POLAR-A: Preventive Treatment of OxaLiplatin Induced peripherAl neuRopathy in Adjuvant Colorectal Cancer

• Sponsor: Egetis Therapeutics (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT04034355
• Collaborator: Solasia Pharma K.K. (Industry)
• Enrollment: 301
• Locations: 65
• Arms: 2
• Actual Duration (Months): 19.8
• Patients Per Site: 4.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study is to evaluate PledOx for prevention of chronic chemotherapy induced peripheral neuropathy induced by oxaliplatin in patients with Stage III or high-risk Stage II colorectal cancer (CRC).

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer; Chemotherapy-induced Peripheral Neuropathy	Drug: Calmangafodipir (5 µmol/kg); Other: Placebo	Phase 3

Detailed Description

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 later discontinues oxaliplatin, treatment with 5-FU/folinate and IMP may be continued.

As of March 2nd., all patients have to stop IMP but may continue mFOLFOX6.

Study Design

• Study Type: Interventional
• Actual Enrollment: 301 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Patients with colorectal cancer (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 chemotherapyPatients with colorectal cancer (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
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: Double-blind, placebo-controlled
• Primary Purpose: Prevention
• Official 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
• Actual Study Start Date: Jan 7, 2019
• Actual Primary Completion Date: Aug 31, 2020
• Actual Study Completion Date: Aug 31, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PledOx (5 µmol/kg) Calmangafodipir 5 µmol/kg	Drug: 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.; Other Names: PledOx
Placebo Comparator: Placebo 0.9% sodium chloride in 20 mL vials	Other: 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.

Outcome Measures

Primary Outcome Measures

1. Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy (CIPN) [9 months]

   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.

Secondary Outcome Measures

1. Mild, Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy [9 months]

   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.

2. Sensitivity to Touching Cold Items [Baseline and 8 weeks]

   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).

3. Cumulative Dose of Oxaliplatin During Chemotherapy [9 months]

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

4. Vibration Sensitivity on the Lateral Malleolus [Baseline and 9 months]

   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)

5. Worst Pain in Hands or Feet [Baseline and 9 months]

   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

6. Functional Impairment (in the Non-dominant Hand) [Baseline and 9 months]

   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

7. Patients With Disease Free Survival [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]

   Patients with disease free survival.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

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 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Onze-Lieve-Vrouwziekenuis Aalst	Aalst		Belgium
2	Imelda GI Clinical Research Center	Bonheiden		Belgium
3	Cliniques Universitaires St-Luc	Brussels		Belgium
4	UZ Gent	Gent		Belgium
5	CHU Liège	Liège		Belgium
6	AZ Sint Maarten	Mechelen		Belgium
7	AZ Delta	Roeselare		Belgium
8	CHU UCL Namur - Site Godinne	Yvoir		Belgium
9	Nemocnice Benesov	Benesov		Czechia
10	Nemocnice Horovice	Horovice		Czechia
11	Nemocnice Na Pleši	Nová Ves pod Plesi		Czechia
12	General University Hospital	Prague 2		Czechia
13	Onkologická Klinika 1. Lf Uk A Tn	Prague		Czechia
14	Clinique Pasteur-Lanroze	Brest Cedex 2		France
15	CHRU de Brest - Hôpital Morvan	Brest		France
16	Centre Hospitalier Départemental de Vendée - Unité de recherche clinique	La Roche-sur-Yon		France
17	Centre Oscar Lambret	Lille		France
18	Hôpital Edouard Herriot - HCL	LYON Cedex 03		France
19	Hôpital Nord Franche-Comté Site du Mittan	Montbéliard		France
20	CHU Nice L'Archet 2	Nice		France
21	Clinique Ste Anne	Strasbourg		France
22	Hopitaux Universitaires de Strasbourg	Strasbourg		France
23	Hämatolgisch-onkologische Praxis Augsburg	Augsburg		Germany
24	Onkozentrum Dresden	Dresden		Germany
25	Universitätsklinikum Carl Gustav Carus	Dresden		Germany
26	Onkodok GmbH / Onkologische Schwerpunktpraxis	Gütersloh		Germany
27	Klinikum Neuperlach	Munchen		Germany
28	Oncologia Istituti Ospitalieri	Cremona		Italy
29	Irccs Irst	Meldola - FC		Italy
30	Hospital San Gerardo	Monza		Italy
31	Istituto Nazionale Tumori	Napoli		Italy
32	IRCCS Policlinico San Matteo	Pavia		Italy
33	Ospedale degli infermi	Ponderano		Italy
34	IRCCS azienda Ospedaliera S Maria Nuova	Reggio Emilia		Italy
35	Casa Sollievo della Sofferenza	San Giovanni Rotondo		Italy
36	Fukuoka University Hospital	Fukuoka		Japan
37	Kyushu University Hospital	Fukuoka		Japan
38	St. Marianna University School of Medicine Hospital	Kawasaki		Japan
39	Aichi Cancer Center Hospital	Nagoya		Japan
40	National Hospital Organization Osaka National Hospital	Osaka		Japan
41	Osaka International Cancer Institute	Osaka		Japan
42	Osaka University Hospital	Osaka		Japan
43	Sapporo Medical University Hospital	Sapporo		Japan
44	Shizuoka Cancer Center	Shizuoka		Japan
45	The Cancer Institute Hospital of JFCR	Tokyo		Japan
46	Fujita Health University Hospital	Toyoake		Japan
47	Hallym University Sacred Heart Hospital	Anyang-si		Korea, Republic of
48	Dong-A University Hospital	Busan		Korea, Republic of
49	Chonnam National University Hwasun Hospital	Gwangju		Korea, Republic of
50	Seoul National University Bundang Hospital	Seongnam-si		Korea, Republic of
51	Korea University Guro Hospital	Seoul		Korea, Republic of
52	Seoul National University Hospital	Seoul		Korea, Republic of
53	Granvia de L´Hospitalet 199-203	Barcelona		Spain
54	Hospital de La Santa Creu I Sant Pau	Barcelona		Spain
55	Vall d'hebron university hospital	Barcelona		Spain
56	Centro Integral Oncologico	Madrid		Spain
57	H.G.U.Gregorio Marañón	Madrid		Spain
58	Hospital Universitario Puerta de Hierro	Majadahonda		Spain
59	Hospital Univ Virgen Macarena	Sevilla		Spain
60	Hospital Quironsalud Valencia	Valencia		Spain
61	KMUH: Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung		Taiwan
62	Mid Essex Hospital Services NHS Trust - Broomfield Hospital	Chelmsford		United Kingdom
63	North Tyneside General Hospital	North Shields		United Kingdom
64	Mount Vernon Cancer Centr	Northwood		United Kingdom
65	The Royal Marsden Hospital (Surrey)	Sutton		United Kingdom

Sponsors and Collaborators

• Egetis Therapeutics
• Solasia Pharma K.K.

Investigators

• Study Director: Stefan Carlsson, MD, Chief Medical Officer

Study Documents (Full-Text)

• Study Protocol - May 15, 2020
• Statistical Analysis Plan - Sep 2, 2020

More Information

Publications

None provided.

• Responsible Party: Egetis Therapeutics
• ClinicalTrials.gov Identifier: NCT04034355
• Other Study ID Numbers: PP06489; 2017-004707-43
• First Posted: Jul 26, 2019
• Last Update Posted: Jan 26, 2022
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Egetis Therapeutics: colorectal cancer; cancer; peripheral neuropathy; neuropathy
• Additional relevant MeSH terms: Colorectal Neoplasms; Peripheral Nervous System Diseases

Study Results

Participant Flow

Recruitment Details

Patients were recruited in the EU and Asia between 7 January 2019 and 1 March 2020. The Sponsor placed recruitment/dosing in the POLAR program on hold following interactions with the French regulatory authority and the US clinical hold of study POLAR-M on 23 January 2020. As of 2 March 2020, no more patients were enrolled or IMP administered. Enrolled patients were followed until the data cut-off date of 31 August 2020 and these patients have been assigned as "completed" in the disposition.

Pre-assignment Detail

371 patients were screened in the 28 days before the start of treatment, 301 were randomised and 297 were treated.

Arm/Group Title	PledOx (5 µmol/kg)	Placebo
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	151	150
Treated	147	150
COMPLETED	117	115
NOT COMPLETED	34	35

Baseline Characteristics

Arm/Group Title	PledOx (5 µmol/kg)	Placebo	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	147	150	297
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.3 (10.4)	62.4 (10.2)	62.9 (10.3)
Sex: Female, Male (Count of Participants)
Female	69 46.9%	61 40.7%	130 43.8%
Male	78 53.1%	89 59.3%	167 56.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	43 29.3%	43 28.7%	86 29%
Native Hawaiian or Other Pacific Islander	1 0.7%	0 0%	1 0.3%
Black or African American	1 0.7%	0 0%	1 0.3%
White	87 59.2%	93 62%	180 60.6%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	15 10.2%	14 9.3%	29 9.8%
Body Mass Index (kg/m^2) [Median (Full Range) ]
Median (Full Range) [kg/m^2]	24.20	23.60	24.20
ECOG performance status (Count of Participants)
0	118 80.3%	122 81.3%	240 80.8%
1	29 19.7%	28 18.7%	57 19.2%

Outcome Measures

1. Primary Outcome

Title	Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy (CIPN)
Description	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.
Time Frame	9 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	PledOx (5 µmol/kg)	Placebo
Arm/Group Description	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.	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.
Measure Participants	120	119
Count of Participants [Participants]	68 46.3%	46 30.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PledOx (5 µmol/kg), Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0280
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.5210
	Confidence Interval	(2-Sided) 95%; 1.0462 to 2.2113
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Mild, Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy
Description	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.
Time Frame	9 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	PledOx (5 µmol/kg)	Placebo
Arm/Group Description	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.	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.
Measure Participants	120	119
Count of Participants [Participants]	89 60.5%	74 49.3%

3. Secondary Outcome

Title	Sensitivity to Touching Cold Items
Description	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).
Time Frame	Baseline and 8 weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	PledOx (5 µmol/kg)	Placebo
Arm/Group Description	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.	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.
Measure Participants	120	126
Least Squares Mean (95% Confidence Interval) [Scores on a scale]	4.38	4.08

4. Secondary Outcome

Title	Cumulative Dose of Oxaliplatin During Chemotherapy
Description	Mean cumulative dose of oxaliplatin administered per patient during mFOLFOX6 chemotherapy, 9 months after the first dose of Investigational Medicinal Product
Time Frame	9 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	PledOx (5 µmol/kg)	Placebo
Arm/Group Description	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.	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.
Measure Participants	138	140
Least Squares Mean (95% Confidence Interval) [mg/m^2]	747.3	755.0

5. Secondary Outcome

Title	Vibration Sensitivity on the Lateral Malleolus
Description	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)
Time Frame	Baseline and 9 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	PledOx (5 µmol/kg)	Placebo
Arm/Group Description	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.	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.
Measure Participants	108	107
Mean (Standard Deviation) [Scores on a scale]	-1.38 (1.61)	-1.43 (1.84)

6. Secondary Outcome

Title	Worst Pain in Hands or Feet
Description	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
Time Frame	Baseline and 9 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	PledOx (5 µmol/kg)	Placebo
Arm/Group Description	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.	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.
Measure Participants	114	118
Least Squares Mean (95% Confidence Interval) [Scores on a scale]	2.55	2.16

7. Secondary Outcome

Title	Functional Impairment (in the Non-dominant Hand)
Description	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
Time Frame	Baseline and 9 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	PledOx (5 µmol/kg)	Placebo
Arm/Group Description	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.	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.
Measure Participants	104	107
Mean (Standard Deviation) [seconds]	16.23 (48.91)	-0.39 (42.58)

8. Secondary Outcome

Title	Patients With Disease Free Survival
Description	Patients with disease free survival.
Time Frame	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	PledOx (5 µmol/kg)	Placebo
Arm/Group Description	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.	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.
Measure Participants	147	150
Number [participants]	7 4.8%	15 10%

Adverse Events

Time Frame	From screening until 30 days after the end of treatment visit which occurred after up to 6 months of treatment
Arm/Group Title	PledOx (5 µmol/kg)		Placebo
Arm/Group Description	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.		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.
All Cause Mortality
	PledOx (5 µmol/kg)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/147 (0.7%)		1/150 (0.7%)
Serious Adverse Events
	PledOx (5 µmol/kg)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/147 (13.6%)		20/150 (13.3%)
Blood and lymphatic system disorders
Febrile neutropenia	0/147 (0%)	0	1/150 (0.7%)	1
Cardiac disorders
Angina pectoris	0/147 (0%)	0	1/150 (0.7%)	1
Myocardial infarction	0/147 (0%)	0	1/150 (0.7%)	1
Ear and labyrinth disorders
Sudden hearing loss	1/147 (0.7%)	1	0/150 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/147 (0%)	0	1/150 (0.7%)	1
Colitis	1/147 (0.7%)	1	0/150 (0%)	0
Crohn's disease	0/147 (0%)	0	1/150 (0.7%)	1
Ileus	1/147 (0.7%)	1	0/150 (0%)	0
Large intestine perforation	0/147 (0%)	0	1/150 (0.7%)	1
Small intestinal obstruction	1/147 (0.7%)	1	1/150 (0.7%)	1
Vomiting	0/147 (0%)	0	1/150 (0.7%)	1
General disorders
Administration site cellulitis	0/147 (0%)	0	1/150 (0.7%)	1
Hepatobiliary disorders
Cholecystitis acute	0/147 (0%)	0	1/150 (0.7%)	1
Immune system disorders
Anaphylactic reaction	2/147 (1.4%)	2	0/150 (0%)	0
Drug hypersensitivity	1/147 (0.7%)	1	0/150 (0%)	0
Infusion related reaction	3/147 (2%)	5	0/150 (0%)	0
Infections and infestations
Clostridium difficile infection	1/147 (0.7%)	1	0/150 (0%)	0
Corona virus infection	0/147 (0%)	0	1/150 (0.7%)	1
Device related infection	0/147 (0%)	0	1/150 (0.7%)	1
Gastroenteritis	0/147 (0%)	0	1/150 (0.7%)	1
Infection	0/147 (0%)	0	1/150 (0.7%)	1
Influenza	0/147 (0%)	0	1/150 (0.7%)	1
Osteomyelitis	0/147 (0%)	0	1/150 (0.7%)	1
Pneumonia	0/147 (0%)	0	1/150 (0.7%)	1
Urinary tract infection	1/147 (0.7%)	1	1/150 (0.7%)	1
Injury, poisoning and procedural complications
Gastrointestinal stoma complications	0/147 (0%)	0	1/150 (0.7%)	1
Pubis fracture	1/147 (0.7%)	1	0/150 (0%)	0
Metabolism and nutrition disorders
Decreased appetitie	0/147 (0%)	0	1/150 (0.7%)	1
Diabetic metabolic decompensation	0/147 (0%)	0	1/150 (0.7%)	1
Hypokalaemia	0/147 (0%)	0	1/150 (0.7%)	1
Nervous system disorders
Cerebral infarction	1/147 (0.7%)	1	0/150 (0%)	0
Generalised tonic-clonic seizure	1/147 (0.7%)	1	0/150 (0%)	0
Product Issues
Device extrusion	1/147 (0.7%)	1	0/150 (0%)	0
Renal and urinary disorders
Acute kidney injury	1/147 (0.7%)	1	1/150 (0.7%)	1
Renal failure	1/147 (0.7%)	1	0/150 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pharyngeal inflammation	0/147 (0%)	0	1/150 (0.7%)	1
Pulmonary embolism	2/147 (1.4%)	2	1/150 (0.7%)	1
Vascular disorders
Deep vein thrombosis	0/147 (0%)	0	1/150 (0.7%)	1
Embolism	1/147 (0.7%)	1	0/150 (0%)	0
Vena cava thrombosis	1/147 (0.7%)	1	0/150 (0%)	0
Other (Not Including Serious) Adverse Events
	PledOx (5 µmol/kg)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	146/147 (99.3%)		146/150 (97.3%)
Blood and lymphatic system disorders
Anaemia	17/147 (11.6%)	24	17/150 (11.3%)	20
Leukopenia	18/147 (12.2%)	34	19/150 (12.7%)	40
Neutropenia	62/147 (42.2%)	144	68/150 (45.3%)	203
Thrombocytopenia	46/147 (31.3%)	69	58/150 (38.7%)	134
Gastrointestinal disorders
Abdominal pain	13/147 (8.8%)	18	14/150 (9.3%)	18
Abdominal pain upper	8/147 (5.4%)	9	15/150 (10%)	21
Constipation	30/147 (20.4%)	38	25/150 (16.7%)	39
Diarrhoea	59/147 (40.1%)	120	56/150 (37.3%)	90
Dry mouth	4/147 (2.7%)	4	9/150 (6%)	9
Dyspepsia	10/147 (6.8%)	10	11/150 (7.3%)	13
Nausea	88/147 (59.9%)	193	69/150 (46%)	155
Stomatitis	50/147 (34%)	67	31/150 (20.7%)	37
Vomiting	27/147 (18.4%)	33	27/150 (18%)	34
General disorders
Asthenia	32/147 (21.8%)	87	36/150 (24%)	73
Fatigue	39/147 (26.5%)	61	36/150 (24%)	78
Malaise	8/147 (5.4%)	23	7/150 (4.7%)	9
Pyrexia	10/147 (6.8%)	13	13/150 (8.7%)	18
Immune system disorders
Infusion related reaction	8/147 (5.4%)	9	2/150 (1.3%)	2
Infections and infestations
Nasopharyngitis	8/147 (5.4%)	8	7/150 (4.7%)	7
Investigations
Alanine aminotransferase increased	11/147 (7.5%)	18	17/150 (11.3%)	26
Aspartate aminotransferase increased	11/147 (7.5%)	19	15/150 (10%)	23
Metabolism and nutrition disorders
Decreased appetite	42/147 (28.6%)	66	37/150 (24.7%)	62
Hypokalaemia	3/147 (2%)	5	11/150 (7.3%)	19
Musculoskeletal and connective tissue disorders
Back pain	9/147 (6.1%)	11	2/150 (1.3%)	3
Muscle spasms	9/147 (6.1%)	12	6/150 (4%)	6
Pain in extremity	8/147 (5.4%)	10	2/150 (1.3%)	2
Pain in jaw	5/147 (3.4%)	8	8/150 (5.3%)	12
Nervous system disorders
Dizziness	11/147 (7.5%)	14	4/150 (2.7%)	4
Dysaesthesia	7/147 (4.8%)	15	13/150 (8.7%)	22
Dysgeusia	35/147 (23.8%)	43	34/150 (22.7%)	47
Headache	12/147 (8.2%)	14	13/150 (8.7%)	18
Neuropathy peripheral	67/147 (45.6%)	187	73/150 (48.7%)	217
Paraesthesia	30/147 (20.4%)	82	33/150 (22%)	98
Peripheral sensory neuropathy	49/147 (33.3%)	132	39/150 (26%)	129
Psychiatric disorders
Insomnia	8/147 (5.4%)	8	3/150 (2%)	3
Respiratory, thoracic and mediastinal disorders
Cough	7/147 (4.8%)	7	13/150 (8.7%)	14
Epistaxis	12/147 (8.2%)	14	12/150 (8%)	12
Skin and subcutaneous tissue disorders
Alopecia	23/147 (15.6%)	25	18/150 (12%)	19
Palmar-plantar erythrodysaesthesia syndrome	11/147 (7.5%)	29	15/150 (10%)	21
Rash	8/147 (5.4%)	8	5/150 (3.3%)	5
Vascular disorders
Hypertension	11/147 (7.5%)	16	8/150 (5.3%)	10

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.