Preventive Treatment of OxaLiplatin Induced peripherAl ne... | NCT04034355

ID	Type	Description	Link
2017-004707-43	EudraCT Number

Status Module

Name	Class
Solasia Pharma K.K.	INDUSTRY

Description Module

Label	Type	Description	Intervention Names
PledOx (5 µmol/kg)	Experimental	Calmangafodipir 5 µmol/kg	Drug: Calmangafodipir (5 µmol/kg)
Placebo	Placebo Comparator	0.9% sodium chloride in 20 mL vials	Other: Placebo

Name	Type	Description	Arm Group Labels	Other Names
Calmangafodipir (5 µmol/kg)	Drug	PledOx will be given to patients as an i.v. infusion, on top of mFOLFOX6 chemotherapy. PledOx is a solution in 20 mL single dose glass vials.	PledOx (5 µmol/kg)

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy (CIPN)	Percentage of patients (with moderate or severe chronic CIPN) scoring 3 or 4 in at least 1 of the first 4 items of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity-13-item subscale (FACT/GOG-NTX-13; i.e., FACT/GOG-NTX-4) 9 months after the first dose of IMP (i.e. PledOx or placebo administered on Day 1, Cycle 1 of mFOLFOX6 chemotherapy). The FACT/GOG-13 questionnaire includes 13 items that measure the severity and impact of symptoms of neurotoxicity over the past 7 days. Patients rate each item as 0 ("not at all"), 1 (" a little bit"), 2 ("somewhat"), 3 ("quite a bit") or 4 ("very much"). These 13 items are summed to create a total score, ranging from 0 to 52, with a higher score representing a worse outcome. The FACT/GOG-NTX-4 is a 4 item subscale targeting numbness, tingling or discomfort in hands and/or feet.	9 months

Secondary Outcomes

Measure	Description	Time Frame
Mild, Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy	Percentage 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 Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity-13-item subscale (FACT/GOG-NTX-13; i.e., FACT/GOG-NTX-4) 9 months after the first dose of IMP (i.e. PledOx or placebo administered on Day 1, Cycle 1 of mFOLFOX6 chemotherapy). The FACT/GOG-13 questionnaire includes 13 items that measure the severity and impact of symptoms of neurotoxicity over the past 7 days. Patients rate each item as 0 ("not at all"), 1 (" a little bit"), 2 ("somewhat"), 3 ("quite a bit") or 4 ("very much"). These 13 items are summed to create a total score, ranging from 0 to 52, with a higher score representing a worse outcome. The FACT/GOG-NTX-4 is a 4 item subscale targeting numbness, tingling or discomfort in hands and/or feet.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Signed informed consent form before any study related assessments and willing to follow all study procedures.
Male or female aged ≥18 years.
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).
The patient has undergone curative (R0) surgical resection performed within 12 weeks prior to randomization
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).
No prior anti-cancer therapy for CRC except radiotherapy or concomitant chemo-radiotherapy using a fluoropyrimidine alone for locoregional rectal cancer.
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.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Adequate hematological parameters: hemoglobin ≥100 g/L, absolute neutrophil count ≥1.5 x 109 /L, platelets ≥100 x 109 /L.
Adequate renal function: creatinine clearance >50 cc/min using the Cockcroft and Gault formula or measured.
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.
Baseline blood manganese (Mn) level <2.0 x ULN.
For patients with a history of diabetes mellitus, HbA1c ≤7%.
Negative pregnancy test for women of child-bearing potential (WOCBP).
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:

Any evidence of metastatic disease.
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.
Any grade of neuropathy from any cause.
Any evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, cardiac, unresolved bowel obstruction, hepatic or renal disease).
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.
Any history of seizures.
A surgical incision that is not healed.
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.
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.
Known dihydropyrimidine dehydrogenase deficiency.
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).
Major psychiatric disorder (major depression, psychosis), alcohol and/or drug abuse.
Patients with a history of second or third degree atrioventricular block or a family heredity.
A history of a genetic or familial neuropathy.
Treatment with any investigational drug within 30 days prior to randomization.
Pregnancy, lactation or reluctance to using contraception.
Any other condition that, in the opinion of the Investigator, places the patient at undue risk.
Previous exposure to mangafodipir or calmangafodipir.
Welders, mine workers or other workers in occupations (current or past) where high Mn exposure is likely.

Name	Affiliation	Role
Stefan Carlsson, MD	Chief Medical Officer	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Onze-Lieve-Vrouwziekenuis Aalst		Aalst			Belgium
Imelda GI Clinical Research Center

PubMed Identifier	Type	Citation	Retractions
36308441	Derived	Pfeiffer P, Lustberg M, Nasstrom J, Carlsson S, Persson A, Nagahama F, Cavaletti G, Glimelius B, Muro K. Calmangafodipir for Prevention of Oxaliplatin-Induced Peripheral Neuropathy: Two Placebo-Controlled, Randomized Phase 3 Studies (POLAR-A/POLAR-M). JNCI Cancer Spectr. 2022 Nov 1;6(6):pkac075. doi: 10.1093/jncics/pkac075.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	PledOx (5 µmol/kg)	Calmangafodipir 5 µmol/kg Calmangafodipir (5 µmol/kg): PledOx will be given to patients as an i.v. infusion, on top of mFOLFOX6 chemotherapy. PledOx is a solution in 20 mL single dose glass vials.
FG001	Placebo

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	May 15, 2020	Jul 21, 2021

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG00063.3± 10.4 BG00162.4± 10.2 BG00262.9± 10.3

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00069 BG00161 BG002

Race (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
American Indian or Alaska Native	BG0000 BG0010 BG002

Body Mass Index

Median

Full Range

kg/m^2

Title

Denominators

Categories

Title	Measurements
	BG00024.20(16.9 to 38.9) BG00123.60(16.8 to 49.7) BG002

ECOG performance status

The ECOG performance scale is a six point functional scale (0 to 5) rating the extent of effect on daily living with higher scores representing a worse outcome. A score 0 represents "fully active, able to carry on all pre-disease performance without restriction" and a score 1 represents "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".

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
0	BG000118 BG001

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy (CIPN)

Percentage of patients (with moderate or severe chronic CIPN) scoring 3 or 4 in at least 1 of the first 4 items of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity-13-item subscale (FACT/GOG-NTX-13; i.e., FACT/GOG-NTX-4) 9 months after the first dose of IMP (i.e. PledOx or placebo administered on Day 1, Cycle 1 of mFOLFOX6 chemotherapy). The FACT/GOG-13 questionnaire includes 13 items that measure the severity and impact of symptoms of neurotoxicity over the past 7 days. Patients rate each item as 0 ("not at all"), 1 (" a little bit"), 2 ("somewhat"), 3 ("quite a bit") or 4 ("very much"). These 13 items are summed to create a total score, ranging from 0 to 52, with a higher score representing a worse outcome. The FACT/GOG-NTX-4 is a 4 item subscale targeting numbness, tingling or discomfort in hands and/or feet.

Modified ITT (mITT) analysis set including patients that fulfilled at least one of the following criteria:

the patient was randomized prior to 1 Dec 2019 (i.e. the patient was eligible for at least 3 months of IMP) and had at least one post-baseline assessment for efficacy, or
the 3 month Assessment Visit occurred prior to 1 Mar 2020, or
the patient received the 6th cycle of IMP after 1 Mar 2020.

Posted

Count of Participants

Participants

9 months

ID	Title	Description
OG000	PledOx (5 µmol/kg)	Calmangafodipir 5 µmol/kg Calmangafodipir (5 µmol/kg): PledOx will be given to patients as an i.v. infusion, on top of mFOLFOX6 chemotherapy. PledOx is a solution in 20 mL single dose glass vials.
OG001	Placebo	0.9% sodium chloride in 20 mL vials Placebo: Placebo will be administered via the same route as PledOx (i.v. infusion). Placebo is a solution in 20 mL single dose glass vials.

Units	Counts
Participants	OG000120 OG001119

Title

Denominators

Categories

Title	Measurements
	OG00068 OG00146

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Cochran-Mantel-Haenszel		0.0280		Risk Ratio (RR)	1.5210			2-Sided	95	1.0462	2.2113					Superiority

Secondary

Mild, Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy

Percentage 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 Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity-13-item subscale (FACT/GOG-NTX-13; i.e., FACT/GOG-NTX-4) 9 months after the first dose of IMP (i.e. PledOx or placebo administered on Day 1, Cycle 1 of mFOLFOX6 chemotherapy). The FACT/GOG-13 questionnaire includes 13 items that measure the severity and impact of symptoms of neurotoxicity over the past 7 days. Patients rate each item as 0 ("not at all"), 1 (" a little bit"), 2 ("somewhat"), 3 ("quite a bit") or 4 ("very much"). These 13 items are summed to create a total score, ranging from 0 to 52, with a higher score representing a worse outcome. The FACT/GOG-NTX-4 is a 4 item subscale targeting numbness, tingling or discomfort in hands and/or feet.

Modified ITT (mITT) analysis set including patients that fulfilled at least one of the following criteria:

the patient was randomized prior to 1 Dec 2019 (i.e. the patient was eligible for at least 3 months of IMP) and had at least one post-baseline assessment for efficacy, or
the 3 month Assessment Visit occurred prior to 1 Mar 2020, or
the patient received the 6th cycle of IMP after 1 Mar 2020.

Posted

Count of Participants

Participants

9 months

ID	Title	Description
OG000	PledOx (5 µmol/kg)	Calmangafodipir 5 µmol/kg Calmangafodipir (5 µmol/kg): PledOx will be given to patients as an i.v. infusion, on top of mFOLFOX6 chemotherapy. PledOx is a solution in 20 mL single dose glass vials.

Secondary

Sensitivity to Touching Cold Items

Mean change from baseline in sensitivity to touching cold items on Day 2, Cycle 4 (cycle is 14 days) of mFOLFOX6 chemotherapy, as assessed by the Cold Sensitivity questionnaire. Cold sensitivity was rated 0 (not at all) to 10 (as bad as you can imagine).

Modified ITT (mITT) analysis set including patients that fulfilled at least one of the following criteria:

the patient was randomized prior to 1 Dec 2019 (i.e. the patient was eligible for at least 3 months of IMP) and had at least one post-baseline assessment for efficacy, or
the 3 month Assessment Visit occurred prior to 1 Mar 2020, or
the patient received the 6th cycle of IMP after 1 Mar 2020.

Posted

Least Squares Mean

95% Confidence Interval

Scores on a scale

Baseline and 8 weeks

ID	Title	Description
OG000	PledOx (5 µmol/kg)	Calmangafodipir 5 µmol/kg Calmangafodipir (5 µmol/kg): PledOx will be given to patients as an i.v. infusion, on top of mFOLFOX6 chemotherapy. PledOx is a solution in 20 mL single dose glass vials.
OG001	Placebo	0.9% sodium chloride in 20 mL vials Placebo: Placebo will be administered via the same route as PledOx (i.v. infusion). Placebo is a solution in 20 mL single dose glass vials.

Secondary

Cumulative Dose of Oxaliplatin During Chemotherapy

Mean cumulative dose of oxaliplatin administered per patient during mFOLFOX6 chemotherapy, 9 months after the first dose of Investigational Medicinal Product

Modified ITT (mITT) analysis set including patients that fulfilled at least one of the following criteria:

the patient was randomized prior to 1 Dec 2019 (i.e. the patient was eligible for at least 3 months of IMP) and had at least one post-baseline assessment for efficacy, or
the 3 month Assessment Visit occurred prior to 1 Mar 2020, or
the patient received the 6th cycle of IMP after 1 Mar 2020.

Posted

Least Squares Mean

95% Confidence Interval

mg/m^2

9 months

ID	Title	Description
OG000	PledOx (5 µmol/kg)	Calmangafodipir 5 µmol/kg Calmangafodipir (5 µmol/kg): PledOx will be given to patients as an i.v. infusion, on top of mFOLFOX6 chemotherapy. PledOx is a solution in 20 mL single dose glass vials.
OG001	Placebo	0.9% sodium chloride in 20 mL vials Placebo: Placebo will be administered via the same route as PledOx (i.v. infusion). Placebo is a solution in 20 mL single dose glass vials.

Units	Counts

Secondary

Vibration Sensitivity on the Lateral Malleolus

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 Investigational Medicinal Product. When the tuning fork was struck against the ball of the thumb, the base of the tuning fork was placed over the appropriate bony surface (i.e. lateral malleolus left and right) and the patient was asked to indicate the moment when the vibration was no longer detected. The intensity at which the patient no longer detected the vibration is reported on a scale of 0 (minimum score, representing the maximum vibration amplitude) to 8 (maximum score, representing the minimum vibration amplitude)

Modified ITT (mITT) analysis set including patients that fulfilled at least one of the following criteria:

the patient was randomized prior to 1 Dec 2019 (i.e. the patient was eligible for at least 3 months of IMP) and had at least one post-baseline assessment for efficacy, or
the 3 month Assessment Visit occurred prior to 1 Mar 2020, or
the patient received the 6th cycle of IMP after 1 Mar 2020.

Posted

Mean

Standard Deviation

Scores on a scale

Baseline and 9 months

ID	Title	Description
OG000	PledOx (5 µmol/kg)	Calmangafodipir 5 µmol/kg Calmangafodipir (5 µmol/kg): PledOx will be given to patients as an i.v. infusion, on top of mFOLFOX6 chemotherapy. PledOx is a solution in 20 mL single dose glass vials.
OG001	Placebo

Secondary

Worst Pain in Hands or Feet

Mean change from baseline in worst pain in hands or feet in the past week, using a numerical rating scale (Numeric Rating Scale; Scale range of 0-10;0 = no pain, 10= pain as bad as you can imagine), at 9 months after the first dose of Investigational Medicinal Product

Modified ITT (mITT) analysis set including patients that fulfilled at least one of the following criteria:

the patient was randomized prior to 1 Dec 2019 (i.e. the patient was eligible for at least 3 months of IMP) and had at least one post-baseline assessment for efficacy, or
the 3 month Assessment Visit occurred prior to 1 Mar 2020, or
the patient received the 6th cycle of IMP after 1 Mar 2020.

Posted

Least Squares Mean

95% Confidence Interval

Scores on a scale

Baseline and 9 months

ID	Title	Description
OG000	PledOx (5 µmol/kg)	Calmangafodipir 5 µmol/kg Calmangafodipir (5 µmol/kg): PledOx will be given to patients as an i.v. infusion, on top of mFOLFOX6 chemotherapy. PledOx is a solution in 20 mL single dose glass vials.
OG001	Placebo	0.9% sodium chloride in 20 mL vials Placebo: Placebo will be administered via the same route as PledOx (i.v. infusion). Placebo is a solution in 20 mL single dose glass vials.

Secondary

Functional Impairment (in the Non-dominant Hand)

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 Investigational Medicinal Product

Modified ITT (mITT) analysis set including patients that fulfilled at least one of the following criteria:

the patient was randomized prior to 1 Dec 2019 (i.e. the patient was eligible for at least 3 months of IMP) and had at least one post-baseline assessment for efficacy, or
the 3 month Assessment Visit occurred prior to 1 Mar 2020, or
the patient received the 6th cycle of IMP after 1 Mar 2020.

Posted

Mean

Standard Deviation

seconds

Baseline and 9 months

ID	Title	Description
OG000	PledOx (5 µmol/kg)	Calmangafodipir 5 µmol/kg Calmangafodipir (5 µmol/kg): PledOx will be given to patients as an i.v. infusion, on top of mFOLFOX6 chemotherapy. PledOx is a solution in 20 mL single dose glass vials.
OG001	Placebo	0.9% sodium chloride in 20 mL vials Placebo: Placebo will be administered via the same route as PledOx (i.v. infusion). Placebo is a solution in 20 mL single dose glass vials.

Units	Counts

Secondary

Patients With Disease Free Survival

Patients with disease free survival.

Safety analysis set consisting of all randomized patients who received at least one dose of IMP. Patients were analyzed according to the study treatment they actually received.

Posted

Number

participants

Analysis was planned at 24 months but performed based on available data at cut-off 31 August 2020 as the study was terminated early by the Sponsor

ID	Title	Description
OG000	PledOx (5 µmol/kg)	Calmangafodipir 5 µmol/kg Calmangafodipir (5 µmol/kg): PledOx will be given to patients as an i.v. infusion, on top of mFOLFOX6 chemotherapy. PledOx is a solution in 20 mL single dose glass vials.
OG001	Placebo	0.9% sodium chloride in 20 mL vials Placebo: Placebo will be administered via the same route as PledOx (i.v. infusion). Placebo is a solution in 20 mL single dose glass vials.

Units	Counts
Participants	OG000

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Febrile neutropenia	Blood and lymphatic system disorders	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected147 at risk EG0011 events1 affected150 at risk
Angina pectoris	Cardiac disorders	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected147 at risk EG0011 events1 affected150 at risk
Myocardial infarction	Cardiac disorders	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected147 at risk EG0011 events1 affected150 at risk
Sudden hearing loss	Ear and labyrinth disorders	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected147 at risk EG0010 events0 affected150 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected147 at risk EG0011 events1 affected150 at risk
Colitis	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected147 at risk EG0010 events0 affected150 at risk
Crohn's disease	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected147 at risk EG0011 events1 affected150 at risk
Ileus	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected147 at risk EG0010 events0 affected150 at risk
Large intestine perforation	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected147 at risk EG0011 events1 affected150 at risk
Small intestinal obstruction	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected147 at risk EG0011 events1 affected150 at risk
Vomiting	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected147 at risk EG0011 events1 affected150 at risk
Administration site cellulitis	General disorders	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected147 at risk EG0011 events1 affected150 at risk
Cholecystitis acute	Hepatobiliary disorders	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected147 at risk EG0011 events1 affected150 at risk
Anaphylactic reaction	Immune system disorders	MedDRA 23.0	Systematic Assessment	EG0002 events2 affected147 at risk EG0010 events0 affected150 at risk
Drug hypersensitivity	Immune system disorders	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected147 at risk EG0010 events0 affected150 at risk
Infusion related reaction	Immune system disorders	MedDRA 23.0	Systematic Assessment	EG0005 events3 affected147 at risk EG0010 events0 affected150 at risk
Clostridium difficile infection	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected147 at risk EG0010 events0 affected150 at risk
Corona virus infection	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected147 at risk EG0011 events1 affected150 at risk
Device related infection	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected147 at risk EG0011 events1 affected150 at risk
Gastroenteritis	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected147 at risk EG0011 events1 affected150 at risk
Infection	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected147 at risk EG0011 events1 affected150 at risk
Influenza	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected147 at risk EG0011 events1 affected150 at risk
Osteomyelitis	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected147 at risk EG0011 events1 affected150 at risk
Pneumonia	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected147 at risk EG0011 events1 affected150 at risk
Urinary tract infection	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected147 at risk EG0011 events1 affected150 at risk
Gastrointestinal stoma complications	Injury, poisoning and procedural complications	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected147 at risk EG0011 events1 affected150 at risk
Pubis fracture	Injury, poisoning and procedural complications	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected147 at risk EG0010 events0 affected150 at risk
Decreased appetitie	Metabolism and nutrition disorders	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected147 at risk EG0011 events1 affected150 at risk
Diabetic metabolic decompensation	Metabolism and nutrition disorders	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected147 at risk EG0011 events1 affected150 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected147 at risk EG0011 events1 affected150 at risk
Cerebral infarction	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected147 at risk EG0010 events0 affected150 at risk
Generalised tonic-clonic seizure	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected147 at risk EG0010 events0 affected150 at risk
Device extrusion	Product Issues	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected147 at risk EG0010 events0 affected150 at risk
Acute kidney injury	Renal and urinary disorders	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected147 at risk EG0011 events1 affected150 at risk
Renal failure	Renal and urinary disorders	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected147 at risk EG0010 events0 affected150 at risk
Pharyngeal inflammation	Respiratory, thoracic and mediastinal disorders	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected147 at risk EG0011 events1 affected150 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA 23.0	Systematic Assessment	EG0002 events2 affected147 at risk EG0011 events1 affected150 at risk
Deep vein thrombosis	Vascular disorders	MedDRA 23.0	Systematic Assessment	EG0000 events0 affected147 at risk EG0011 events1 affected150 at risk
Embolism	Vascular disorders	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected147 at risk EG0010 events0 affected150 at risk
Vena cava thrombosis	Vascular disorders	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected147 at risk EG0010 events0 affected150 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA 23.0	Systematic Assessment	EG00024 events17 affected147 at risk EG00120 events17 affected150 at risk
Leukopenia	Blood and lymphatic system disorders	MedDRA 23.0	Systematic Assessment	EG00034 events18 affected147 at risk EG00140 events19 affected150 at risk
Neutropenia	Blood and lymphatic system disorders	MedDRA 23.0	Systematic Assessment	EG000144 events62 affected147 at risk EG001203 events68 affected150 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA 23.0	Systematic Assessment	EG00069 events46 affected147 at risk EG001134 events58 affected150 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG00018 events13 affected147 at risk EG00118 events14 affected150 at risk
Abdominal pain upper	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0009 events8 affected147 at risk EG00121 events15 affected150 at risk
Constipation	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG00038 events30 affected147 at risk EG00139 events25 affected150 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG000120 events59 affected147 at risk EG00190 events56 affected150 at risk
Dry mouth	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0004 events4 affected147 at risk EG0019 events9 affected150 at risk
Dyspepsia	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG00010 events10 affected147 at risk EG00113 events11 affected150 at risk
Nausea	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG000193 events88 affected147 at risk EG001155 events69 affected150 at risk
Stomatitis	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG00067 events50 affected147 at risk EG00137 events31 affected150 at risk
Vomiting	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG00033 events27 affected147 at risk EG00134 events27 affected150 at risk
Asthenia	General disorders	MedDRA 23.0	Systematic Assessment	EG00087 events32 affected147 at risk EG00173 events36 affected150 at risk
Fatigue	General disorders	MedDRA 23.0	Systematic Assessment	EG00061 events39 affected147 at risk EG00178 events36 affected150 at risk
Malaise	General disorders	MedDRA 23.0	Systematic Assessment	EG00023 events8 affected147 at risk EG0019 events7 affected150 at risk
Pyrexia	General disorders	MedDRA 23.0	Systematic Assessment	EG00013 events10 affected147 at risk EG00118 events13 affected150 at risk
Infusion related reaction	Immune system disorders	MedDRA 23.0	Systematic Assessment	EG0009 events8 affected147 at risk EG0012 events2 affected150 at risk
Nasopharyngitis	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0008 events8 affected147 at risk EG0017 events7 affected150 at risk
Alanine aminotransferase increased	Investigations	MedDRA 23.0	Systematic Assessment	EG00018 events11 affected147 at risk EG00126 events17 affected150 at risk
Aspartate aminotransferase increased	Investigations	MedDRA 23.0	Systematic Assessment	EG00019 events11 affected147 at risk EG00123 events15 affected150 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA 23.0	Systematic Assessment	EG00066 events42 affected147 at risk EG00162 events37 affected150 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA 23.0	Systematic Assessment	EG0005 events3 affected147 at risk EG00119 events11 affected150 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 23.0	Systematic Assessment	EG00011 events9 affected147 at risk EG0013 events2 affected150 at risk
Muscle spasms	Musculoskeletal and connective tissue disorders	MedDRA 23.0	Systematic Assessment	EG00012 events9 affected147 at risk EG0016 events6 affected150 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 23.0	Systematic Assessment	EG00010 events8 affected147 at risk EG0012 events2 affected150 at risk
Pain in jaw	Musculoskeletal and connective tissue disorders	MedDRA 23.0	Systematic Assessment	EG0008 events5 affected147 at risk EG00112 events8 affected150 at risk
Dizziness	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG00014 events11 affected147 at risk EG0014 events4 affected150 at risk
Dysaesthesia	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG00015 events7 affected147 at risk EG00122 events13 affected150 at risk
Dysgeusia	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG00043 events35 affected147 at risk EG00147 events34 affected150 at risk
Headache	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG00014 events12 affected147 at risk EG00118 events13 affected150 at risk
Neuropathy peripheral	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG000187 events67 affected147 at risk EG001217 events73 affected150 at risk
Paraesthesia	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG00082 events30 affected147 at risk EG00198 events33 affected150 at risk
Peripheral sensory neuropathy	Nervous system disorders	MedDRA 23.0	Systematic Assessment	EG000132 events49 affected147 at risk EG001129 events39 affected150 at risk
Insomnia	Psychiatric disorders	MedDRA 23.0	Systematic Assessment	EG0008 events8 affected147 at risk EG0013 events3 affected150 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 23.0	Systematic Assessment	EG0007 events7 affected147 at risk EG00114 events13 affected150 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA 23.0	Systematic Assessment	EG00014 events12 affected147 at risk EG00112 events12 affected150 at risk
Alopecia	Skin and subcutaneous tissue disorders	MedDRA 23.0	Systematic Assessment	EG00025 events23 affected147 at risk EG00119 events18 affected150 at risk
Palmar-plantar erythrodysaesthesia syndrome	Skin and subcutaneous tissue disorders	MedDRA 23.0	Systematic Assessment	EG00029 events11 affected147 at risk EG00121 events15 affected150 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA 23.0	Systematic Assessment	EG0008 events8 affected147 at risk EG0015 events5 affected150 at risk
Hypertension	Vascular disorders	MedDRA 23.0	Systematic Assessment	EG00016 events11 affected147 at risk EG00110 events8 affected150 at risk

ID	Term
D015179	Colorectal Neoplasms
D009369	Neoplasms
D010523	Peripheral Nervous System Diseases

ID	Term
D007414	Intestinal Neoplasms
D005770	Gastrointestinal Neoplasms
D004067	Digestive System Neoplasms
D009371	Neoplasms by Site
D004066	Digestive System Diseases
D005767	Gastrointestinal Diseases
D003108	Colonic Diseases
D007410	Intestinal Diseases
D012002	Rectal Diseases
D009468	Neuromuscular Diseases
D009422	Nervous System Diseases

ID	Title	Description
BG000	PledOx (5 µmol/kg)	Calmangafodipir 5 µmol/kg Calmangafodipir (5 µmol/kg): PledOx will be given to patients as an i.v. infusion, on top of mFOLFOX6 chemotherapy. PledOx is a solution in 20 mL single dose glass vials.
BG001	Placebo	0.9% sodium chloride in 20 mL vials Placebo: Placebo will be administered via the same route as PledOx (i.v. infusion). Placebo is a solution in 20 mL single dose glass vials.
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	PledOx (5 µmol/kg)	Calmangafodipir 5 µmol/kg Calmangafodipir (5 µmol/kg): PledOx will be given to patients as an i.v. infusion, on top of mFOLFOX6 chemotherapy. PledOx is a solution in 20 mL single dose glass vials.	1	147	20	147	146	147
EG001	Placebo	0.9% sodium chloride in 20 mL vials Placebo: Placebo will be administered via the same route as PledOx (i.v. infusion). Placebo is a solution in 20 mL single dose glass vials.	1	150	20	150	146	150