (in the non-dominant hand) 
• The sustained efficacy on prevention of CIPN during long-term follow-up 
Safety 
• DFS 
• Safety and tolerability 
4.1.3 Exploratory Objectives 
To compare PledOx vs placebo regarding the following: 
• Chronic CIPN by supporting analysis using the full Functional Assessment of Cancer 
Therapy/Gynecologic 
Oncology 
Group-Neurotoxicity-13-item 
subscale 
(FACT/GOG-NTX-13) 
• The cumulative dose of 5-FU during chemotherapy 
• For both oxaliplatin and 5-FU: Dose intensity, number of cycles, dose reductions, 
reason(s) for dose reductions, patients with dose delays, and length of dose delays 
• The functional impairment (in the non-dominant hand) during long-term follow-up. 
• The worst pain in hands or feet during long-term follow-up 
• QoL/health status 
• Health economic impact 
4.2 RATIONALE 
There are currently no effective preventive or therapeutic treatments for CIPN. Several agents 
have been tested, but all have failed to demonstrate a convincing benefit. The American Society 
of Clinical Oncology has recognized this limitation but made a moderate recommendation for 
duloxetine for the treatment of existing CIPN (Hershman et al. 2014). No pharmacologic 
intervention can be recommended for the prevention of CIPN.  
The suggested dose of 5 µmol/kg has sufficient support in the PLIANT data. The 5 µmol/kg 
dose is the preferred dose based on available data, with an OR = 0.12 (p=0.018) vs placebo on 
the variable most like the primary endpoint in the POLAR studies (i.e., percentage of patients 


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PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
with patient-reported Leonard scoring 3 or more on either numbness, tingling or burning 
pain/discomfort with cold at FU2, which is approximately 10 months after first dose).  
Overall, it can therefore be concluded that there is a clear unmet medical need for the 
prevention of CIPN, and the PLIANT data justifies a confirmatory study of PledOx in this 
setting. 


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PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
5. INVESTIGATIONAL PLAN 
5.1 ENDPOINTS 
5.1.1 Primary Endpoint 
• Proportion of patients (with moderate or severe chronic CIPN) scoring 3 or 4 in at least 
1 of the first 4 items of the FACT/GOG-NTX-13 (i.e., FACT/GOG-NTX-4), targeting 
numbness, tingling or discomfort in hands and/or feet, 9 months after the first dose of 
investigational medicinal product (IMP; i.e. PledOx or placebo administered on Day 1, 
Cycle 1 of mFOLFOX6 chemotherapy) 
5.1.2 Secondary Endpoints 
Efficacy 
• Proportion of patients (with mild, moderate or severe chronic CIPN) scoring 2, 3, or 4, 
in at least 1 of the first 4 items of the FACT/GOG-NTX-13 (i.e. FACT/GOG-NTX-4), 
targeting numbness, tingling or discomfort in hands and/or feet, 9 months after the first 
dose of IMP 
• Mean change from baseline in sensitivity to touching cold items on Day 2, Cycle 4 of 
mFOLFOX6 chemotherapy, as assessed by the Cold Sensitivity questionnaire 
• Mean cumulative dose of oxaliplatin administered per patient during mFOLFOX6 
chemotherapy, 9 months after the first dose of IMP 
• Mean change from baseline in vibration sense, on the lateral malleolus (left and right), 
using a graduated tuning fork, at 9 months after the first dose of IMP 
• Mean change from baseline in worst pain in hands or feet in the past week, using a 
numerical rating scale (NRS), at 9 months after the first dose of IMP 
• Mean change from baseline in the time to complete the grooved Pegboard with the 
non-dominant hand, at 9 months after the first dose of IMP 
• Proportion of patients scoring 3 or 4 in at least 1 of the first 4 items of the 
FACT/GOG-NTX-13 (i.e. FACT/GOG-NTX-4), targeting numbness, tingling or 
discomfort in hands and/or feet, 12, 18, and 24 months after the first dose of IMP 
Safety 
• DFS at 12 and 24 months 
• Safety and tolerability as assessed by AEs, laboratory variables and vital signs 
• Proportion of patients with PledOX toxicities in addition to chemotherapy-related 
toxicities graded using the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) v4.03 
5.1.3 Exploratory Endpoints 
• Proportion of patients with any CIPN scoring 1, 2, 3 or 4, in any of the first 4 items of 
the FACT/GOG-NTX-13 (i.e. FACT/GOG-NTX-4), targeting numbness, tingling or 
discomfort in hands and/or feet, at all other timepoints after the first dose of IMP 
• Mean score of the first 4 items of the FACT/GOG-NTX-13 (i.e. FACT/GOG-NTX-4), at 
9 months after the first dose of IMP 
• Mean score of the 13 items of the FACT/GOG-NTX-13, at 9 months after the first dose 
of IMP 


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This protocol has been written in accordance with current ICH-GCP guidelines  
• Mean cumulative dose of 5-FU administered per patient during mFOLFOX6 
chemotherapy, 9 months after the first dose of IMP 
• For both oxaliplatin and 5-FU: Dose intensity, mean number of cycles per patient, 
proportion of patients with any dose reduction, reason(s) for dose reductions, proportion 
of patients with any dose delay, and mean duration of dose delay 
• Mean health index and mean VAS score, using the EQ-5D-5L, at 9, 12, 18, and 24 months 
after the first dose of IMP 
• Mean health index, using the FACT/GOG, at 9, 12, 18, and 24 months after the first dose 
of IMP 
• Mean time to complete the grooved Pegboard, with the non-dominant hand, at 12, 18, 
and 24 months after the first dose of IMP 
• Mean change from baseline in worst pain in hands or feet in the past week, using a NRS, 
at 12, 18, and 24 months after the first dose of IMP 
• The proportion of patients with a 2-point, 3-point and 4-point increase in worst pain in 
hands or feet in the past week, using a NRS, at 9, 12, 18, and 24 months after the first 
dose of IMP 
• Health economic impact, measured by the combined impact of medical resource 
utilization (hospitalizations, outpatient visits, medical procedures and medical use), 
patient impact (AEs, fall accidents, functional loss) and indirect societal costs (loss of 
ability to work), at 6, 12, 18 and 24 months after the first dose of IMP 
5.2 OVERALL STUDY DESIGN AND PLAN 
This is a Phase 3, multicenter, double-blind, placebo-controlled study using PledOx for 
prevention of chronic CIPN induced by oxaliplatin in patients with pathologically confirmed 
CRC, who are indicated for adjuvant mFOLFOX6 chemotherapy for up to 6 months.  
Patients will be randomized in a 1:1 ratio to 1 of 2 treatment arms: 
• 
Arm A: PledOx (5 µmol/kg) + mFOLFOX6 chemotherapy 
• 
Arm B: Placebo + mFOLFOX6 chemotherapy 
There will be 2 types of study visits: 
• 
Treatment Visits: Before March 2nd., 2020, Visits occurred on the first day of each 
mFOLFOX6 cycle when the patient received IMP.  
As of March 2nd., 2020, treatment visits will be done for patients receiving 
mFOLFOX6 on the first day of each cycle, without IMP, until Cycle 12. 
• 
Assessment Visits: Visits will be performed every 3 months from the first dose of IMP, 
for up to 12 months and thereafter every 6 months for up to 24 months. 
 
 


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PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
Figure 1 
Polar-A Study Design (As of March 2nd., 2020, no more IMP will be given) 
 
t=0 (baseline: Day 1, Cycle 1); R=randomization; EoT=end of treatment; DFS=disease free survival 
Note: CIPN will be evaluated by the first 4 items of the FACT/GOG-NTX-13 (i.e. FACT/GOG-NTX-4), targeting numbness, 
tingling or discomfort in hands and/or feet, also at 9, 12, 18 and 24 months after the first dose of IMP 
Treatment Phase 
Before March 2nd., 2020, patients were treated with IMP (i.e. PledOx or placebo) on top of 
the background chemotherapy (mFOLFOX6), unless preceded by disease recurrence, 
intolerable toxicity or withdrawal of consent. 
As of March 2nd.,2020, dosing with IMP is stopped. Patients may continue their scheduled 
Treatment visits with mFOLFOX6 background therapy and without IMP until cycle 12, 
unless preceded by disease progression, intolerable toxicity or withdrawal of consent. If a 
patient discontinues oxaliplatin, an EOT visit will be done and the patients will continue in 
the Follow-up Phase. 
If a patient discontinues oxaliplatin, treatment with 5-FU/folinate may be continued. 
Following the completion of the Treatment Phase, patients may continue to receive 
mFOLFOX6 at the discretion of the Investigator,  
 
Follow-up Phase 
After the end of treatment (EOT) visit, patients will enter the Follow-up Phase and will have 
an Assessment Visit every 3 months from the first dose of IMP (±1 week) up to Month 12, then 
every 6 months (±1 week) up to Month 24. Any patient who discontinues from IMP for any 
reason (other than death or withdrawal of consent) will continue to have Assessment Visits 
(with the exception of tumor assessments for patients who have disease progression). 
As of March 2nd., 2020, from which date onwards no IMP is given anymore, any patient who 
discontinues from mFOLFOX6 for any reason (other than death or withdrawal of consent) will 
continue to have Assessment visits (with the exception of tumor assessments for patients who 
have disease recurrence). 
End of Study (EOS) 
Before March 2nd., 2020, for each patient, the Treatment Phase and Follow-up Phase lasted a 
total of 24 months (i.e. time from first dose of IMP to last Assessment Visit). 
As of March 2nd., 2020, patients who are still in the Treatment Phase by the estimated data 
cut-off date of 30 September 2020, will have an EoT visit on day 14 ± 3 days of the last 


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mFOLFOX6 cycle. 
As of March 2nd., 2020, for patients who are still in the Follow-up Phase by the estimated 
data cut-off date of 30 September 2020, the EOS will be within 1 week prior to the data 
cut-off date. EOS information (date, primary reason for EOS) can be collected during on-site 
assessment visit if applicable or over the phone or from any other available medical resource. 
At the EOS visit, all assessments planned for Month 24 visit (Follow-up Phase) will be 
performed. 
Steering Committee 
A Study Steering Committee (SSC) will be appointed by PledPharma AB prior to study start 
comprising 3-4 Investigators participating in the study and PledPharma AB representatives 
from the clinical study team.  
The SSC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SSC will review 
protocol amendments as appropriate. The details of the role of the SSC will be defined in the 
Steering Committee Charter. 
Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) will monitor accumulating safety, 
efficacy and other types of data throughout the study. DSMB members must be satisfied that 
the timeliness, completeness, and accuracy of the data submitted to them for review are 
sufficient for evaluation of the safety and welfare of study participants. The DSMB should also 
assess the performance of overall study operations and any other relevant issues, as necessary. 
The complete roles and responsibilities of the DSMB and its membership will be defined in a 
separate Charter. 
5.2.1 Study Procedures  
All assessments will be performed according to the Schedule of Assessments in Appendix 1. 
5.2.1.1 Screening Period 
As of March 2nd., 2020, no more patients will be screened. This section further describes 
how screening was done before March 2nd., 2020.  
Evaluations to determine the patient’s study eligibility will be performed ≤28 days before the 
first dose of IMP (Treatment Visit 1) and will include the following: 
• Written informed consent must be obtained prior to any study-specific evaluations being 
performed. Results of all pre-treatment evaluations must be reviewed by the Investigator 
(or his/her designee) to ensure that all eligibility criteria have been satisfied prior to 
patient enrollment 
• HbA1c assessment for patients with history of diabetes. For patients with a history of 
diabetes mellitus, HbA1c assessment will be performed. Assessments performed as 
Standard of Care before the Informed Consent Form signature, but within 28 days prior 
to the first IMP dose are acceptable. 
• Computer tomography (CT) or MRI scan (of thorax, abdomen and pelvis) and disease 
assessment (according to RECIST v1.1); results from a scan performed ≤42 days before 
surgery (or after surgery) are acceptable. 
• Blood manganese (Mn) sample 


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Within 7 days prior to randomization: 
• Carcinoembryonic antigen (CEA) 
• Medical history (including an assessment of conditions and symptoms present at 
baseline) and prior medications (including those medications taken 30 days prior to first 
dose of IMP) 
• Physical examination (including height and weight measurements, and a neurologic 
assessment performed prior oxaliplatin treatment according to local practice) 
• Vital signs (including temperature, pulse rate, and blood pressure) 
• Eastern Cooperative Oncology Group (ECOG) performance status 
• Serum β-human choriongonadotropin pregnancy (β-HCG) test in women of childbearing 
potential (WOCBP) 
• Demography 
• Hematology sample to assess white blood cell (WBC) count differential, absolute 
neutrophil count (ANC), red blood cell (RBC) count, platelet count and hemoglobin (to 
be analyzed by a local laboratory) 
• Serum biochemistry sample to assess ALP, total bilirubin, alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), serum creatinine and albumin (to be analyzed 
by a local laboratory) 
• 12-lead ECG 
• The Cold Sensitivity questionnaire (paper diary) 
5.2.1.2 Randomization 
As of March 2nd., 2020, no more patients will be randomized.  
This section further describes how randomization was done before March 2nd., 2020. 
When the Investigator confirms that a patient complies with all inclusion/exclusion criteria, 
the patient will be randomized into 1 of 2 treatment arms (1:1) using the electronic 
randomization system within the electronic case report form (eCRF). This is not a patient 
visit. 
The Investigator will then request the unblinded pharmacist/designee to prepare the IMP 
according to the randomization schedule available only to the unblinded hospital staff. 
5.2.1.3 Treatment Phase 
Each treatment cycle of chemotherapy will last for 2 weeks. 
Treatment Visit 1 (Week 0): Day 1 of Cycle 1 of mFOLFOX6 chemotherapy 
As of March 2nd., 2020, no patients will be having a Treatment Visit 1 anymore. 
This section below describes how Treatment Visits 1 were done before March 2nd., 2020. 
 
Before IMP infusion 
• Concomitant medications 
• Vital signs and weight 
• ECOG performance status 
• Check of hematology, biochemistry and serum β-HCG pregnancy test results from 
samples taken within 7 days prior to Randomization or from new samples prior to start 
of infusion at Treatment Visit 1 
• Review of results of blood Mn sample 


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• FACT/GOG-NTX-13 
• Grooved pegboard 
• Vibration sensitivity test, performed using a graduated tuning fork 
• EQ-5D-5L questionnaire 
• Pain NRS questionnaire 
• Health economic impact 
• AEs 
IMP infusion 
• PledOx or placebo will be administered by an i.v. infusion over approximately 
10 minutes, 15 minutes prior to mFOLFOX6 
After IMP infusion 
• AEs 
mFOLFOX6 infusion 
Treatment Visits 2, 3, 4, 5, 6 (Weeks 2, 4, 6, 8, 10 ±2 days) 
Assessments at these visits are similar to Treatment Visit 1 with the following exceptions: 
• Biochemistry parameters are assessed every 4 weeks i.e. Treatment Visit 3 and 5 only 
(samples to be taken in advance of the visit to have the results available before the start 
of the new chemotherapy) 
• EQ-5D-5L, is assessed at Treatment Visit 4 only 
As of March 2nd., 2020, no more Blood Mn samples are taken with the exception for 
patients with Parkinson-like symptoms. 
During the COVID-19 pandemic, remote data collection via either telephone call or 
mailing of rating scales may be implemented for EQ-5D-5L 
• The Cold Sensitivity questionnaire (paper diary) is completed before mFOLFOX6 
infusion at Treatment Visits 2 and 4; and on Days 1, 2, and 3 after the mFOLFOX6 
infusion at Day 1 
During the COVID-19 pandemic, remote data collection via either telephone call or 
mailing of the Cold Sensitivity Questionnaire may be implemented. 
• Health economic impact data are not collected at these visits 
• In case the chemotherapy are delayed and the patient is present at hospital, the patient 
should complete the predose assessments and the results will be recorded in EDC. When 
a patient comes for a delayed treatment visit, the predose assessments will be completed 
before the treatment and the results will be recorded in EDC as an unscheduled visit. If 
the delay is 14 days or more, it should be repeated again. For details please refer to the 
last version of eCRF completion guideline.  
 
Assessment Visit: Month 3 (Week 12±1 week) 
During the COVID-19 pandemic, a visit window of ±6 weeks is allowed for the Assessments 
Visits. 
During the treatment phase, the assessment visits will be calculated on a weekly basis, 
i.e., Month 3 corresponds to Week 12 ±1 week. 


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Note: If the patient continues with mFOLFOX6, relevant Treatment Visit will be combined 
with the Month 3 Assessment Visit. The Assessment Visit at Month 3 will be performed as a 
separate visit only if a patient stops mFOLFOX6 prior to Treatment Visit 7 (Week 12). In 
this case, Assessment Visit at Month 3 can be combined with End of Treatment (EOT) visit if 
EOT visit is performed 3 months after first IMP dose. 
 
If a patient terminated the mFOLFOX6 prior to Month 3, the Month 3 visit will be calculated 
as 3 months (± 1 week) after C1D1. 
The following assessments will be performed at each Assessment Visit: 
• Concomitant medications (up to 30 days after the EOT visit) 
• Physical examination 
• Vital signs 
• ECOG performance status 
• Hematology sample 
• FACT/GOG-NTX-13 
• Grooved pegboard 
• Vibration sensitivity test, performed using a graduated tuning fork 
• EQ-5D-5L 
• Pain NRS questionnaire 
• AEs 
• DFS 
• During the COVID-19 pandemic, remote data collection via either phone call or mailing 
of 
rating 
scales 
may 
be 
implemented 
for 
ECOG 
performance 
status; 
FACT/GOG-NTX-13; EQ-5D-5L; Pain NRS questionnaire, AEs. 
Treatment Visit 7, 8, 9, 10, 11, 12 (Weeks 12, 14, 16, 18, 20, 22 ±2 days) 
Assessments at these visits are similar to Treatment Visit 1 with the following exceptions: 
• Biochemistry parameters are assessed every 4 weeks i.e. Treatment Visit 7, 9 and 11 only 
(samples to be taken in advance of the visit to have the results available before the start 
of the new chemotherapy) 
• QoL/health status (EQ-5D-5L) is assessed at Treatment Visits 8 and 12 only. During 
the COVID-19 pandemic, remote data collection via either phone call or mailing of 
EQ-5D-5L may be implemented. 
• As of March 2nd., 2020, no more Blood Mn samples are taken with the exception for 
patients with Parkinson-like symptoms. 
• The Cold Sensitivity questionnaire (paper diary) is completed before mFOLFOX6 
infusion at Treatment Visit 8 and on Days 1, 2, and 3 after mFOLFOX6 infusion at 
day 1. 
During the COVID-19 pandemic, remote data collection via either telephone call or 
mailing of Cold Sensitivity Questionnaire may be implemented. 
• Health economic impact data are not collected at these visits 
• In case the chemotherapy are delayed and the patient is present at hospital, the patient 
should complete the predose assessments and the results will be recorded in EDC. When 
a patient comes for a delayed treatment visit, the predose assessments will be completed 
before the treatment and the results will be recorded in EDC as an unscheduled visit. If 


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the delay is 14 days or more, it should be repeated again. For details please refer to the 
last version of eCRF completion guideline.  
Assessment Visit: Month 6 (Week 24±1 week) 
During the treatment phase, the assessment visits will be calculated on a weekly basis, 
i.e., Month 6 corresponds to Week 24 ±1 week. 
During the COVID-19 pandemic, a visit window of ±6 weeks is allowed for the Assessments 
Visits. 
Note: If the patient continues with mFOLFOX6 without IMP until Treatment Visit 12 
(Week 22), the relevant Treatment Visit or the EOT Visit will be combined with the 
Assessment Visit at Month 6. The Assessment Visit at Month 6 will be performed as a 
separate visit only if a patient stops mFOLFOX6 prior to Treatment Visit 12 (Week 22). 
 
If a patient terminated mFOLFOX6 without IMP  prior to Month 6, the Month 6 visit will be 
calculated as 6 months (± 1 week) after C1D1. 
 
Assessments will be as per the Assessment at Month 3 (see above) with addition of health 
economic impact data collection. 
EOT Visit  
The following assessments will be performed at Day 14 (±3 days) of the last cycle of 
mFOLFOX6 (without IMP) before Cycle 12 or at Cycle 12 (whichever comes first) : 
 
• CEA 
• Concomitant medications (up to 30 days after the EOT visit) 
• Physical examination 
• Vital signs and weight 
• ECOG performance status 
• Hematology sample 
• Biochemistry sample 
• Blood Mn sample 
As of March 2nd., 2020, no more Mn samples are being taken except in case of 
Parkinson-like symptoms 
• FACT/GOG-NTX-13 
• Grooved pegboard 
• Vibration sensitivity test, performed using a graduated tuning fork 
• EQ-5D-5L 
• Pain NRS questionnaire 
• AEs 
• During the COVID-19 pandemic, remote data collection via either phone call or mailing 
of 
rating 
scales 
may 
be 
implemented 
for 
ECOG 
performance 
status; 
FACT/GOG-NTX-13; EQ-5D-5L; Pain NRS questionnaire, AEs. 
 
Concomitant medications will be recorded until 30 days after the EOT visit.All AEs 
including SAEs will be collected up to 30 days after the EOT visit and followed until 


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resolution. 
 
5.2.1.4 Follow-up Phase 
During the follow-up period, visit dates are calculated on a monthly calendar basis after 
C1D1. All patients will be followed for 24 months from first dose of IMP, with Assessment 
Visits every 3 months until Month 12 and every 6 months thereafter. Any patient who 
discontinued from mFOLFOX6 for any reason during the treatment phase other than death or 
withdrawal of consent will continue to have CIPN and tumor assessments every 3 months.  
As of March 2nd., 2020, patients will have their assessment visits until the estimated data 
cut-off date by 30 September 2020. 
An EOS visit will be done within 1 week of the data cut-off date.  
At the EOS visit, all assessments planned for Month 24 visit (Follow-up Phase) will be 
performed. 
Assessment Visits: Months 9, 12, 18, and 24 (±1 week) 
During the COVID-19 pandemic, a visit window of ± 6 weeks is allowed. 
• CT or MRI scan and disease assessment (at Month 12 and Month 24 [EOS] only) 
• CEA (at Month 12 and Month 24 [EOS] only) 
• Physical examination 
• Vital signs 
• ECOG performance status 
• FACT/GOG-NTX-13 
• Grooved pegboard 
• Vibration sensitivity test, performed using a graduated tuning fork 
• EQ-5D-5L 
• Pain NRS questionnaire 
• Health economic impact (at Months 12, 18 and 24 only) 
• DFS 
• During the COVID-19 pandemic, remote data collection via either phone call or mailing 
of paper copies of rating scales may be implemented for ECOG performance status; 
FACT/GOG-NTX-13; EQ-5D-5L; Pain NRS questionnaire, Health Economic Impact. 
 
5.3 RANDOMIZATION AND BLINDING 
5.3.1 Randomization 
Randomization will be performed after eligibility has been confirmed and within 3 days prior 
to the start of infusion of the first cycle of mFOLFOX6 chemotherapy.  
Patients will be randomized in blocks into 1 of 2 arms in a 1:1 ratio using the electronic 
randomization system within the eCRF: 
• Arm A: PledOx (5 µmol/kg) + mFOLFOX6 chemotherapy 
• Arm B: Placebo + mFOLFOX6 chemotherapy 


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5.3.2 Blinding 
This is a double-blind, placebo-controlled study. Blinding is critical to the integrity of this 
clinical study.  
The IMP will be prepared by a qualified unblinded pharmacist/designee not otherwise involved 
in the study to ensure the blinding. The unblinded pharmacist/designee will prepare the IMP in 
an amber colored syringe masking the colored appearance on the IMP or another type of 
syringe depending on site procedure. The prepared IMP, i.e. the syringe and amber colored 
tubing (or any other system maintaining the blinding depending on site preference), is provided 
to the blinded nurse who will perform the administration, not knowing which treatment is 
given, or to an unblinded nurse not performing any other assessment in the study. The blinding 
of the patient will be maintained in any case, but the process in each site may differ. Thus, the 
process at each site will be closely monitored from the initiation and regularly assessed during 
the study.  
5.4 STUDY TREATMENTS 
5.4.1 Identity of Investigational Medicinal Product 
PledOx and placebo will be supplied to each site. All used and unused IMP must be kept at the 
site for accountability purposes. 
Batch number(s) and expiry date(s) will be documented in the Drug Accountability Log in the 
Trial Master File and will be included in the final Clinical Study Report (CSR). 
5.4.2 Packaging 
PledOx in colorless glass vials, each containing 20 mL of solution, will be packed into a kit. 
Each kit will contain 4 vials. Kits will be transported frozen within -25°C to -15°C.  
Placebo vials, each containing 20 mL of solution, will be packed into a kit. Each kit will contain 
4 vials. Kits will be transported at ambient temperature, i.e. within 15°C to 25°C. 
5.4.3 Labelling 
A booklet label in the local language and in compliance with applicable regulations and 
guidelines will be attached to the vials and the kits. 
Each vial label will have a detachable part containing vial and batch number. This part will be 
removed by the unblinded pharmacist/designee preparing the correct dose and stuck onto the 
unblinded drug accountability log. 
5.4.4 Storage 
All IMP (i.e. PledOx or placebo) should be stored in a safe place with limited access. 
PledOx (vials) is to be protected from light and stored frozen at -15°C to -25°C. 
The standard procedure is to thaw the IMP at 5°C ± 3°C (41°F± 5°F) overnight before the 
planned infusion preparation. If needed there is also a possibility to thaw the vial by holding it 
in the hand for at least 5 minutes for defrosting, shortly before the planned infusion (i.e. at the 
day of infusion). Thawed vials can be stored at 5°C ± 3°C for maximum 6 days. An unopened 
vial may be thawed and refrozen once. The thawed vial needs to be refrozen the same day. 


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The non-diluted IMP (50 mM solution) is stable in room temperature (i.e. 20°C to 25°C [68°F 
to 77°F]) for a maximum of 24 hours. The diluted solution (prepared syringe) is stable for 
3 hours in room temperature (i.e. 20°C to 25°C [68°F to 77°F]) or 5 hours when refrigerated at 
2°C to 8°C (36°F to 46°F). If refrigerated, the diluted IMP should come to room temperature 
before administration (storage in room temperature following the 2°C to 8°C storage can be 
allowed for 1 hour). 
Temperature logs must be kept for the freezer and refrigerator where the IMP is stored. The 
log should be updated by site personnel twice per week (unless automatic temperature readings 
are available). 
Placebo will be stored within ambient temperature. 
5.4.5 Destruction of IMP 
The unblinded monitors should account for all IMP at the study site. However, there is no need 
to account for used IMP vials by the unblinded monitor before the destruction of the IMP if the 
entire IMP use and destruction is documented in the patient and study accountability logs. All 
IMP will be accounted for and disposed at the sites. Unused IMP vials should be kept and sent 
for destruction (if applicable). 
5.4.6 Background Therapy 
All background therapy, i.e. non-IMPs, will be used according to their respective approved 
Summary of Product Characteristics (SmPC). 
5.5 DURATION OF STUDY PARTICIPATION 
During the Treatment Phase, enrolled patients will receive IMP (i.e. PledOx or placebo) on top 
of mFOLFOX6 chemotherapy. Subsequently, patients will attend Follow-up visits every 
3 months for the first 12 months and then every 6 months up to 24 months.  
The entire study will run for approximately 24 months from first dose of IMP. 
 
An estimated data cut-off date will be implemented by 30 September 2020 when all patients 
should discontinue study participation. 
5.6 DISCONTINUATION CRITERIA 
The discontinuation criteria for individual patients, parts of study and the entire study are 
presented in Sections 6.3 to 6.5. 
5.7 INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
It is the responsibility of the Investigator to establish a system for handling the IMP and to 
ensure that: 
• Deliveries of such products are correctly received and recorded by a designated and 
properly trained person 
• IMP are handled and stored safely and properly 
• IMP is prepared by an unblinded pharmacist/designee who has no other contact with the 
patient, and is not involved in any other care or recording of any data related to the study 
• IMP are given only to study patients in accordance with the protocol 


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• All unused IMP and empty vials are stored until they have been checked by the monitor 
• It is possible to reconcile records of all used and unused stocks as confirmed by 
Investigator’s signature 
5.8 CODE BREAKS 
Unblinding will be controlled through the randomization system. In case of such emergency 
that it is crucial for the Investigator (or any other treating physician) to know whether the 
patient has received PledOx or placebo, unblinding can be requested in the system. If 
unblinding occurs, this must be documented in the patient’s hospital records with date and 
name of the Investigator who decided to unblind the study treatment. The Sponsor must be 
notified prior to unblinding, except in cases where an immediate need for unblinding exists for 
reasons of patient safety at which time the Investigator can unblind the patient prior to notifying 
the Sponsor. However, the Investigator will have the final decision and unilateral right for 
unblinding in matters involving the safety of study patients.  
In the event of an SAE, the Investigator may unblind the study treatment if the appropriate 
future management of the patient necessitates knowledge of the current treatment. Although it 
is advantageous to retain the blind for all patients prior to final study analysis, when a SAE 
may be a serious adverse reaction unexpected or otherwise judged reportable on an expedited 
basis, it is recommended that the blind should be broken only for that specific patient, by the 
sponsor, even if the Investigator has not broken the blinding. 
The treatment code will not be broken until all assessments have been performed, all data have 
been entered into the database and the database has been locked after a formal clean file has 
been produced. 
The DSMB will monitor data according to the DSMB Charter. 
5.9 SOURCE DATA 
The eCRF is essentially considered a data entry form and should not constitute the original (or 
source) medical records unless otherwise specified. Source documents are all documents used 
by the Investigator or hospital that relate to the patient’s medical history, that verifies the 
existence of the patient, the inclusion and exclusion criteria, and all records covering the 
patient’s participation in the study. They include laboratory notes, memoranda, material 
dispensing records, patient files, etc. 
The Investigator is responsible for maintaining source documents. These will be made available 
for inspection by the monitor at each monitoring visit. The Investigator must submit a 
completed eCRF for each patient who signed the Informed Consent Form (ICF). All supportive 
documentation submitted with the eCRF, such as laboratory or hospital records, should be 
clearly identified with the study ID and patient number. Any personal information, including 
patient name, should be removed or rendered illegible to preserve individual confidentiality. 
5.10 DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF CONTROL GROUPS 
Oxaliplatin, in combination with 5-FU plus folinate (or capecitabine), has increased survival 
in stage III CRC and prolonged life in stage IV patients, but its use is compromised because of 
severe toxicity. CIPN is the most problematic dose-limiting toxicity of oxaliplatin. No 
treatments have been clinically proven to prevent CIPN. There is a body of evidence that CIPN 


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is caused by cellular oxidative stress. Clinical and preclinical data suggest that the Mn chelate 
and superoxide dismutase mimetic MnDPDP and (PledOx, Ca4Mn(DPDP)5) are efficacious 
inhibitors of CIPN and other conditions caused by cellular oxidative stress, without interfering 
negatively with the tumoricidal activity of chemotherapy. MnPLED, the main active metabolite 
of Ca4Mn(DPDP)5, can potentially modulate cellular oxidative stress at several critical levels 
such as superoxide generation, peroxynitrite formation and inactivation of the SOD-enzyme as 
well as hydroxyl radical formation. Results from a placebo-controlled, Phase 2 study 
(PLIANT) suggest efficacy of calmangafodipir in preventing CIPN. 
Since no pharmacologic intervention can be recommended for the prevention of CIPN, placebo 
controlled studies are appropriate. It is acknowledged that 2 studies, 1 in the adjuvant setting 
and 1 in the metastatic setting (excluding adjuvant exposed patients) will present a favorable 
study program. A study in the adjuvant setting alleviates the concerns about the heterogeneity 
in patient population, and available chemotherapy combinations/regimens as well as potential 
confounding from treatment breaks. A study in the metastatic setting allows assessment of 
absence of signs of a detrimental effect on the underlying treatment. 
PledPharma AB has designed the POLAR-A study for the continued development of PledOx 
with the ambition of forming the basis for registration. 
Overall, it can therefore be concluded that there is a clear unmet medical need for the 
prevention of CIPN, and the PLIANT data justifies a confirmatory study of PledOx in this 
setting. 


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6. SELECTION AND WITHDRAWAL OF PATIENTS 
6.1 PATIENT INCLUSION CRITERIA 
Patients are eligible to be included in the study if they meet the following criteria: 
1. 
Signed informed consent form before any study related assessments and willing to 
follow all study procedures. 
2. 
Male or female aged ≥18 years. 
3. 
Pathologically confirmed adenocarcinoma of the colon or rectum including: Stage 
III carcinoma (any T N1,2 M0) or Stage II carcinoma (T3,4 N0 M0). 
4. 
The patient has undergone curative (R0) surgical resection performed within 
12 weeks prior to randomization. 
5. 
The patient has a postsurgical CEA level ≤1.5x upper limit of normal (ULN, in 
current smokers, CEA level ≤2.0 x ULN is allowed). 
6. 
No prior anti-cancer therapy for CRC except radiotherapy or concomitant 
chemo-radiotherapy using a fluoropyrimidine alone for locoregional rectal cancer. 
7. 
Patient indicated for up to 6 months of oxaliplatin-based chemotherapy and without 
pathological findings of a neurologic exam performed prior to oxaliplatin treatment 
according to local practice.  
8. 
ECOG performance status of 0 or 1. 
9. 
Adequate hematological parameters: hemoglobin ≥100 g/L, ANC ≥1.5 x 109/L, 
platelets ≥100 x 109/L. 
10. 
Adequate renal function: creatinine clearance >50 cc/min using the Cockcroft and 
Gault formula or measured. 
11. 
Adequate hepatic function: total bilirubin ≤1.5 x ULN (except in the case of known 
Gilbert’s syndrome); AST and ALT ≤3 x ULN. 
12. 
Baseline blood Mn level <2.0 x ULN. 
13. 
For patients with a history of diabetes mellitus, HbA1c ≤7%. 
14. 
Negative pregnancy test for WOCBP. 
15. 
For men and WOCBP, use of adequate contraception (oral contraceptives, 
intrauterine device or surgically sterile) while on study drug and for at least 
6 months after completion of study therapy. 
6.2 PATIENT EXCLUSION CRITERIA 
Patients will be ineligible if 1 or more of the following statements are applicable: 
1. 
Any evidence of metastatic disease.  
2. 
Any unresolved toxicity by NCI-CTCAE v.4.03 >Grade 1 from previous 
anti-cancer therapy (including radiotherapy), except alopecia. 
3. 
Any grade of neuropathy from any cause. 
4. 
Any evidence of severe or uncontrolled systemic diseases (e.g., unstable or 
uncompensated respiratory, cardiac, unresolved bowel obstruction, hepatic or renal 
disease). 
5. 
Chronic infection or uncontrolled serious illness causing immunodeficiency. 
Patients with known history of chronic hepatitis B can be enrolled if they are asymptomatic 
and an acute and active HBV infection can be excluded. 
6. 
Any history of seizures. 
7. 
A surgical incision that is not healed. 


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8. 
Known hypersensitivity to any of the components of mFOLFOX6 and, if 
applicable, therapies to be used in conjunction with the chemotherapy regimen or 
any of the excipients of these products. 
9. 
History of other malignancies (except for adequately treated basal or squamous cell 
carcinoma or carcinoma in situ) within 5 years, unless the patient has been disease 
free for that other malignancy for at least 2 years. 
10. 
Known dihydropyrimidine dehydrogenase deficiency. 
11. 
Pre-existing 
neurodegenerative 
disease 
(e.g., 
Parkinson’s, 
Alzheimer’s, 
Huntington’s) or neuromuscular disorder (e.g., multiple sclerosis, amyotrophic 
lateral sclerosis, polio, hereditary neuromuscular disease). 
12. 
Major psychiatric disorder (major depression, psychosis), alcohol and/or drug 
abuse. 
13. 
Patients with a history of second or third-degree atrioventricular block or a family 
heredity. 
14. 
A history of a genetic or familial neuropathy. 
15. 
Treatment with any investigational drug within 30 days prior to randomization. 
16. 
Pregnancy, lactation or reluctance to using contraception. 
17. 
Any other condition that, in the opinion of the Investigator, places the patient at 
undue risk. 
18. 
Previous exposure to mangafodipir or calmangafodipir. 
19. 
Welders, mine workers or other workers in occupations (current or past) where high 
Mn exposure is likely. 
6.3 PATIENT WITHDRAWAL CRITERIA 
6.3.1 Removal of Patients from Therapy or Assessment 
The patient will be advised in the ICF that they have the right to withdraw from the study at 
any time without providing an explanation and without affecting their right to an appropriate 
follow-up investigation. 
Once a patient has been included in the study, the Investigator should make every reasonable 
effort to keep the patient in the study.  
Patients may be discontinued from the study at any time at the discretion of the Investigator, 
the Covance or the Sponsor. In the event that the patient drops out of the study or is withdrawn 
from the study, the withdrawal page in the patient’s eCRF should be completed, including the 
date and reason for withdrawal. Specific reasons for discontinuing a patient from further 
assessments include: 
• Withdrawal of informed consent 
• Patient lost to follow-up (i.e. drop-outs) 
• Death 
• Substantial Clinical Study Protocol violation 
• The Investigator’s decision 
• Pregnancy 
Patients who discontinue from IMP for any reason (other than death or withdrawal of consent) 
will continue to have Assessment Visits (with the exception of tumor assessments for patients 
who have disease recurrence), as per protocol. 


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This protocol has been written in accordance with current ICH-GCP guidelines  
As of March 2nd., 2020, no new patients can be included in the study and all patients should 
be discontinued from IMP. Patients who are still in the treatment phase and continue on 
mFOLFOX6 will continue the planned Treatment Phase Visits till Cycle 12 and EOT; 
following which they will move into the follow-up phase and have Assessment Visits. 
At the time of the data cut-off date estimated by 30 September 2020, all patients will 
discontinue the study. 
Any AEs must be followed until resolution unless, in the Investigator’s opinion, the condition 
is unlikely to resolve because of the patient’s underlying condition, even after withdrawal from 
the study. 
Patients withdrawn from the study will not be replaced. 
The Investigator will make every reasonable effort to complete the procedures outlined for the 
end of treatment visit for patients who has received study medication and are subsequently 
withdrawn from the study. 
6.3.1.1 Stop Criteria 
Stop criteria are as follows: 
• Any patient who has elevated Mn levels (>2 times ULN) confirmed by MRI that shows 
Mn accumulation should be immediately withdrawn from further treatment with the 
IMP. 
• Patients may be withdrawn from the IMP treatment at the discretion of the Investigator. 
• Pregnant study patients must be withdrawn from treatment immediately, whereas male 
patients may continue in the study should pregnancy of female partners occur. 
• Disease progression 
• Patients with a seizure, regardless of intensity, or an anaphylactoid reaction/allergic 
infusion reaction (hypersensitivity), with moderate or severe intensity and judged to be 
related to IMP should discontinue dosing. 
• Intolerable toxicity.  
• As of March 2nd., 2020, all patients have to stop IMP but may continue on 
mFOLFOX6. 
6.3.2  Pregnancy 
Sexually active males and WOCBP, must use adequate contraception (see below; oral 
contraceptives, intrauterine device or surgically sterile) while on study drug and at least 
6 months after the completion of the chemotherapy. 
A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche 
and until becoming post-menopausal unless permanently sterile. Permanent sterilization 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.  
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a post-menopausal state in women not using hormonal contraception or 
hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient. 
Highly Effective Methods That Are User Independent1 


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• 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition 
of ovulation 
o 
Oral  
o 
Intravaginal  
o 
Transdermal 
• 
Progestogen only hormonal contraception associated with inhibition of ovulation 
o 
Oral  
o 
Injectable  
o 
Implantable2 
• 
Intrauterine device (IUD)2 
• 
Intrauterine hormone-releasing system (IUS)2 
• 
Bilateral tubal occlusion2 
• 
Vasectomized partner2  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used.  
• 
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.  
1: Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local 
regulations regarding the use of contraceptive methods for participants participating in clinical studies.  
2: Contraception methods that in the context of this guidance are considered to have low user dependency 
WOCBP must have a negative pregnancy test at Screening to be eligible for enrolment. 
Pregnancy testing should be done monthly and maintained until the end of systemic exposure 
to IMP. 
6.4 PREMATURE TERMINATION OF STUDY IN A STUDY CENTER 
The study may be terminated at an individual study site if it becomes apparent that patient 
enrolment is unsatisfactory with respect to quality and/or quantity. Sites may also be closed if 
they prove to be unable to comply with the requirements of the protocol or GCP, or data 
recording is inaccurate and/or incomplete. 
In a case where the study is terminated in an individual site for any reason, the Investigator 
must make every effort to follow up all patients as planned according to the protocol. 
Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs) and regulatory 
authorities will be informed about reason and time of termination according to the applicable 
laws and regulations. 
An initiative for site closure or study termination can be taken at any time either by the Sponsor 
or by the Investigator, provided there is reasonable cause and sufficient notice is given in 
advance of the intended termination. Reasons for such action taken by the Sponsor include, but 
are not limited to the following: 
• Successful completion of the study at the site 
• The required number of patients for the study has been recruited 


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• Failure of the Investigator to comply with the protocol, the Sponsor’s procedures, or 
GCP/regulatory guidelines 
• A major protocol violation was identified or developed during the study 
• Safety concerns 
• Sufficient data suggesting lack of efficacy 
• Inadequate recruitment of patients by the Investigator 
Replacement of sites is allowed, and new sites may be initiated. 
6.5 TERMINATION OF STUDY 
Both the Sponsor and the Investigator reserve the right to terminate the study according to the 
study contract. The Investigator should notify the IEC/IRB in writing of the study’s completion 
or early termination and send a copy of the notification to the Sponsor. 
6.6 FURTHER TREATMENT AFTER THE END OF THE TREATMENT PHASE 
Following the completion of the Treatment Phase, patients may continue to receive 
mFOLFOX6 at the discretion of the Investigator, but without IMP on top, as part of the 
Follow-up Phase. 
 
As of March 2nd., 2020, the EOT Visit will be done at Day 14 (± 3 days) at Cycle 12 for 
patients who, at the discretion of the Investigator, continue mFOLFOX6 treatment beyond 
Cycle 12. 
Patients who are still in the Treatment Phase by the estimated data cut-off date of 
30 September 2020, will have an EoT visit on day 14 ±3 days of the last mFOLFOX6 cycle. 
Concomitant medications and SAEs/AEs will be recorded until 30 days after the EOT visit. 


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7. TREATMENT OF PATIENTS 
7.1 TREATMENTS ADMINISTERED 
7.1.1 Investigational Product 
PledOx drug product is composed of the drug substance in an aseptically prepared, sterile 
filtered, aqueous formulation for parenteral administration using compendial excipients. 
Clinical formulations consist of 50 mM calmangafodipir provided as a sterile, bright yellow 
clear solution in 20 mL colorless, single dose, glass vials. The pH is adjusted between 7.4 and 
7.6 with sodium hydroxide.  
The active ingredient is calmangafodipir. Other excipients are sodium chloride, sodium 
hydroxide and water for injection. 
PledOx, corresponding to 5 µmol/kg calmangafodipir, will be given to patients as an 
i.v. infusion, on top of mFOLFOX6 chemotherapy. 
7.1.2 Control Product 
Placebo: 0.9% sodium chloride in 20 mL vials. 
Placebo will be administered via the same route as PledOx (i.v. infusion). 
7.1.3 Background Therapy 
All patients will be treated with mFOLFOX6 chemotherapy given in 2-week cycles. 
mFOLFOX6 is administered on Day 1 and 2 of each cycle as specified in Table 2. 
Background therapy will be used according to their respective approved SmPC. 
7.2 METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUPS 
The patients will be randomized in a 1:1 ratio: 
• Arm A: PledOx 5 µmol/kg + mFOLFOX6 chemotherapy 
• Arm B: Placebo + mFOLFOX6 chemotherapy 
Randomization is performed centrally using an Interactive Web Response System. 
7.3 SELECTION OF DOSES IN THE STUDY 
The suggested dose of 5 µmol/kg has sufficient support in the PLIANT data (refer to the 
Investigator’s Brochure [IB]). The 5 µmol/kg dose is the preferred dose based on available 
data, with an OR = 0.12 (p=0.018) vs placebo on the variable most like the primary endpoint 
in the POLAR studies (i.e. percentage of patients with patient-reported Leonard scoring 3 or 
more on either numbness, tingling or burning pain/discomfort with cold at FU2, which is 
approximately 10 months after first dose). Current knowledge suggests the dose in question 
has an acceptable safety and tolerability profile. 


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7.4 SELECTION AND TIMING OF DOSE FOR EACH PATIENT 
7.4.1 PledOx/Placebo Administration 
PledOx/Placebo will be administered by an i.v. infusion over approximately 10 minutes, 
15 minutes prior to each mFOLFOX6 cycle. As a premedication antihistamine, 
diphenhydramine (1–2 mg/kg or 25–50 mg) shall be given slowly via i.v. in combination with 
ranitidine (50 mg diluted in 5% dextrose to a total volume of 20 mL) over approximately 5 min 
(Roselló et al. 2017). Alternative products, doses, or ways of administrations of anti-histamines 
to those given above may be used, according to local clinical practice. 
 
Table 1 
PledOx/Placebo Administration Schedule 
Arm 
Drug 
Dose* 
Administration 
Duration 
Infusate/ 
Preparation 
Time point 
A+B
* 
Diphenhydr
amine (1–2 
mg/kg or 
25–50 mg). 
ranitidine 
(50 mg) 
Shall be given 
slowly via i.v. in 
combination 
Approximately 
5 min 
Ranitidine 
diluted in 5% 
dextrose to a 
total volume 
of 20 mL 
Approximately 5 min 
before IMP 
A** 
PledOx 
5 µmol/kg 
i.v. infusion 
Approximately 
10 minutes 
Ready-to-use 
formulation 
Approximately 
15 minutes prior to start 
of chemotherapy (Day 1 
of each cycle) 
B** 
Placebo 
* Alternative products, doses, or ways of administrations of anti-histamines to those given above may be used, according to 
local clinical practice. 
** A specific template for dose calculation will be provided all patients will receive 20 mL i.e. the volume of PledOx/placebo 
will be based on body weight 
PledOx comes as ready-to-use formulation in 20 mL glass vials containing PledOx 
calmangafodipir 50 mM. 
Placebo comes as ready-to-use formulation in 20 mL glass vials containing 0.9% NaCl. 
An unblinded person (pharmacist/designee) not otherwise involved in the study will prepare 
the IMP. Administration of the IMP will be done by a blinded treating nurse. If administration 
is done by an unblinded nurse, this should be well documented and this unblinded nurse should 
not be involved in any other assessment in the study. Vials containing either PledOx or placebo 
and the corresponding infusion set will be hidden from the patient and the blinded study team. 
Further details about the drug preparation will be provided in the Instructions for Handling of 
IMP. 


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This protocol has been written in accordance with current ICH-GCP guidelines  
7.4.2 Chemotherapy (mFOLFOX6) Administration 
All patients will receive 5-FU, calcium-folinate or calcium-levofolinate and oxaliplatin, 
according to the mFOLFOX6 regimen, and pre-treatment with anti-emetics and corticosteroids 
will be given, as specified in Table 2 and the approved SmPC, approved label and national 
guidance. The infusion line and the port should be flushed between the administrations. This is 
particularly important between IMP and oxaliplatin administration. 
 
 


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Table 2 
Chemotherapy Administration Schedule 
Drug 
  
Dose 
Administration 
Duration 
Infusate/ 
Preparation 
Time point 
Ondansetron* 
8 mg* 
i.v. injection 
 
  
At least 30 min 
prior to start of 
chemotherapy 
Beta-methasone*  
8 mg* 
i.v. injection  
 
  
At least 30 min 
prior to start of 
chemotherapy  
Oxaliplatin 
85 mg/m2 
i.v. infusion 
0-2 hours 
0.5 L glucose 5% 
Start of 
chemotherapy 
(regarded as time 
point 0) 
Ca-levofolinate  
or  
Ca-folinate 
100 or 
200 mg/m2 
200 or 400 
mg/m2 
i.v. infusion 
 
i.v. infusion 
0-2 hours 
 
0-2 hours 
0.5 L glucose 5% 
 
0.5 L glucose 5% 
Start of 
chemotherapy 
(regarded as time 
point 0) 
5-FU 
400 mg/m2 
i.v. bolus 
 
Recommendation 
50-100 ml NaCl 
0.9% 
Approximately 2 h 
after time point 0 
5-FU 
2400 mg/m2 
i.v. continued 
infusion 
2-48 
hours 
 
Approximately 2 h 
after time point 0 
* For anti-emetics and corticosteroids, alternative doses to those given above, or alternative products may be used, according 
to local clinical practice. 
7.5 DOSE ADJUSTMENT CRITERIA 
Any dose change to the IMP (i.e. PledOx or placebo), chemotherapy (mFOLFOX6), or other 
therapy must be recorded in the eCRF, including the reason for the change. 
7.5.1 Treatment Requirements and Delays 
Prior to each administration of chemotherapy, the patient’s hematology must be adequate (as 
per local practice), and all toxicities (other than alopecia) should be resolved to Grade 0 or 1.  
In case of febrile neutropenia and the patient’s recovery to Grade 0 or 1, please see Table 3 for 
dose reduction recommendations. All pre-treatment lab data including hematology, 
biochemistry, pregnancy testing, may not be older than 72 hours before Day 1 of applicable 
cycle.  
If these criteria are not met at the time of a planned treatment, the following general rules for 
the management of treatment delays apply: 
• In the case of mFOLFOX6 related toxicity (see Section 7.5.2), the start of the next cycle 
will be delayed until toxicities (other than alopecia) are resolved to Grade 0 or 1. 
• If administration of mFOLFOX6 is delayed for more than 6 weeks (3 cycles) after the 
first day of the previous cycle due to toxicity, treatment with that therapy can be 
discontinued at the Investigator’s discretion. 


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7.5.2 Chemotherapy Related Adverse Events and Dose Modification 
The following sections include guidelines for dose modifications and delays associated with 
specific symptoms. 
Every Grade 3 or 4 toxicity according to NCI-CTCAE v4.03 that, in the opinion of the 
Investigator, put the patient at risk should be evaluated and adequate dose reduction/treatment 
delay should be considered. All dose modifications and the reasons should be recorded in 
applicable sections of the eCRF. 
If other symptoms not discussed in this protocol occur, the treating Investigator should be 
consulted regarding the appropriate course of action with regard to dose modification or delay. 
7.5.2.1 Dose Modification of Oxaliplatin due to Neuropathy  
Neuropathy dose modifications should be performed according to the table below (Table 3) but 
may also be performed according to local practice. Table 3 provides a guideline on the grade 
and duration of the toxicity and oxaliplatin dose modifications. 
Table 3 
Neuropathy Dose Modification of Oxaliplatin 
Grade 
Duration of Toxicity 
1 - 7 days 
>7 days – persistent between treatment cycles 
1 
No dose reduction 
No dose reduction 
2 
No dose reduction 
25% dose reduction* 
3 
Discontinue oxaliplatin 
Discontinue oxaliplatin 
4 
Discontinue oxaliplatin 
Discontinue oxaliplatin 
*If repeat events of neurosensory toxicity occur; local practice should be followed with the management of the toxicities being 
fully documented in the patient’s medical records 
Modification of infusion duration of oxaliplatin: infusion time may be increased from 1-2 hours 
to 6 hours in case of NCI-CTCAE Grade ≤2 allergy or in case of laryngeal spasm syndrome. 
If treatment with oxaliplatin must be stopped due to toxicity, treatment with 5-FU/folinate and 
IMP may be continued. 
 
Table 4 
Definition of Neuropathy According to NCI-CTCAE v4.03 
Grade 
Definition: Peripheral sensory neuropathy 
Grade 0 
No change or none 
Grade 1 
Asymptomatic; loss of deep tendon reflexes or paresthesia 
Grade 2 
Moderate symptoms, limiting instrumental ADL 
Grade 3 
Severe symptoms; limiting self-care ADL 
Grade 4 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
Death 
ADL = activities of daily living 
 


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7.5.2.2 Central Nervous System Toxicity 
All central neurologic toxicity should be evaluated by the Investigator and in case of Grade 3 
and 4 toxicities, according to NCI-CTCAE v4.03, mFOLFOX6 treatment should be stopped 
until neurological symptoms is reduced to Grade 1 or 0. 
7.5.2.3 Hematological Dose Modification of Oxaliplatin and 5-Fluorouracil 
Prior to each administration of chemotherapy, the patient’s hematology must be adequate (as 
per local practice), and toxicities should be resolved to Grade 0 or 1.  
Hematological dose modifications (based on nadir) are recommended to be performed 
according to the table below (Table 5), but may also be performed according to the discretion 
of the investigator, according to local practice and in the interest of the patient. 
Table 5 
Hematological Dose Modification of Oxaliplatin and 5-FU 
Neutropenia 
Duration (counting from 
pre-dose of the cycle) 
Action 
Grade 3/4 first time 
≤7 days 
No dose reduction when recovered 
Grade 3/4 second time 
≤7 days 
Dose reduction to 75% of full dose 
when recovered (which can mean 
dose delay) 
Grade 3/4 first time 
>7 days 
Dose reduction to 75% of full dose 
when recovered (which can mean 
dose delay) 
Grade 3/4 second time  
>7 days 
Dose reduction to 75% of previous 
dose when recovered (which can 
mean dose delay) 
Febrile neutropenia 
- 
Dose reduction to 75% of previous 
dose when recovered (which can 
mean dose delay) 
 
Platelet count 
decreased  
Oxaliplatin 
5-FU 
Grade 1/2  
No dose reduction 
No dose reduction 
Grade 3/4 
Dose reduction 75% 
Dose reduction 75% 
Definition for neutropenia according to NCI-CTCAE v4.03 based on ANC: 
• Grade 1: <Lower limit of normal - 1.5 x 109/L (<1500/mm3) 
• Grade 2: <1.5 x 109/L (<1500/mm3) and ≥1.0 x 109/L (≥1000/mm3) 
• Grade 3: <1.0 x 109/L (<1000/mm3) and ≥0.5 x 109/L (≥500/mm3) 
• Grade 4: <0.5 x 109/L (<500/mm3) 
Definition of platelet count decreased according to NCI-CTCAE v4.03 
• Grade 1: <Lower limit of normal -75.0 x 109/L (<75.000/mm3) 
• Grade 2: <75.0 x 109/L (<75,000/mm3) and ≥50.0 x 109/L (≥50,000/mm3) 
• Grade 3: <50.0 x 109/L (<50,000/mm3) and ≥25.0 x 109/L (≥25,000/mm3) 
• Grade 4: <25.0 x 109/L (<25,000/mm3) 


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7.5.2.4 Diarrhea Dose Modification of 5-Fluorouracil 
Table 6 shows the dose modifications of 5-FU due to diarrhea. 
Table 6 
Diarrhea Dose Modification of 5-FU 
Grade of toxicity 
Diarrhea 
5-FU dose 
0 
No diarrhea and no 
increase in stool 
frequencies 
No dose reduction 
1 
<4 stools/day 
No dose reduction 
2 
4-6 stools/day 
Stop until resumed to Grade 1 or less 
 
1st time: 100% 
 
2nd time: 75% 
 
3rd time: 50% 
3 
7-9 stools/day 
Stop until resumed to Grade 1 or less 
 
1st time: 75% 
 
2nd time: 50% 
4 
≥10 stools/day 
Stop treatment 
7.6 CONCOMITANT MEDICATION 
Medication history (prior medications) is needed prior to study start. Prescription medications, 
over-the-counter medications, and herbal products should be asked for. Any prior anti-cancer 
treatment should also be recorded. 
The Investigator or designee should assess changes in concomitant medications throughout the 
study by asking the patient at each visit. Any changes reported by the patient should be recorded 
in the eCRF. Medications will be coded according to the World Health Organization’s 
Anatomic Therapeutic Chemical classification system classification. 
Any other anti-cancer treatment given during the study should be recorded as concomitant 
medications on the patient’s eCRF. 
 
Non-steroidal anti-inflammatory drugs and opioid analogues may be given as symptomatic 
treatment for neuropathic pain, other drugs prescribed for neuropathic pain may be used to treat 
side effects at the Investigator’s discretion, however it is of major importance that all 
medications used is recorded in the concomitant medication log including start and end date 
and the dose. 
The use of growth factors (i.e. granulocyte-colony stimulating factor [G-CSF]) in patients who 
require G-CSF or GM-CSF therapeutically will be allowed at the discretion of the Investigator 
and may also be used to treat side effects at the Investigator’s discretion.  
Prophylactic treatment for neuropathic pain (anti-depressants, anti-epileptics, local anesthetics) 
is not permitted, but may be used to treat side effects at the discretion of the Investigator. 
Other rescue medication may be used as the discretion of the Investigator. 
7.7 ASSESSMENT OF COMPLIANCE 
Assessment of patient compliance is not applicable as the IMP is administered at the clinic by 
a blinded study nurse as an infusion. Trained medical personnel will administer the IMP 
(i.e. PledOx or placebo), mFOLFOX6 therapy (oxaliplatin, 5-FU, and FA). 


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The Investigator has the responsibility to ensure that all IMP dispensed is recorded in the 
accountability log and in the medical records. 


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8. ASSESSMENT OF EFFICACY 
8.1 EFFICACY PARAMETERS 
8.1.1 Primary Efficacy Variable 
8.1.1.1 Neuropathy Assessment - FACT/GOG-NTX 
The primary efficacy parameter will be chronic CIPN assessed using a patient reported 
outcomes questionnaire. The FACT/GOG-NTX-13 (Version 4) includes 13 items that measure 
the severity and impact of symptoms of neurotoxicity over the past 7 days. Patients rate each 
item from 0 (“not at all”) to 4 (“very much”). These 13 items are summed to create a total 
score, ranging from 0 to 52. A major strength of this instrument is that it was developed with 
patient input. The FACT/GOG-NTX-13 is included in Appendix 2. 
The key symptoms of numbness or tingling in the hands or feet, as well as discomfort, can also 
be assessed reliably using a subscale of the first 4 questions/items of the FACT/GOG-NTX-13 
(i.e. FACT/GOG-NTX-4). The FACT/GOG-NTX-4 was described and further validated by 
Huang (2007) in gynecologic oncology patients receiving cisplatin/paclitaxel. The 4 items 
capture 80% if the treatment difference and more than 60% of the longitudinal change. The 
FACT/GOG-NTX-4 was also used on approximately 1720 patients in the multinational large 
(N=6088 patients, SCOT trial; Iveson et al. 2017) adjuvant study with either mFOLFOX6 or 
CapeOx in patients with stage III or high-risk stage II CRC. The 4 selected questions are the 
most responsive to change in the onset of peripheral neuropathy. Furthermore, CIPN-related 
numbness, tingling and discomfort in hands and feet was assessed by FACT/GOG-NTX-13 to 
evaluate the effect of duloxetine compared to placebo (Smith 2013). This is the study on which 
ASCO based its recommendation for the use of duloxetine in CIPN (Hershman 2014). 
Patients will complete this questionnaire electronically (on a hand-held device/tablet) in the 
hospital, within 72 hours before mFOLFOX6 infusion (Day 1 of each mFOLFOX6 cycle) 
during the Treatment Phase and at each Assessment Visit. In case of technical issues with the 
device/tablet, the patient may provide the PRO on a paper and this will be recorded in the 
system remotely. 
During the COVID-19 pandemic, the FACT/GOG-NTX-13 questionnaire may be completed 
during a telephone call or by completing the paper version of the scale that has been mailed 
to the patient’s home, if a site visit is not feasible. 
8.1.2 Secondary Efficacy Variables 
8.1.2.1 Cold Sensitivity Questionnaire 
Acute CIPN during chemotherapy will be assessed using the “Cold Sensitivity” patient 
questionnaire (see Appendix 3). The questionnaire (paper diary) will be completed according 
to the Schedule of Assessments (Appendix 1). 
Each patient will be asked if they experienced sensitivity to touching cold items within the last 
24 hours. Cold sensitivity will be rated 0 (not at all) to 10 (as bad as you can imagine).  
During the COVID-19 pandemic the Cold Sensitivity questionnaire may be completed during 
a telephone call or by completing the paper version of the scale that has been mailed to the 
patient’s home, if a site visit is not feasible. 


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8.1.2.2 Assessment of Dose Modifications of Oxaliplatin and 5-FU 
It is the responsibility of the Investigator to evaluate the need for dose reduction and/or 
treatment delay of mFOLFOX6 based toxicities and AEs assessed according to NCI-CTCAE 
v4.03 being probably or definitely related to the mFOLFOX6 according to Section 7.5 of the 
protocol. 
The dose of oxaliplatin and 5-FU administered per patient during mFOLFOX6 chemotherapy 
will be recorded. For both oxaliplatin and 5-FU, dose, number of cycles per patient, any dose 
reduction or delay and reason(s) for dose reduction/delay will be recorded in the eCRF. 
8.1.2.3 Vibration Sensitivity Test  
Vibration sensitivity will be assessed within 72 hours before mFOLFOX6 infusion, according 
to the Schedule of Assessments (Appendix 1), using the graduated tuning fork. The assessor 
needs to compare the first measured (recorded) value to the second measurement (recorded as 
well). If there is no significant difference, the first value can be used. If there is a significant 
difference (ie, >1), then a new measurement needs to be performed. 
This test allows a reliable assessment of vibration perception using a 128-Hz graduated tuning 
fork. When the tuning fork is struck against the ball of the thumb, the base of the tuning fork 
is placed over the appropriate bony surface (i.e., lateral malleolus left and right) and the patient 
is asked to indicate the moment when the vibration is no longer detected. The intensity at which 
the patient no longer detects the vibration is reported on a scale of 0 to 8 (Martina et al. 1998; 
Cavaletti et al. 2004). 
Detailed instructions will be provided by PledPharma AB in a separate procedure manual. 
8.1.2.4 Grooved Pegboard Test 
Functional impairment in the non-dominant hand will be assessed within 72 hours before 
mFOLFOX6 infusion, according to the Schedule of Assessments (Appendix 1), using the 
grooved pegboard.This is a manipulative dexterity test of visual-motor coordination and has 
been used in various settings in which neuropathy is a complication, including CIPN 
(Miaskowski et al. 2017). 
Detailed instructions for will be provided by PledPharma AB in a separate procedure manual. 
8.1.2.5 Pain Numerical Rating Scale 
Pain (in hands or feet) will be assessed using a simple NRS (3 questions) shown in Appendix 4. 
Patients will complete the questionnaire within 72 hours before mFOLFOX6 infusion, 
according to the Schedule of Assessments (Appendix 1), on a tablet in the hospital. In case of 
technical issues with the device/tablet, the patient may provide the PRO on a paper and this 
will be recorded in the system remotely. 
During the COVID-19 pandemic, the Pain Numerical Rating Scale may be completed during 
a telephone call or by completing a paper version of the scale that has been mailed to the 
patient’s home, if a site visit is not feasible. 
The 3 NRS questions will assess the worst pain in the hands and feet in the past week (7 days), 
pain on average, and pain right now. Questions are rated by the patient from 0 (no pain) to 10 
(pain as bad as you can imagine). 


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8.1.2.6 EQ-5D-5L 
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome. It is often 
referred to as a QoL questionnaire. The EQ-5D-5L comprises 5 dimensions of health: mobility, 
ability to self-care, ability to undertake usual activities, pain and discomfort, and anxiety and 
depression. There are 5 options (levels) under each domain. An example is shown in  
Appendix 5. 
Patients should complete the EQ-5D-5L questionnaire within 72 hours before mFOLFOX6 
infusion, according to the Schedule of Assessments (Appendix 1), on a tablet in the hospital. 
In case of technical issues with the device/tablet, the patient may provide the PRO on a paper 
and this will be recorded in the system remotely. 
During the COVID-19 pandemic, the EQ-5D-5L may be completed during a telephone call or 
by completing a paper version of the scale that has been mailed to the patient’s home, if a site 
visit is not feasible.  
8.1.2.7 Health Economic Impact 
The health economic impact will be assessed at Day 1 (before IMP infusion) and then at 6, 12, 
18 and 24 months after the first dose of IMP measured by the combined impact of medical 
resource utilization (hospitalizations, outpatient visits, medical procedures and medical use), 
patient impact (AEs, fall accidents, functional loss) and indirect societal costs (loss of ability 
to work). 
Pharmacoeconomic analyses will be performed to assess the clinical and economic impact of 
PledOx vs placebo in a cost-effectiveness and budget impact analysis. The objective will be to 
summarize and evaluate treatment group differences in total resource use, patient burden and 
societal costs of disease and AEs. 
During the COVID-19 pandemic, the Health Economic Impact may be assessed during a 
telephone call or by completing a paper version that has been mailed to the patient’s home, if 
a site visit is not feasible. 


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9. ASSESSMENT OF SAFETY 
9.1 SAFETY PARAMETERS 
9.1.1 Adverse Events 
9.1.1.1 Adverse Event Definition 
An AE in this study is defined as any untoward medical occurrence in a patient after signing 
the ICF. The occurrence does not necessarily need to have a causal relationship with the IMP. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the administration of IMP, 
whether or not causally related. 
The occurrence of an AE may come to the attention of study personnel during study visits and 
interviews of a study recipient presenting for medical care, or upon review by a study monitor 
who is scrutinizing relevant source data. 
All AEs, including chemotherapy related toxicities, will be graded using the NCI-CTCAE 
v4.03. 
Clarifications 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs. However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE. For example, an acute appendicitis that 
begins during the AE reporting period should be reported as “acute appendicitis” and the 
resulting appendectomy noticed under Comments. Pre-study conditions, which led to elective 
surgery during the time of the study, are not to be reported as AEs. 
If an abnormal laboratory value or vital sign is associated with corresponding clinical signs and 
symptoms, the sign/symptom should be reported as the AE and the associated laboratory result 
or vital sign should be considered additional information that is to be collected in the eCRF. 
9.1.1.2 Serious Adverse Events 
An SAE in this study is defined as any untoward medical occurrence that meets 1 of the 
following criteria: 
• Results in death* 
• Is life threatening** 
• Requires inpatient hospitalization*** or prolongation of existing hospitalization*** 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Other medically important condition 
* If a death is an outcome of an event, the AE/SAE that result in the death should be recorded 
and reported as the SAE. Efforts to complete an autopsy should be made and documented in 
the clinical notes. All results should be reported. 
** The term “life threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it was more severe. 


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*** Hospitalizations for the following reasons should not be reported as SAEs: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• Elective or pre-planned treatment for a pre-existing condition during the study that has 
not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the patient’s general 
condition 
• Treatment on an emergency outpatient basis that does not result in hospital admission 
and involves an event not fulfilling any of the definitions of a SAE given above 
Events deemed as serious must be reported to Covance and PledPharma AB within 24 hours 
after the Investigator’s awareness of the SAE. This short time frame is in compliance with 
international regulations. All SAEs should be reported by the site staff in the eCRF.  
If the eCRF is not accessible, in case of electronic system failure, etc. which may cause a delay 
in safety data reporting within the required timelines, the Investigator will use a paper SAE 
form for reporting to Covance by fax.  
Covance Pharmacovigilance 
Email: GlobalSAEinbox@covance.com 
or 
Fax:  Europe: 00 800 529 34043 
 
Taiwan: (886) 800 529 34043 
 
South Korea: (82) 002 800 529 34043 
 
Hong Kong: (852) 001 800 529 34043 
 
Japan:  IDC: (81) 0061010 800-529-34043 
 
 
KDDI: (81) 001010 800-529-34043 
 
 
NTT: (81) 0033010 800-529-34043 
In such cases, the Investigator will also need to record the previously reported information on 
the SAE in the eCRF as soon as the system is available again. 
The Covance contact details will be pre-printed on the SAE form distributed to all Investigators 
participating in the clinical trial. 
If the initial report is not complete, it should be followed by submission of a more detailed 
report within 5 calendar days. 
All SAEs must be followed until the Investigator assesses the event has returned to baseline or 
has resolved. 
After receiving the SAE report form from the Investigator, PledPharma AB or designee will 
make a causality (relationship) assessment. The term SADR (Serious Adverse Drug Reaction) 
is to be used whenever either the Investigator or PledPharma AB or designee deems the SAE 
as possibly or probably related to the IMP.  
If the event is not described before in any clinical study of PledOx, e.g. in the current IB, the 
event is a SUSAR (Suspected Unexpected Serious Adverse Reaction). PledPharma AB or 


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designee has the obligation to submit SUSAR reports electronically to the EudraVigilance 
database within: 
• 7 calendar days if fatal or life-threatening (follow-up information within an additional 
8 calendar days) 
• 15 calendar days if non-fatal and non-life-threatening (follow-up information as soon as 
possible) 
The following bodies are recipients of the reports, and procedures for such reports are familiar 
to PledPharma AB or designee: 
• Competent authority 
• European Medicines Agency 
• The study approving IEC/IRB 
PledPharma AB has delegated the task of reporting SADR/SUSARs to Covance, but has the 
ultimate responsibility for the fulfilment of these tasks. This delegation is enforced in a written 
note. 
9.1.1.3 Pregnancy  
Any pregnancy that occurs during study participation must be reported. Pregnant study patients 
must be withdrawn from treatment immediately, whereas male patients may continue in the 
study should pregnancy of female partners occur. In this case, a separate informed consent will 
be obtained from the female partner for collection of information regarding the pregnancy. 
Each pregnancy must be reported to the Sponsor (or designee) within 24 hours of learning of 
its occurrence. The pregnancy must be followed-up to determine outcome (including premature 
termination) and status of mother and child. The child must be followed at least to the age of 
1 month. Pregnancy complications and elective terminations for medical reasons must be 
reported as an AE or SAE. Spontaneous abortions must be reported as an SAE. Any SAE 
occurring in association with a pregnancy brought to the Investigator’s attention after the 
patient has completed the trial and considered by the Investigator as possibly related to the 
IMP, must be promptly reported to the Sponsor (or designee). 
9.1.1.4 Treatment-Emergent Adverse Events 
All AEs will be recorded in the eCRF.  
Non-treatment emergent AEs will include any AEs that occur between informed consent and 
the first dose of IMP. 
Treatment-emergent AEs will include AEs that occur after the first dose of IMP (i.e. day 1, 
Cycle 1) and end at the EOT visit (i.e. 14 days after the last dose of IMP). AEs will also be 
considered treatment-emergent if they are ongoing at first IMP infusion or start ≤30 days after 
the last dose of IMP.  
The Investigator is to record all directly observed AEs and all AEs spontaneously reported by 
the patient in the patient’s records (source data) and in the eCRFs using concise medical 
diagnostic terminology. The diagnosis/cause of an AE should be recorded rather than the 
symptoms of the AE. If no diagnosis is available each sign and symptom should be recorded 
as individual AEs. 
All AEs must be graded for: 


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• Seriousness 
• Intensity 
• Causality (possible relationship) to the IMP 
The question asked will be “Have you had any health problems since your last evaluation?” If 
no AE has occurred during the period concerned, this should actively be noted in the eCRF. 
All AEs including SAEs will be collected up to 30 days after the EOT visit and followed until 
resolution. 
During the COVID-19 pandemic the AEs and SAEs may be collected by telephone call or by 
paper mailed to the patient’s home for completion, if a site visit is not feasible. 
9.1.1.5 Adverse Events of Special Interest 
Only AESIs which are considered serious are reportable to the safety team. 
Chemotherapy 
Treatment-related toxicity of mFOLFOX6 chemotherapy will be assessed prior to each 
treatment cycle and reported as AEs. Chemotherapy related AEs of special interest may 
include, but are not limited to, peripheral sensory neuropathy, hematological toxicities, ANC, 
febrile neutropenia, WBC count, and thrombocytopenia. Chemotherapy related toxicity may 
enforce dose modifications and dose delays (see Section 7.5.2). 
PledOx  
PledOx related AEs of special interest may include, but are not limited to, seizures, 
anaphylactoid reactions, allergic infusion reactions (hypersensitivity) or diarrhea. 
For patients whose Mn concentrations are >2 x ULN at Cycle 4, Cycle 8, Cycle 12, EOT, and 
any subsequent cycle when Mn sampling is scheduled (in case patients continue with 
mFOLFOX6 and IMP after Cycle 12), a brain MRI and neurological examination will be 
performed to evaluate any cerebral neurological impact (see Section 9.1.2.3). In patients who 
develop any Parkinson-like symptoms, an additional blood Mn sample will be collected and 
analyzed (see Section 9.1.3.6). If Mn levels are elevated (>2 x ULN), an MRI and neurological 
examination will be performed and evaluated. Refer to Figure 2 and Section 9.1.2.3. 
As of March 2nd., 2020, no more blood Mn samples will be collected 
9.1.1.6 Intensity of Adverse Events 
The expression intensity of AEs means the intensity of the event in the opinion of the patient. 
The intensity of each AE is to be graded by the Investigator according to NCI-CTCAE v4.03. 
The severity is graded 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening) or 5 (death related 
to AE). 
9.1.1.7 Causality to the Investigational Medicinal Product  
The relationship between the IMP and each AE has to be classified by the Investigator using 1 
of the following terms: 
Not related: 
An AE for which there is no reasonable temporal association between 
its onset and administration of the IMP, or that can reasonably be 


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explained 
by 
other 
factors, 
including 
underlying 
disease, 
complications, concomitant drugs or concurrent treatment. 
Note: Even if the Investigator feels there was no relationship to IMP, 
the AE experience is to be reported. 
Unlikely to be related: A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship 
improbable, and in which other drugs, chemicals or underlying disease 
provide plausible explanations. 
Possibly related: 
An AE for which there is a reasonable temporal association between its 
onset and administration of the IMP (including the course of treatment 
after withdrawal of the drug) for which other causal factors may not be 
excluded. 
Probably related: 
An AE for which there is a reasonable temporal association between its 
onset and administration of the IMP, including the course after 
treatment withdrawal, and which is more likely to be explained by the 
test drug than by any other cause (e.g. underlying disease, 
complications, concomitant drugs or concurrent treatment). 
Definitely related: 
An AE that is judged as undeniably related to administration of IMP. 
Factors taken into consideration when a definite relationship is 
assigned include whether the AE: 
• Followed a clear temporal sequence from administration of IMP. 
• Could not be possibly explained by the known characteristics of 
the patient’s clinical state, environmental or toxic factors, other 
modes of therapy administered to the patient. 
• Disappeared or decreased on cessation or reduction in dose of 
IMP. 
• Reappeared or worsened when IMP was re-administered. 
• Followed a response pattern known to be associated with 
administration of IMP. 
9.1.1.8 Action Taken for Adverse Events 
For each AE, the following options for ‘Action taken’ will be available on the eCRF: 
• Dose not changed 
• Dose reduced 
• Dose delayed 
• Drug interrupted 
• Drug withdrawn 
• Not applicable 
• Unknown 
9.1.1.9 Recording and Reporting Adverse Event/Intercurrent Illnesses 
It is the responsibility of the Investigator to document all AEs that occur during the study. 
Patient entry into the study is defined as the time at which informed consent is obtained (this 


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must be before any Protocol-specific diagnostic procedures or interventions). All subsequent 
AEs must be reported regardless of whether or not they are considered drug related.  
An AE includes any noxious, pathological or unintended change in anatomical, physiological 
or metabolic functions as indicated by physical signs, symptoms and/or laboratory changes 
whether associated with the study drug and whether or not considered drug related. This 
includes an exacerbation of pre-existing conditions or events, intercurrent illnesses, drug 
interaction or the significant worsening of the indication under investigation that is not recorded 
elsewhere in the eCRF under specific efficacy assessments. Anticipated day-to-day 
fluctuations of pre-existing conditions, including the disease under study, that do not represent 
a clinically significant exacerbation or worsening need not be considered AEs. 
Death is an outcome of an event. The AE that resulted in the death should be recorded and 
reported as the SAE. If an autopsy is performed, efforts should be made to obtain the results. 
Progression of disease should not be reported as an SAE. 
The Investigator must report in detail all adverse signs and symptoms which are either 
volunteered by patients or observed during or following the course of IMP administration on 
the appropriate eCRF page.  
Included in the description should be the nature of the sign or symptom; the date of onset; date 
of resolution (duration); the severity; the relationship to study treatment or other therapy; the 
action taken (if any), and the outcome. 
An unexpected (serious) AE is one not previously reported (in nature, severity or incidence) in 
the current IB, in the clinical plan, or elsewhere. 
In the event of a serious or unexpected AE or ADR, the Investigator will immediately notify 
Covance Pharmacovigilance. 
The IRB/IEC must be informed if the serious or unexpected AE, in the opinion of the Sponsor 
or the Investigator, is likely to affect the safety of the patients or the conduct of the study. 
All Investigators participating in the study will also be notified of the unexpected SAEs. 
9.1.1.10 Adverse Event Follow-up Procedures 
All AEs including SAEs will be collected up to 30 days after the the EOT visit and followed 
until resolution. 
During the COVID-19 pandemic, AEs and SAEs may be collected by phone or by paper 
mailed to the patient’s home, if a site visit is not feasible. 
9.1.2 Laboratory Evaluation 
Blood samples for laboratory evaluation will be collected according to the Schedule of 
Assessments (Appendix 1). 
In addition to the sample timepoints shown in the Schedule of Assessments, blood samples 
may be taken whenever necessary according to the Investigator’s judgement (according to local 
guidelines and practice). 
For each value outside the normal ranges, the Investigator should mark the value as “Clinically 
Significant” (CS) or “Not Clinically Significant” (NCS). 


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9.1.2.1 Hematology  
Blood samples (approximately 4.5 mL per sample) for hematology evaluations should be 
collected by venipuncture or capillary sampling from the finger. The exact timepoint for 
collection of the samples will be noted in the eCRF.  
Hematology: WBC count differential (neutrophils, lymphocytes, monocytes, eosinophils and 
basophils), ANC, RBC count, platelet count, and hemoglobin. 
Local laboratories will be used to analyze hematology samples. 
9.1.2.2 Biochemistry  
Blood (serum) samples (approximately 4.5 mL per sample) for biochemistry evaluations 
should be collected by venipuncture. The exact timepoint for collection of the samples will be 
noted in the eCRF.  
Biochemistry: Alkaline phosphatase (ALP), total bilirubin, ALT, AST, serum creatinine, and 
albumin. 
Local laboratories will be used to analyze biochemistry samples.  
9.1.2.3 Blood Manganese 
As of March 2nd., 2020, Blood Manganese testing will only be done in patients with 
Parkinson-like symptoms following previous use of IMP. 
Before March 2nd., 2020, Blood samples (approximately 6.0 mL per sample) will be collected 
for assessment of Mn at Screening and at timepoints according to the Schedule of Assessments 
(Appendix 1) at the day of treatment and before IMP infusion. 
Figure 2 shows a flow chart of monitoring increased Mn levels and/or Parkinson-like 
symptoms. Patients that show Mn concentrations >2 x ULN at Cycle 4, Cycle 8, Cycle 12, 
EOT, and any subsequent cycle when Mn sampling is scheduled (in case patients continue with 
mFOLFOX6 and IMP after Cycle 12) will be referred to a brain MRI investigation and a 
neurological examination (see Section 9.1.3.6). 
Blood for Mn assessment will be taken in the case of Parkinson-like symptoms. If the Mn level 
is >2 x ULN, an MRI of the brain should be performed (as above). If the Mn level is ≤2 x ULN 
then the patient can continue in the study according to the protocol. 
However, in case of increased Mn levels, patients will be followed up at each Assessment visit 
throughout the study, i.e. their blood Mn level will be checked again, until resolution or the 
above applies. 
All Mn samples must be shipped immediately for analysis by a central laboratory. 
Detailed sampling and shipment instructions will be provided separately to the investigational 
sites. 


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Figure 2 
Flow Chart of Monitoring Increased Mn Levels and/or Parkinson-like 
Symptoms 
 
9.1.2.4 Seizures, Anaphylactoid Reactions, or Allergic Infusion Reactions 
In the ongoing POLAR program, 2 patients on IMP have been reported having seizures; 1 
during infusion preceding a fatal outcome and the other at 2 days after IMP infusion. One 
seizure has also been reported in a previous study in a patient who was treated with 
antiepileptics 2 days after IMP infusion. Refer to IB, Section 6 for details. 
In the ongoing program there has also been 3 patients having had anaphylactoid reactions or 
allergic infusion reactions. 
Patients with an anaphylactoid reaction/allergic infusion reaction (hypersensitivity), with 
moderate or severe intensity and judged to be related to IMP should discontinue dosing but still 
continue in the study to be followed-up. 
9.1.2.5 Carcinoembryonic Antigen  
Tumor marker assessments will be performed according to the Schedule of Assessments 
(Appendix 1). 
9.1.3 Other Study Specific Parameters 
9.1.3.1 Vital Signs 
Vital signs will be recorded at time points according to the Schedule of Assessments 
(Appendix 1). 
Vital signs include resting pulse (beats per minute), body temperature, and resting systolic and 
diastolic blood pressure and should be measured on the same arm after at least 5 minutes of 
supine rest. 


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Weight will be measured at Screening, each Treatment Visit (within 72 hours before 
mFOLFOX6 infusion), and the EOT visit. 
Height will be recorded at Screening only. 
9.1.3.2 Physical Examination 
A physical examination will be performed at time points according to the Schedule of 
Assessments (Appendix 1). 
The physical examination including a neurologic assessment (specifically including, but not 
limited to, tendon reflexes and sensation) should be performed according to local clinical 
practice prior to oxaliplatin treatment. Any abnormal/pathological findings should be recorded 
and judged as CS or NCS by the Investigator. Any clinically significant abnormalities should 
be recorded as medical history, or as AEs if started after signing ICF. 
9.1.3.3 ECOG Performance Status 
ECOG performance status (Table 7) will be recorded at time points according to the Schedule 
of Assessments (Appendix 1) and within 72 hours before mFOLFOX6 infusion. 
 
During the COVID-19 pandemic, the ECOG Performance Status may be collected by phone 
or by completing the paper version of the scale that has been mailed to the patient’s home, 
when a site visit is not feasible. 
 
Table 7 
ECOG Performance Status* 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours. 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair. 
5 
Dead. 
* As published in Oken et al. 1982. 
9.1.3.4 12-lead Electrocardiogram  
No more ECGs are being done. 
9.1.3.5 Tumor/Disease Assessments 
Baseline radiographic assessment of disease will be performed within 42 days prior to surgery 
or after surgery if not done previously. The period from surgery to start of therapy should be 
as soon as possible, preferably within 12 weeks.  


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The CT or MRI scan of the thorax, abdomen and pelvis will be performed according to the 
Schedule of Assessments (Appendix 1) to identify any signs for CRC recurrence. The method 
chosen, CT (preferred) or MRI, is optional and should be in accordance with local guidelines 
and practice, but for each patient the same assessment should be performed throughout the 
study. CT/MRI scans will be read locally. 
Assessment of DFS will include objective review of signs or symptoms of recurrence of CRC. 
Signs and symptoms may include any assessment result that, in the opinion of the Investigator, 
provides evidence for the recurrence of the disease, including CT or MRI, CEA, hematology, 
biochemistry, etc. 
9.1.3.6 Brain MRI and Neurological Examination 
For patients whose Mn concentrations are >2 x ULN after Cycle 4, Cycle 8, Cycle 12, EOT, 
and any subsequent Cycle when Mn sampling is scheduled (in case patients continue with 
mFOLFOX6 and IMP after Cycle 12), a brain MRI and neurological examination will be 
performed to evaluate any cerebral neurological impact. If the patient is NOT receiving the 
IMP anymore, there is no requirement to perform any brain MRI nor neurological examination. 
The following assessments may be included in the neurological examination: 
• Muscle strength 
• Sensory and cranial nerve status 
• Tendon reflexes 
• Balance 
• Pronation/supination hands => coordination test 
• Rigidity observation (arm extension) 
• Presence of tremor 
• Walking test 
• Bradykinesia 
9.2 APPROPRIATENESS OF MEASUREMENTS 
The measures used to assess safety and efficacy in this study are consistent with those used in 
most conventional oncology trials. 
All laboratory and other assessments (pregnancy tests, vital signs, ECG, physical examination, 
etc.) are regarded as standard, i.e. are widely used and generally recognized as reliable, accurate 
and relevant. 
The maximum volume of blood collected for study purposes per patient at a visit will be 
20.5 mL. Details are shown in Table 8. Some of the assessments shown below will not be 
collected at all visits (see Appendix 1 for the Schedule of Assessments). 
 
 


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Table 8 
Maximum Volume of Blood Collected for Study Purposes at a Single Visit 
Assessment 
Volume (mL) 
CEA 
0.6 
Pregnancy test (serum) in WOCBP only 
4.9 
Hematology 
4.5 
Biochemistry 
4.5 
Mn 
6.0 
Total 
20.5 
 


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10. STATISTICS 
10.1 STATISTICAL METHODS 
A Statistical Analysis Plan (SAP) will be finalized as a separate document following the 
global study hold and describes the technical and detailed description of the planned 
statistical summaries taking into account the premature study hold. The power of the study 
has been affected as a result of the premature stop of IMP dosing in individual patients.  
For that reason the statistical analyses will be done on the combined dataset of the POLAR-A 
and POLAR-M studies, with data from POLAR-A and POLAR-M cohorts of patients being 
evaluated as separate strata. 
The details of the combined and stratified analyses are layed out in the SAP..  
Unless otherwise stated tabulation of summary statistics and data analysis will be performed 
using SAS® (Version 9.4 or later). 
The Statistical Methods as originally planned are detailed below. 
10.1.1 Analysis Populations 
Four analysis populations will be defined: 
• All patients randomized will be included in the All Randomized Patients population, 
according to their randomized treatment 
• The intention to treat principle is used to define the primary analysis population, the Full 
Analysis Set (FAS), which will consist of all randomized patients who receive at least 
1 dose of the study treatment 
• The Per Protocol Set (PPS) is defined as a subset of the FAS constituted by patients 
who: (a) meet all inclusion/exclusion criteria liable to affect the efficacy assessment, and 
(b) do not present any major protocol deviations 
• The Safety Analysis Set will consist of all patients included in the study and treated with 
at least 1 dose of study treatment 
10.1.2 General Considerations 
Demographic and baseline characteristics (e.g. age [years], gender [male, female], race [White, 
Asian, Black, other], body weight [kg], height [cm], etc.), will be summarized by treatment 
group and overall. 
Baseline characteristics and endpoints will be presented using descriptive statistics: continuous 
variables in terms of number of patients (n), mean, median, standard deviation (SD), and range 
(minimum and maximum). Categorical variables will be summarized by counts and 
percentages. Unless otherwise stated the calculation of proportions will be based on the sample 
size of the population of interest. 
Missing data will be handled according to the SAP. 
The primary endpoint will be analyzed only once when patients have completed and reached 
12 months. Analysis of primary endpoint, major secondary endpoints and current safety data 
will be performed after all patients have completed treatment and reached 12 and 24 months 
after first dose of IMP. In addition, survival data will be analyzed after 24 months. Final 
evaluation and analysis of study data will be performed after all patients have completed the 
study. 


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The FAS will be primarily used in the analysis of efficacy. The primary efficacy analysis and 
the secondary efficacy analyses will be repeated for the PPS. The Safety Analysis Set will be 
considered for safety analyses. 
Protocol deviations will be defined as any change, divergence, or departure from the study 
design or procedures. Further details will be presented in the SAP.  
10.1.3 Statistical Hypothesis 
The active arm will be statistically tested against placebo. For the test the statistical hypothesis 
is:  
H0: PledOx treatment arm is equal to placebo with respect to the primary efficacy endpoint. 
H1: PledOx treatment arm is not equal to placebo with respect to the primary efficacy endpoint. 
For the primary endpoint, the Cochran-Mantel-Haenszel test will test the following two-sided 
hypothesis:  
H0: Ψ=1 versus H1: Ψ≠1 
where Ψ defines the common OR of PledOx to placebo. An OR <1 favors the PledOx group. 
Other secondary endpoints will be using two-sided hypothesis testing and details will be 
presented in the SAP. 
10.1.4 Primary Efficacy Endpoint Analysis 
The primary efficacy endpoint will be analyzed using the FAS population. A summary table 
showing responses from all cycles, including change from baseline, will be presented by visit 
and treatment group. 
The primary endpoint will be presented descriptively (n, %) together with its corresponding 
95% CI based on the Wilson-score method and will be presented for both treatment groups. 
The Cochran-Mantel-Haenszel test will be performed adjusting for baseline score of 
FACT/GOG-NTx (2 levels) and treatment. 
The OR, 95% CI and p-value using the Cochran-Mantel-Haenszel test for the difference in 
event rates between the 2 treatment groups will be presented. The results from the 
Cochran-Mantel-Haenszel test are considered the primary analysis results using the FAS. 
An identical analysis, as described above, based upon the PPS will be performed. 
In addition, a logistic regression analysis will be performed for the primary endpoint to adjust 
for treatment in the estimation of the odds. These results will be interpreted as exploratory 
findings. 
10.1.5 Secondary Endpoint Analyses 
Secondary endpoints with regard to categorical endpoints will be analyzed using the same 
methods as described for the primary endpoint. 
Secondary endpoints with regard to continuous endpoints will be evaluated using ANCOVA, 
with treatment as fixed factor and baseline as a covariate.  


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10.1.5.1 Subgroup Analysis 
A sub group analysis will be performed for categories of important prognostic factors and 
demography. Further details will be described in the SAP. 
10.1.6 Extent of Exposure 
Dosing data will be summarized by treatment group to include duration of treatment (weeks), 
number of patients treated by cycle, number of cycles per patient, cumulative dose, dose 
intensity and relative dose intensity, number (%) of patients with dose modifications (reduced 
or delayed), and mean duration of dose delay.  
10.1.7 Safety Analysis 
The safety and tolerability of PledOx/placebo is determined by reported AEs, laboratory tests, 
and vital signs. All safety parameters will be summarized using the Safety Analysis Set. 
All AEs recorded on the eCRF will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary (using the most recent version). All AEs and SAEs will be 
summarized using descriptive statistics. The incidence and percentage of patients with at least 
1 occurrence of a preferred term will be included, according to the most severe NCI CTCAE 
v.4.03 grade. The number of AEs reported per MedDRA preferred term will also be 
summarized. Causality (relationship to study therapy) will be summarized separately. Duration 
of AEs will be determined and included in listings along with action taken and outcome). 
Laboratory results will be classified according to NCI-CTCAE v.4.03. Incidence of laboratory 
abnormalities will be summarized; laboratory results not corresponding to an NCI-CTCAE 
v.4.03 term will not be graded. 
The results from physical examinations, and vital signs measurement will be tabulated. 
Descriptive statistics will be provided as appropriate. 
10.1.7.1 Tumor/Disease Assessment, Disease Free Survival 
DFS is defined as the time from the date of randomization until the date of objectively 
determined signs or symptoms of recurrence of CRC or death due to any cause. Signs and 
symptoms may include any assessment result that, in the opinion of the Investigator, provides 
evidence for the recurrence of the disease. Patients without objectively determined disease 
recurrence who are alive at the end of the follow-up period (or who were lost to follow up) will 
be censored on the date of the patient’s last assessment of disease recurrence; if no baseline or 
post baseline radiologic assessment is available, the patient will be censored at the date of 
randomization. 
Kaplan-Meier survival curves (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics (median survival time, 25% and 75% 
percentiles with their respective 95% CIs, and minimum and maximum).  
The HR (including 95% CI) of PledOx compared to placebo will be calculated by Cox 
Proportional Hazards regression using treatment as a fixed factor in the model. A HR <1 favors 
the PledOx group.  
These analyses will be performed on the FAS.  


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10.1.7.2 ECG Analysis 
ECG will also be presented by listings of the major parameters (e.g. QTc). 
10.1.8 Interim Analysis 
No interim analysis for efficacy is planned. 
10.2 SAMPLE SIZE 
The primary endpoint is defined as the proportion of patients scoring 3 or 4, derived as the 
maximum score of items NTX 1 to 4, in any of the symptoms of numbness, tingling and 
discomfort in hands and feet in the FACT/GOG-NTX-13, after 9 months after the first dose. 
The assumption of the proportion of patients who will satisfy the criteria for the primary 
endpoint in the untreated (placebo) study population is based on the results in the SCOT trial. 
Results were presented at ASCO 2017 and roughly 40% of the placebo population had 
symptoms graded “quite a bit/very much”, which corresponds to 3 or more in this study. 
With 112 patients per group, the POLAR-A study has 91% power to detect a reduction 
(improvement) from 40% to 20% (OR = 0.375) in the primary endpoint using two-sided test 
controlled at the 0.05 type-I error rate. To account for 20% dropout in the study, in total 
280 patients (140 patients per arm) will be randomized. 
Sample size assumptions will be monitored in a blinded fashion as part of the regular 
monitoring of the study. In case there are indications these are not met; a re-estimation of the 
sample size may occur. 
10.3 LEVEL OF SIGNIFICANCE 
The Type I error rate of 0.05 will be used for testing the primary and the main secondary 
efficacy endpoints and will be controlled using the following 3-family wise serial gatekeeping 
multiple comparisons procedure (MCP). Following this MCP, progression to the next family 
will only occur if the null hypothesis within the current family is rejected at a family-specific 
overall significance level. If the null hypothesis within a family is not rejected, the statistical 
tests corresponding to all subsequent families will be considered not statistically significant.  
All hypothesis tests will be 2-sided.  
• The first family will include the primary endpoint: The p-value for the null hypothesis 
must be less than 0.05 to be considered to have met the primary efficacy objective. If 
the primary efficacy null hypotheses is not rejected (i.e. p-value >0.05), all subsequent 
statistical tests will not be considered statistically significant. 
The second family will include the key secondary endpoints (see below) and they will be tested 
using an overall type I error rate of 0.05 by means of a hierarchical procedure, i.e. in a 
predefined order to control for multiplicity within this family. This will be done only if the 
primary endpoint has met its criteria for rejecting the null hypothesis, i.e. if p<0.05 for PledOx 
5 µmol/kg vs placebo. Subsequently, the test for the next secondary endpoints within that 
family will be performed only if the preceding hypothesis test shows p<0.05. The predefined 
(hierarchical) order to test the key secondary variables will be the following: 
• 
Proportion of patients (with mild, moderate or severe chronic CIPN) scoring 2, 3 or 
4, in at least one of the first 4 items of the FACT/GOG-NTX-13 (i.e. 


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FACT/GOG-NTX-4), targeting numbness, tingling or discomfort in hands and/or 
feet, 9 months after first dose of IMP. 
• 
Mean change from baseline in sensitivity to touching cold items on day 2 of Cycle 
4 of mFOLFOX6 chemotherapy, as assessed by the Cold Sensitivity questionnaire. 
• 
Mean cumulative dose of oxaliplatin administered per patient during mFOLFOX6 
chemotherapy, 9 months after the first dose of IMP. 
The third family will include the remaining key secondary endpoints (see below) and they will 
be tested using an overall type I error rate of 0.05 by means of a (hierarchical) predefined 
procedure in order to control for multiplicity within this family. This will be done only if the 
family 1 and family 2 endpoints have met their criteria for rejecting the null hypothesis, and 
the order to test the remaining key secondary variables will be the following: 
• 
Mean change from baseline in worst pain in hands or feet, using an NRS (Brief Pain 
Inventory short form), at 9 months after the first dose of IMP. 
• 
Mean change from baseline in the time to complete the grooved Pegboard with the 
non-dominant hand, at 9 months after first dose of IMP. 
• 
The sustained efficacy of the primary endpoint defined as the proportion of patients 
scoring 3 or 4 in at least 1 of the first 4 items of the FACT/GOG-NTX-13 
(i.e. FACT/GOG-NTX-4), targeting numbness, tingling or discomfort in hands 
and/or feet, 12, 15, 18, 21 and 24 months after the first dose of IMP. 
10.4 CRITERIA FOR THE TERMINATION OF THE STUDY 
Refer to Sections 6.4 and 6.5. 
10.5 PROCEDURE FOR ACCOUNTING FOR MISSING, UNUSED AND SPURIOUS DATA 
All reasonable efforts will be made to obtain complete data for all patients; however, missing 
observations may occur due to patients being lost to follow-up or non-compliant with the 
required protocol assessments. 
There are several imputation methods used for missing values of the primary endpoint. 
The first and main analysis for imputation of missing values will be done using the placebo 
multiple imputation method, pMI, assuming a statistical behavior of placebo- and active drug 
treated patients after dropout as the statistical behavior of placebo-treated patients, where 
missing values will be imputed based on the observed data in the placebo patients, using an 
imputation regression model with parameters estimated from the placebo arm (group). There 
will be several sensitivity analyses done for imputation of missing data. 
Further details will be presented in the SAP. 
10.6 DEVIATIONS FROM THE ORIGINAL STATISTICAL PLAN 
Any deviations from the original statistical plan as described in this Protocol will be agreed by 
the Sponsor and Covance and documented and justified in an amendment, the final SAP or the 
final CSR, as appropriate. 


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11. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The clinical monitor(s) should be given direct access to primary patient data (i.e. source data) 
which supports the data on the eCRFs for the study, i.e., general practice charts, hospital notes, 
appointment books, original laboratory records etc. Because this enters into the realm of patient 
confidentiality, this fact must be included in the ICF that the patient signs. Other authorized 
persons such as auditors may need to have direct access to this source data.  
11.1 SOURCE DATA 
Source data is defined as all information in original records and certified copies of original 
records of clinical findings, observations or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study. Source data are contained in source documents 
(original records or certified copies). 
11.2 SOURCE DOCUMENTS 
Source documents are defined as original documents, data and records (e.g. hospital records, 
clinical and office charts, laboratory notes, memoranda, diaries or evaluation check lists, 
pharmacy dispensing records, recorded data from automated instruments, copies or 
manuscripts certified after verification as being accurate copies, microfiches, photographic 
negatives, microfilm or magnetic media, X-rays, patient files, records kept at the pharmacy, at 
the laboratories and at medico-technical departments involved in the clinical study).  
11.3 DIRECT ACCESS 
Direct access is defined as the permission to examine, analyze, verify and reproduce any 
records and reports that are important to evaluation of a clinical study. Any party (e.g. domestic 
and foreign regulatory authorities, Sponsor/ Covance monitors and auditors) with direct access 
should take all reasonable precautions within the constraints of the applicable regulatory 
requirements to maintain the confidentiality of patient identities and Sponsor proprietary 
information. 


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12. QUALITY CONTROL AND QUALITY ASSURANCE 
An independent audit at the study site may take place at any time during or after the study. The 
independent audit can be carried by the Quality Assurance & Compliance (QA) Department at 
Covance, the QA department of the Sponsor, or a regulatory authority.  
12.1 QUALITY CONTROL 
Quality Control is defined as the operational techniques and activities undertaken within the 
QA system to verify that the requirements for quality of the study related activities have been 
fulfilled. 
Quality Control should be applied to each stage of data handling to ensure that all data are 
reliable and have been processed correctly. 
12.2 QUALITY ASSURANCE 
QA is defined as the planned and systematic actions that are established to ensure that the study 
is performed, and the data are generated, documented (recorded) and reported in compliance 
with GCP and the applicable regulatory requirements. 
12.2.1 Inspection 
An Inspection is defined as the act by a regulatory authority of conducting an official review 
of documents, facilities, records and any other resources that are deemed by the authorities to 
be related to the clinical study and that may be located at the site of the study, or at the Sponsor’s 
and/or Covance’s facilities, or at any other establishments deemed appropriate by the 
regulatory authorities. 
12.2.2 Audit 
An Audit is a systematic and independent review of study related activities and documents to 
determine whether the validated study related activities were conducted, and the data were 
recorded, analyzed and accurately reported according to the Protocol, designated SOPs, GCP 
and the applicable regulatory requirements. 
 


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13. ETHICS 
13.1 ETHICAL CONDUCT OF THE STUDY 
This clinical study will be conducted in compliance with this Protocol, and in accordance with 
the provisions of the guidelines of the World Medical Association Declaration of Helsinki, 
GCP, designated SOPs, and with local laws and regulations relevant to the use of new 
therapeutic agents in the country of conduct. 
The IEC/IRB must be constituted according to the local laws/guidelines. 
13.2 INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE APPROVAL 
Before initiating a study, the Investigator should have written and dated approval/favorable 
opinion from the relevant IRB/IEC for the study Protocol (and any amendments), written ICF, 
ICF updates, patient recruitment procedures (e.g. advertisements), and any other written 
information to be provided to patients. Approval will be indicated in writing with reference to 
the final Protocol number and date. Details of the IRB/IEC’s constitution including names of 
its members and what function they perform on the committee (e.g. chairman, specialist, 
lay-member) should be made available to Covance. 
During the study, the Investigator should provide to the IRB/IEC all documents that are patient 
to review. 
Each participating center will submit the Protocol to the local IRB/IEC and their written, 
unconditional approval obtained and submitted to the Sponsor before the start of the study. 
Verification of the IRB/IEC’s unconditional approval of the Protocol will be transmitted to the 
Sponsor prior to the start of the study. This approval must refer to the study by exact Protocol 
title and number, identify the documents reviewed and state the date of review and/or approval. 
The IRB/IEC must be informed by the Investigator of all subsequent Protocol amendments and 
of unexpected serious adverse reactions occurring during the study which are likely to affect 
the safety of the patients or the conduct of the study. Approval for such changes must be 
transmitted in writing to the Sponsor by the Investigator. 
The Investigator should provide written reports to the IRB/IEC annually or more frequently if 
requested on any change significantly affecting the conduct of the study and/or increasing risk 
to the patients. A final report of study outcome, if required, should also be submitted by the 
Investigator to the IRB/IEC. 
13.3 INFORMED CONSENT 
The principles of informed consent in the Declaration of Helsinki should be implemented in 
this clinical study before Protocol-specified procedures are carried out. Information should be 
given in both oral and written form whenever possible and deemed appropriate by the IRB/IEC. 
Patients and their relatives must be given ample opportunity to inquire about details of the 
study. 
The Investigator or designee will explain the nature, purpose and risks of the study and provide 
the patient with a copy of the patient information sheet. The patient will be given sufficient 
time to consider the study’s implications before deciding whether to participate.  


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Consent forms must be in a language fully comprehensible to the prospective patient. Informed 
consent will be documented by the use of a written consent form approved by the IRB/IEC and 
signed by the patient and the Investigator obtaining the consent. The ICF will also be annotated 
with the study patient number. 
The written consent document will embody the elements of informed consent as described in 
the Declaration of Helsinki and will also comply with local regulations. Consent must be 
documented by the patient’s dated signature. The signature confirms the consent is based on 
information that has been understood. Each patient’s signed ICF must be kept on file by the 
Investigator for possible inspection by regulatory authorities and the Sponsor. 
Should there be any amendments to the final Protocol, such that would directly affect the 
patient’s participation in the study e.g. a change in any procedure, the ICF must be amended to 
incorporate this modification and the patient must agree to sign this amended ICF indicating 
that they re-consenting to participate in the study. 
Patients will be instructed that they are free to obtain further information from the Investigator 
at any time and that they are free to withdraw their consent and discontinue participation in the 
study at any time without prejudice. 
The prospective patient will also be advised that access to medical records would be required, 
and his/her general practitioner would be informed of the patient’s intention to participate in 
this study. 
13.4 MODIFICATION OF PROTOCOL 
The Investigator or Covance should not implement any deviation from, or changes of, the 
Protocol without agreement by the Sponsor and prior review and documented 
approval/favorable opinion from the IRB/IEC of an amendment. The only exceptions are where 
necessary to eliminate an immediate hazard(s) to study patients, or when the change(s) involves 
only logistical or administrative aspects of the study (e.g. change in monitor[s], change of 
telephone number[s]). Non-substantial Protocol amendments may or may not be required to be 
submitted for approval/notification to the IRB/IECs and regulatory agencies. 
As soon as possible, the implemented deviation or change, the reasons for it, and, if appropriate, 
the proposed Protocol amendment(s) should be submitted (according to national legislation): 
a) 
To the IRB/IEC for review and approval/favorable opinion 
b) 
To the Sponsor for agreement and, if required 
c) 
To the regulatory authority(ies) 
The party initiating an amendment must confirm it clearly in writing and it must be signed and 
dated by the Sponsor and the Coordinating Investigator. Covance will ensure that the 
Investigators submit necessary Protocol amendments to the appropriate IRB/IEC. 
All agreed Protocol amendments must be clearly documented using standard procedures as 
defined by the Sponsor, and must be signed and dated by the Sponsor and the Investigator. 


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14. DATA HANDLING AND RECORD KEEPING 
14.1 COMPLETION OF ELECTRONIC CASE REPORT FORMS 
Investigators will be provided with detailed eCRF Completion Guidelines that will identify the 
required data points to be collected, how to document them and when the data should be 
documented. Appropriate training in electronic data capture and support will be provided.  
It is the responsibility of the Investigator to maintain adequate and accurate eCRFs to record 
(according to the eCRF Completion Guidelines) all observations and other data pertinent to the 
clinical trial obtained during scheduled or unscheduled visits. All eCRFs should be fully 
completed to ensure accurate data interpretation.  
The computerized handling of the data after receipt of the eCRFs may generate additional 
requests via electronic queries to which the Investigator is obliged to respond by confirming or 
modifying the data questioned. These requests with their responses will be appended to the 
eCRFs held by the Investigator and Sponsor. 
The electronic data capture system is 21 CFR Part 11 compliant. 
14.2 ARCHIVING 
According to ICH-GCP, the documents which should be archived are ‘essential documents’ 
which individually and collectively permit the evaluation of the conduct of a study and the 
quality of the data produced. 
Source documentation must also be archived. This may include observations and source data 
contained in medical records (certified copies or originals are acceptable for archiving 
purposes), data collection forms or eCRFs and research related records held in support 
departments. All hard copies of source documents must be retained for a period dependent on 
the local regulations. If electronic records of documents exist these must be backed up and 
retained with the hard copies. 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or planned marketing 
applications in an ICH region (that is at least 25 years) or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the product. However, these documents 
should be retained for a longer period if required by the applicable regulatory requirements or 
by an agreement with the Sponsor. It is the responsibility of the Sponsor to inform the 
Investigator as to when these documents no longer need to be retained.  


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15. FINANCING AND INSURANCE 
Financial disclosure information must be provided by all Investigators and Sub-Investigators 
and will be collected by Covance prior to the start of the study. 
The sponsor holds and will maintain an adequate insurance policy covering damages arising 
out the study. The level of compensation will be in accordance with the country specific clinical 
trial insurance requirements. 


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16. PUBLICATION POLICY 
An integrated clinical and statistical study report shall be written by PledPharma AB in 
consultation with the Coordinating Investigator. The results of the study may be published as 
an original article in an appropriate medical journal. The choice of journal will be made by 
PledPharma, AB with agreement from the coauthors. In a multicenter study, the first 
publication will be a full publication of all data from all sites. Any publications of the results, 
either in part or in total (abstracts in journals or newspapers, oral presentations, etc.) by 
Investigators or their representatives will require pre-submission review and approval by 
PledPharma AB. 
All authors must meet at least 2 of the following criteria: 
• Substantial contribution to the conception and design of the study 
• Substantial contribution to the recruitment of patients (i.e., 1 of the 6 best recruiting 
centers within the study) 
• Substantial contribution to analysis and interpretation of the data 
• Substantial contribution to drafting the article or revising it critically for important 
intellectual content 
The Coordinating Investigator(s) will be given the choice to be the first or the last author. The 
subsequent authors and their order will be based on scientific input to the study and recruitment 
(number of patients randomized and data quality). PledPharma AB will retain the right to 
decide on authors and to include in the authorship list names other than those of Investigators. 
 


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17. COVANCE SPECIFIC ADMINISTRATIVE PROCEDURES 
17.1 STUDY PERSONNEL 
Prior to the start of the study, each Investigator must supply Covance with the names and 
curricula vitae of the clinically responsible Sub-Investigators of the study and the names of 
other possible participants and their professional backgrounds (e.g. medical doctor, nurse, etc.). 
17.2 STUDY MONITORING 
The Sponsor and Covance are responsible for ensuring the proper conduct of the study with 
regards to Protocol adherence and validity of the data recorded on the eCRFs. Covance has 
therefore assigned both an Investigator and a clinical monitor to the study. With duties to aid 
the Investigator and at the same time, Covance, in the maintenance of complete, legible, 
organized and easily retrievable data. In addition, a clinical monitor will explain, interpret and 
ensure the Investigator’s understanding of all applicable regulations concerning the clinical 
evaluation of a pharmaceutical product and ensure an understanding of the Protocol, reporting 
responsibilities and the validity of the data. 
The Investigator should ensure the accuracy, completeness, legibility, and timeliness of the 
data transcribed on the eCRFs and in all required reports. Data transcribed on the eCRF, which 
are derived from source documents, should be consistent with the source documents or the 
discrepancies should be explained. 
17.2.1 Review of Case Report Forms 
Before acceptance, the clinical monitor will review the eCRFs for completeness and adherence 
to the protocol. 
17.3 PRE-STUDY DOCUMENTATION REQUIREMENTS 
Prior to shipment of IMP, all relevant documents must be submitted/returned to Covance by 
the Investigator. Refer to ICH GCP Section 8 for a list of documents. 
 


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18. REFERENCES 
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Oncol. 2001; 18: 18-25.  
André T, Boni C, Mounedji-Boudiaf L, et al. Multicenter International Study of 
Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) 
Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. 
N Engl J Med. 2004; 350: 2343-51. 
André T, Boni C, Navarro M et al. Improved overall survival with oxaliplatin, fluorouracil, and 
leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin 
Oncol 2009; 27: 3109-3116. 
Bennett GJ, Doyle T, Salvemini D. Mitotoxicity in distal symmetrical sensory peripheral 
neuropathies. Nat Rev Neurol. 2014; 10: 326-336. 
Boisen MK, Johansen JS, Dehlendorff C, et al. Primary tumor location and bevacizumab 
effectiveness in patients with metastatic colorectal cancer. Ann. Oncol. 2013; 24: 2554-2559. 
Brule SY, Jonker DJ, Karapetis CS, et al. Location of colon cancer (right-sided versus 
left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17. 
Eur J Cancer 2015; 51: 1405-1414. 
Cascinu S, Catalano V, Cordella L, et al. Neuroprotective effect of reduced glutathione on 
oxaliplatin-based chemotherapy in advanced colorectal cancer: a randomized, double-blind, 
placebo-controlled trial. J Clin Oncol. 2002; 20: 3478–3483. 
Cavaletti G, Bogliun G, Marzorati L, et al. Early predictors of peripheral neurotoxicity in 
cisplatin and paclitaxel combination chemotherapy. Ann Oncol. 2004; 15: 1439-1442. 
Coriat R, Alexandre J, Nicco C, et al. Treatment of oxaliplatin-induced peripheral neuropathy 
by intravenous mangafodipir. J Clin Invest. 2014; 124: 262-72. 
Dienstmann R, Vermeulen L, Guinney J, et al. Consensus molecular subtypes and the evolution 
of precision medicine in colorectal cancer. Nat Rev Cancer. 2017; 17: 79-92.  
Driessen CML, de Kleine-Bolt KME, Vingerhoets AJJM, et al. Assessing the impact of 
chemotherapy-induced peripheral neurotoxicity on the quality of life of cancer patients. 
Support Care Cancer. 2012; 20: 877-881. 
Gamelin L, Capitain O, Morel A, et al. Predictive factors of Oxaliplatin neurotoxicity: the 
involvement of the oxalate outcome pathway. Clin Cancer Res. 2007; 13: 6359–6368. 
Glimelius B, Manojlovic N, Pfeiffer P, Mosidze B, Kurteva G, Karlberg M, Mahalingam D, 
Buhl Jensen P, Kowalski J, Bengtson M, Nittve M, Näsström J. Persistent prevention of 
oxaliplatin-induced 
peripheral 
neuropathy 
using 
calmangafodipir 
(PledOx®): 
a 
placebo-controlled randomised phase II study (PLIANT). Acta Oncol. 2017; 
Guilarte TR. Manganese and Parkinson’s disease: A critical review and new findings. Environ 
Health Perspectives. 2010; 118: 1071-1080. 


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CONFIDENTIAL 
PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal 
cancer. Nat Med. 2015; 21: 1350-1356. 
Hershman DL, Lacchetti C, Dworkin RH, et al. Prevention and management of 
chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society 
of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014; 32: 1941-1967. 
Iveson T, Kerr R, Saunders MP, et al. Final DFS results of the SCOT study: An international 
phase III randomised (1:1) non-inferiority trial comparing 3 versus 6 months of oxaliplatin 
based adjuvant chemotherapy for colorectal cancer. ASCO Annual Meeting 2017, abstr 3502. 
Karlsson JO, Kurz T, Flechsig S, et al. Superior therapeutic index of calmangafodipir in 
comparison to mangafodipir as a chemotherapy adjunct. Transl Oncol. 2012; 5: 492-502. 
Karlsson JO, Ignarro LJ, Lundström I, Jynge P, Almén T. Calmangafodipir [Ca4Mn(DPDP)5], 
mangafodipir (MnDPDP) and MnPLED with special reference to their SOD mimetic and 
therapeutic properties. Drug Discov Today. 2015; 20(4): 411-21. 
Lehky TJ, Leonard GD, Wilson RH, et al. Oxaliplatin-induced neurotoxicity: Acute 
hyperexcitability and chronic neuropathy. Muscle Nerve. 2004; 29: 387-392.  
Leonard GD, Wright MA, Quinn MG. Survey of oxaliplatin-associated neurotoxicity using an 
interview-based questionnaire in patients with metastatic colorectal cancer. BMC Cancer. 
2005; 5: 116–125. 
Lin PC, Lee MY, Wang WS, et al. N‑acetylcysteine has neuroprotective effects against 
oxaliplatin-based adjuvant chemotherapy in colon cancer patients: preliminary data. Support 
Care Cancer. 2006; 14: 484–487. 
Loprinzi CL, Qin R, Dakhil SR, et al. Phase III randomized, placebo-controlled, double-blind 
study of intravenous calcium and magnesium to prevent oxaliplatin-induced sensory 
neurotoxicity (N08CB/Alliance). J Clin Oncol. 2014; 32: 997-1005.  
Maindrault-Goebel F, Lledo G, Chibaudel B, et al. Final results of OPTIMOX2, a large 
randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after 
FOLFOX in patients with metastatic colorectal cancer (MRC): A GERCOR study. J Clin 
Oncol. 2007; 25(18S, 20 Suppl): 4013. 
Majithia N, Loprinzi CL, Smith TJ. New Practical Approaches to Chemotherapy-Induced 
Neuropathic Pain: Prevention, Assessment, and Treatment. Oncology. 2016; 30: 1020-9. 
Martina IS, van Koningsveld R, Schmitz PI, et al. Measuring vibration threshold with a 
graduated tuning fork in normal aging and in patients with polyneuropathy. European 
Inflammatory Neuropathy Cause and Treatment (INCAT) group. J Neurol Neurosurg 
Psychiatry. 1998; 65: 743-747. 
McCleary NJ, Benson AB, Dienstmann R. Personalizing Adjuvant Therapy for Stage II/III 
Colorectal Cancer. Am Soc Clin Oncol Educ Book 2017; 37: 232-245. 
Miaskowski C, Mastick J, Paul SM et al. Chemotherapy-induced neuropathy in cancer 
survivors. J Pain Symptom Manage. 2017; 54(2): 204-218. 
Moretto R, Cremolini C, Rossini D, et al. Location of primary tumor and benefit from 
anti-epidermal growth factor receptor monoclonal antibodies in patients with RAS and BRAF 
wild-type metastatic colorectal cancer. Oncologist. 2016; 21: 988-994. 


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CONFIDENTIAL 
PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982; 
5: 649-655. 
Pachman DR, Loprinzi CL, Grothey A, et al. The search for treatments to reduce 
chemotherapy-induced peripheral neuropathy. J Clin Invest. 2014; 124: 72-74. 
Pachman DR, Qin R, Seisler DK, et al. Clinical course of patients with Oxaliplatin-associated 
neuropathy: N08CB (alliance) J Clin Oncol. 2015; 33: 3416-22. 
Roselló S, Blasco I, García Fabregat L, et al. Management of infusion reactions to systemic 
anticancer therapy: ESMO Clinical Practice Guidelines. Ann Oncol. 2017;28 (suppl_4): 
iv100-iv118. 
Sargent D, Shi Q, Yothers G, et al. Adjuvant Colon Cancer End-points (ACCENT) Group. 
Two or three year disease-free survival (DFS) as a primary end-point in stage III adjuvant colon 
cancer trials with fluoropyrimidines with or without oxaliplatin or irinotecan: data from 12,676 
patients from MOSAIC, X-ACT, PETACC-3, C-06, C-07 and C89803. Eur J Cancer 2011; 47: 
990-996. 
Sereno M, Gutiérrez-Gutiérrez G, Gómez-Raposo C, López-Gómez M, Merino-Salvador M, 
Tébar FZ, Rodriguez-Antona C, Casado E. Oxaliplatin induced-neuropathy in digestive 
tumors. Crit Rev Oncol Hematol. 2014; 89(1): 166-78. 
Shi Q, Sobrero AF, Shields AF et al. Prospective pooled analysis of six phase III trials 
investigating duration of adjuvant oxaliplatin-based therapy (3 vs 6 months) for patients with 
stage III colon cancer. ASCO Annual Meeting 2017; LBA1. 
Siegel RL, Miller KD and Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017; 67: 7-30. 
Takagi Y, Okada A, Sando K, Wasa M, Yoshida H, Hirabuki, N. Evaluation of indexes of in 
vivo manganese status and the optimal intravenous dose for adult patients undergoing home 
parenteral nutrition1. Am J Clin Nutr. 2002; 75: 112-8. 
Tejpar S, Stintzing S, Ciardiello F, et al. Prognostic and predictive relevance of primary tumor 
location in patients with RAS wild-type metastatic colorectal cancer: Retrospective analyses 
of the CRYSTAL and FIRE-3 trials. JAMA Oncol. 2017; 3: 194–201. 
Tofthagen C, Overcash J, Kip K. Falls in persons with chemotherapy-induced peripheral 
neuropathy. Support Care Cancer. 2012; 20: 583-589. 
Tournigand C, Cervantes A, Figer A, et al. OPTIMOX1: a randomized study of FOLFOX4 or 
FOLFOX7 with oxaliplatin in a stop and go fashion in advanced colorectal cancer - a GERCOR 
study. J Clin Oncol. 2006; 24: 394-400. 
Ventzel L, Madsen CS, Jensen AB, Jensen TS, Finnerup NB. Assessment of acute 
oxaliplatin-induced cold allodynia: a pilot study. Acta Neurol Scand. 2016; 133: 152-155. 
Weickhardt A, Wells K and Messersmith W. Oxaliplatin-induced neuropathy in colorectal 
cancer. J Oncol. 2011; 2011: 201593. 
Wilson RH, Lehky T, Thomas RR, et al. Acute oxaliplatin-induced peripheral nerve 
hyperexcitability. J Clin Oncol. 2002; 20: 1767-74. 


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CONFIDENTIAL 
PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
Zheng H, Xiao WH and Bennett GJ. Functional deficits in peripheral nerve mitochondria in 
rats with paclitaxel- and oxaliplatin-evoked painful peripheral neuropathy. Exp Neurol. 2011; 
232: 154-161. 
Zimmerman C, Atherton PJ, Pachman D, et al. MC11C4: a pilot randomized, 
placebo-controlled, double-blind study of venlafaxine to prevent oxaliplatin-induced 
neuropathy. Support Care Cancer. 2016; 24: 1071-1078. 


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This protocol has been written in accordance with current ICH-GCP guidelines  
19. APPENDICES 
Appendix 1 
 
Schedule of Assessments 
Appendix 2 
 
FACT/GOG-NTX-13 (Version 4) 
Appendix 3 
 
Cold Sensitivity Patient Questionnaire 
Appendix 4 
 
Pain NRS Questionnaire 
Appendix 5 
 
EQ-5D-5L 
Appendix 6 
 
Study Acknowledgement / Protocol Signature Page 
 


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This protocol has been written in accordance with current ICH-GCP guidelines  
Appendix 1 
Schedule of Assessments: Screening, Randomization and Treatment Phase (Week 0 to Week 10) 
Visit  
Visit Window 
(±2 days, if applicable) 
Screening 
≤28 days prior 
to start of IMP 
Rando-
mization 
Not a 
patient visit 
(within 3 
days before 
Cycle 1 Day 
1) 
Treatment 
Visit 1 
Day 1, 
Cycle 1 
Week 0 
Month 0 
Treatment 
Visit 2 
Day 1, 
Cycle 2 
Week 2 
 
Treatment 
Visit 3 
Day 1, 
Cycle 3 
Week 4 
 
Treatment 
Visit 4 
Day 1, 
Cycle 4 
Week 6 
 
Treatment 
Visit 5 
Day 1, 
Cycle 5 
Week 8 
 
Treatment 
Visit 6 
Day 1, 
Cycle 6 
Week 10 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
X 
 
 
 
 
 
 
CT/MRI Scan 
and Disease Assessment1 
X 
 
 
 
 
 
 
 
CEA 
X 
(within 7 days 
prior to rando-
mization) 
 
 
 
 
 
 
 
Medical History and  
Prior Medication  
X 
(within 7 days 
prior to rando-
mization) 
 
 
 
 
 
 
 
Physical Examination 
(per standard of care) 
X 
(within 7 days 
prior to rando-
mization) 
 
 
 
 
 
 
 
Vital Signs (all Visits) and 
Weight (only for Treatment 
Visits) 
X 
(within 7 days 
prior to rando-
mization) 
 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
* As of March 2nd., 2020, this will read as ‘before mFOLFOX6 infusion’ 


Protocol Number: PP06489 (POLAR-A) 
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Version 8.0 
 
  
CONFIDENTIAL 
PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
Visit  
Visit Window 
(±2 days, if applicable) 
Screening 
≤28 days prior 
to start of IMP 
Rando-
mization 
Not a 
patient visit 
(within 3 
days before 
Cycle 1 Day 
1) 
Treatment 
Visit 1 
Day 1, 
Cycle 1 
Week 0 
Month 0 
Treatment 
Visit 2 
Day 1, 
Cycle 2 
Week 2 
 
Treatment 
Visit 3 
Day 1, 
Cycle 3 
Week 4 
 
Treatment 
Visit 4 
Day 1, 
Cycle 4 
Week 6 
 
Treatment 
Visit 5 
Day 1, 
Cycle 5 
Week 8 
 
Treatment 
Visit 6 
Day 1, 
Cycle 6 
Week 10 
 
ECOG Performance Status 
X 
(within 7 days 
prior to rando-
mization) 
 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
Pregnancy Test2 
X 
(within 7 days 
prior to rando-
mization) 
 
X 
before IMP 
infusion* 
 
X 
before IMP 
infusion* 
 
X 
before IMP 
infusion* 
 
Demographics 
X 
(within 7 days 
prior to rando-
mization) 
 
 
 
 
 
 
 
Hematology3 
X 
(within 7 days 
prior to rando-
mization) 
 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
Biochemistry4 
X 
(within 7 days 
prior to rando-
mization) 
 
X 
before IMP 
infusion* 
 
X 
before IMP 
infusion* 
 
X 
before IMP 
infusion* 
 
Blood Mn5 
X 
Sample taken 
within 28 days 
prior to first dose 
of IMP 
 
 
 
 
X 
before IMP 
infusion* 
 
 
* As of March 2nd., 2020, this will read as ‘before mFOLFOX6 infusion’ 


Protocol Number: PP06489 (POLAR-A) 
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Version 8.0 
 
  
CONFIDENTIAL 
PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
Visit  
Visit Window 
(±2 days, if applicable) 
Screening 
≤28 days prior 
to start of IMP 
Rando-
mization 
Not a 
patient visit 
(within 3 
days before 
Cycle 1 Day 
1) 
Treatment 
Visit 1 
Day 1, 
Cycle 1 
Week 0 
Month 0 
Treatment 
Visit 2 
Day 1, 
Cycle 2 
Week 2 
 
Treatment 
Visit 3 
Day 1, 
Cycle 3 
Week 4 
 
Treatment 
Visit 4 
Day 1, 
Cycle 4 
Week 6 
 
Treatment 
Visit 5 
Day 1, 
Cycle 5 
Week 8 
 
Treatment 
Visit 6 
Day 1, 
Cycle 6 
Week 10 
 
Screening ECG (QTc) 
X 
(within 7 days 
prior to rando-
mization) 
 
 
 
 
 
 
 
Randomization6 
 
X 
 
 
 
 
 
 
FACT/GOG-NTX-137 
 
 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
Before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
Cold Sensitivity Patient 
Questionnaire (Paper Diary) 
X 
(within 7 days 
prior to rando-
mization) 
 
 
X 
before IMP* 
infusion and 
Days 1, 2, 3 
after IMP and 
mFOLFOX6 
infusion at Day 
1 
 
X 
before IMP* 
infusion and 
Days 1, 2, 3 
after IMP and 
mFOLFOX6 
infusion at Day 
1 
 
 
Grooved Pegboard  
 
 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
Vibration Sensitivity Test 
(Graduated Tuning Fork) 
 
 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
QoL/Health Status  
(EQ-5D-5L)7 
 
 
X 
before IMP 
infusion* 
 
 
X 
before IMP 
infusion* 
 
 
Pain NRS7 
 
 
X 
X 
X 
X 
X 
X 


Protocol Number: PP06489 (POLAR-A) 
Page 92 of 109 
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Version 8.0 
 
  
CONFIDENTIAL 
PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
Visit  
Visit Window 
(±2 days, if applicable) 
Screening 
≤28 days prior 
to start of IMP 
Rando-
mization 
Not a 
patient visit 
(within 3 
days before 
Cycle 1 Day 
1) 
Treatment 
Visit 1 
Day 1, 
Cycle 1 
Week 0 
Month 0 
Treatment 
Visit 2 
Day 1, 
Cycle 2 
Week 2 
 
Treatment 
Visit 3 
Day 1, 
Cycle 3 
Week 4 
 
Treatment 
Visit 4 
Day 1, 
Cycle 4 
Week 6 
 
Treatment 
Visit 5 
Day 1, 
Cycle 5 
Week 8 
 
Treatment 
Visit 6 
Day 1, 
Cycle 6 
Week 10 
 
Before IMP 
infusion* 
Before IMP 
infusion* 
Before IMP 
infusion* 
Before IMP 
infusion* 
Before IMP 
infusion* 
Before IMP 
infusion* 
IMP (PledOx or Placebo) 
Administration8 
 
 
X 
Only on Day 1, 
15 min before 
chemotherapy 
infusion 
X 
Only on Day 1, 
15 min before 
chemotherapy 
infusion 
X 
Only on Day 1, 
15 min before 
chemotherapy 
infusion 
X 
Only on Day 1, 
15 min before 
chemotherapy 
infusion 
X 
Only on Day 1, 
15 min before 
chemotherapy 
infusion 
X 
Only on Day 1, 
15 min before 
chemotherapy 
infusion 
Concomitant Medication9 
 
 
X 
X 
X 
X 
X 
X 
AEs9 
X 
(after signing 
the ICF) 
X 
X 
X 
X 
X 
X 
X 
Brain MRI and Blood Mn 
incl. Neurological Exam10 
 
 
(X)10 
(X)10 
(X)10 
(X)10 
(X)10 
(X)10 
Health Economic Impact12 
 
 
X 
before IMP 
infusion* 
 
 
 
 
 
DFS 
 
 
 
 
 
 
 
 
* As of March 2nd., 2020, this will read as ‘before mFOLFOX6 infusion’ 
1  CT-scan or MRI, but the same assessment should be performed throughout the study for each patient. For screening, results from a scan performed within 42 days prior to surgery or after surgery are allowed. Tumors 
will be analyzed and records will be evaluated locally. 
2  WOCBP must give a negative serum pregnancy test at screening and then every 4 weeks while patient is on IMP treatment 
3  Hematology (every Treatment Visit): WBC count differential, ANC, RBC count, platelet count, and hemoglobin. Analyzed by a local hospital laboratory. 
4  Biochemistry (every 4 weeks or every 2nd Treatment Visit): ALP, total bilirubin, ALT, AST, serum creatinine, and albumin. Analyzed by a local hospital laboratory. 


Protocol Number: PP06489 (POLAR-A) 
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PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
5  Blood Mn (full blood): Collected at Day -28 Visit, Treatment Visit 4, 8, 12 and EOT. A patient can be enrolled without the result of Mn level analysis before the randomization, but the result should be confirmed prior 
to Cycle 1 Day 1. Mn samples will also be taken whenever Parkinson-like symptoms occur. Analyzed by a central laboratory. 
As of March 2nd., 2020, no more Blood Mn samples will be taken with the exception for patients with Parkinson-like symptoms.  
6  Randomization (within 3 days before Cycle 1 Day 1)– this is not a patient visit. This is the moment when the Investigator will confirm that a patient complies with all inclusion/exclusion criteria and the patient will be 
randomized into a treatment arm using the electronic randomization system within eCRF. The Investigator will then request the unblinded pharmacist/designee to prepare the study treatment according to the randomization 
schedule available only to the unblinded hospital staff. 
7  Questionnaire to be completed prior to chemotherapy treatment by a patient in the hospital. 
During the COVID-19 pandemic, remote data collection via either phone call or mailing of paper copies of rating scales for completion at home may be implemented. 
8 IMP (PledOx or placebo) will be administered before the background chemotherapy (mFOLFOX6). Study treatment will be stopped in case of mFOLFOX6 treatment discontinuation, disease progression, intolerable 
toxicity or withdrawal of consent. 
As of March 2nd., 2020, the IMP administration is stopped in ongoing patients and no new patients are included in the study.  
9 All AEs including SAEs and concomitant medications will be collected up to 30 days after the last administration of IMP and AEs will be followed until resolution. 
As of March 2nd.,2020, all AEs including SAEs and concomitant medications will be collected up to 30 days after the EOT visit and followed until resolution 
10 In patients who develop Parkinson-like symptoms, a neurological examination and a brain MRI will be performed and an additional blood Mn sample will be analyzed. A brain MRI and neurological examination should 
also be performed if elevated Mn is found during the scheduled Mn samples.  
11 If the patient continues with the study treatment until Treatment Visit 12 (Week 22), the relevant Treatment Visit or the End of Treatment Visit will be combined with the Assessment visit at Month 6. The 
Assessment visit at Month 6 will be performed as a separate visit only if a patient stops study treatment prior to Treatment Visit 12 (Week 22). 
As of March 2nd., 2020, if the patient continues with mFOLFOX6 without IMP until Treatment Visit 12 (Week 22), the relevant Treatment Visit or End of Treatment Visit will be combined with the Assessment 
Visit at Month 6. The Assessment Visit of Month 6 will be performed as a separate visit only if a patient stops mFOLFOX6 prior to Treatment Visit 12 (Week 22) 
12 The Health Economic Impact Questionnaire will be completed by the Investigator or well-trained site staff. 
During the COVID-19 pandemic, remote data collection via either phone call or mailing of rating scales for completion at home may be implemented for the Health Economic Impact Questionnaire. 
 
 


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PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
Schedule of Assessments: Treatment Phase (Month 3 to Month ≥6) and End of Treatment Visit 
Visit  
Visit Window 
(±2 days, if applicable) 
Assessment 
Visit 
 
Month 3 
Treatment 
Visit 7 
Day 1,  
Cycle 7 
Week 12 
Treatment 
Visit 8 
Day 1,  
Cycle 8 
Week 14 
Treatment 
Visit 9 
Day 1,  
Cycle 9 
Week 16 
Treatment 
Visit 10 
Day 1, 
Cycle 10 
Week 18 
Treatment 
Visit 11 
Day 1,  
Cycle 11 
Week 20 
Treatment 
Visit 12 
Day 1,  
Cycle 12 
Week 22 
Assessment 
Visit 
 
Month 611 
EOT Visit 
Day 14  
Cycle 12  
(or Last Cycle if 
before Cycle 
12) 
(±3 days) 
Informed Consent 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
 
 
 
 
 
 
 
 
CT/MRI Scan 
and Disease Assessment1 
 
 
 
 
 
 
 
 
 
CEA 
 
 
 
 
 
 
 
 
X 
Medical History and  
Prior Medication  
 
 
 
 
 
 
 
 
 
Physical Examination 
(per Standard of Care) 
X 
 
 
 
 
 
 
X 
X 
Vital Signs (all Visits) and 
Weight (only for Treatment 
Visits and EOT visit) 
X 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
X 
ECOG Performance Status 
X 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
X 
Pregnancy Test2 
 
X 
before IMP 
infusion* 
 
X 
before IMP 
infusion* 
 
X 
before IMP 
infusion* 
 
 
X 
Demographics 
 
 
 
 
 
 
 
 
 


Protocol Number: PP06489 (POLAR-A) 
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CONFIDENTIAL 
PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
Visit  
Visit Window 
(±2 days, if applicable) 
Assessment 
Visit 
 
Month 3 
Treatment 
Visit 7 
Day 1,  
Cycle 7 
Week 12 
Treatment 
Visit 8 
Day 1,  
Cycle 8 
Week 14 
Treatment 
Visit 9 
Day 1,  
Cycle 9 
Week 16 
Treatment 
Visit 10 
Day 1, 
Cycle 10 
Week 18 
Treatment 
Visit 11 
Day 1,  
Cycle 11 
Week 20 
Treatment 
Visit 12 
Day 1,  
Cycle 12 
Week 22 
Assessment 
Visit 
 
Month 611 
EOT Visit 
Day 14  
Cycle 12  
(or Last Cycle if 
before Cycle 
12) 
(±3 days) 
Hematology3 
X 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
X 
Biochemistry4 
 
X 
before IMP 
infusion* 
 
X 
before IMP 
infusion* 
 
X 
before IMP 
infusion* 
 
 
X 
Blood Mn5 
 
 
X 
before IMP 
infusion* 
 
 
 
X 
before IMP 
infusion* 
 
X 
Screening ECG (QTc) 
 
 
 
 
 
 
 
 
 
Randomization6 
 
 
 
 
 
 
 
 
 
FACT/GOG-NTX-137 
X 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
X 
Cold Sensitivity Patient 
Questionnaire (Paper Diary)  
 
 
X 
before IMP* 
infusion and 
Days 1, 2, 3 after 
IMP and 
mFOLFOX6 
infusion at Day 1 
 
 
 
 
 
 
Grooved Pegboard  
X 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
X 
* As of March 2nd., 2020, this will read as ‘before mFOLFOX6 infusion’ 


Protocol Number: PP06489 (POLAR-A) 
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15 May 2020 
Version 8.0 
 
  
CONFIDENTIAL 
PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
Visit  
Visit Window 
(±2 days, if applicable) 
Assessment 
Visit 
 
Month 3 
Treatment 
Visit 7 
Day 1,  
Cycle 7 
Week 12 
Treatment 
Visit 8 
Day 1,  
Cycle 8 
Week 14 
Treatment 
Visit 9 
Day 1,  
Cycle 9 
Week 16 
Treatment 
Visit 10 
Day 1, 
Cycle 10 
Week 18 
Treatment 
Visit 11 
Day 1,  
Cycle 11 
Week 20 
Treatment 
Visit 12 
Day 1,  
Cycle 12 
Week 22 
Assessment 
Visit 
 
Month 611 
EOT Visit 
Day 14  
Cycle 12  
(or Last Cycle if 
before Cycle 
12) 
(±3 days) 
Vibration Sensitivity Test 
(Graduated Tuning Fork) 
X 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
X 
QoL/Health Status  
(EQ-5D-5L) 7 
X 
 
X 
before IMP 
infusion* 
 
 
 
X 
before IMP 
infusion* 
X 
X 
Pain NRS7 
X 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
before IMP 
infusion* 
X 
X 
IMP (PledOx or Placebo) 
Administration8 
 
X 
15 min before 
chemotherapy 
infusion only on 
Day 1 
X 
15 min before 
chemotherapy 
infusion only on 
Day 1 
X 
15 min before 
chemotherapy 
infusion only on 
Day 1 
X 
15 min before 
chemotherapy 
infusion only on 
Day 1 
X 
15 min before 
chemotherapy 
infusion only on 
Day 1 
X 
15 min before 
chemotherapy 
infusion only on 
Day 1 
 
 
Concomitant Medication9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Brain MRI and Blood Mn 
incl. Neurological Exam10 
(X)10 
(X)10 
(X)10 
(X)10 
(X)10 
(X)10 
(X)10 
 
(X)10 
Health Economic Impact12 
 
 
 
 
 
 
 
X 
 
DFS 
X 
 
 
 
 
 
 
X 
 
* As of March 2nd., 2020, this will read as ‘before mFOLFOX6 infusion’ 
1  CT-scan or MRI, but the same assessment should be performed throughout the study for each patient. Tumors will be analyzed and the records will be evaluated locally.  
2  WOCBP must give a negative serum pregnancy test at screening and then every 4 weeks while patient is on IMP treatment. 
3  Hematology (every Treatment Visit): WBC count differential, ANC, RBC count, platelet count, and hemoglobin. Analyzed by a local hospital laboratory. 


Protocol Number: PP06489 (POLAR-A) 
Page 97 of 109 
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CONFIDENTIAL 
PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
4  Biochemistry (every 4 weeks or every 2nd Treatment Visit): ALP, total bilirubin, ALT, AST, serum creatinine, and albumin. Analyzed by a local hospital laboratory. 
5  Blood Mn (full blood): Collected at Day -28 Visit, Treatment Visit 4, 8, 12 and EOT. A patient can be enrolled without the result of Mn level analysis before the randomization, but the result should be 
confirmed prior to Cycle 1 Day 1. Mn samples will also be taken whenever Parkinson-like symptoms occur. Analyzed by a central laboratory. 
As of March 2nd., 2020, no more Blood Mn samples will be taken with the exception for patients with Parkinson-like symptoms. 
6  Randomization (within 3 days before Cycle 1 Day 1)– this is not a patient visit. This is the moment when the Investigator will confirm that a patient complies with all inclusion/exclusion criteria and the patient will be 
randomized into a treatment arm using the electronic randomization system within eCRF. The Investigator will then request the unblinded pharmacist/designee to prepare the study treatment according to the 
randomization schedule available only to the unblinded hospital staff. 
7  Questionnaire to be completed prior to chemotherapy treatment by a patient in the hospital.  
During the COVID-19 pandemic, remote data collection via either phone call or mailing of rating scales for completion at home may be implemented. 
8 IMP (PledOx or placebo) will be administered before the background chemotherapy (mFOLFOX6). Study treatment will be stopped in case of mFOLFOX6 treatment discontinuation, disease progression, intolerable 
toxicity or withdrawal of consent. 
As of March 2nd., 2020, the IMP administration is stopped in ongoing patients and no new patients are included in the study.  
9 All AEs including SAEs and concomitant medications will be collected up to 30 days after the last administration of IMP and AEs will be followed until resolution. 
As of March 2nd.,2020, all AEs including SAEs and concomitant medications will be collected up to 30 days after the EOT visit and followed until resolution 
10 In patients who develop Parkinson-like symptoms, a neurological examination and a brain MRI will be performed and an additional blood Mn sample will be analyzed. A brain MRI and neurological examination should 
also be performed if elevated Mn is found during the scheduled Mn samples.  
11 If the patient continues with the study treatment until Treatment Visit 12 (Week 22), the relevant Treatment Visit or the End of Treatment Visit will be combined with the Assessment visit at Month 6. The 
Assessment visit at Month 6 will be performed as a separate visit only if a patient stops study treatment prior to Treatment Visit 12 (Week 22). 
As of March 2nd., 2020, if the patient continues with mFOLFOX6 without IMP until Treatment Visit 12 (Week 22), the relevant Treatment Visit or the End of Treatment Visit will be combined with the Assessment 
Visit at Month 6. The assessment Visit at Month 6 will be performed as a separate visit only if a patient stops mFOLFOX6 prior to Treatment Visit 12 (Week 22) 
12 The Health Economic Impact Questionnaire will be completed by the Investigator or well-trained site staff. 
During the COVID-19 pandemic, remote data collection via either phone call or mailing of rating scales for completion at home may be implemented. 
 
 
 


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CONFIDENTIAL 
PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
Schedule of Assessments: Follow-up Phase (Month 9 to Month 24 [EOS]) 
Visit  
Visit Window 
(±1 week) 
Assessment 
Visit 
Month 9 
Assessment 
Visit 
Month 12 
Assessment 
Visit 
Month 18 
EOS Visit 
Month 24 
Informed Consent 
 
 
 
 
Inclusion/Exclusion Criteria 
 
 
 
 
CT/MRI Scan 
and Disease Assessment1 
 
X 
 
X 
CEA 
 
X 
 
X 
Medical History and  
Prior Medication  
 
 
 
 
Physical Examination 
(per Standard of Care) 
X 
X 
X 
X 
Vital Signs (all Visits) and 
Weight (only for Treatment Visit) 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
Pregnancy Test2 
 
 
 
 
Demographics 
 
 
 
 
Hematology3 
 
 
 
 
Biochemistry4 
 
 
 
 
Blood Mn5 
 
 
 
 
Screening ECG (QTc) 
 
 
 
 
Randomization6 
 
 
 
 
FACT/GOG-NTX-137 
X 
X 
X 
X 
Cold Sensitivity Patient 
Questionnaire (Paper Diary)  
 
 
 
 


Protocol Number: PP06489 (POLAR-A) 
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CONFIDENTIAL 
PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
Visit  
Visit Window 
(±1 week) 
Assessment 
Visit 
Month 9 
Assessment 
Visit 
Month 12 
Assessment 
Visit 
Month 18 
EOS Visit 
Month 24 
Grooved Pegboard  
X 
X 
X 
X 
Vibration Sensitivity Test 
(Graduated Tuning Fork) 
X 
X 
X 
X 
QoL/Health Status7 
(EQ-5D-5L) 
X 
X 
X 
X 
Pain NRS7 
X 
X 
X 
X 
IMP (PledOx or Placebo) 
Administration8 
 
 
 
 
Concomitant Medication9 
 
 
 
 
AEs9 
 
 
 
 
Brain MRI and Blood Mn incl. 
Neurological Exam10 
 
 
 
 
Health Economic Impact12 
 
X 
X 
X 
DFS 
X 
X 
X 
X 
1  CT-scan or MRI, but the same assessment should be performed throughout the study for each patient. Tumors will be analyzed and the records will be evaluated locally. 
2  WOCBP must give a negative serum pregnancy test at screening and then every 4 weeks while patient is on IMP treatment. 
3  Hematology (every Treatment Visit): WBC count differential, ANC, RBC count, platelet count, and hemoglobin. Analyzed by a local hospital laboratory. 
4  Biochemistry (every 4 weeks or every 2nd Treatment Visit): ALP, total bilirubin, ALT, AST, serum creatinine, and albumin. Analyzed by a local hospital laboratory. 
5  Blood Mn (full blood): Collected at Day -28 Visit, Treatment Visit 4, 8, 12 and EOT. A patient can be enrolled without the result of Mn level analysis before the randomization, but the result should be 
confirmed prior to Cycle 1 Day 1. Mn samples will also be taken whenever Parkinson-like symptoms occur. Analyzed by a central laboratory. 
As of March 2nd., 2020, no more Blood Mn samples will be taken with the exception for patients with Parkinson-like symptoms.  
6  Randomization (within 3 days before Cycle 1 Day 1)– this is not a patient visit. This is the moment when the Investigator will confirm that a patient complies with all inclusion/exclusion criteria and the patient will be 
randomized into a treatment arm using the electronic randomization system within eCRF. The Investigator will then request the unblinded pharmacist/designee to prepare the study treatment according to the 
randomization schedule available only to the unblinded hospital staff. 
7  Questionnaire to be completed prior to chemotherapy treatment by a patient in the hospital.  
During the COVID-19 pandemic, remote data collection via phone call or mailing of paper copies of rating scales for completion at home may be implemented. 
8 IMP (PledOx or placebo) will be administered before the background chemotherapy (mFOLFOX6). Study treatment will be stopped in case of mFOLFOX6 treatment discontinuation, disease progression, intolerable 
toxicity or withdrawal of consent. 
As of March 2nd., 2020, the IMP administration is stopped in ongoing patients and no new patients are included in the study.  


Protocol Number: PP06489 (POLAR-A) 
Page 100 of 109 
15 May 2020 
Version 8.0 
 
  
CONFIDENTIAL 
PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
9 All AEs including SAEs and concomitant medications will be collected up to 30 days after the last administration of IMP and AEs will be followed until resolution. 
As of March 2nd., 2020, all AEs including SAEs and concomitant medications will be collected up to 30 days after the EOT visit  and followed until resolution.  
10 In patients who develop Parkinson-like symptoms, a neurological examination and a brain MRI will be performed and an additional blood Mn sample will be analyzed. A brain MRI and neurological examination should 
also be performed if elevated Mn is found during the scheduled Mn samples.  
11 
If the patient continues with the study treatment until Treatment Visit 12 (Week 22), the relevant Treatment Visit or the End of Treatment Visit will be combined with the Assessment visit at Month 6. The 
Assessment visit at Month 6 will be performed as a separate visit only if a patient stops study treatment prior to Treatment Visit 12 (Week 22). 
As of March 2nd., 2020, if the patient continues with mFOLFOX6 without IMP until Treatment Visit 12 (Week 22), the relevant Treatment Visit or the End of Treatment Visit will be combined with the Assessment 
Visit at Month 6. The assessment Visit at Month 6 will be performed as a separate visit only if a patient stops mFOLFOX6 prior to Treatment Visit 12 (Week 22)12 The Health Economic Impact Questionnaire will be 
completed by the Investigator or well-trained site staff. 
During the COVID-19 pandemic, remote data collection via either phone call or mailing of paper copies of rating scales for completion at home may be implemented for the Health Economic Impact Questionnaire. 


Protocol Number: PP06489 (POLAR-A) 
Page 101 of 109 
15 May 2020 
Version 8.0 
 
  
CONFIDENTIAL 
PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
Appendix 2 
FACT/GOG-NTX-13 (Version 4) 
 
 
 
FACT/GOG-NTX-13 (Version 4) 
Below is a list of statements that other people with your illness have said are important. Please circle 
or mark one number per line to indicate your response as it applies to the past 7 days. 
GP! 
GPZ 
GP3 
GP4 
GP5 
GP6 
GP7 
GS ! 
GSZ 
GS3 
GS4 
GS5 
GS6 
Q I 
GS7 
PHYSICAL WELL-BEING 
Not 
at all 
I have a lack of energy .................................. ..................... 
0 
I have nausea ...................................................................... 
0 
Because of my physical condition, I have trouble 
meeting the needs of my family ......................................... 
0 
I have pain ......................................................... .. ........ .... .. . 
0 
I am bothered by side effects of treatment.. ....................... 
0 
I feel ill ............................................................................... 
0 
I am forced to spend time in bed ................... .................. ... 
0 
SOCIAL/FAMILY WELL-BEING 
Not 
at all 
I feel close to my friends........ ............................................ 
0 
I get emotional support from my family....... .............. ....... 
0 
I get support from my friends. ............................................ 
0 
My family has accepted my illness . ... . .. .. . ... . . . ... . .. . . . ... . .. .. ... 
0 
I am satisfied with family communication about my 
illness.................................................................................. 
0 
I feel close to my partner ( or the person who is my main 
support).............................................................................. 
0 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box D and go to the next section. 
I am satisfied with my sex life . . . . ... . .. . . . ... ... ... ... . ...... .. . . . ... ... . 
0 
English (Univa-sal) 
Ccpyright 1987, 1997 
A little 
bit 
A little 
bit 
Some-
what 
2 
2 
2 
2 
2 
2 
2 
Some-
what 
2 
2 
2 
2 
2 
2 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
16Nov€!1lba-2007 
Page 1 of3 


Protocol Number: PP06489 (POLAR-A) 
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CONFIDENTIAL 
PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
 
 
 
FACT/GOG-NTX-13 (Version 4) 
Please circle 01· mark one number per line to indicate your response as it applies to the past 7 
days. 
EMOTIONAL WELL-BEING 
GEi 
I feel sad ........................................................ .... .............. .... 
GE2 
I am satisfied with how I am coping with my illness .......... 
GE3 
I am losing hope in the fight against my illness .................. 
GE4 
I feel nervous ....................................................................... 
GE5 
I worry about dying ........................ ..................................... 
GE6 
I wony that my condition will get worse ...... ............ ........ .. 
FUNCTIONAL WELL-BEING 
GFI 
I am able to work (include work at home) .......................... 
GF2 
My work (include work at home) is fulfilling ..................... 
GF3 
I am able to enjoy life .......................................................... 
GF4 
I have accepted my illness ................................................... 
GF5 
I am sleeping well ............................................................... 
GF6 
I am enjoying the things I usually do for fun ...................... 
GF7 
I am content with the quality of my life right now .............. 
English (Univa-sal) 
Ccpyright 1987, 1997 
Not 
at all 
0 
0 
0 
0 
0 
0 
Not 
at all 
0 
0 
0 
0 
0 
0 
0 
A little 
Some-
bit 
what 
2 
2 
2 
2 
2 
2 
A little 
Some-
bit 
what 
2 
2 
2 
2 
2 
2 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
16Nov€!1lba-2007 
Page 2 of3 


Protocol Number: PP06489 (POLAR-A) 
Page 103 of 109 
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Version 8.0 
 
  
CONFIDENTIAL 
PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
 
 
 
FACT/GOG-NTX-13 (Version 4) 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
ADDITIONAL CONCERNS 
NTX 
I have numbness or tingling in my hands ............................ 
I 
NTX 
I have numbness or tingling in my feet ............ ................... 
NTX 
I feel discomfort in my hands .......................... ............ ........ 
3 
NTX 
I feel discomfort in my feet.. ............................................... 
NTX 
I have joint pain or muscle cramps ..................................... 
Hl12 
I feel weak all over ......................... ..................................... 
NTX 
I have trouble hearing ...................................................... .... 
6 
NTX 
I get a ringing or buzzing in my ears ................................... 
7 
NTX 
I have trouble buttoning buttons ......................................... 
8 
NTX 
I have trouble feeling the shape of small objects when 
9 
they are in my hand ............................................................. 
An6 
I have trouble walking ......................................................... 
NTX 
I have pain in my hands or feet when I am exposed to 
10 
cold temperatures ................................................................ 
NTX 
I have difficulty breathing when I am exposed to cold 
11 
temperatures ........................................................................ 
English (Univa-sal) 
Ccpyright 1987, 1997 
Not at 
all 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
A little 
Some-
bit 
what 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
16Nov€!1lba-2007 
Page 3 of3 


Protocol Number: PP06489 (POLAR-A) 
Page 104 of 109 
15 May 2020 
Version 8.0 
 
  
CONFIDENTIAL 
PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
Appendix 3 
Cold Sensitivity Patient Questionnaire  
 
 
 
 
 
L Didi y,ou expe;ri:eincie se11sitivity to toudl Tng col di item.s Ivitilli11 the la,st 24 hem rs? 
Not at 
al 
0 
2. 
3 
4 
5 
6 
7 
9 
2. Didi you e,cpeirteinlle diiscomfort Slivallov,i11g roli:I ~q11ids wittirn tile last 24 hours? 
Not at 
al 
0 
2. 
3 
4 
5 
6 
7 
3. 
Didi you 1101!ire any IJhrnat llisoomfurt witll'i n tlhe last 24 lilo11rs? 
Not at 
al 
0 
2. 
3 
4 
5 
6 
4. 
Didi y,ou r.llffer frnm 1n1.1,scle oram~ w,itlhi'11 tile last 24 hours? 
Not at 
al 
0 
2. 
3 
4 
5 
6 
7 
7 
9 
!l 
9 
!l 
9 
As bad 
as it 
C-31!1i · -
ro 
As bad 
as it 
C-31!1i 
2' 
ro 
As bad 
as i't 
can ~ 
ro 
As bad 
as i't 
can ~ 
ro 


Protocol Number: PP06489 (POLAR-A) 
Page 105 of 109 
15 May 2020 
Version 8.0 
 
  
CONFIDENTIAL 
PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
Appendix 4 
Pain Numerical Rating Scale (NRS) Questions 
 
 
 
 
 
 
During the past week, have you experienced any pain in your lla11ds or fe,et? 
If yes, answer the following three questions; 
1. Please rate your pain by circling t ne numbe r that best describes your pain at its worst in 
last 7 days. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Nlo 
Pain 
Pain as bad as 
you ca11 imagine 
2. Please rate your pain by circling t ne numbe r that best describes your pain o n the average. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Nlo 
Pain 
Pain as bad as 
you ca11 imagine 
3. Please rate your pain by circling t ne o ne number t hat tells how much pain you have right 
now. 
0 
Nlo 
Pain 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Pain as bad as 
you ca11 imagine 


Protocol Number: PP06489 (POLAR-A) 
Page 106 of 109 
15 May 2020 
Version 8.0 
 
  
CONFIDENTIAL 
PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
Appendix 5 
EQ-5D-5L 
 
https://euroqol.org/wp-content/uploads/2016/10/Sample_UK__English__EQ-5D-
5L_Paper_Self_complete_v1.0__ID_24700.pdf 
 
 
 
 
.. 
ECl-5D-9L 
Healtlh Questionna·r,e 
English vers·o:n for the UK 


Protocol Number: PP06489 (POLAR-A) 
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This protocol has been written in accordance with current ICH-GCP guidelines  
 
 
 
Under eaoh heading, pl'ease Udl th.e ONE box that best desoribes your h.ealth TODAY_ 
MOBILITY 
I have 110 pro )lems ·n walking about 
I have slight problems in walking about 
I have mod'erate problems in walking about 
I have severe problems in walking, about 
I am unable to walk about 
SELF-CAIRE 
I have ,,o pro )lems washing or dressingI myself 
I have slight problems washing or dressing myself 
I have moderate problems washing or dressing myself 
I have severe problems washing or dress·ng myself 
I am unable to wash or dress ~nysern 
US1II.JIAL ACTIVITIES (e.g. work, study, housework, famiJy or 
feisure activities) 
I have Ino problems oo·ng my usual acti,vities 
I have slight problems doing my 11s1.ml aotivities 
I have moderate problems d'.o·ng my usual actiwies 
I have severe problems doing 1ny u;sual activities 
I am unable to do my Uisual aotivities 
PA!IN I DISCOMFORT 
I have 110 pain or disoomfort 
I have slight pain or discomfort 
I have moderate pa·n or di,soornfmt 
I have severe pain or d'isoomfort 
I have extreme pain or diiSComfort 
ANXIET"{ I DE:PRESSIO:N 
I am not anxious or depressed 
I am slightly anxious or d.epressed 
I am moderately anxious or de;prassecl 
I am severeliy anxious or depressed 
I am extremely ar,xious or d'.epressed 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 


Protocol Number: PP06489 (POLAR-A) 
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PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
 
 
 
• We would like to kllOW h.ow good or bad your llealth is TODA y -
• 
This scale is numbered from O to 1011 
• 
100 means the best health you can imagine_ 
0 means the worsl health you can imagine. 
• Maril{ an X on the scale to indicate how your health is TODAY_ 
• 
r:m, please wm:e the number youi mal1\ed on the scale in the box 
below. 
YOUR HEALTH TODAY = D 
a 
UK (Eng/i.sh) 0 2009 EuroQol Group EQ-5D"' is a lr.ade roam ot /he EtJTOQd Group 
The best he.al 
you 1can imagine 
f 
100 
95 
90 
t 
85 
80 
75 
70 
65 
60 
55 
50 
45 
40 
35 
30 
! 
25 
I 
20 
15 
10 
! 
5 
_t_ 
0 
The worst he.allh 
you can imagine 


Protocol Number: PP06489 (POLAR-A) 
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PledPharma AB 
This protocol has been written in accordance with current ICH-GCP guidelines  
Appendix 6 
STUDY ACKNOWLEDGEMENT / PROTOCOL SIGNATURE PAGE 
Investigator’s Statement: 
I have read and understand the foregoing Protocol entitled “A Phase 3, double-blind, multicenter, 
placebo-controlled study of PledOx used on top of Modified FOLFOX6 (5-FU/FA and 
Oxaliplatin) to prevent chemotherapy induced peripheral neuropathy (CIPN) in the adjuvant 
treatment of patients with Stage III or high-risk Stage II colorectal cancer”, protocol number 
PP06489 (POLAR-A), and agree to conduct the study in compliance with Good Clinical Practice 
(CPMP/ICH/135/95), ICH GCP, designated standard operating procedures, national laws and 
regulations of the countries conducting the study and within the principles of the Declaration 
of Helsinki as outlined herein. 
 
 
 
Investigator’s Name (please print) 
Investigator’s Title 
 
 
Date (dd mmm yyyy) 
Investigator’s Signature 
 
 
 

SAP_001.pdf: 
 
 
 
 
 
POLAR 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
Author 
 
 
 
Anders Persson 
Title  
 
 
 
Biostatistician 
Date  
 
 
 
2 September 2020 
Version 
 
 
 
1.0 
 
 
 


POLAR Statistical Analysis Plan 
2 September 2020  
 
 
 
Version 1.0 
 
 
2(38) 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION 
5 
2. 
STUDY OBJECTIVES AND DESIGN 
6 
2.1 
POLAR-A 
6 
2.1.1 
Primary Objective 
6 
2.1.2 
Secondary Objectives 
7 
2.1.3 
Exploratory Objectives 
7 
2.1.4 
Study Design 
7 
2.2 
POLAR-M 
8 
2.2.1 
Primary Objective 
8 
2.2.2 
Secondary Objectives 
8 
2.2.3 
Exploratory Objectives 
8 
2.2.4 
Study Design 
9 
2.3 
VISIT STRUCTURE 
9 
2.4 
SAMPLE SIZE 
9 
2.5 
CHANGES FROM THE PROTOCOL PLANNED ANALYSIS 
10 
3. 
GENERAL STATISTICAL PRINCIPLES 
11 
3.1 
ANALYSIS SETS 
11 
3.2 
HYPOTHESIS TO BE TESTED 
11 
3.3 
HANDLING OF DROPOUTS OR MISSING DATA 
12 
3.4 
HANDLING OF UNSCHEDULED OR REPEATED MEASUREMENTS 
13 
4. 
STUDY PATIENTS 
13 
4.1 
PATIENT DISPOSITION 
13 
4.2 
PROTOCOL DEVIATIONS 
13 
4.3 
BACKGROUND AND DEMOGRAPHIC CHARACTERISTICS 
13 
4.3.1 
Demography 
13 
4.3.2 
Medical History, Ongoing Medical Conditions and Prior Anti-cancer Therapy 
14 
4.3.3 
Prior and Concomitant Medications 
14 
4.3.4 
ECOG Performance Status 
14 
4.3.5 
ECG at Screening 
14 
4.4 
ADMINISTRATION OF INVESTIGATIONAL MEDICAL PRODUCT AND CHEMOTHERAPY 
14 
4.4.1 
Investigational Medical Product (IMP) 
14 
4.4.2 
Oxaliplatin 
15 
4.4.3 
5-FU 
15 
4.4.4 
Calcium-folinate or Calcium-levofolinate 
16 
5. 
EFFICACY EVALUATION 
16 
5.1 
PRIMARY ENDPOINT 
17 
5.1.1 
Moderate to Severe CIPN 
17 
5.2 
HANDLING OF MISSING DATA IN THE PRIMARY ENDPOINT 
21 
5.3 
SECONDARY EFFICACY ENDPOINTS 
22 
5.3.1 
Mild to Severe CIPN 
22 
5.3.2 
Cold Sensitivity 
23 


POLAR Statistical Analysis Plan 
2 September 2020  
 
 
 
Version 1.0 
 
 
3(38) 
5.3.3 
Cumulative Dose of Oxaliplatin 
23 
5.3.4 
Vibration Sensitivity Test 
23 
5.3.5 
Pain (NRS) 
24 
5.3.6 
Grooved Pegboard 
24 
5.3.7 
Long-term Moderate to Severe CIPN 
25 
5.4 
EXPLORATORY ENDPOINTS 
25 
5.4.1 
Any CIPN 
25 
5.4.2 
Mean Score of FACT/GOG NTX1-4 
26 
5.4.3 
Mean Score of FACT/GOG NTX1-13 
26 
5.4.4 
Cumulative Dose of 5-FU 
26 
5.4.5 
Pharmacokinetics 
27 
5.4.6 
ECG QT/QTc 
27 
5.4.7 
EQ-5D-5L and Health VAS Score 
28 
5.4.8 
Long-term Grooved Pegboard 
29 
5.4.9 
Long-term Pain (NRS) 
29 
5.4.10 
Change in Pain (NRS) 
29 
5.4.11 
Health Economic Impact 
30 
6. 
SAFETY EVALUATION 
30 
6.1 
ADVERSE EVENTS 
30 
6.1.1 
Adverse Events of Special Interest 
32 
6.2 
LABORATORY EVALUATION 
33 
6.3 
BLOOD MANGANESE 
34 
6.4 
BRAIN MRI AND NEUROLOGIC EXAMINATION 
34 
6.5 
VITAL SIGNS 
35 
6.6 
WEIGHT AND BMI 
35 
6.7 
PHYSICAL EXAMINATION 
36 
6.8 
ECOG PERFORMANCE STATUS 
36 
6.9 
OVERALL RESPONSE RATE (POLAR-M ONLY) 
36 
6.10 
PROGRESSION-FREE SURVIVAL (POLAR-M ONLY) 
37 
6.11 
OVERALL SURVIVAL (POLAR-M ONLY) 
37 
6.12 
DISEASE-FREE SURVIVAL (POLAR-A ONLY) 
38 
7. 
REFERENCES 
38 
 
 
 




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1. INTRODUCTION 
The pivotal Phase 3 POLAR program, studying calmangafodipir for the prevention of chemotherapy 
induced peripheral neuropathy, consists of two studies: POLAR-A and POLAR-M. 
• 
POLAR-A is a placebo controlled, randomised (1:1) Phase III study of calmangafodipir 
5 µmol/kg in combination with mFOLFOX6 compared to placebo+mFOLFOX6 in patients with 
adjuvant treatment of stage III or high-risk stage II colorectal cancer. 
• 
POLAR-M is a placebo controlled, randomised (1:1:1) Phase III study of calmangafodipir in two 
different doses, 2 µmol/kg and 5 µmol/kg in combination with mFOLFOX6 compared to 
placebo+mFOLFOX6 in patients with metastatic CRC. 
Patient recruitment in the POLAR-A and POLAR-M studies was initiated in late 2018 with the first 
patient randomised in on January 15, 2019, in POLAR-A and on POLAR-M on January 21, 2019. 
On January 23, 2020, the Sponsor announced that the US Food and Drug Administration (FDA) had 
issued a clinical hold in the US of the POLAR program. The implication was that recruitment and dosing 
of patients in the POLAR-M study was halted in the US. Based on the evaluation of the independent 
Drug Safety Monitoring Board (DSMB), the Sponsor’s position was that the overall safety profile for 
PledOx supported the continuation of the POLAR program and both studies continued as planned in 
Europe and Asia with dosing and further recruitment. 
On March 1, 2020, the Sponsor decided to place recruitment and dosing of patients in the POLAR 
program on hold.  The decision followed interactions with the French regulatory authority, ANSM, and 
the clinical hold issued by the US Food and Drug Administration (FDA) earlier in the year and was due 
to 4 observed events related to seizure. The Sponsor maintained its position that these events are not 
related to calmangafodipir, a position which was also supported by the DSMB and an additional 
independent external evaluation of these cases. 
On April 6, 2020, the Sponsor decided to close the POLAR program early with a data cut-off targeted 
for the third quarter 2020 (further detailed later in this document). The decision was taken after a 
recommendation from the DSMB to stop the studies due to an accumulation of severe allergic 
reactions, primarily observed after repeated dosing. 
Based on the development of the POLAR studies, a re-assessment of the sample size assumptions is 
needed to determine a reasonable statistical approach to the analysis of the POLAR studies. 
The POLAR studies were designed based on the following sample size assumptions: 
• 
POLAR-A: With 112 patients per group, the POLAR-A study has 91% power to detect a 
reduction (improvement) from 40% to 20% (OR = 0.375) in the primary endpoint using two-
sided test controlled at the 0.05 type-I error rate. To account for 20% dropout in the study, in 
total 280 patients (140 patients per arm) will be randomised. 
• 
POLAR-M: With 112 patients per group, the POLAR-M study has 91% power to detect a 
reduction (improvement) from 40% to 20% (odds ratio = 0.375) in the primary endpoint using 
two-sided test controlled at the 0.05 type-I error rate. To account for 20% dropout in the 
study, in total 420 patients (140 patients per arm) will be randomised. 
 
 


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Table 1: Patient disposition in the POLAR studies 
 
POLAR-A 
POLAR-M 
Total 
Number of patients randomised  
301 
290 
591 
Number of patients dosed with ≥1 cycle of IMP 
297 
285 
582 
Number of patients dosed with ≥6 cycles of IMP 
257 
194 
451 
Number of patients dosed with ≥12 cycles of IMP 
107 
98 
205 
 
A total of 591 patients was randomised in the POLAR program and 582  patients dosed, of which 451  
patients completed 6 cycles and 205 patients completed 12 cycles (see Table 1).  
There are two main contributing factors to take into account when designing a reasonable statistical 
approach to the analysis of the POLAR studies: 
1) POLAR-M only randomised 290 out of the planned 420 patients. This, together with the 
reduced dosing of patients (see bullet 2 below) means a separate primary analysis based on 
this data set cannot be supported. 
2) Due to the Sponsor’s decision to place the dosing of patients on hold on March 1, 2020, not 
all patients have had sufficient dosing of IMP to expect the full treatment effect of active 
treatment as assumed in the sample size calculation. 
Taking these two aspects into consideration account (the fewer number of randomised patients and 
the reduced dosing of patients) a reasonable statistical approach is to conduct a combined primary 
analysis across the two studies, with the data from the two studies regarded as strata, based on a 
modified ITT analysis set defined by the eligibility of dosing with IMP as intended in the clinical study 
protocol. In addition, a standalone analysis of the primary endpoint in the fully recruited POLAR-A 
study will be conducted if the combined analysis is statistically significant. This approach will be further 
detailed in this document.  
All analyses will be provided using the combined data from the two studies. However, both POLAR 
studies will also be analysed and reported separately. 
This SAP is based on protocol versions 7.0/8.0 dated 09JAN2020/17APR2020 and will cover both 
POLAR-A, POLAR-M and the combined analyses across studies. The SAP will be reviewed at the blind 
review of the data before database lock and will be finalised before breaking the blind and database 
lock. 
The table, listing and figure shells will be supplied in a separate document “POLAR – Statistical Output 
Specification”. 
The analysis and statistics reporting will be conducted at Binomial Sweden AB using SAS version 9.4. 
2. STUDY OBJECTIVES AND DESIGN 
2.1 POLAR-A 
2.1.1 Primary Objective 
The primary objective of the study is to compare PledOx (5 µmol/kg) vs placebo with respect to the 
proportion of patients with moderate or severe chronic CIPN. 


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2.1.2 Secondary Objectives 
The secondary objectives of the study are to compare PledOx vs placebo regarding the following: 
Efficacy 
• 
The proportion of patients with mild, moderate or severe chronic CIPN 
• 
The sensitivity to touching cold items 
• 
The cumulative dose of oxaliplatin during chemotherapy 
• 
The vibration sensitivity on the lateral malleolus 
• 
The worst pain in hands or feet 
• 
The functional impairment (in the non-dominant hand) 
• 
The sustained efficacy on prevention of CIPN during long-term follow-up 
Safety 
• 
DFS 
• 
Safety and tolerability 
2.1.3 Exploratory Objectives 
The exploratory objectives of the study are to compare PledOx vs placebo regarding the following: 
• 
Chronic CIPN by supporting analysis using the full Functional Assessment of Cancer 
Therapy/Gynecologic Oncology Group-Neurotoxicity-13-item subscale (FACT/GOG-NTX-13) 
• 
The cumulative dose of 5-FU during chemotherapy 
• 
For both oxaliplatin and 5-FU: Dose intensity, number of cycles, dose reductions, reason(s) for 
dose reductions, patients with dose delays, and length of dose delays 
• 
The functional impairment (in the non-dominant hand) during long-term follow-up. 
• 
The worst pain in hands or feet during long-term follow-up 
• 
QoL/health status 
• 
Health economic impact 
2.1.4 Study Design 
POLAR-A is a Phase 3, multicenter, double-blind, placebo-controlled study using PledOx for 
prevention of chronic CIPN induced by oxaliplatin in patients with pathologically confirmed CRC, who 
are indicated for adjuvant mFOLFOX6 chemotherapy for up to 6 months. 
Patients will be randomised in a 1:1 ratio to 1 of 2 treatment arms: 
• 
Arm A: PledOx (5 µmol/kg) + mFOLFOX6 chemotherapy 
• 
Arm B: Placebo + mFOLFOX6 chemotherapy 
 
 


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Figure 1 
Polar-A Study Design 
 
t=0 (baseline: Day 1, Cycle 1); R=randomization; EoT=end of treatment; DFS=disease free survival 
Note: CIPN will be evaluated by the first 4 items of the FACT/GOG-NTX-13 (i.e. FACT/GOG-NTX-4), targeting numbness, 
tingling or discomfort in hands and/or feet, also at 9, 12, 18 and 24 months after the first dose of IMP 
2.2 POLAR-M 
2.2.1 Primary Objective 
The primary objective of the study is to compare each dose of PledOx (2 and 5 µmol/kg) vs placebo 
with respect to the proportion of patients with moderate or severe chronic CIPN. 
2.2.2 Secondary Objectives 
The secondary objectives of the study are to compare each dose of PledOx vs placebo regarding the 
following: 
Efficacy 
• 
The proportion of patients with mild, moderate or severe chronic CIPN 
• 
The sensitivity to touching cold items 
• 
The cumulative dose of oxaliplatin during chemotherapy 
• 
The vibration sensitivity on the lateral malleolus 
• 
The worst pain in hands or feet 
• 
The functional impairment (in the non-dominant hand) 
• 
The sustained efficacy on prevention of CIPN during long-term follow-up 
Safety 
• 
Overall response rate (ORR)  
• 
Progression-free survival (PFS)  
• 
Overall survival (OS)  
• 
Safety and tolerability 
2.2.3 Exploratory Objectives 
The exploratory objectives of the study are to compare each dose of PledOx vs placebo regarding the 
following: 
• 
Chronic CIPN by supporting analysis using the full FACT/GOG-NTX-13 
• 
The cumulative dose of 5-FU during chemotherapy  


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• 
For both oxaliplatin and 5-FU: Dose intensity, number of cycles, dose reductions, reason(s) for 
dose reductions, patients with dose delays, and length of dose delays 
• 
The pharmacokinetic (PK) profile of PledOx with multiple dosing (only at pre-selected sites 
and in 84 patients in total) 
• 
The QT/QTc interval using a 12-lead electrocardiogram (ECG) only at pre-selected sites and in 
84 patients in total) 
• 
The functional impairment (in the non-dominant hand) during long-term follow-up 
• 
The worst pain in hands or feet during long-term follow-up 
• 
QoL/health status 
• 
Health economic impact 
2.2.4 Study Design 
POLAR-M is a Phase 3, multicenter, double-blind, placebo-controlled study to establish the efficacious 
dose of PledOx in prevention of chronic CIPN induced by oxaliplatin.  Patients with metastatic CRC, 
who are indicated for first-line modified FOLFOX-6 (mFOLFOX6) chemotherapy for at least 3 months, 
without any pre-planned treatment breaks, will be randomised in a 1:1:1 ratio, stratified by region 
(Asia, non-Asia) and PK sub-study (yes, no), to one of three treatment arms: 
• 
Arm A: PledOx (2 µmol/kg) + mFOLFOX6 chemotherapy  
• 
Arm B: PledOx (5 µmol/kg) + mFOLFOX6 chemotherapy 
• 
Arm C: Placebo + mFOLFOX6 chemotherapy 
Figure 2. POLAR-M Study Design 
 
t=0 (baseline: Day 1, Cycle 1); R=randomization; EoT=end of treatment; PFS=progression-free survival; OS=overall survival; 
EoS=end of study  
Note: CIPN will be evaluated by the first 4 items of the FACT/GOG-NTX-13 (i.e. FACT/GOG-NTX-4), targeting numbness, 
tingling or discomfort in hands and/or feet, also at 12, 15, 18, 21 and 24 months after the first dose of IMP 
2.3 Visit Structure 
The visit structure and scheduled assessments are detailed in Section 5.2 and Appendix 1 in the study 
protocols. 
2.4 Sample Size 
As stated in Introduction the dosing of IMP stopped earlier than planned.  Hence, the sample size 
assumptions originally stated in the protocols do not longer hold.  In POLAR-A a total of n=301 patients 
have been randomised as compared to the planned n=280, and in POLAR-M n=290 patients have been 
randomised as compared to the planned n=420.  The sample size protocol text below are stated for 
reference. 


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Protocol text (Section 10.2 in the CSPs) 
The assumption of the proportion of patients who will satisfy the criteria for the primary endpoint in 
the untreated (placebo) study population is based on the results in the SCOT trial.  Results were 
presented at ASCO 2017 and roughly 40% of the placebo population had symptoms graded “quite a 
bit/very much”, which corresponds to 3 or more in this study. 
With 112 patients per group, the POLAR-A study has 91% power to detect a reduction (improvement) 
from 40% to 20% (OR = 0.375) in the primary endpoint using two-sided test controlled at the 0.05 
type-I error rate.  To account for 20% dropout in the study, in total 280 patients (140 patients per arm) 
will be randomised. 
With 112 patients per group, the POLAR-M study has 91% power to detect a reduction (improvement) 
from 40% to 20% (odds ratio = 0.375) in the primary endpoint using two-sided test controlled at the 
0.05 type-I error rate. To account for 20% dropout in the study, in total 420 patients (140 patients per 
arm) will be randomised. 
Sample size assumptions will be monitored in a blinded fashion as part of the regular monitoring of 
the study. In case there are indications these are not met; a re-estimation of the sample size may 
occur. 
2.5 Changes From the Protocol Planned Analysis 
Premature stop of administration of IMP in both POLAR-A and POLAR-M as well as the premature stop 
of recruitment in POLAR-M has several implications for the statistical analyses and the evaluation of 
the study data: 
• 
Primary analysis. The Cochran-Mantel-Haenszel method described in the protocols has been 
fully specified to also include adjustment for cumulative oxaliplatin exposure.  This amounts 
to replacing N, the number of subjects, in the divisor of the event rate calculation with 
cumulative oxaliplatin exposure.  Also, in the protocols the CMH approach also adjust for 
FACT/GOG at baseline, but since there were very few patients with CIPN at baseline the 
primary analysis described in Section 5.1.1. does not include FACT/GOG at baseline. 
• 
A negative binomial model will also be applied to the primary endpoint data as a supportive 
or exploratory analysis. 
• 
Earlier stop of recruitment in POLAR-M has resulted in actual n=290 randomised patients as 
compared to the planned n=420. 
• 
The primary analysis will be on the combined dataset including both POLAR-A and POLAR-M 
where study will be used as a stratification factor in all statistical analyses.  Both studies will 
also be reported separately (see details in Section 3). 
• 
Due to the lack of exposure of IMP a modified ITT (mITT) analysis set has been defined that 
will replace the Full Analysis Set (FAS).  See further details in Section 3.1. 
• 
Statistical analyses and summary tables will include data up to 12 months after the first dose 
of IMP (Assessment Visit 4).  Data that has been collected after Assessment Visit 4 will only be 
included in the listings by patient. 
Miscellaneous changes from the protocol planned analyses: 
• 
The endpoint “mean health index using the FACT/GOG” as stated in the protocols will not be 
analysed. 
• 
The variable Body Temperature although specified in vital signs section of the protocol has 
not been collected in the studies. 
• 
In the CSP it says “PledOx Toxicities” but has been re-defined here in the SAP as “IMP 
Toxicities“ since that is the way the data is collected and reported. 


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3. GENERAL STATISTICAL PRINCIPLES 
Testing Procedure.  The formal testing procedure of the primary endpoint is first to perform the 
analysis on PledOx 5 μmol/kg vs Placebo on both POLAR-A and POLAR-M studies combined.  If the 
results are statistically significant then the same analysis will be performed on the POLAR-A study 
alone.  All tests will be done on the 0.05 level of significance. 
Statistical analyses will include stratification factors for study (POLAR-A / POLAR-M) and region 
(Asia/non-Asia). 
3.1 Analysis Sets 
The analysis set “All randomised patients (ITT)” consists of all patients who were assigned a 
randomisation number, irrespective of the treatment they received, if any. 
The modified ITT (mITT) analysis set includes patients that fulfil at least one of the following criteria: 
1. the patient was randomised prior to December 1, 2019 (ie the patient was eligible for at 
least 3 months of IMP) and had at least one post-baseline assessment for efficacy, or 
2. the 3 month Assessment Visit occurred prior to 1 March, 2020, or 
3. the patient received the 6th cycle of IMP after 1 March, 2020. 
Patients will be analysed according to the treatment they are assigned to at randomisation, 
irrespective of what treatment they actually received. 
The safety analysis set (SAF) consists of all randomised patients who receive at least one dose of 
IMP.  Patients will be analysed according to the randomised study treatment actually received. 
The list of patients to be included in each of the analysis sets is to be agreed between the project 
statistician and the Sponsor prior to unblinding, once all study data is available. 
All enrolled patients will be listed indicating their membership to each analysis set along with the 
reason for exclusion. 
The PK population (POLAR-M only) includes a subset of patients at pre-selected sites in all participating 
regions, where blood samples will be collected for pharmacokinetics and ECG assessments. 
3.2 Hypothesis to be Tested 
With respect to the primary endpoint Moderate to Severe CIPN at 9 months after first dose of IMP the 
statistical hypothesis to test is: 
 
H0: 𝜇5𝜇𝑚𝑜𝑙/𝑘𝑔= 𝜇𝑝𝑙𝑎𝑐𝑒𝑏𝑜 
 
H1: 𝜇5𝜇𝑚𝑜𝑙/𝑘𝑔≠𝜇𝑝𝑙𝑎𝑐𝑒𝑏𝑜 
where 𝜇𝑥 represents the oxaliplatin-dose adjusted Moderate to Severe CIPN event rate at 9 months 
on treatment 𝑥. The treatment effect will be captured as the ratio of event rates, 
Ψ = 𝜇5𝜇𝑚𝑜𝑙/𝑘𝑔/𝜇𝑝𝑙𝑎𝑐𝑒𝑏𝑜, so that the preceding null and alternative hypotheses can be reframed as  
H0: Ψ = 1  versus  H1: Ψ ≠1   
A rate ratio <1 favours the PledOx 5μmol/kg group over placebo. 


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3.3 Handling of Dropouts or Missing Data 
All reasonable efforts will be made to obtain complete data for all patients.  However, missing 
observations may occur due to patients being lost to follow-up or non-compliant with the required 
protocol assessments. 
Baseline 
In all situations where baseline values are not recorded or not taken at the baseline visit (in most cases 
Cycle 1, Day 1), the value recorded from the last visit prior to Cycle 1 Visit will be used as the baseline 
value. 
Handling of Incomplete Dates 
Incomplete (partial or missing) dates will be presented in data listings as provided on the eCRF.  
However, for use in calculations (e.g. to calculate the duration of an AE or medication use) dates will 
be estimated as follows. 
For partial start-dates: 
• 
If the year is unknown, then the date will not be imputed and will be assigned a missing value. 
• 
If the month is unknown, then: 
i) 
If the year matches the year of the first dose date, then impute the month and day of the 
first dose date. 
ii) Otherwise, assign ‘January’. 
• 
If the day is unknown, then: 
i) 
If the month and year match the month and year of the first dose date, then impute 
the day of the first dose date. 
ii) 
Otherwise, assign ‘01’. 
For partial end-dates: 
• 
If the year is unknown, then the date will not be imputed and will be assigned a missing value. 
• 
If the month is unknown, then assign ‘December’. 
• 
If the day is unknown, then assign the last day of the month 
If the above rules for end-dates result in an illogical date with regards to the dates the patient 
was in the study, then the end date will be replaced with the patient’s date of 
completion/withdrawal.  Furthermore, should the above rules not result in the most 
conservative date (as described below), then the imputed value may be replaced by a date 
that will lead to a more conservative analysis. 
After implementing the rules above, to determine whether AEs with incomplete start or stop 
dates are non-treatment-emergent or treatment-emergent the following strategy will be 
used: 
• 
If the start date and stop date are both missing, the most conservative approach is taken and 
the AE is considered to be treatment-emergent. 
• 
If the start date is missing but the stop date is not missing and is on or after the day of first 
study drug administration then the most conservative approach is taken and the AE is 
considered to be treatment-emergent. 
• 
If the start date is missing but the stop date is not missing and is before the day of first study 
drug administration then the AE is considered to be non-treatment-emergent. 
If the date of first and/or last dose of study drug administration is missing then duration of exposure 
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3.4 Handling of Unscheduled or Repeated Measurements 
Descriptive summaries and by-visit analyses will be presented according to the planned (scheduled) 
visits, unless otherwise specified.  Discontinuation visits will be summarised at a scheduled visit 
providing the discontinuation visit occurs within the protocol specified visit windows.  The protocol 
specified visit windows are to be completed. 
In case data collection is done at an Unscheduled Visit rather than at the planned Assessment Visit, 
that measurement will be allocated to the nearest Assessment Visit.  This allocation will be 
implemented in the Reporting Data Base. 
4. STUDY PATIENTS 
Study Patients data will be presented by descriptive statistics by treatment group and total.  
Continuous variables will be summarised by number of patients (n), mean, standard deviation (SD), 
minimum, median and maximum, while categorical variables by counts and percentages.  Unless 
otherwise stated the calculation of proportions will be based on the size of the analysis set of interest. 
Listings will include all enrolled patients unless specified otherwise. 
Summaries for Study Patients variables will be provided for both the mITT and the safety analysis set. 
4.1 Patient Disposition 
The number and percentage of all patients screened, randomised, randomised who did not receive 
IMP, included in the safety analysis set, included in the modified ITT analysis set, prematurely 
discontinued IMP, prematurely withdrawn from the study, and patients who completed the study 
will be presented by treatment group and total. 
The number and percentage of patients will be summarised by their reasons for withdrawal 
(including Adverse Event, Death, Recurrent Disease, High Manganese Within the CNS, Lack of 
Efficacy, Lost to follow up, Non-Compliance With Study Drug, Physician Decision, Pregnancy, 
Progressive Disease, Protocol Deviation, Recovery, Site Terminated by Sponsor, Study Terminated by 
Sponsor, Technical Problems, Withdrawal by Subject, Other). 
Individual reasons for withdrawal will be presented in the listing. 
4.2 Protocol Deviations 
All responses to the inclusion and exclusion criteria and all protocol deviations will be listed by patient.  
All important protocol deviations may also be summarised by treatment group, total for pre-specified 
categories, as appropriate. 
4.3 Background and Demographic Characteristics 
Summaries for background and demographic characteristics will be provided for both the mITT and 
the safety analysis set. 
4.3.1 Demography 
Demographic characteristics (age [years], gender [male, female] and race [Asian, Black or African 
American, White]) and body measurements (height, weight and BMI) collected at Screening will be 
summarised for each treatment group and total. 
Age (years) is calculated in years as: 
integer(date of first dose of IMP – date of birth).  
Body Mass Index (BMI) is calculated as: Weight (kg) / Height (m)². 


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4.3.2 Medical History, Ongoing Medical Conditions and Prior Anti-cancer Therapy 
Medical history and ongoing medical conditions will be coded using the MedDRA Dictionary, Version 
23.0.  The number and percentage of patients will be presented for ongoing conditions and previous 
conditions separately by system organ class (SOC) and preferred term (PT) for each treatment group 
and total.  Also, the number and percentage of patients with prior anti-cancer therapy will be 
presented for each treatment group and total.  All events will be listed by patient. 
4.3.3 Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the WHO Drug Dictionary (WHODRUG 
GLOBAL B3 September 1, 2017).  The number and percentage of patients will be presented for prior 
and concomitant medications separately by system organ class (SOC) and Anatomical Therapeutic 
Chemical (ATC) classification system for each treatment group and total.  All events will be listed by 
patient. 
4.3.4 ECOG Performance Status 
The number and percentage of patients in the categories of the ECOG performance status (see Table 
1) at baseline (time of administration of the first dose of IMP – day 1, cycle 1) will be presented by 
treatment group and total. 
Table 1  ECOG Performance Status 
Grade  
ECOG status 
0  
Fully active, able to carry on all pre-disease performance without restriction  
1  
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work  
2  
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about 
more than 50% of waking hours  
3  
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours  
4  
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair  
5  
Dead  
 
4.3.5 ECG at Screening 
The 12-lead electrocardiogram and QTcF interval is measured at screening only. 
Data presentations 
- 
Table:  number (%) of patients with normal/abnormal ECG by treatment group and total. 
- 
Table:  descriptive statistics of QTcF by treatment group and total. 
All observed values of the 12-lead ECG and QTcF will be listed by patient. 
4.4 Administration of Investigational Medical Product and Chemotherapy 
4.4.1 Investigational Medical Product (IMP) 
The following variables related to the administration of IMP will be summarised and listed: 
• 
Number and percentage of patients receiving IMP by cycle 
• 
Cumulative dose of IMP 
• 
Duration of IMP administration (weeks) 
• 
Dose intensity (mL/week) = cumulative dose (mL) / treatment duration (weeks) 
• 
Mean number of treatment cycles of IMP 


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Data presentations 
- 
Table:  number (%) of patients receiving IMP by treatment group and total for each treatment 
cycle 
- 
Table:  descriptive statistics of cumulative dose of IMP by treatment group and total 
- 
Table:  descriptive statistics of duration of IMP by treatment group and total 
- 
Table:  descriptive statistics of dose intensity of IMP by treatment group and total 
- 
Table:  descriptive statistics of number of treatment cycles of IMP by treatment group and 
total 
All observed values of the administration of IMP will be listed by patient. 
4.4.2 Oxaliplatin 
The following variables related to the administration of oxaliplatin will be summarised and listed: 
• 
Number and percentage of patients receiving oxaliplatin by cycle 
• 
Cumulative dose of oxaliplatin (see also Section 5.3.3) 
• 
Duration of oxaliplatin administration (weeks) 
• 
Dose intensity (mg/m2/week) = cumulative dose (mg/m2) / treatment duration (weeks) 
• 
Number and percentage of patients with dose modifications (reduced or delayed) of 
Oxaliplatin 
• 
Duration of dose delay(s) 
• 
Mean number of treatment cycles of Oxaliplatin 
Data presentations 
- 
Table:  number (%) of patients receiving oxaliplatin by treatment group and total for each 
treatment cycle 
- 
Table:  descriptive statistics of cumulative dose of oxaliplatin by treatment group and total 
- 
Table:  descriptive statistics of duration of oxaliplatin by treatment group and total 
- 
Table:  descriptive statistics of dose intensity of oxaliplatin by treatment group and total 
- 
Table:  number (%) of patients with dose modifications (reduced or delayed) of oxaliplatin by 
treatment group and total for each treatment cycle 
- 
Table:  descriptive statistics of duration of dose delays of oxaliplatin by treatment group and 
total 
- 
Table:  descriptive statistics of number of treatment cycles of oxaliplatin by treatment group 
and total 
- 
Figure:  the proportion of patients receiving oxaliplatin will be graphically depicted (lineplot) 
vs treatment cycle/assessment visit by treatment group. 
All observed values of the administration of oxaliplatin will be listed by patient. 
4.4.3 5-FU 
The following variables related to the administration of 5-FU (IV Bolus/IV Continued Infusion) will be 
summarised and listed: 
• 
Number and percentage of patients receiving 5-FU by cycle 
• 
Cumulative dose of 5-FU (see also Section 5.4.4) 
• 
Duration of 5-FU administration (weeks) 
• 
Dose intensity (mg/m2/week) = cumulative dose (mg/m2) / treatment duration (weeks) 
• 
Number and percentage of patients with dose modifications (reduced or delayed) of 5-FU 
• 
Duration of dose delay(s) 
• 
Mean number of treatment cycles of 5-FU 


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Data presentations 
- 
Table:  number (%) of patients receiving 5-FU by treatment group and total for each treatment 
cycle 
- 
Table:  descriptive statistics of cumulative dose of 5-FU (IV Bolus/IV Continued Infusion) by 
treatment group and total 
- 
Table:  descriptive statistics of duration of 5-FU by treatment group and total 
- 
Table:  descriptive statistics of dose intensity of 5-FU (IV Bolus/IV Continued Infusion) by 
treatment group and total 
- 
Table:  number (%) of patients with dose modifications (reduced or delayed) of 5-FU by 
treatment group and total for each treatment cycle 
- 
Table:  descriptive statistics of duration of dose delays of 5-FU by treatment group and total 
- 
Table:  descriptive statistics of number of treatment cycles of 5-FU by treatment group and 
total 
All observed values of the administration of 5-FU (IV Bolus/IV Continued Infusion) will be listed by 
patient. 
4.4.4 Calcium-folinate or Calcium-levofolinate 
The following variables related to the administration of Calcium-folinate or Calcium-levofolinate will 
be summarised and listed: 
• 
Number and percentage of patients receiving Calcium-folinate or Calcium-levofolinate by 
cycle 
• 
Cumulative dose of Calcium-folinate or Calcium-levofolinate 
• 
Duration of Calcium-folinate or Calcium-levofolinate administration (weeks) 
• 
Dose intensity (mg/m2/week) = cumulative dose (mg/m2) / treatment duration (weeks) 
• 
Number and percentage of patients with dose modifications (reduced or delayed) of Calcium-
folinate or Calcium-levofolinate 
• 
Mean number of treatment cycles of Calcium-folinate or Calcium-levofolinate 
Data presentations 
- 
Table:  number (%) of patients receiving Calcium-folinate or Calcium-levofolinate by treatment 
group and total for each treatment cycle 
- 
Table:  descriptive statistics of cumulative dose of Calcium-folinate or Calcium-levofolinate by 
treatment group and total 
- 
Table:  descriptive statistics of duration of Calcium-folinate or Calcium-levofolinate by 
treatment group and total 
- 
Table:  descriptive statistics of dose intensity of Calcium-folinate or Calcium-levofolinate by 
treatment group and total 
- 
Table:  number (%) of patients with dose modifications (reduced or delayed) of Calcium-
folinate or Calcium-levofolinate by treatment group and total for each treatment cycle 
- 
Table:  descriptive statistics of number of treatment cycles of Calcium-folinate or Calcium-
levofolinate by treatment group and total 
All observed values of the administration of Calcium-folinate or Calcium-levofolinate will be listed by 
patient. 
5. EFFICACY EVALUATION 
Unless otherwise stated, all efficacy variables will be analysed using the mITT analysis set.  The general 
principles for handling unscheduled or repeated measurements is described in Section 3.4. 


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5.1 Primary Endpoint 
5.1.1 Moderate to Severe CIPN 
The primary endpoint is defined as the proportion of patients (with moderate or severe chronic CIPN) 
scoring 3 or 4 in at least 1 of the first 4 items of the FACT/GOG-NTX-13 (i.e., FACT/GOG-NTX-4), 
targeting numbness, tingling or discomfort in hands and/or feet, 9 months after the first dose of IMP 
(i.e. PledOx or placebo administered on Day 1, Cycle 1 of mFOLFOX6 chemotherapy). 
Baseline is defined as the time of administration of the first dose of IMP (Day 1, Cycle 1). 
Moderate to Severe CIPN will derived (SAS) as follows: 
  cipn=0; 
  IF ntx1_std=. AND ntx2_std=. AND ntx3_std=. AND ntx4_std=. THEN cipn=.; 
  ELSE IF ntx1_std IN('3','4') OR ntx2_std IN('3','4') OR  
          ntx3_std IN('3','4') OR ntx4_std IN('3','4') THEN cipn=1; 
 
Primary Analysis – Cochran-Mantel-Haenszel.  The primary analysis of the primary endpoint 
Moderate to Severe CIPN (yes/no) at 9 months after first dose of IMP will be analysed by the 
Cochran-Mantel-Haenszel (CMH) estimate of the common relative risk of Moderate to Severe CIPN.  
The treatment effect will be assessed by estimating the ratio of the incidence rates of CIPN in PledOx 
5μmol/kg versus Placebo along with its 95% confidence interval and corresponding p-value.  The 
CMH estimate will be adjusted for cumulative exposure of oxaliplatin and stratified by study and 
region.  Incidence rates (95% CIs) for each treatment will also be presented. 
Notations.  The combined analysis includes two studies (POLAR-A and POLAR-M) and two 
geographical regions (Asia/Non-Asia), and so there are 4 strata, where 
1 = POLAR-A / Asia 
2 = POLAR-A / Non-Asia 
3 = POLAR-M / Asia 
4 = POLAR-M / Non-Asia 
 
Treatments are denoted by 1 and 2, where 1 = PledOx 5μmol/kg and 2 = Placebo.  For treatment j in 
the ith strata the cumulative exposure of oxaliplatin is Tij and Eij is CIPN events.  Let 
2
i
1i
i
T
T
T
+
=
•
 
and 
2
i
1i
i
E
E
E
+
=
•
denote total cumulative exposure of oxaliplatin and total CIPN events in the ith 
strata. 
CMH point estimate of the common relative risk across strata.  Under 𝐻0: 𝑅1 = 𝑅2 = 𝑅, Breslow and 
Day [1] provide the stratified Cochran-Mantel-Haenszel estimate of the common relative risk as  


=
•
=
•
−
=
k
1
i
i
1
i
2
i
k
1
i
i
2
i
1
i
H
M
T
T
E
T
T
E
Rˆ
 
Also, Robins, Breslow and Greenland [2] provide an estimate of the variance of log
H
M
Rˆ
−
 as 


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(
)


(
)
2
k
1
i
H
M
1i
2
i
i
i
2
i
1i
H
M
k
1
i
2
i
i
2
i
1i
H
M
Rˆ
T
T
T
E
T
T
Rˆ
T
E
T
T
Rˆ
log
Vˆ






+
=


=
−
•
•
−
=
•
•
−
 
Then, a 95% confidence interval for the common relative risk across strata is, 
exp⁡{𝑙𝑜𝑔(𝑅̂𝑀−𝐻) ± 1.96 × 𝑆𝐸} 
where 𝑆𝐸= √𝑉̂[log(𝑅̂𝑀−𝐻)]. 
The statistic 𝑍=
𝑙𝑜𝑔(𝑅̂𝑀−𝐻)
𝑆𝐸
~𝑁(0,1) so the 2-sided p-value is calculated by 2 × (1 −𝐶𝐷𝐹(|𝑧|)). 
 
CMH event rates for each treatment.  The Cochran-Mantel-Haenszel oxaliplatin exposure weighted 
incidence rate estimate for treatment j across strata is given by 


=
=

=
k
1
i
i
k
1
i
ij
i
j
w
w
U
, j=1,2 and 
ij
ij
ij
T
E
=

 (i.e the event rate for treatment j in strata i) and 
2
i
1i
i
T
1
T
1
2
w
+
=
 (i.e. the harmonic mean cumulative exposure of oxaliplatin in strata i). 
CMH variance of the event rates.  The variance of Cochran-Mantel-Haenszel oxaliplatin exposure 
weighted incidence rate estimate for treatment j across strata is given by 


( )
(
)
2
k
1
i
i
k
1
i
ij
2
i
k
1
i
i
k
1
i
ij
i
j
w
Var
w
w
w
Var
U
Var




=
=
=
=

=









=
 
and hence 


( )
(
)
(
)
(
)
2
k
1
i
i
k
1
i
2
ij
ij
2
i
2
k
1
i
i
k
1
i
ij
2
ij
2
i
2
k
1
i
i
k
1
i
ij
2
i
j
w
T
E
w
w
E
ˆ
w
w
ˆ
Var
w
U
ar
Vˆ






=
=
=
=
=
=
=

=

=
 
Further, 
(
)




(
)
(
)
(
)
(
)
(
)
(
)
2
k
1
i
ij
i
k
1
i
ij
2
i
2
k
1
i
i
k
1
i
ij
2
i
2
k
1
i
ij
i
2
k
1
i
i
j
2
j
j
w
Var
w
w
Var
w
w
w
U
Var
U
1
U
log
Var






=
=
=
=
=
=


=



=
=
 
and so 


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(
)


( )
(
)
(
)
2
k
1
i
ij
ij
i
k
1
i
2
ij
ij
2
i
2
k
1
i
ij
i
k
1
i
ij
2
ij
2
i
2
k
1
i
ij
i
k
1
i
ij
2
i
j
T
E
w
T
E
w
ˆ
w
E
ˆ
w
ˆ
w
ˆ
Var
w
U
log
ar
Vˆ






=


=


=






=
=
=
=
=
=
 
Then, a 95% confidence interval for the Cochran-Mantel-Haenszel oxaliplatin exposure weighted 
incidence rate estimate across strata is, 
𝑈𝑗× exp⁡ {±1.96√𝑉𝑎𝑟
̂ [𝑙𝑜𝑔(𝑈𝑗)]} 
 
Interpretation of parameter estimates.  The Cochran-Mantel-Haenszel method provide estimates of 
oxaliplatin-dose adjusted Moderate to Severe CIPN event rates at 9 months.  The associated unit of 
measurement for the CMH estimates is therefore the CIPN event rate per unit dose of oxaliplatin.  To 
aid in clinical interpretation and understanding, the CMH estimates will be scaled to a relevant clinical 
dose eg 800 mg/m2 to allow the event rate to be expressed per 100 patients relative to this dose.  It 
can also be used to represent the number of events saved when receiving active treatment as 
compared to placebo.  The example data below illustrates this in more detail. 
The exact same interpretation can be done for the event rates (LSmeans) estimated from the negative 
binomial model as described further below. 
Table 2  Example data 
 
Placebo 
PledOx 5 µmol/kg 
 
No CIPN 
70 (59%) 
86 (73%) 
156 
CIPN 
48 (41%) 
32 (27%) 
80 
 
118 
118 
236 
 
Table 3  Example data: Cochran-Mantel-Haenszel estimates of Moderate to severe CIPN 9 months 
after first dose of IMP 
 
N 
Estimate 
95% CI 
P-value 
PledOx 5 µmol/kg 
Placebo 
PledOx 5 µmol/kg vs Placebo 
118 
118 
236 
0.000317 
0.000462 
0.6869 
[0.000222; 0.000454] 
[0.000343; 0.000623] 
[0.4391; 1.0745] 
- 
- 
0.0999 
 
Suppose the mean cumulative dose overall of oxaliplatin is 800 mg/m2 so the event rates are 
estimated by: 
PledOx 5 µmol/kg 
0.000317 x 800 = 0.25 CIPN events per patient per 800 mg/m2 of oxaliplatin 
Placebo 
 
0.000462 x 800 = 0.37 CIPN events per patient per 800 mg/m2 of oxaliplatin 
This translates into: 
PledOx 5 µmol/kg 
25 CIPN events per 100 patients treated 
Placebo 
 
37 CIPN events per 100 patients treated 
This represents a saving of 12 CIPN events per 100 patients treated with PledOx 5 µmol/kg. 


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In the results presentation of the CSR the observed mean cumulative dose of oxaliplatin will be used. 
 
Supportive Analysis of the primary endpoint - Negative Binomial Regression.  A supportive analysis 
of the primary endpoint Moderate to Severe CIPN (yes/no) at 9 months after first dose of IMP will be 
analysed by a negative binomial regression model adjusted for study (POLAR-A / POLAR-M) and 
region (Asia / non-Asia).  An offset variable will also be used to adjust for the oxaliplatin exposure 
defined as the logarithm of the cumulative dose of oxaliplatin received by each patient.  Estimate of 
the treatment contrast (rate ratio) and its corresponding 95% confidence interval will be based on 
the anti-log of the model parameter estimate and CI. 
SAS Code Example Negative Binomial Regression using PROC GENMOD 
PROC GENMOD; 
  CLASS study region trt; 
  MODEL cipn = study region trt/DIST=negbin LINK=log SCALE=deviance OFFSET=log_exp; 
  ESTIMATE 'PledOx 5 µmol/kg vs Placebo' trt 1 -1; 
  LSMEANS trt / CL EXP; 
RUN; 
 
If convergence criterion is not met using PROC GENMOD an alternative using PROC NLMIXED will be 
used. 
SAS Code Example Negative Binomial Regression using PROC NLMIXED 
PROC NLMIXED;  
  PARMS b0 -2 b1 .1 b2 -.01 b3 .1 phi .1; 
  eta = log_exp + b0 + b1*(study=1) + b2*(region=1) + b3*(trt=0);  
  mu = exp(eta);  
  LL = y*log(phi*mu) - (y+(1/phi))*log(1+(phi*mu)) + lgamma(y+(1/phi)) - 
lgamma(1/phi) - lgamma(y+1);  
  MODEL y ~ general(LL); 
RUN; 
 
Exploratory Analysis – Exact Logistic Regression.  An exploratory analysis of the primary endpoint 
Moderate to Severe CIPN at 9 months after first dose of IMP will be analysed by exact logistic 
regression model adjusted for study (POLAR-A / POLAR-M) and region (Asia / non-Asia).  Estimate of 
the treatment effect and its corresponding 95% confidence interval will be based on the odds-ratio. 
SAS Code Example Exact Logistic Regression 
PROC LOGISTIC DESC; 
 
CLASS study region trt(ref='0: Placebo'); 
 
MODEL cipn = study region trt; 
EXACT trt; 
RUN; 
 
Using the same example data presented above, a crude estimate of the odds-ratio then is: 
(0.27/0.73) / (0.41/0.59) = 0.53 
Table 4  Example data: Exact Logistic Regression of Moderate to severe CIPN 9 months after first 
dose of IMP 
 
N 
CIPN (%) 
Odds-ratio 
95% CI 
P-value 
PledOx 5 µmol/kg 
Placebo 
PledOx 5 µmol/kg vs Placebo 
118 
118 
236 
27.1 
40.7 
- 
- 
- 
0.54 
- 
- 
[0.31;0.94] 
- 
- 
0.0293 
 


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Data Presentations 
- 
Table:  the primary analysis of Moderate to Severe CIPN based on the Cochran-Mantel-
Haenszel estimate will be presented by number of patients (N), treatment estimates and its 
95% CIs.  The rate ratio between PledOx 5 µmol/kg and Placebo will be presented by the 
estimate, 95% CI and p-value. 
- 
Table:  the supportive analysis of Moderate to Severe CIPN based on the negative binomial 
regression model will be presented by number of patients (N), treatment estimates and its 
95% CIs.  The rate ratio between PledOx 5 µmol/kg and Placebo will be presented by the 
estimate, 95% CI and p-value. 
- 
Table:  the number and percentage of patients with Moderate to Severe CIPN along with its 
95% CI presented by treatment group and total for each treatment visit/assessment visit.  The 
confidence intervals will be based on the method of Clopper-Pearson (exact). 
- 
Table:  the exploratory analysis of Moderate to Severe CIPN based on the exact logistic 
regression model will be presented by number of patients (N), number of patients (%) with 
Moderate to Severe CIPN at 9 months after first does of IMP for each treatment group, and 
odds-ratio, 95% CI and p-value for the treatment comparison. 
- 
Figure:  the proportion (including 95% CIs) of patients with Moderate to Severe CIPN will be 
graphically depicted (lineplot) vs treatment cycle/assessment visit by treatment group. 
- 
All observed values of Moderate to Severe CIPN will be listed by patient. 
Missing values of the primary endpoint will be handled as described in Section 5.2. 
5.2 Handling of Missing Data in the Primary Endpoint 
For the primary endpoint Moderate to Severe CIPN (yes/no) the following methods of imputation will 
be used for the primary analysis in case of missing: 
1. Observed cases (no imputation) 
2. “Non-responder” if missing (ie 3 or 4 on FACT/GOG) 
3. Tipping point analysis – combinations of missing data values that would change the 
conclusion. References eg Yan (2009), Rubin (2012) 
A tipping point analysis assesses the potential impact of informative missingness by progressively 
penalizing patients with missing data in the experimental arm.  The goal is to find the level of 
penalization that results in loss of statistical significance on the primary endpoint. 
The steps to perform the tipping point analysis are as follows: 
1. The NB model as described in Section 5.1.1 is applied to each randomised treatment arm 
separately based on the observed data in that arm.  This will give two parameters for each of 
the experimental and control groups, the event rate, 𝜇, and the dispersion rate, 𝜅. 
2. For each subject, 𝑖, in the experimental arm who had 𝑡𝑖 < 9 months follow-up and who did not 
record a primary endpoint event in the period (0 −⁡𝑡𝑖], simulate their event rate,⁡𝜇𝑖, by 
randomly sampling an observation from a  𝐺𝑎𝑚𝑚𝑎(𝑠ℎ𝑎𝑝𝑒= 1 𝜅
⁄ , 𝑠𝑐𝑎𝑙𝑒= 1 (𝜅𝜇)
⁄
) 
distribution. 
3. Using ⁡𝜇𝑖, the time to event for subject 𝑖 in the period (𝑡𝑖, 9]⁡is given by  ∆𝑖= −ln(1 −𝜔𝑖) ⁡𝜇𝑖
⁄
 
where 𝜔𝑖 is a random deviate from a 𝑈(0,1) distribution. 
4. If 𝑡𝑖+ ∆𝑖⁡≤  9 then subject 𝑖 is considered to have had an event at with an exposure time of 
𝑡𝑖+ ∆𝑖.   If 𝑡𝑖+ ∆𝑖 > 9 then subject 𝑖 is considered not to have event at with an exposure time 
of 9 months. 
5. Steps 2-4 will result in a full dataset with no missing primary endpoint data over the period (0-
9] months. 


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6. This full dataset is then analysed in the same manner as described for the primary endpoint 
using the Cochran-Mantel-Haenszel approach and the treatment effect and associated SE are 
estimated. 
7. Steps 2-6 are repeated multiple times and the resulting treatment effect estimates and SEs 
are combined in SAS via PROC MIANALYZE using Rubin’s rules.  This will provide the estimated 
treatment effect having imputed missing data under a missing at random assumption. 
8. Return to Step 2 and now, for each subject, 𝑖, in the experimental arm who had 𝑡𝑖 < 9 months 
follow-up and who did not record a primary endpoint event in the period (0 −⁡𝑡𝑖], resimulate 
their event rate, ⁡𝜇𝑖, by randomly sampling an observation from a  𝐺𝑎𝑚𝑚𝑎(𝑠ℎ𝑎𝑝𝑒=
1 𝜅
⁄ , 𝑠𝑐𝑎𝑙𝑒= 1 (𝜅(𝜇+ 𝜀)
⁄
) distribution where 𝜀 is some small, positive number.  Imputation 
of control treated patients is unchanged. 
9. Repeat Steps 2-7.  This will provide the estimated treatment effect having imputed missing 
data under a missing not at random with the event rate on experimental penalised by the 
amount 𝜀. 
10. Repeat steps 2-9 for penalising the experimental event rate by 𝜀, 2𝜀, 3𝜀, …. until statistical 
significance is lost. 
5.3 Secondary Efficacy Endpoints 
5.3.1 Mild to Severe CIPN 
Proportion of patients (with mild, moderate or severe chronic CIPN) scoring 2, 3, or 4, in at least 1 of 
the first 4 items of the FACT/GOG-NTX-13 (i.e. FACT/GOG-NTX-4), targeting numbness, tingling or 
discomfort in hands and/or feet, 9 months after the first dose of IMP. 
Baseline is defined as the time of administration of the first dose of IMP (Day 1, Cycle 1). 
Mild to Severe CIPN will derived (SAS) as follows: 
  cipn2=0; 
  IF ntx1_std=. AND ntx2_std=. AND ntx3_std=. AND ntx4_std=. THEN cipn2=.; 
  ELSE IF ntx1_std IN('2','3','4') OR ntx2_std IN('2','3','4') OR  
          ntx3_std IN('2','3','4') OR ntx4_std IN('2','3','4') THEN cipn2=1; 
 
Mild to Severe CIPN will be analysed using the method of Cochran-Mantel-Haenszel as described in 
detail in Section 5.1.1. 
Data Presentations 
- 
Table:  the analysis of Mild to Severe CIPN based on the negative binomial regression model 
will be presented by number of patients (N), treatment estimates and its 95% CIs.  The rate 
ratio between PledOx 5 µmol/kg and Placebo will be presented by the estimate, 95% CI and 
p-value. 
- 
Table:  the number and percentage of patients with Mild to Severe CIPN along with its 95% CI 
presented by treatment group and total for each treatment visit/assessment visit.  The 
confidence intervals will be based on the method of Clopper-Pearson (exact). 
- 
Figure:  the proportion (including 95% CIs) of patients with Mild to Severe CIPN will be 
graphically depicted (lineplot) vs treatment cycle/assessment visit by treatment group. 
- 
All observed values of Mild to Severe CIPN will be listed by patient. 
All the analyses of Mild to Severe CIPN will be based on the observed cases.  Hence, no imputation of 
missing values will be done. 


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5.3.2 Cold Sensitivity 
Mean change from baseline in sensitivity to touching cold items on day 2, Cycle 4 of mFOLFOX6 
chemotherapy, as assessed by the Cold Sensitivity questionnaire (ordinal scale 0-10). 
Baseline is defined as the Screening measurement. 
Analysis of Covariance.  Cold Sensitivity will be analysed by Analysis of Covariance (ANCOVA) using 
the cold sensitivity baseline value as a continuous covariate and study (POLAR-A / POLAR-M), region 
(Asia / non-Asia) and treatment as factors.  Least square means and its corresponding 95% confidence 
intervals will be presented. 
Data Presentations 
- 
Table:  the analysis cold sensitivity based on the ANCOVA model will be presented by number 
of patients (N), estimate (LSM) and 95% CI for each treatment group.  The treatment contrast 
(PledOx 5 µmol/kg vs Placebo) will be presented by estimate (difference in LSM), 95% CI and 
p-value. 
- 
Table:  descriptive statistics of observed values of cold sensitivity by treatment and total for 
each visit (baseline (screening), cycle 2,4 and 8) and measurements within each treatment 
visit (pre-infusion day 1, post-infusion day 1, post-infusion day 2 and, post-infusion day 3). 
- 
Figure:  shift plot (with jitter) of cold sensitivity at baseline vs cycle 4, day 2 
The same output (except for the ANCOVA analysis) will be produced also for the other 3 variables 
included in the Cold Sensitivity questionnaire: 
- 
Swallowing cold liquids 
- 
Throat discomfort 
- 
Muscle cramps 
5.3.3 Cumulative Dose of Oxaliplatin 
Mean cumulative dose of oxaliplatin administered per patient during mFOLFOX6 chemotherapy, 
9 months after the first dose of IMP.  Summary statistics of oxaliplatin related variables are presented 
in Section 4.4.2. 
In case the patient receives more than 12 cycles of oxaliplatin, that will also be accounted for when 
deriving the cumulative dose. 
Analysis of Variance.  Mean cumulative dose of oxaliplatin will be analysed by Analysis of Variance 
(ANOVA) using study (POLAR-A / POLAR-M), region (Asia / non-Asia) and treatment as factors.  Least 
square means and its corresponding 95% confidence intervals will be presented. 
Data presentation 
- 
Table:  ANCOVA analysis - Number of patients (N), Point Estimate (LSM), 95% CI and P-value 
by treatment group/treatment comparison (PledOx 5 µmol/kg vs Placebo). 
All observed values of mean cumulative dose of oxaliplatin will also be listed by patient. 
5.3.4 Vibration Sensitivity Test 
Mean change from baseline in vibration sense (0-8 ordinal scale), on the lateral malleolus (left and 
right), using a graduated tuning fork, at 9 months after the first dose of IMP. 
Baseline is defined as the time of administration of the first dose of IMP (Day 1, Cycle 1). 
Analysis of Covariance.  Vibration sense will be analysed by Analysis of Covariance (ANCOVA) using 
the vibration sense baseline value as a continuous covariate and study (POLAR-A / POLAR-M), region 


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(Asia / non-Asia) and treatment as factors.  Least square means and its corresponding 95% confidence 
intervals will be presented. 
Data presentations 
- 
Table:  ANCOVA analysis - Number of patients (N), Point Estimate (LSM), 95% CI and P-value 
by treatment group/treatment comparison (PledOx 5 µmol/kg vs Placebo) 
- 
Table: descriptive statistics of observed values by treatment and total for each treatment cycle 
- 
Table: descriptive statistics of change from baseline by treatment and total for each treatment 
cycle 
- 
Figure: shift plot (using jitter) of baseline vs 9-month assessment visit 
All observed values of Vibration Sensitivity Test will also be listed by patient. 
5.3.5 Pain (NRS) 
Mean change from baseline in worst pain in hands or feet in the past week, using a numerical rating 
scale (NRS), at 9 months after the first dose of IMP.  NRS is measured on an ordinal scale 0-10. 
Baseline is defined as the time of administration of the first dose of IMP (Day 1, Cycle 1). 
Analysis of Covariance.  Pain will be analysed by Analysis of Covariance (ANCOVA) using the pain 
baseline value as a continuous covariate and study (POLAR-A / POLAR-M), region (Asia / non-Asia) and 
treatment as factors.  Least square means and its corresponding 95% confidence intervals will be 
presented. 
Data presentations 
- 
Table:  ANCOVA analysis - Number of patients (N), Point Estimate (LSM), 95% CI and P-value 
by treatment group/treatment comparison (PledOx 5 µmol/kg vs Placebo). 
- 
Table: descriptive statistics of observed values by treatment and total for each treatment 
cycle. 
- 
Table: descriptive statistics of change from baseline by treatment and total for each treatment 
cycle. 
- 
Figure: shift plot (using jitter) of baseline vs 9-month assessment visit. 
All observed values of worst pain in hands or feet will also be listed by patient. 
5.3.6 Grooved Pegboard 
Mean change from baseline in the time (seconds) to complete the Grooved Pegboard with the 
non-dominant hand, at 9 months after the first dose of IMP. 
Baseline is defined as the time of administration of the first dose of IMP (Day 1, Cycle 1). 
Analysis of Covariance.  Grooved pegboard will be analysed by Analysis of Covariance (ANCOVA) using 
the grooved pegboard baseline value as a continuous covariate and study (POLAR-A / POLAR-M), 
region (Asia / non-Asia) and treatment as factors.  Least square means and its corresponding 95% 
confidence intervals will be presented. 
Data presentations 
- 
Table:  ANCOVA analysis - Number of patients (N), Point Estimate (LSM), 95% CI and P-value 
by treatment group/treatment comparison (PledOx 5 µmol/kg vs Placebo). 
- 
Table: descriptive statistics of observed values by treatment and total for each treatment 
cycle. 
- 
Table: descriptive statistics of change from baseline by treatment and total for each treatment 
cycle. 
- 
Figure: shift plot (using jitter) of baseline vs 9-month assessment visit. 


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Figure: scatter plot (using jitter) by treatment group for each treatment cycle. 
All observed values of grooved pegboard will also be listed by patient. 
5.3.7 Long-term Moderate to Severe CIPN 
Long-term Moderate to Severe CIPN is defined as the proportion of patients scoring 3 or 4 in at least 
1 of the first 4 items of the FACT/GOG-NTX-13 (i.e. FACT/GOG-NTX-4), targeting numbness, tingling or 
discomfort in hands and/or feet 12 months after the first dose of IMP. 
Baseline is defined as the time of administration of the first dose of IMP (Day 1, Cycle 1). 
Moderate to Severe CIPN will derived (SAS) as follows (same as primary endpoint): 
  cipn=0; 
  IF ntx1_std=. AND ntx2_std=. AND ntx3_std=. AND ntx4_std=. THEN cipn=.; 
  ELSE IF ntx1_std IN('3','4') OR ntx2_std IN('3','4') OR  
          ntx3_std IN('3','4') OR ntx4_std IN('3','4') THEN cipn=1; 
 
Long-term Moderate to Severe CIPN will be analysed using the method of Cochran-Mantel-Haenszel 
as described in detail in Section 5.1.1. 
All the analyses of Long-term Moderate to Severe CIPN will be based on observed cases.  Hence, no 
imputation of missing values will be done. 
Data Presentations 
- 
Table:  the analysis of Long-term Moderate to Severe CIPN based on the negative binomial 
regression model will be presented by number of patients (N), treatment estimates and its 
95% CIs.  The rate ratio between PledOx 5 µmol/kg and Placebo will be presented by the 
estimate, 95% CI and p-value. 
5.4 Exploratory Endpoints 
5.4.1 Any CIPN 
Any CIPN is defined as the proportion of patients with any CIPN scoring 1, 2, 3 or 4, in any of the first 
4 items of the FACT/GOG-NTX-13 (i.e. FACT/GOG-NTX-4), targeting numbness, tingling or discomfort 
in hands and/or feet, at all other timepoints after the first dose of IMP. 
Baseline is defined as the time of administration of the first dose of IMP (Day 1, Cycle 1). 
Any CIPN will derived (SAS) as follows: 
  cipn3=0; 
  IF ntx1_std=. AND ntx2_std=. AND ntx3_std=. AND ntx4_std=. THEN cipn3=.; 
  ELSE IF ntx1_std IN('1','2','3','4') OR ntx2_std IN('1','2','3','4') OR  
          ntx3_std IN('1','2','3','4') OR ntx4_std IN('1','2','3','4') THEN 
cipn3=1; 
 
Data Presentations 
- 
Table:  the number and percentage of patients with Any CIPN along with its 95% CI presented 
by treatment group and total for each treatment visit/assessment visit.  The confidence 
intervals will be based on the method of Clopper-Pearson (exact) 
- 
Figure:  the proportion (including 95% CIs) of patients with Any CIPN will be graphically 
depicted (lineplot) vs treatment cycle/assessment visit by treatment group. 
- 
All observed values of Any CIPN will be listed by patient 


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The analysis of Any CIPN will be based on observed cases.  Hence, no imputation of missing values will 
be done. 
5.4.2 Mean Score of FACT/GOG NTX1-4 
Mean score of the first 4 items of the FACT/GOG-NTX-13 (i.e. FACT/GOG-NTX-4), at 9 months after the 
first dose of IMP. 
Baseline is defined as the time of administration of the first dose of IMP (Day 1, Cycle 1). 
Analysis of Covariance.  Mean score of FACT/GOG NTX1-4 will be analysed by Analysis of Covariance 
(ANCOVA) using the baseline value as a continuous covariate and study (POLAR-A / POLAR-M), region 
(Asia / non-Asia) and treatment as factors.  Least square means and its corresponding 95% confidence 
intervals will be presented. 
Data presentations 
- 
Table:  ANCOVA analysis - Number of patients (N), Point Estimate (LSM), 95% CI and P-value 
by treatment group/treatment comparison (PledOx 5 µmol/kg vs Placebo). 
- 
Table: descriptive statistics of observed values by treatment and total for each treatment 
cycle. 
- 
Table: descriptive statistics of change from baseline by treatment and total for each treatment 
cycle. 
- 
Figure: shift plot of baseline vs 9-month assessment visit. 
All observed values of the Mean Score of FACT/GOG NTX1-4 will also be listed by patient. 
5.4.3 Mean Score of FACT/GOG NTX1-13 
Endpoint.  Mean score of the 13 items of the FACT/GOG-NTX-13, at 9 months after the first dose of 
IMP. 
Baseline.  Defined as the time of administration of the first dose of IMP (Day 1, Cycle 1). 
Analysis of Covariance.  Mean score of FACT/GOG-NTX-13 will be analysed by Analysis of Covariance 
(ANCOVA) using the baseline value as a continuous covariate and study (POLAR-A / POLAR-M), region 
(Asia / non-Asia) and treatment as factors.  Least square means and its corresponding 95% confidence 
intervals will be presented. 
Data presentations 
- 
Table:  ANCOVA analysis - Number of patients (N), Point Estimate (LSM), 95% CI and P-value 
by treatment group/treatment comparison (PledOx 5 µmol/kg vs Placebo). 
- 
Table: descriptive statistics of observed values by treatment and total for each treatment 
cycle. 
- 
Table: descriptive statistics of change from baseline by treatment and total for each treatment 
cycle. 
- 
Figure: shift plot of baseline vs 9-month assessment visit. 
All observed values of the Mean Score of FACT/GOG NTX1-13 will also be listed by patient. 
5.4.4 Cumulative Dose of 5-FU 
Endpoint.  Mean cumulative dose of 5-FU (IV Bolus/IV Continued Infusion) administered per patient 
during mFOLFOX6 chemotherapy, 9 months after the first dose of IMP.  Summary statistics of 5-FU 
related variables are presented in Section 4.4.3. 
In case the patient receives more than 12 cycles of 5-FU, that will also be accounted for when deriving 
the cumulative dose. 


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Analysis of Variance.  Mean cumulative dose of 5-FU will be analysed by Analysis of Variance (ANOVA) 
using study (POLAR-A / POLAR-M), region (Asia / non-Asia) and treatment as factors.  Least square 
means and its corresponding 95% confidence intervals will be presented.  In case the distribution of 
the endpoint deviates from normality the endpoint will be log-transformed and the inference will be 
based on the geometric mean, ratio of geometrics means and corresponding 95% CIs. 
Data presentation 
- 
Table:  ANOVA analysis - Number of patients (N), Point Estimate (LSM), 95% CI and P-value by 
treatment group/treatment comparison (PledOx 5 µmol/kg vs Placebo). 
All observed values of mean cumulative dose of 5-FU will also be listed by patient. 
5.4.5 Pharmacokinetics 
The PK population (POLAR-M only) includes a subset of patients at pre-selected sites in all participating 
regions, where blood samples will be collected for pharmacokinetic assessments.  Blood samples to 
measure plasma concentrations of PledOx will be taken pre-dose, 6 min post-dose, 15 min post-dose, 
30 min post-dose, 60 min post-dose, and 240 min post-dose at treatment visit 1, 4 and 8.  In addition, 
the PK parameters Cmax, tmax, AUC0-last of PledOx will be derived. 
Values below LLOQ will be set to LLOQ/2. 
Data presentations 
- 
Table:  descriptive statistics of plasma concentrations of PlexOx by visit and time point. 
- 
Table:  descriptive statistics of pharmacokinetic parameters of PlexOx. 
- 
Graph:  mean plasma concentrations of PledOx by time for each cycle. 
The analyses will be done on the PK population.  All observed values of plasma concentrations and PK 
parameters of PledOx will also be listed by patient. 
5.4.6 ECG QT/QTc 
Mean QT/QTc interval using a 12-lead ECG at all measured time points. 
The ECG variables is measured pre- and post-dose at cycle 1, 4 and 8, and at the End of Treatment 
visit.  Baseline is defined as the time of administration of the first dose of IMP (Day 1, Cycle 1). 
ECG variables: 
• 
ECG Mean heart rate 
• 
Interpretation 
• 
PR interval 
• 
QRS duration 
• 
QT interval 
• 
QTcB interval 
• 
QTcF interval 
• 
RR interval 
Data presentations 
- 
Table:  number (%) of patients with abnormal ECG by visit and time point. 
- 
Table:  descriptive statistics of each continuous ECG variable by visit and time point. 
The ECG analyses will be done on the PK population.  All observed values of the ECG variables will also 
be listed by patient. 


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5.4.7 EQ-5D-5L and Health VAS Score 
Mean EQ-5D-5L health index and Health VAS score at 9 and 12 months after the first dose of IMP. 
EQ-5D-5L Health Index.  The EQ-5D-5L is a standardized instrument for use as a measure of health 
outcome.  It is often referred to as a Quality of Life (QoL) questionnaire.  The EQ-5D-5L comprises 5 
dimensions of health: 
• 
Mobility 
• 
Ability to self-care 
• 
Ability to undertake usual activities 
• 
Pain and discomfort 
• 
Anxiety and depression 
There are 5 options (levels, ordinal scale) under each dimension. 
Endpoint.  Mean health index is defined as the mean value of the 5 dimensions of the EQ-5D-5L 
questionnaire and will be analysed 9 and 12 months after the first dose of IMP, respectively. 
Baseline.  Baseline is defined as the time of administration of the first dose of IMP (Day 1, Cycle 1). 
Analysis of Covariance.  Mean health index will be analysed by Analysis of Covariance (ANCOVA) using 
the baseline value as a continuous covariate and study (POLAR-A / POLAR-M), region (Asia / non-Asia) 
and treatment as factors.  Least square means and its corresponding 95% confidence intervals will be 
presented. 
Data presentations 
- 
Table:  ANCOVA analysis - Number of patients (N), Point Estimate (LSM), 95% CI and P-value 
by treatment group/treatment comparison (PledOx 5 µmol/kg vs Placebo). 
- 
Table:  descriptive statistics of observed values by treatment and total 
- 
Table:  descriptive statistics of change from baseline by treatment and total 
All observed values of Mean Health Index and Mean VAS Score will also be listed by patient. 
Endpoint.  Health VAS Score, the patient health status is also measured on a Visual Analogue Scale 
(VAS) ranging from 0 to 100, where 100 means best health and 0 worst health. 
Baseline.  Baseline is defined as the time of administration of the first dose of IMP (Day 1, Cycle 1). 
Analysis of Covariance.  Health VAS score will be analysed by Analysis of Covariance (ANCOVA) using 
the baseline value as a continuous covariate and study (POLAR-A / POLAR-M), region (Asia / non-Asia) 
and treatment as factors.  Least square means and its corresponding 95% confidence intervals will be 
presented. 
Data presentations 
- 
Table:  ANCOVA analysis - Number of patients (N), Point Estimate (LSM), 95% CI and P-value 
by treatment group/treatment comparison (PledOx 5 µmol/kg vs Placebo). 
- 
Table:  descriptive statistics of observed values by treatment and total 
- 
Table:  descriptive statistics of change from baseline by treatment and total 
All observed values of Health VAS Score will also be listed by patient. 
Endpoint.  Number and percentage of patients by level of severity of the 5 dimensions of the EQ-5D-
5L questionnaire. 
Baseline.  Baseline is defined as the time of administration of the first dose of IMP (Day 1, Cycle 1). 
 


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Data presentations 
- 
Table:  Number and percentage (%) of patients by level of severity of the 5 dimensions of the 
EQ-5D-5L questionnaire by treatment, total and visit 
All observed values of the level of severity of the 5 dimensions of the EQ-5D-5L questionnaire will also 
be listed by patient. 
5.4.8 Long-term Grooved Pegboard 
Mean change from baseline in the time (seconds) to complete the Grooved Pegboard, with the non-
dominant hand, at 12 months after the first dose of IMP. 
Baseline is defined as the time of administration of the first dose of IMP (Day 1, Cycle 1). 
Analysis of Covariance.  Long-term grooved pegboard will be analysed by Analysis of Covariance 
(ANCOVA) using the baseline value as a continuous covariate and study (POLAR-A / POLAR-M), region 
(Asia / non-Asia) and treatment as factors.  Least square means and its corresponding 95% confidence 
intervals will be presented. 
Data presentations 
- 
Table:  ANCOVA analysis - Number of patients (N), Point Estimate (LSM), 95% CI and P-value 
by treatment group/treatment comparison (PledOx 5 µmol/kg vs Placebo). 
- 
Table: descriptive statistics of observed values by treatment and total for each treatment 
cycle. 
- 
Table: descriptive statistics of change from baseline by treatment and total for each treatment 
cycle. 
- 
Figure: shift plot (using jitter) of baseline vs 12-month assessment visit. 
All observed values of Grooved Pegboard will also be listed by patient. 
5.4.9 Long-term Pain (NRS) 
Mean change from baseline in worst pain in hands or feet in the past week, using a NRS, at 12 months 
after the first dose of IMP.  NRS is measured on an ordinal scale 0-10. 
Baseline is defined as the time of administration of the first dose of IMP (Day 1, Cycle 1). 
Analysis of Covariance.  Long-term pain will be analysed by Analysis of Covariance (ANCOVA) using 
the baseline value as a continuous covariate and study (POLAR-A / POLAR-M), region (Asia / non-Asia) 
and treatment as factors.  Least square means and its corresponding 95% confidence intervals will be 
presented. 
Data presentations 
- 
Table:  ANCOVA analysis - Number of patients (N), Point Estimate (LSM), 95% CI and P-value 
by treatment group/treatment comparison (PledOx 5 µmol/kg vs Placebo). 
- 
Table: descriptive statistics of observed values by treatment and total for each treatment 
cycle. 
- 
Table: descriptive statistics of change from baseline by treatment and total for each treatment 
cycle. 
- 
Figure: shift plot (using jitter) of baseline vs 12-month assessment visit. 
All observed values of worst pain in hands or feet will also be listed by patient. 
5.4.10 Change in Pain (NRS) 
The proportion of patients with a 2-point, 3-point and 4-point increase vs baseline in worst pain in 
hands or feet in the past week using NRS at 9 and 12 months after the first dose of IMP. 


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Baseline is defined as the time of administration of the first dose of IMP (Day 1, Cycle 1). 
Exact Logistic Regression.  The proportion of patients with a 2-point, 3-point and 4-point increase 
from baseline in worst pain in hands or feet will be analysed by an exact logistic regression model 
adjusted for study (POLAR-A / POLAR-M) and region (Asia / non-Asia).  Estimate of the treatment effect 
and its corresponding 95% confidence interval will be based on the odds-ratio. 
Data presentations 
- 
Table:  number and percentage of patients having a 2-point, 3-point and 4-point increase in 
worst pain in hands or feet based on the exact logistic regression model will be presented by 
number of patients (N), number of patients (%) with 2-point, 3-point and 4-point increase in 
worst pain in hands or feet at 9 and 12 months after first does of IMP, respectively for each 
treatment group, and odds-ratios, 95% CIs and p-values for the treatment comparisons. 
All values will also be listed by patient. 
The analyses will be based on the observed cases.  Hence, no imputation of missing values will be 
done. 
5.4.11 Health Economic Impact 
Health economic impact, measured by the combined impact of medical resource utilization 
(hospitalizations, outpatient visits, medical procedures and medical use), patient impact (AEs, fall 
accidents, functional loss) and indirect societal costs (loss of ability to work), at 6 and 12 months after 
the first dose of IMP. 
Baseline is defined as the time of administration of the first dose of IMP (Day 1, Cycle 1). 
Data presentations 
All health economic variables will be presented by summary statistics (including change from baseline 
where appropriate) by treatment group and total for each visit. 
All observed values of health economic impact will also be listed by patient. 
6. SAFETY EVALUATION 
All safety evaluations will be performed on the safety analysis set unless specified otherwise. 
6.1 Adverse Events 
Adverse events will be recorded in the eCRF and will be coded according to the MedDRA dictionary 
Version 23.0.  All AEs including SAEs will be collected up to 30 days after the last administration of 
IMP (or as of March 2nd., 2020, up to 30 days after the EOT) and followed until resolution. 
A treatment-emergent adverse event (TEAE) is defined as an adverse event that started or worsened 
after the start of the administration of IMP.  Treatment-emergent AEs will include AEs that occur 
after the first dose of IMP (i.e. day 1, Cycle 1) and end at the EOT visit (i.e. 14 days after the last dose 
of IMP).  AEs will also be considered treatment-emergent if they are ongoing at first IMP infusion or 
start ≤30 days after the last dose of IMP.  Adverse events with unknown start date/time will be 
assumed to be treatment-emergent unless the end date/time is known to be before administration 
of the first dose of IMP.  Non-treatment emergent AEs will include any AEs that occur between 
informed consent and the first dose of IMP. 
Allocation of AEs to study periods 
All AEs and SAEs will be allocated to a study period depending on the onset date in relation to the 
date of administration of IMP: 


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Period 1:  Time of informed consent until time before first dose of IMP (non-TEAE) 
Period 2: Time of first dose of IMP until time of last dose of IMP + 30 days (TEAE) 
Period 3: Time of last dose of IMP + 31 days and onwards (non-TEAE) 
In case of complete or partial missing start or end date of an AE see details in Section 3.3. 
Causality to the Investigational Medical Product (IMP) 
• 
Not related 
• 
Unlikely related 
• 
Possibly related 
• 
Probably related 
• 
Definitely related 
An AE/SAE is defined as related to IMP if the event is classified as Possibly, Probably or Definitely 
related. 
Intensity of Adverse Events 
• 
Mild 
• 
Moderate 
• 
Severe 
• 
Life-threatening 
• 
Death related to AE 
No summaries will be done of AE/SAE by intensity but will be included in the listings. 
Data presentations 
If a patient experienced more than one TEAE the patient will be counted once for each SOC and once 
for each PT.  System organ class and preferred terms will be ordered alphabetically first by SOC and 
then all PTs alphabetically within a SOC.  Non-TEAEs will not be presented in summary tables, only in 
listings. 
Tables: treatment-emergent AEs 
• 
Number and percentage of patients experiencing TEAEs by SOC and PT for each treatment 
group and total 
• 
Number and percentage of patients experiencing TEAEs leading to withdrawal of IMP by SOC 
and PT for each treatment group and total 
• 
Number and percentage of patients experiencing TEAEs related to IMP by SOC and PT for 
each treatment group and total 
• 
Number and percentage of patients experiencing TEAEs leading to death by SOC and PT for 
each treatment group and total 
Tables: Serious treatment-emergent AEs 
• 
Number and percentage of patients experiencing Serious TEAEs by SOC and PT for each 
treatment group and total 
• 
Number and percentage of patients experiencing Serious TEAEs leading to withdrawal of 
IMP by SOC and PT for each treatment group and total 


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• 
Number and percentage of patients experiencing Serious TEAEs related to IMP by SOC and 
PT for each treatment group and total 
All AEs will be listed by patient including subject-id, treatment group, AE Term, SOC, PT, Time of onset 
(in relation to first dose of IMP), time of resolution (in relation to first dose of IMP), Intensity, Causality, 
Action taken, Outcome and a flag for TEAE/non-TEAE.  The following listings will be provided: 
• 
All AEs (including SAEs) 
• 
All SAEs 
• 
All AEs leading to withdrawal of IMP 
• 
All AEs leading to hospitalization 
• 
All AEs leading to death 
6.1.1 Adverse Events of Special Interest 
AEs/SAEs of special interest are selected based on following SMQs from the Medical Dictionary for 
Regulatory Activities (MedDRA): 
• 
Convulsions 
• 
Neuropathy 
• 
Hypersensitivity 
Data presentations 
- 
Table:  Number and percentage of patients with Convulsions, Neuropathy or 
Hypersensitivity related AEs by SOC and PT for each treatment group and total 
- 
Table:  Number and percentage of patients with Convulsions, Neuropathy or 
Hypersensitivity related SAEs by SOC and PT for each treatment group and total 
Chemotherapy-related AEs/SAEs recorded in the eCRF are also of special interest.  Examples of such 
events are peripheral sensory neuropathy, hematological toxicities, ANC, febrile neutropenia, WBC 
count and thrombocytopenia. 
Data presentations 
- 
Table:  Number and percentage of patients with chemotherapy-related AEs by SOC and PT 
for each treatment group and total 
- 
Table:  Number and percentage of patients with chemotherapy-related SAEs by SOC and PT 
for each treatment group and total 
IMP toxicity-related AEs/SAEs are recorded in the eCRF defined as an AE that is considered to be 
chemotherapy-related toxicity and also is possibly, probably or definitely related to the IMP treatment 
using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
v4.03. 
In SAS IMP toxicity will be derived as: 
  imp_tox=0; 
  IF aechemtx EQ 'Yes' AND aerel IN('Definitely Related', 
                                    'Possibly Related', 
                                    'Probably Related') THEN imp_tox=1; 
where,  
• 
aechemtx = Is this AE considered to be chemotherapy-related toxicity? 
• 
aerel = Is there a reasonable possibility of a causal relationship between the IMP treatment 
and the AE? 


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A patient is counted only once in case of multiple events for a given patient. 
Data presentations 
- 
Table:  Number and percentage of patients with IMP toxicity-related AEs by SOC and PT for 
each treatment group and total 
- 
Table:  Number and percentage of patients with IMP toxicity-related SAEs by SOC and PT for 
each treatment group and total 
6.2 Laboratory Evaluation 
Laboratory testing will be performed at each visit just before IMP administration.  Local laboratories 
will be used to analyse the samples, and the local units will be standardised using SI-units for all 
reporting of laboratory tests. 
Hematology 
Hematology test will be performed at screening, treatment visit 1-12, End of Treatment visit, and 
assessment visit 1-8.  The following hematology tests will be performed: 
Hematology Test 
SI-unit 
Hemoglobin 
g/L 
Leukocytes 
10^9/L 
Neutrophils (Differential) 
% 
Lymphocytes (Differential) 
% 
Monocytes (Differential) 
% 
Eosinophils (Differential) 
% 
Basophils (Differential) 
% 
Neutrophils (absolute) 
10^9/L 
Erythrocytes (absolute) 
10^12/L 
Platelet 
10^9/L 
 
Biochemistry 
Biochemistry test will be performed at screening, treatment visit 1, 4, 8, 12 and End of Treatment visit.  
The following biochemistry tests will be performed: 
Biochemistry Test 
SI-unit 
Alkaline Phosphatase (ALP) 
IU/L 
Total Bilirubin 
umol/L 
Alanine Aminotransferase (ALT) 
IU/L 
Aspartate Aminotransferase (AST) 
IU/L 
Creatinine 
umol/L 
Albumin 
g/L 
 
Baseline 
For hematology and biochemistry laboratory tests baseline is defined as the sample taken prior to first 
dose of IMP.  In case of missing, the screening measurement will be used instead. 
Derived variables 
- 
For all laboratory tests change from baseline will derived for all post-baseline measurements. 
- 
A laboratory value marked as LLOQ or having a registered value <LLOQ will be imputed by 
LLOQ/2.  In case >50% of the values at a timepoint are <LLOQ the mean will be set to LLOQ. 


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Values outside normal ranges 
Laboratory values outside the normal ranges will be flagged in the laboratory report.  For each flagged 
value the Investigator should mark the value as “Clinically Significant” (CS) or “Not Clinically 
Significant” (NCS). 
Data presentations 
- 
Table:  for each laboratory test, descriptive statistics of observed values by treatment group, 
total and by treatment/assessment visit. 
- 
Table:  for each laboratory test, descriptive statistics of change from baseline by treatment 
group, total and by treatment/assessment visit. 
- 
Figure:  for each laboratory test, scatterplot (using jitter) of observed values by treatment 
group and treatment/assessment visit. 
- 
Table:  for each laboratory test, number and percentage of patients with clinically significant 
values outside normal ranges by treatment group and treatment/assessment visit. 
All laboratory tests will be listed and patients with clinically significant (according to the Investigator’s 
criteria) abnormal values (out of normal range reported by the laboratory) will be flagged and listed 
separately.  Significant findings made after drug administration that meet the definition of an AE must 
be reported under the AE section. 
6.3 Blood Manganese 
Blood samples will be collected for assessment of manganese (Mn) at screening, treatment cycle 4, 8, 
12 and End of Treatment.  Blood manganese are available in both ug/L and nmol/L.  The latter will be 
used in the summary tables and listings. 
Baseline 
Baseline is defined as the measurement at screening. 
Derived variables 
- 
Change from baseline will derived for all post-baseline measurements. 
- 
Indicator variable if blood manganese is >2xULN. 
Data presentations 
- 
Table:  descriptive statistics of observed values by treatment group, total and by treatment 
visit. 
- 
Table:  descriptive statistics of change from baseline by treatment group, total and by 
treatment visit. 
- 
Figure:  scatterplot (using jitter) of observed values by treatment group and treatment visit. 
- 
Table:  number and percentage of patients with blood manganese values >2xULN by 
treatment group and treatment visit. 
All blood Mn results for individual patients will be listed and patients with clinically significant 
(according to the Investigator’s criteria) abnormal values (out of normal range reported by the 
laboratory) will be flagged and listed separately. 
6.4 Brain MRI and Neurologic Examination 
Monitoring of increased Mn levels and/or Parkinson-like symptoms will be performed.  Any patient 
who has elevated Mn levels (>2xULN) confirmed by MRI that shows Mn accumulation should be 
immediately withdrawn from further treatment with the IMP. 


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Patients that show Mn concentrations >2xULN before Cycle 5 or Cycle 9 will be referred to a brain MRI 
investigation and a neurological examination.  If the MRI is positive (i.e. T1-weighted images (MRI 
intensity) and T1 images in the globus pallidus), the patient will be discontinued from the study and 
followed every 3 months until resolution (i.e. MRI intensity is low/none). 
Blood for Mn assessment will also be taken in the case of Parkinson-like symptoms.  If the Mn level is 
>2xULN, an MRI of the brain should be performed (as above).  If the Mn level is ≤2xULN then the 
patient can continue in the study according to the protocol. 
Any results from MRI scan and neurological examinations following an elevated (>2x ULN) blood Mn 
will be listed per patient. 
6.5 Vital Signs 
Vital signs variables include: 
• 
Resting pulse (beats per minute) 
• 
Resting systolic blood pressure (mmHg) 
• 
Resting diastolic blood pressure (mmHg) 
Baseline 
For vital signs baseline is defined as the sample taken prior to first dose of IMP.  In case of missing, the 
screening measurement will be used instead. 
Derived variables 
For all vital signs change from baseline will derived for all post-baseline measurements. 
Data presentations 
- 
Table:  for each vital sign variable, descriptive statistics of observed values by treatment group, 
total and by treatment/assessment visit. 
- 
Table:  for each vital sign variable, descriptive statistics of change from baseline by treatment 
group, total and by treatment/assessment visit. 
All vital signs variables will be listed by patient. 
6.6 Weight and BMI 
Baseline 
For both weight and BMI baseline is defined as the sample taken prior to first dose of IMP.  In case of 
missing, the screening measurement will be used instead. 
Derived variables 
- 
Body Mass Index (BMI) is calculated as: Weight (kg) / Height (m)². 
- 
For both weight and BMI change from baseline will derived for all post-baseline 
measurements. 
Data presentations 
- 
Table:  for both weight and BMI, descriptive statistics of observed values by treatment group, 
total and by treatment/assessment visit. 
- 
Table:  for both weight and BMI, descriptive statistics of change from baseline by treatment 
group, total and by treatment/assessment visit. 
Both weight and BMI will be listed by patient. 


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6.7 Physical Examination 
The number and percentage of patients with abnormal physical examination findings will be 
presented for each body system by treatment group and total for each visit.  Individual patient 
physical examination data will be listed for all enrolled patients. 
Table 5  Physical Examination – Body System Examined 
Cardiovascular / Circulatory 
Digestive / Excretory 
Endocrine 
Integumentary / Exocrine 
Lymphatic / Immune 
Muscular 
Nervous 
Renal / Urinary 
Reproductive 
Respiratory 
Skeletal 
 
6.8 ECOG Performance Status 
The number and percentage of patients in the categories of the ECOG performance status will be 
presented by treatment group and total for each visit.  Individual patient ECOG performance status 
will be listed for all patients. 
Table 6  ECOG Performance Status 
Grade  
ECOG status 
0  
Fully active, able to carry on all pre-disease performance without restriction  
1  
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work  
2  
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about 
more than 50% of waking hours  
3  
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours  
4  
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair  
5  
Dead  
 
6.9 Overall Response Rate (POLAR-M only) 
Patients will be evaluated for response according to RECIST v1.1 guidelines.  The overall response rate 
(ORR) is the best response (CR or PR) recorded during chemotherapy treatment.  Overall response 
data is collected at treatment visits 5, 7, 9, end of treatment, and assessment visits month 3, 6, 9, 12 
and 15. 
The following categories of the overall response assessment will be recorded: 
• 
CR = Complete Response 
• 
PR = Partial Response 
• 
SD = Stable Disease 
• 
PD = Progressive Disease 
• 
NE = Not Evaluable 
Derived variables 
Overall response rate (ORR) is defined as the best overall response (CR or PR). 


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Data presentations 
- 
Table:  overall response (OR) - number and percentage of patients by treatment group and 
treatment/assessment visit. 
- 
Table:  overall response rate (ORR) - number and percentage of patients by treatment group 
and treatment/assessment visit. 
Overall response will be listed by patient. 
6.10 Progression-Free Survival (POLAR-M only) 
Endpoint.  Progression-Free Survival (PFS) is defined as the time from the date of randomisation until 
the date of objectively determined PD (according to RECIST v1.1) or death due to any cause.  Patients 
without objectively determined PD who are alive at the end of the follow-up period (or who were lost 
to follow up) will be censored on the date of the patient’s last complete radiographic tumor 
assessment.  If no baseline or post-baseline radiologic assessment is available, the patient will be 
censored at the date of randomisation. 
Cox Proportional Hazards Model.  Time (number of days) from randomisation to event or censoring 
will be analysed by a cox proportional hazards model using region (Asia / non-Asia) and Treatment as 
fixed factors in the model.  The hazard ratio along with its 95% confidence interval of the PledOx doses 
compared to placebo will be estimated. 
Data presentations 
- 
Table:  Progression-free survival based on the cox proportional hazards model will be 
presented by the number and percentage of events (N, %), Hazard Ratio (95% CI), Minimum, 
Q1, Median, Q3 and Maximum time to event or censoring by treatment group and total. 
- 
Figure:  Progression-free survival will be depicted graphically by a Kaplan-Meier plot by 
treatment group. 
All PFS data will be listed by patient. 
6.11 Overall Survival (POLAR-M only) 
Endpoint.  Overall Survival (OS) is defined as the time from the date of randomisation until the date 
of death from any cause.  If the patient was alive at the end of the follow-up period (or was lost to 
follow-up), the patient will be censored on the last date the patient was known to be alive. 
Cox Proportional Hazards Model.  Time (number of days) from randomisation to event or censoring 
will be analysed by a cox proportional hazards model using region (Asia / non-Asia) and Treatment as 
fixed factors in the model.  The hazard ratio along with its 95% confidence interval of the PledOx doses 
compared to placebo will be estimated. 
Data presentations 
- 
Table:  Overall survival based on the cox proportional hazards model will be presented by the 
number and percentage of events (N, %), Hazard Ratio (95% CI), Minimum, Q1, Median, Q3 
and Maximum time to event or censoring by treatment group and total. 
- 
Figure:  Overall survival will be depicted graphically by a Kaplan-Meier plot by treatment 
group. 
All OS data will be listed by patient. 


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6.12 Disease-Free Survival (POLAR-A only) 
Endpoint.  Disease-Free Survival (DFS) is defined as the time from the date of randomisation until the 
date of objectively determined signs or symptoms of recurrence of Colorectal Cancer (CRC) or death 
due to any cause.  Signs and symptoms may include any assessment result that, in the opinion of the 
Investigator, provides evidence for the recurrence of the disease.  Patients without objectively 
determined disease recurrence who are alive at the end of the follow-up period (or who were lost to 
follow up) will be censored on the date of the patient’s last assessment of disease recurrence.  If no 
baseline or post-baseline radiologic assessment is available, the patient will be censored at the date 
of randomisation. 
Cox Proportional Hazards Model.  Time (number of days) from randomisation to event or censoring 
will be analysed by a cox proportional hazards model using region (Asia / non-Asia) and Treatment as 
fixed factors in the model.  The hazard ratio along with its 95% confidence interval of PledOx 5 µmol/kg 
compared to placebo will be estimated. 
Data presentations 
- 
Table:  Disease-free survival based on the cox proportional hazards model will be presented 
by the number and percentage of events (N, %), Hazard Ratio (95% CI), Minimum, Q1, Median, 
Q3 and Maximum time to event or censoring by treatment group and total. 
- 
Figure:  Disease-free survival will be depicted graphically by a Kaplan-Meier plot by treatment 
group. 
All DFS data will be listed by patient. 
7. REFERENCES 
1. Breslow NE, Day NE (1987). The Design and Analysis of Cohort Studies. IARC Scientific 
Publications No. 82 Lyon, France, page 110. 
2. Robins J, Breslow N, Greenland S (1986). Estimators of the Mantel-Haenszel variance 
consistent in both sparse data and large-strata limiting models. Biometrics 42:311-323.