Preventive Treatment of Oxaliplatin Induced Peripheral Neuropathy in Metastatic Colorectal Cancer (POLAR-M)

• Sponsor: Egetis Therapeutics (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03654729
• Collaborator: Solasia Pharma K.K. (Industry)
• Enrollment: 291
• Locations: 98
• Arms: 3
• Actual Duration (Months): 21.8
• Patients Per Site: 3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer; Chemotherapy-induced Peripheral Neuropathy	Drug: Calmangafodipir (2 µmol/kg); Drug: Calmangafodipir (5 µmol/kg); Drug: Placebo	Phase 3

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 291 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: This is a Phase 3, multicenter, double-blind, placebo-controlled study to establish the efficacious dose of PledOx in prevention of chronic chemotherapy induced peripheral neuropathy (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) + m Arm C: Placebo + mFOLFOX6 chemotherapyThis is a Phase 3, multicenter, double-blind, placebo-controlled study to establish the efficacious dose of PledOx in prevention of chronic chemotherapy induced peripheral neuropathy (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) + m Arm C: Placebo + mFOLFOX6 chemotherapy
• Masking: Triple (Participant, Care Provider, Investigator)
• 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 Patients With First-line mCRC
• Actual Study Start Date: Nov 7, 2018
• Actual Primary Completion Date: Aug 31, 2020
• Actual Study Completion Date: Aug 31, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PledOx (2 µmol/kg) Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy.	Drug: Calmangafodipir (2 µmol/kg); Solution in 20 mL single dose glass vials; Other Names: PledOx
Experimental: PledOx (5 µmol/kg) Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy.	Drug: Calmangafodipir (5 µmol/kg); Solution in 20 mL single dose glass vials; Other Names: PledOx
Placebo Comparator: Placebo Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy.	Drug: Placebo; 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 (CIPN) [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 of mFOLFOX6 chemotherapy, as assessed by the Cold Sensitivity Questionnaire (measuring sensitivity when touching or swallowing cold objects/fluid). 10 point scale from 0 meaning no sensitivity/discomfort at all to 10 meaning sensitivity/discomfort as bad as it can be.

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 IMP.

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 IMP. 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 the Pain Assessment (Numerical Rating Scale (NRS)), at 9 months after the first dose of IMP. The NRS is a 10 point scale with 0 as no pain at all and 10 as pain as bad as you can imagine and evaluates the intensity of pain in hands and feet during the past week. A higher value means worse outcome.

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 IMP.

7. Overall Response Rate (ORR) [12, 15 and 18 months]

   Percentage of patients with an overall response (complete response or partial response) according to RECIST v1.1 for target lesions and assessed by CT (preferred) or MRI. Complete response=disappearance of all target lesions; partial response >=30% decrease in the sum of the longest diameter of target lesions.

8. Progression-free Survival (PFS) [Analyses at 12 and 24 months were planned; the analysis was performed once based on available data at cut-off 31 August 2020 as the study was terminated early by the Sponsor]

   Patients with progression-free survival

9. Overall Survival (OS) [An analysis at 36 months was planned. The analysis was performed based on available data at cut-off 31 August 2020 as the study was terminated early by the Sponsor]

   Patients with overall survival

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Signed informed consent form before any study related assessments and willing to follow all study procedures.

• Male or female aged >=18 years.

• Non-resectable metastatic (stage IV) CRC, pathologically confirmed adenocarcinoma of the colon or rectum.

• No prior chemotherapy (within the previous 12 months) and/or biologic/targeted therapy for mCRC.

• Measurable disease according to RECIST 1.1.

• Patient indicated for at least 3 months of oxaliplatin-based chemotherapy (without any pre-planned treatment breaks) and without any clinically observed neurological disorders.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

• Adequate hematological parameters: hemoglobin >=100 g/L, absolute neutrophil count (ANC) >=1.5 x 10^{9 /L, platelets >=100 x 10}9 /L.

• Adequate renal function: creatinine clearance >50 cc/min using the Cockroft and Gault formula or measured.

• Adequate hepatic function: total bilirubin <=1.5 times the upper limit of normal (ULN) (except in the case of known Gilbert's syndrome); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=3 times ULN (AST and ALT <=5 times ULN in case of liver metastases).

• Baseline blood manganese (Mn) level <2.0 times ULN.

• For patients with a history of diabetes mellitus, HbA1c <=7%.

• Negative pregnancy test for females of child-bearing potential.

• For men and females of childbearing potential, use of adequate contraception (oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) while on study drug and for at least 6 months after completion of study therapy.

Exclusion Criteria:

• Any unresolved toxicity by Common Terminology Criteria for Adverse Events Version (CTCAE v4.03) > 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.

• Any history of seizures.

• A surgical incision that is not healed.

• Significant hemorrhage (>30 mL/bleeding episode in previous 3 months), hemoptysis (>5 mL fresh blood in previous 4 weeks) or thrombotic event (including transient ischemic attack) in the previous 12 months if the patient is expected to receive anti-VEGF/VEGFR therapy.

• Known hypersensitivity to any of the components of mFOLFOX6 and, if applicable, biological 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 manganese exposure is likely.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	California Cancer Associates	Fresno	California	United States	93720
2	Mid Florida Hematology and Oncology Center	Orange City	Florida	United States	32763
3	Cancer Center of Kansas	Wichita	Kansas	United States	67214
4	Willis-Knighton Cancer Center	Shreveport	Louisiana	United States	71103
5	Mercy Clinic Oncology and Hematology	Saint Louis	Missouri	United States	63141
6	Mercy Clinic - Cancer & Hematology	Springfield	Missouri	United States	65804
7	CHI St Francis Cancer Treatment Center	Grand Island	Nebraska	United States	68803
8	Hunterdon Hematology Oncology	Flemington	New Jersey	United States	08822
9	Montefiore Medical Research	Bronx	New York	United States	10461
10	Monter Cancer Center	Lake Success	New York	United States	11042
11	Scott & White Vasicek Cancer Treatment Center	Temple	Texas	United States	76508
12	Onze-Lieve-Vrouwziekenuis Aalst	Aalst		Belgium
13	Imelda GI Clinical Research Center	Bonheiden		Belgium
14	Cliniques Universitaires St-Luc	Brussels		Belgium
15	UZ Gent	Gent		Belgium
16	CHU Liège	Liege		Belgium
17	AZ Sint Maarten	Mechelen		Belgium
18	AZ Delta	Roeselare		Belgium
19	CHU UCL Namur - Site Godinne	Yvoir		Belgium
20	Nemocnice Benesov	Benešov		Czechia
21	Nemocnice Horovice	Hořovice		Czechia
22	Nemocnice Na Pleši	Nová Ves Pod Pleší		Czechia
23	General University Hospital	Prague 2		Czechia
24	Hospital Na Bulovce	Prague		Czechia
25	Onkologická Klinika 1. Lf Uk A Tn	Prague		Czechia
26	Clinique Pasteur-Lanroze	Brest Cedex 2		France
27	CHRU de Brest - Hôpital Morvan	Brest		France
28	Centre Hospitalier Départemental de Vendée - Unité de recherche clinique	La Roche-sur-Yon		France
29	Centre Oscar Lambret	Lille		France
30	Hôpital Edouard Herriot - HCL	LYON Cedex 03		France
31	Hôpital Nord Franche-Comté Site du Mittan	Montbéliard Cedex		France
32	Institut de Cancérologie de l'Ouest	Nantes		France
33	Hopital l'Archet, CHU de Nice	NICE Cedex 3		France
34	Hôpital Robert Debré	Reims		France
35	Centre Hospitalier Privé Saint-Grégoire	Saint-Grégoire		France
36	Clinique Ste Anne	Strasbourg		France
37	Hopitaux Universitaires de Strasbourg	Strasbourg		France
38	Hämatolgisch-onkologische Praxis Augsburg	Augsburg		Germany
39	Onkozentrum Dresden	Dresden		Germany
40	Universitätsklinikum Carl Gustav Carus	Dresden		Germany
41	Agaplesion Markus Krankenhaus	Frankfurt		Germany
42	Onkodok GmbH	Gütersloh		Germany
43	Klinikum Neuperlach	München		Germany
44	Queen Mary Hospital	Hong Kong		Hong Kong
45	Országos Onkológiai Intézet	Budapest		Hungary
46	Semmelweis Egyetem	Budapest		Hungary
47	Borsod-Abaúj-Zemplén Megyei Központi Kórház és Egyetemi Oktatókórház	Miskolc		Hungary
48	Tolna Megyei Balassa Janos Korhaz	Szekszárd		Hungary
49	Jász-Nagykun-Szolnok Megyei Hetényi Géza Kórház-Rendelőintézet	Szolnok		Hungary
50	IRCCS Candiolo	Candiolo		Italy
51	Oncologia Istituti Ospitalieri	Cremona		Italy
52	Irccs Irst	Meldola - FC		Italy
53	Azienda Ospedaliero - Universitaria di Modena Policlinico	Modena		Italy
54	Hospital San Gerardo	Monza		Italy
55	Istituto Nazionale Tumori	Napoli		Italy
56	IRCCS Policlinico San Matteo	Pavia		Italy
57	Ospedale degli infermi	Ponderano		Italy
58	Ospedale S. Maria delle Croci - Ravenna	Ravenna		Italy
59	IRCCS azienda Ospedaliera S Maria Nuova	Reggio Emilia		Italy
60	San Camillo Forlanini Hospital	Rome		Italy
61	Casa Sollievo della Sofferenza	San Giovanni Rotondo		Italy
62	Osaka International Cancer Institute	Osaka-shi, Osaka	Osaka	Japan	541-8567
63	Fujita Health University Hospital	Aichi		Japan	470-1192
64	Kyushu University Hospital	Fukuoka-shi, Fukuoka		Japan	812-8582
65	Fukuoka University Hospital	Fukuoka-shi, Fukuoka		Japan	814-0133
66	Kansai Rosai Hospital	Hyōgo		Japan
67	St. Marianna University School of Medicine Hospital	Kanagawa		Japan	216-8511
68	Aichi Cancer Center Hospital	Nagoya-shi, Aichi		Japan	464-8681
69	National Hospital Organization Osaka National Hospital	Osaka-shi, Osaka		Japan	540-0006
70	Osaka University Hospital	Osaka		Japan	565-0871
71	Sapporo Medical University Hospital	Sapporo-shi, Hokkaido		Japan	065-0033
72	Shizuoka Cancer Center	Shizuoka		Japan	411-8777
73	The Cancer Institute Hospital Of JFCR	Tokyo		Japan	135-8550
74	Hallym University Sacred Heart Hospital	Anyang-si		Korea, Republic of
75	Dong-A University Hospital	Busan		Korea, Republic of
76	Chonnam National University Hwasun Hospital	Gwangju		Korea, Republic of
77	Seoul National University Bundang Hospital	Seongnam-si		Korea, Republic of
78	Korea University Guro Hospital	Seoul		Korea, Republic of
79	Seoul National University Hospital	Seoul		Korea, Republic of
80	Hospital de La Santa Creu I Sant Pau	Barcelona		Spain
81	L´Hospitalet de Llobregat (Barcelona)	Barcelona		Spain
82	Vall d'hebron university hospital	Barcelona		Spain
83	Complejo Hospitalario de Jaén	Jaén		Spain
84	Centro Integral Oncologico Clara Campal	Madrid		Spain
85	H.G.U.Gregorio Marañón	Madrid		Spain
86	Hospital Universitario La Paz	Madrid		Spain
87	Hospital Universitario Puerta de Hierro	Majadahonda		Spain
88	Hospital Universitario Virgen Macarena	Sevilla		Spain
89	Hospital Quironsalud Valencia	València		Spain
90	Hospital Miguel Servet	Zaragoza		Spain
91	KMUH: Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung		Taiwan
92	CMMC: Chi Mei Medical Center	Tainan		Taiwan
93	NCKUH: National Cheng Kung University Hospital	Tainan		Taiwan
94	Royal Marsden Hospital	London		United Kingdom	SW3 6JJ
95	North Tyneside General Hospital	North Shields		United Kingdom	NE29 8NH
96	Mount Vernon Cancer Centre	Northwood		United Kingdom	HA6 2RN
97	The Royal Marsden Hospital (Surrey)	Sutton		United Kingdom	SM2 5PT
98	York Teaching Hospital	York		United Kingdom	YO61 8HE

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: NCT03654729
• Other Study ID Numbers: PP06490
• First Posted: Aug 31, 2018
• Last Update Posted: Dec 17, 2021
• 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: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Egetis Therapeutics: Metastatic; Colorectal; Cancer; Metastatic Colorectal Cancer; Oxaliplatin induced CIPN; CIPN; Oxaliplatin
• Additional relevant MeSH terms: Colorectal Neoplasms; Peripheral Nervous System Diseases; Pyridoxal Phosphate; Edetic Acid

Study Results

Participant Flow

Recruitment Details

Patients were recruited in the US, EU and Asia between 2018 and 1 March 2020. The Sponsor placed recruitment/dosing in the POLAR program on hold following interactions with the French regulatory authority and a US clinical hold of the study 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

386 patients were screened in the 28 days before the start of treatment, 291 were randomised and 285 were treated.

Arm/Group Title	PledOx (2 µmol/kg)	PledOx (5 µmol/kg)	Placebo
Arm/Group Description	Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial
Period Title: Overall Study
STARTED	97	96	98
Treated	96	93	96
COMPLETED	66	70	69
NOT COMPLETED	31	26	29

Baseline Characteristics

Arm/Group Title	PledOx (2 µmol/kg)	PledOx (5 µmol/kg)	Placebo	Total
Arm/Group Description	Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial	Total of all reporting groups
Overall Participants	96	93	96	285
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.5 (10.5)	62.9 (9.6)	61.6 (12.4)	62.7 (10.9)
Sex: Female, Male (Count of Participants)
Female	36 37.5%	43 46.2%	40 41.7%	119 41.8%
Male	60 62.5%	50 53.8%	56 58.3%	166 58.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	41 42.7%	40 43%	39 40.6%	120 42.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	1 1.1%	1 1%	2 0.7%
White	49 51%	45 48.4%	51 53.1%	145 50.9%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	6 6.3%	7 7.5%	5 5.2%	18 6.3%
Body Mass Index (kg/m^2) [Median (Full Range) ]
Median (Full Range) [kg/m^2]	23.60	24.20	24.00	24.00
ECOG performance status (Count of Participants)
0	65 67.7%	62 66.7%	53 55.2%	180 63.2%
1	31 32.3%	31 33.3%	41 42.7%	103 36.1%
Unknown	0 0%	0 0%	2 2.1%	2 0.7%

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 (2 µmol/kg)	PledOx (5 µmol/kg)	Placebo
Arm/Group Description	Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial
Measure Participants	54	55	57
Count of Participants [Participants]	31 32.3%	27 29%	25 26%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	PledOx (2 µmol/kg), Placebo
	Comments	Cochran-Mantel-Haenszel estimate of the common relative risk of moderate to severe CIPN.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2266
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.3842
	Confidence Interval	(2-Sided) 95%; 0.8172 to 2.3446
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	PledOx (5 µmol/kg), Placebo
	Comments	Cochran-Mantel-Haenszel estimate of the common relative risk of moderate to severe CIPN.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7434
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.0951
	Confidence Interval	(2-Sided) 95%; 0.6356 to 1.8870
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Mild, Moderate or Severe Chronic Chemotherapy Induced Peripheral Neuropathy (CIPN)
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 (2 µmol/kg)	PledOx (5 µmol/kg)	Placebo
Arm/Group Description	Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial
Measure Participants	54	55	57
Count of Participants [Participants]	43 44.8%	40 43%	42 43.8%

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 of mFOLFOX6 chemotherapy, as assessed by the Cold Sensitivity Questionnaire (measuring sensitivity when touching or swallowing cold objects/fluid). 10 point scale from 0 meaning no sensitivity/discomfort at all to 10 meaning sensitivity/discomfort as bad as it can be.
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 (2 µmol/kg)	PledOx (5 µmol/kg)	Placebo
Arm/Group Description	Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial
Measure Participants	68	66	66
Least Squares Mean (95% Confidence Interval) [Scores on a scale]	3.88	4.13	3.41

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 IMP.
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 (2 µmol/kg)	PledOx (5 µmol/kg)	Placebo
Arm/Group Description	Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial
Measure Participants	80	78	78
Least Squares Mean (95% Confidence Interval) [mg/m^2]	780.69	803.54	764.52

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 IMP. 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 (2 µmol/kg)	PledOx (5 µmol/kg)	Placebo
Arm/Group Description	Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial
Measure Participants	49	49	51
Mean (Standard Deviation) [Scores on a scale]	-1.53 (2.06)	-1.61 (2.09)	-1.36 (1.68)

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 the Pain Assessment (Numerical Rating Scale (NRS)), at 9 months after the first dose of IMP. The NRS is a 10 point scale with 0 as no pain at all and 10 as pain as bad as you can imagine and evaluates the intensity of pain in hands and feet during the past week. A higher value means worse outcome.
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 (2 µmol/kg)	PledOx (5 µmol/kg)	Placebo
Arm/Group Description	Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial
Measure Participants	51	52	54
Least Squares Mean (95% Confidence Interval) [Scores on a scale]	2.19	1.58	1.92

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 IMP.
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 (2 µmol/kg)	PledOx (5 µmol/kg)	Placebo
Arm/Group Description	Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial
Measure Participants	45	47	50
Least Squares Mean (95% Confidence Interval) [seconds]	9.68	14.24	12.01

8. Secondary Outcome

Title	Overall Response Rate (ORR)
Description	Percentage of patients with an overall response (complete response or partial response) according to RECIST v1.1 for target lesions and assessed by CT (preferred) or MRI. Complete response=disappearance of all target lesions; partial response >=30% decrease in the sum of the longest diameter of target lesions.
Time Frame	12, 15 and 18 months

Outcome Measure Data

Analysis Population Description

The safety analysis set consisting of all randomized patients who received at least one dose of IMP. The overall number analyzed represents the total in the safety population treated at the start of the study. ORR was assessed throughout the study when varying numbers of patients in each group remained on study

Arm/Group Title	PledOx (2 µmol/kg)	PledOx (5 µmol/kg)	Placebo
Arm/Group Description	Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial
Measure Participants	96	93	96
Missing	22 22.9%	19 20.4%	19 19.8%
No	6 6.3%	13 14%	12 12.5%
Yes	13 13.5%	12 12.9%	8 8.3%
Missing	9 9.4%	14 15.1%	7 7.3%
No	7 7.3%	7 7.5%	3 3.1%
Yes	6 6.3%	2 2.2%	2 2.1%
Missing	1 1%	3 3.2%	1 1%
No	2 2.1%	3 3.2%	0 0%
Yes	1 1%	0 0%	1 1%

9. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	Patients with progression-free survival
Time Frame	Analyses at 12 and 24 months were planned; the analysis was performed once 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 (2 µmol/kg)	PledOx (5 µmol/kg)	Placebo
Arm/Group Description	Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial
Measure Participants	95	93	95
Number [participants]	40 41.7%	36 38.7%	36 37.5%

10. Secondary Outcome

Title	Overall Survival (OS)
Description	Patients with overall survival
Time Frame	An analysis at 36 months was planned. The analysis was 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 (2 µmol/kg)	PledOx (5 µmol/kg)	Placebo
Arm/Group Description	Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial	Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial	Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial
Measure Participants	95	93	95
Number [participants]	9 9.4%	9 9.7%	16 16.7%

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 (2 µmol/kg)		PledOx (5 µmol/kg)		Placebo
Arm/Group Description	Calmangafodipir (2 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (2 µmol/kg): Solution in 20 mL single dose glass vial		Calmangafodipir (5 µmol/kg) on day 1 every two weeks to patients as an intravenous infusion, combined with mFOLFOX6 chemotherapy. Calmangafodipir (5 µmol/kg): Solution in 20 mL single dose glass vial		Placebo will be given to patients as an intravenous infusion, on top of mFOLFOX6 chemotherapy. Placebo: Solution in 20 mL single dose glass vial
All Cause Mortality
	PledOx (2 µmol/kg)		PledOx (5 µmol/kg)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/96 (9.4%)		9/93 (9.7%)		16/96 (16.7%)
Serious Adverse Events
	PledOx (2 µmol/kg)		PledOx (5 µmol/kg)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/96 (28.1%)		21/93 (22.6%)		24/96 (25%)
Blood and lymphatic system disorders
Febrile neutropenia	0/96 (0%)	0	2/93 (2.2%)	2	2/96 (2.1%)	2
Neutropenia	0/96 (0%)	0	2/93 (2.2%)	2	1/96 (1%)	1
Cardiac disorders
Cardiogenic shock	0/96 (0%)	0	1/93 (1.1%)	1	0/96 (0%)	0
Gastrointestinal disorders
Abdominal pain	2/96 (2.1%)	2	0/93 (0%)	0	0/96 (0%)	0
Colitis	0/96 (0%)	0	1/93 (1.1%)	1	1/96 (1%)	1
Diarrhoea	1/96 (1%)	1	1/93 (1.1%)	1	1/96 (1%)	1
Enterocolitis	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Haemorrhoids	0/96 (0%)	0	0/93 (0%)	0	1/96 (1%)	1
Ileus	2/96 (2.1%)	2	0/93 (0%)	0	2/96 (2.1%)	2
Inguinal hernia	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Intestinal obstruction	0/96 (0%)	0	1/93 (1.1%)	1	2/96 (2.1%)	2
Nausea	2/96 (2.1%)	2	1/93 (1.1%)	1	1/96 (1%)	1
Neutropenic colitis	0/96 (0%)	0	1/93 (1.1%)	1	0/96 (0%)	0
Pancreatitis acute	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Parotitis	0/96 (0%)	0	0/93 (0%)	0	1/96 (1%)	1
Stomatitis	0/96 (0%)	0	1/93 (1.1%)	1	1/96 (1%)	1
Vomiting	3/96 (3.1%)	3	1/93 (1.1%)	1	1/96 (1%)	2
General disorders
Death	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Euthanasia	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Fatigue	0/96 (0%)	0	1/93 (1.1%)	1	0/96 (0%)	0
Generalised oedema	0/96 (0%)	0	0/93 (0%)	0	1/96 (1%)	1
Malaise	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Pyrexia	2/96 (2.1%)	3	0/93 (0%)	0	1/96 (1%)	1
Hepatobiliary disorders
Bile duct obstruction	0/96 (0%)	0	0/93 (0%)	0	1/96 (1%)	1
Cholecystitis	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Immune system disorders
Anaphylactic shock	0/96 (0%)	0	1/93 (1.1%)	1	0/96 (0%)	0
Drug hypersensitivity	0/96 (0%)	0	1/93 (1.1%)	1	0/96 (0%)	0
Hypersensitivity	0/96 (0%)	0	1/93 (1.1%)	1	0/96 (0%)	0
Infusion related reaction	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Urticaria	1/96 (1%)	1	0/93 (0%)	0	1/96 (1%)	1
Infections and infestations
Cellulitis	1/96 (1%)	1	1/93 (1.1%)	1	0/96 (0%)	0
Corona virus infection	0/96 (0%)	0	1/93 (1.1%)	1	0/96 (0%)	0
Device related infection	2/96 (2.1%)	2	0/93 (0%)	0	0/96 (0%)	0
Diverticulitis	1/96 (1%)	1	0/93 (0%)	0	1/96 (1%)	1
Enteritis infectious	0/96 (0%)	0	0/93 (0%)	0	1/96 (1%)	1
Nasopharyngitis	1/96 (1%)	1	1/93 (1.1%)	1	0/96 (0%)	0
Necrotising fasciitis	1/96 (1%)	3	0/93 (0%)	0	0/96 (0%)	0
Neutropenic infection	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Peritonitis	1/96 (1%)	1	0/93 (0%)	0	2/96 (2.1%)	2
Pneumonia	1/96 (1%)	1	1/93 (1.1%)	1	0/96 (0%)	0
Pyelonephritis	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Sepsis	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Wound infection	0/96 (0%)	0	1/93 (1.1%)	1	0/96 (0%)	0
Injury, poisoning and procedural complications
Fall	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Femoral neck fracture	0/96 (0%)	0	0/93 (0%)	0	1/96 (1%)	1
Femur fracture	0/96 (0%)	0	0/93 (0%)	0	1/96 (1%)	1
Toxicity to various agents	0/96 (0%)	0	0/93 (0%)	0	1/96 (1%)	1
Urinary tract stoma complication	0/96 (0%)	0	1/93 (1.1%)	1	0/96 (0%)	0
Wound dehiscence	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Wound haemorrhage	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Investigations
Alanine aminotransferase increased	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Blood bilirubin increased	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Metabolism and nutrition disorders
Cachexia	0/96 (0%)	0	1/93 (1.1%)	1	0/96 (0%)	0
Dehydration	1/96 (1%)	1	1/93 (1.1%)	1	1/96 (1%)	1
Hyperkalaemia	0/96 (0%)	0	0/93 (0%)	0	1/96 (1%)	2
Hypokalaemia	0/96 (0%)	0	3/93 (3.2%)	3	0/96 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/96 (0%)	0	0/93 (0%)	0	1/96 (1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to spine	0/96 (0%)	0	0/93 (0%)	0	1/96 (1%)	1
Tumour perforation	0/96 (0%)	0	0/93 (0%)	0	1/96 (1%)	1
Nervous system disorders
Altered state of consciousness	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Cerebral infarction	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Presyncope	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Syncope	0/96 (0%)	0	0/93 (0%)	0	1/96 (1%)	1
Psychiatric disorders
Completed suicide	0/96 (0%)	0	0/93 (0%)	0	1/96 (1%)	1
Renal and urinary disorders
Renal failure	0/96 (0%)	0	0/93 (0%)	0	2/96 (2.1%)	3
Reproductive system and breast disorders
Ovarian vein thrombosis	0/96 (0%)	0	1/93 (1.1%)	1	0/96 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonitis	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Pulmonary artery thrombosis	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Pulmonary embolism	0/96 (0%)	0	3/93 (3.2%)	3	0/96 (0%)	0
Respiratory distress	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Vascular disorders
Embolism	0/96 (0%)	0	0/93 (0%)	0	1/96 (1%)	1
Hypertension	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Hypotension	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Thrombosis	1/96 (1%)	1	0/93 (0%)	0	0/96 (0%)	0
Other (Not Including Serious) Adverse Events
	PledOx (2 µmol/kg)		PledOx (5 µmol/kg)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	93/96 (96.9%)		91/93 (97.8%)		95/96 (99%)
Blood and lymphatic system disorders
Anaemia	11/96 (11.5%)	17	8/93 (8.6%)	15	14/96 (14.6%)	23
Leukopenia	12/96 (12.5%)	29	10/93 (10.8%)	22	14/96 (14.6%)	26
Neutropenia	40/96 (41.7%)	91	48/93 (51.6%)	97	37/96 (38.5%)	90
Thrombocytopenia	12/96 (12.5%)	26	16/93 (17.2%)	28	16/96 (16.7%)	36
Gastrointestinal disorders
Abdominal pain	16/96 (16.7%)	21	14/93 (15.1%)	21	16/96 (16.7%)	18
Abdominal pain upper	5/96 (5.2%)	5	4/93 (4.3%)	5	5/96 (5.2%)	6
Constipation	24/96 (25%)	26	15/93 (16.1%)	17	14/96 (14.6%)	19
Diarrhoea	32/96 (33.3%)	56	27/93 (29%)	27	41/96 (42.7%)	68
Dyspesia	8/96 (8.3%)	10	6/93 (6.5%)	7	4/96 (4.2%)	4
Nausea	34/96 (35.4%)	67	42/93 (45.2%)	69	47/96 (49%)	82
Stomatitis	29/96 (30.2%)	39	24/93 (25.8%)	41	29/96 (30.2%)	43
Vomiting	11/96 (11.5%)	24	16/93 (17.2%)	32	20/96 (20.8%)	30
General disorders
Asthenia	14/96 (14.6%)	23	17/93 (18.3%)	47	21/96 (21.9%)	41
Fatigue	25/96 (26%)	38	23/93 (24.7%)	33	23/96 (24%)	35
Malaise	6/96 (6.3%)	6	4/93 (4.3%)	5	9/96 (9.4%)	10
Oedema peripheral	6/96 (6.3%)	8	3/93 (3.2%)	3	4/96 (4.2%)	5
Pyrexia	12/96 (12.5%)	15	8/93 (8.6%)	11	9/96 (9.4%)	10
Immune system disorders
Drug hypersensitivity	5/96 (5.2%)	6	2/93 (2.2%)	2	5/96 (5.2%)	5
Infections and infestations
Nasopharyngitis	4/96 (4.2%)	5	4/93 (4.3%)	5	5/96 (5.2%)	5
Paronychia	2/96 (2.1%)	3	7/93 (7.5%)	8	8/96 (8.3%)	9
Investigations
Alanine aminotransferase increased	5/96 (5.2%)	5	7/93 (7.5%)	8	8/96 (8.3%)	16
Aspartate aminotransferase increased	6/96 (6.3%)	7	7/93 (7.5%)	8	7/96 (7.3%)	16
Weight decreased	10/96 (10.4%)	12	4/93 (4.3%)	4	4/96 (4.2%)	6
Metabolism and nutrition disorders
Decreased appetite	30/96 (31.3%)	47	26/93 (28%)	33	27/96 (28.1%)	42
Hypoalbuminaemia	5/96 (5.2%)	6	1/93 (1.1%)	3	2/96 (2.1%)	3
Hypokalaemia	3/96 (3.1%)	5	7/93 (7.5%)	11	9/96 (9.4%)	17
Hypomagnesaemia	5/96 (5.2%)	5	7/93 (7.5%)	8	5/96 (5.2%)	7
Musculoskeletal and connective tissue disorders
Arthralgia	5/96 (5.2%)	5	4/93 (4.3%)	5	6/96 (6.3%)	8
Muscle spasms	1/96 (1%)	1	6/93 (6.5%)	9	4/96 (4.2%)	4
Myalgia	3/96 (3.1%)	3	2/93 (2.2%)	2	10/96 (10.4%)	13
Nervous system disorders
Dizziness	0/96 (0%)	0	5/93 (5.4%)	5	6/96 (6.3%)	8
Dysgeusia	16/96 (16.7%)	18	20/93 (21.5%)	23	21/96 (21.9%)	24
Headache	7/96 (7.3%)	10	7/93 (7.5%)	7	5/96 (5.2%)	6
Neuropathy peripheral	32/96 (33.3%)	89	33/93 (35.5%)	84	36/96 (37.5%)	74
Paraesthesia	17/96 (17.7%)	26	15/93 (16.1%)	25	18/96 (18.8%)	35
Peripheral sensory neuropathy	42/96 (43.8%)	86	40/93 (43%)	79	42/96 (43.8%)	97
Psychiatric disorders
Insomnia	5/96 (5.2%)	5	3/93 (3.2%)	3	5/96 (5.2%)	5
Renal and urinary disorders
Proteinuria	5/96 (5.2%)	6	1/93 (1.1%)	1	2/96 (2.1%)	2
Respiratory, thoracic and mediastinal disorders
Cough	4/96 (4.2%)	4	6/93 (6.5%)	7	6/96 (6.3%)	6
Dyspnoea	3/96 (3.1%)	3	4/93 (4.3%)	4	5/96 (5.2%)	6
Epistaxis	13/96 (13.5%)	18	14/93 (15.1%)	15	9/96 (9.4%)	13
Hiccups	4/96 (4.2%)	10	3/93 (3.2%)	6	5/96 (5.2%)	6
Oropharyngeal pain	2/96 (2.1%)	3	5/93 (5.4%)	5	2/96 (2.1%)	2
Skin and subcutaneous tissue disorders
Alopecia	9/96 (9.4%)	9	11/93 (11.8%)	14	13/96 (13.5%)	13
Dermatitis acneiform	9/96 (9.4%)	15	7/93 (7.5%)	8	10/96 (10.4%)	18
Dry skin	9/96 (9.4%)	9	11/93 (11.8%)	11	4/96 (4.2%)	7
Palmar-plantar erythrodysaesthesia syndrome	7/96 (7.3%)	10	4/93 (4.3%)	6	6/96 (6.3%)	6
Rash	6/96 (6.3%)	13	19/93 (20.4%)	30	14/96 (14.6%)	18
Skin fissures	1/96 (1%)	2	5/93 (5.4%)	7	1/96 (1%)	1
Vascular disorders
Hypertension	12/96 (12.5%)	12	11/93 (11.8%)	16	12/96 (12.5%)	16

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.