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

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

Population: 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.

Mean cumulative dose of oxaliplatin administered per patient during mFOLFOX6 chemotherapy, 9 months after the first dose of IMP.

Time frame: 9 months

Population: 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.

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

Population: 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.

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

Population: 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.

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

Population: 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

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

Population: 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.

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

Population: 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.

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

Population: 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.

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

Population: 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.

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

Population: 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.