Lidocaine for Oxaliplatin-induced Neuropathy

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Completed
• CT.gov ID: NCT03254394
• Collaborator: (none)
• Enrollment: 26
• Location: 1
• Arms: 2
• Actual Duration (Months): 42.5
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

Oxaliplatin-induced neuropathy is a major dose-limiting side effect in patients with colorectal cancer treated with the FOLFOX chemotherapy regimen. Hypersensitivity to cold is the sensory hallmark of oxaliplatin-induced neuropathy, and it can predict the development of long-term neuropathy. In this study, the investigators aim to determine whether intravenous lidocaine can prevent oxaliplatin-induced cold hypersensitivity.

Condition or Disease	Intervention/Treatment	Phase
Neuropathy, Painful; Chemotherapy-induced Peripheral Neuropathy; Colorectal Cancer	Drug: Lidocaine Hydrochloride; Drug: Placebo; Drug: FOLFOX regimen	Phase 1/Phase 2

Detailed Description

Colorectal cancer is the third leading cause of cancer death in the United States, with an estimated incidence of 130.000 cases per year. Oxaliplatin is the first-line chemotherapy regimen for gastro-intestinal cancers. Despite its efficacy, oxaliplatin causes peripheral neuropathy in 72% of the treated patients. Acute oxaliplatin-induced peripheral neuropathy [OIPN] is the most common dose-limiting side effect of oxaliplatin and characterized by profound cold allodynia in the extremities. In about 21% of the patients acute OIPN exacerbates into chronic neuropathic pain, which is treatment resistant to currently approved drugs, pointing towards a great need to identify an effective strategy in preventing OIPN. Recent literature suggests that certain methods of assessing sensory nerve function in neuropathic pain patients may provide a prediction to an individual analgesic response; however, no placebo-controlled studies have been performed with the primary goal of identifying treatment response predictors in preventing OIPN.

In this pilot study we will both determine the tolerability and the efficacy of intravenous Lidocaine, for preventing oxaliplatin-induced cold hypersensitivity in the setting of mFOLFOX6 chemotherapy for advanced colorectal cancer.

The proposed study will be conducted in two phases. The tolerability phase is an open-label study to determine the tolerable dose regimen of IV lidocaine in patients with advanced colorectal cancer receiving oxaliplatin chemotherapy. The efficacy pilot phase is a randomized, double-blinded, controlled study comparing the outcomes between IV lidocaine versus placebo in the same setting of colorectal cancer. Consented subjects will attend a screening visit and six intervention visits, during which they will undergo sensory testing and receive intravenous lidocaine or placebo infusion. Cold hypersensitivity and spontaneous pain will be assessed at baseline, daily for 12 weeks and at follow-up visits. At enrollment, each patient will be assigned a study number, which will match a previously prepared computer-generated list of randomization numbers to determine the interventions lidocaine or placebo. The participants and all other study personnel will be blinded to the treatment allocation.

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Tolerability phase: prospective, open-label Efficacy pilot study: randomized, parallel, double blind, placebo controlledTolerability phase: prospective, open-label Efficacy pilot study: randomized, parallel, double blind, placebo controlled
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: At enrollment, each patient will be assigned a study number, which will match a previously prepared computer-generated list of randomization numbers to determine the interventions. The participants and all other study personnel will be blinded to the treatment allocation.
• Primary Purpose: Prevention
• Official Title: Intravenous Lidocaine for Preventing Painful Oxaliplatin-induced Peripheral Neuropathy (OIPN)
• Actual Study Start Date: Sep 15, 2017
• Actual Primary Completion Date: Sep 28, 2020
• Actual Study Completion Date: Apr 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo + FOLFOX Intravenous infusion of D5W solution over a 130 minute period. FOLFOX: Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.	Drug: Placebo; Dextrose 5% in water will be administered as active comparator.; Drug: FOLFOX regimen; Each cycle (repeated every 14 days): Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.; Other Names: mFOLFOX6
Active Comparator: Lidocaine + FOLFOX Intravenous infusion of lidocaine hydrochloride solution in D5W over a 130 minute period. FOLFOX: Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.	Drug: Lidocaine Hydrochloride; Intravenous lidocaine will be dosed as a brief 1 mg/kg infusion (based on Ideal Body Weight (IBW)) over 10 minutes, followed by a 0.04 mg/kg/min infusion over additional 120 minutes, resulting in a total dose of 5.8 mg/kg IBW. If this dose is tolerable in four consecutive sessions of mFOLFOX6 in six or more of the eight patients in the tolerability phase, we will initiate the randomized efficacy pilot study.; Drug: FOLFOX regimen; Each cycle (repeated every 14 days): Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.; Other Names: mFOLFOX6

Outcome Measures

Primary Outcome Measures

1. Area Under the Curve (AUC) of Intensity of Oxaliplatin-induced Cold Pain/Unpleasantness vs Time [14 weeks]

   The intensity of cold pain and cold unpleasantness is evaluated separately, assessed daily on a 0-10 scale, upon holding a pre-cooled (~8°C) metal cylinder for 10 seconds. the area under the curve of cold pain and cold unpleasantness vs time is calculated per chemotherapy cycle (every two weeks) and serves as a primary outcome measure. For intervention (lidocaine+FOLFOX) and control (placebo+FOLFOX) groups, the average of cold pain AUC and cold unpleasantness AUC over 7 cycles was calculated. The average AUCs over 7 cycles were compared between study arms. The AUC is measured as a score on a 0-10 scale multiplied by 14 days and may range between 0 and 140. Higher AUC values represent more intense cold pain/unpleasantness.

Secondary Outcome Measures

1. CIPN Score on EORTC QLQ-CIPN20 [12 weeks and 34-36 weeks]

   Change in CIPN (Chemotherapy-induced peripheral Neuropathy) score (on EORTC QLQ-CIPN20 tool ) from baseline to the Cycle 6 (12 weeks), and from baseline to last follow-up (34-36 weeks). EORTC QLQ-CIPN20 ranges from 0 (no symptoms) to 100 (worst symptoms). A higher score represents worse neuropathy. The changes in scores are compared between study arms. EORTC QLQ-CIPN20 tool is a quality of life questionnaire (QLQ) from the European Organization for Research and Treatment of Cancer (EORTC) for evaluation of CIPN.

2. Changes in NPSI Score. [6 weeks, 12 weeks, 34-36 weeks]

   Changes in Neuropathic Pain Symptom Inventory (NPSI) descriptors of neuropathic pain over time from baseline to cycle 3(6 weeks), cycle 6 (12 weeks), and the last follow-up (34-36 weeks). The total NPSI score ranges from 0 to 100; a higher NPSI total score represents a worse neuropathy outcome. The changes in scores from baseline are compared between study arms.

3. The Cumulative Dose of Oxaliplatin [24 weeks]

   The cumulative dose of oxaliplatin received over the course (up to 12 cycles) of mFOLFOX6 treatment regimen. It corresponds to the absolute summed up quantity of Oxaliplatin administered to the patient over time. There is no range for this measure. Since this is a dose-limiting neuropathy prevention study, the higher value can be interpreted as better outcome.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Stage III and IV colorectal cancer.

• Scheduled for oxaliplatin treatment in mFOLFOX6-based chemotherapy regimen.

• Able to understand and willing to sign an IRB-approved written informed consent document.

Exclusion Criteria:

• Renal insufficiency (defined as calculated Creatinine clearance < 30mL/min)

• Moderate to severe liver failure (defined as ALT or AST > 3 times upper limit of normal if no liver metastases are present; ALT or AST > 5 times upper limit of normal if liver metastases are present).

• Presence of brain metastases.

• Patients with currently uncontrolled cardiac arrhythmias (non-sinus rhythm).

• Patients with history of arrhythmias under pharmacological/pacemaker control will be allowed, except if receiving antiarrhythmic medication listed in "contra-indicated medications".

• Contraindication or allergy to intravenous lidocaine.

• Pre-existing symmetric peripheral painful neuropathy.

• Treated with chemotherapy within the past 12 months.

• Pregnancy or breastfeeding

• Currently treated with any of the following contraindicated medications: Saquinavir, Lopinavir, Amprenavir, Atazanavir, Delavirdine, Mexiletine (and other types of sodium-channel blocker antiarrhythmics), Phenytoin, Carbamazepine, Oxcarbazepine, Lamotrigine, Amiodarone, Dronedarone, Dihydroergotamine, Cimetidine

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington University School of Medicine/Barnes Jewish Hospital	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Washington University School of Medicine

Investigators

• Principal Investigator: Simon Haroutounian, PhD, Washington University School of Medicine

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 12, 2021

More Information

Publications

• Attal N, Gaudé V, Brasseur L, Dupuy M, Guirimand F, Parker F, Bouhassira D. Intravenous lidocaine in central pain: a double-blind, placebo-controlled, psychophysical study. Neurology. 2000 Feb 8;54(3):564-74.
• Attal N, Rouaud J, Brasseur L, Chauvin M, Bouhassira D. Systemic lidocaine in pain due to peripheral nerve injury and predictors of response. Neurology. 2004 Jan 27;62(2):218-25.
• Seretny M, Currie GL, Sena ES, Ramnarine S, Grant R, MacLeod MR, Colvin LA, Fallon M. Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis. Pain. 2014 Dec;155(12):2461-2470. doi: 10.1016/j.pain.2014.09.020. Epub 2014 Sep 23. Review.

• Responsible Party: simon.haroutounian, Assistant Professor of Anesthesiology, Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT03254394
• Other Study ID Numbers: 201705166
• First Posted: Aug 18, 2017
• Last Update Posted: Mar 9, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by simon.haroutounian, Assistant Professor of Anesthesiology, Washington University School of Medicine: Oxaliplatin; Cold hypersensitivity; Neuropathy; Colorectal cancer; CIPN; Neuropathic Pain
• Additional relevant MeSH terms: Colorectal Neoplasms; Peripheral Nervous System Diseases; Pain; Lidocaine

Study Results

Participant Flow

Arm/Group Title	Placebo + FOLFOX	Lidocaine + FOLFOX
Arm/Group Description	Intravenous infusion of D5W solution over a 130 minute period. FOLFOX: Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days. Placebo: Dextrose 5% in water will be administered as active comparator. FOLFOX regimen: Each cycle (repeated every 14 days): Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.	Intravenous infusion of lidocaine hydrochloride solution in D5W over a 130 minute period. FOLFOX: Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days. Lidocaine Hydrochloride: Intravenous lidocaine will be dosed as a brief 1 mg/kg infusion (based on Ideal Body Weight (IBW)) over 10 minutes, followed by a 0.04 mg/kg/min infusion over additional 120 minutes, resulting in a total dose of 5.8 mg/kg IBW. If this dose is tolerable in four consecutive sessions of mFOLFOX6 in six or more of the eight patients in the tolerability phase, we will initiate the randomized efficacy pilot study. FOLFOX regimen: Each cycle (repeated every 14 days): Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.
Period Title: Overall Study
STARTED	12	14
COMPLETED	12	12
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	Placebo + FOLFOX	Lidocaine + FOLFOX	Total
Arm/Group Description	Intravenous infusion of D5W solution over a 130 minute period. FOLFOX: Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days. Placebo: Dextrose 5% in water will be administered as active comparator. FOLFOX regimen: Each cycle (repeated every 14 days): Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.	Intravenous infusion of lidocaine hydrochloride solution in D5W over a 130 minute period. FOLFOX: Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days. Lidocaine Hydrochloride: Intravenous lidocaine will be dosed as a brief 1 mg/kg infusion (based on Ideal Body Weight (IBW)) over 10 minutes, followed by a 0.04 mg/kg/min infusion over additional 120 minutes, resulting in a total dose of 5.8 mg/kg IBW. If this dose is tolerable in four consecutive sessions of mFOLFOX6 in six or more of the eight patients in the tolerability phase, we will initiate the randomized efficacy pilot study. FOLFOX regimen: Each cycle (repeated every 14 days): Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.	Total of all reporting groups
Overall Participants	12	14	26
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	10 83.3%	10 71.4%	20 76.9%
>=65 years	2 16.7%	4 28.6%	6 23.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.3 (16.4)	50.9 (13.2)	51.5 (14.5)
Sex: Female, Male (Count of Participants)
Female	6 50%	11 78.6%	17 65.4%
Male	6 50%	3 21.4%	9 34.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 7.1%	1 3.8%
White	12 100%	13 92.9%	25 96.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	12 100%	14 100%	26 100%

Outcome Measures

1. Primary Outcome

Title	Area Under the Curve (AUC) of Intensity of Oxaliplatin-induced Cold Pain/Unpleasantness vs Time
Description	The intensity of cold pain and cold unpleasantness is evaluated separately, assessed daily on a 0-10 scale, upon holding a pre-cooled (~8°C) metal cylinder for 10 seconds. the area under the curve of cold pain and cold unpleasantness vs time is calculated per chemotherapy cycle (every two weeks) and serves as a primary outcome measure. For intervention (lidocaine+FOLFOX) and control (placebo+FOLFOX) groups, the average of cold pain AUC and cold unpleasantness AUC over 7 cycles was calculated. The average AUCs over 7 cycles were compared between study arms. The AUC is measured as a score on a 0-10 scale multiplied by 14 days and may range between 0 and 140. Higher AUC values represent more intense cold pain/unpleasantness.
Time Frame	14 weeks

Outcome Measure Data

Analysis Population Description

data for 14 days following the 6th cycle was collected and analyzed.

Arm/Group Title	Placebo + FOLFOX	Lidocaine + FOLFOX
Arm/Group Description	Intravenous infusion of D5W solution over a 130 minute period. FOLFOX: Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days. Placebo: Dextrose 5% in water will be administered as active comparator. FOLFOX regimen: Each cycle (repeated every 14 days): Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.	Intravenous infusion of lidocaine hydrochloride solution in D5W over a 130 minute period. FOLFOX: Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days. Lidocaine Hydrochloride: Intravenous lidocaine will be dosed as a brief 1 mg/kg infusion (based on Ideal Body Weight (IBW)) over 10 minutes, followed by a 0.04 mg/kg/min infusion over additional 120 minutes, resulting in a total dose of 5.8 mg/kg IBW. If this dose is tolerable in four consecutive sessions of mFOLFOX6 in six or more of the eight patients in the tolerability phase, we will initiate the randomized efficacy pilot study. FOLFOX regimen: Each cycle (repeated every 14 days): Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.
Measure Participants	12	12
pain AUC	16.4 (18.3)	9.5 (14.4)
unpleasantness AUC	33.1 (27.8)	25.4 (22.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + FOLFOX, Lidocaine + FOLFOX
	Comments	Null hypothesis: Average AUC of cold pain score over 14 days of a chemotherapy cycle in the Control group is equal or lower than that of the experimental group. The comparison is for average AUC values over 7 cycles of chemotherapy per patient
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.318
	Comments	p-value was not adjusted for any parameter.
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.88
	Confidence Interval	(2-Sided) 95%; -7.09 to 20.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + FOLFOX, Lidocaine + FOLFOX
	Comments	Null hypothesis: Cold hypersensitivity counted as unpleasantness score for 14 days after cycle (AUC) in the Control group is less than that of the experimental group. The difference was calculated for the Cycle 6 visit.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.466
	Comments	p-value was not adjusted for any parameter.
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.67
	Confidence Interval	(2-Sided) 95%; -13.76 to 29.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	CIPN Score on EORTC QLQ-CIPN20
Description	Change in CIPN (Chemotherapy-induced peripheral Neuropathy) score (on EORTC QLQ-CIPN20 tool ) from baseline to the Cycle 6 (12 weeks), and from baseline to last follow-up (34-36 weeks). EORTC QLQ-CIPN20 ranges from 0 (no symptoms) to 100 (worst symptoms). A higher score represents worse neuropathy. The changes in scores are compared between study arms. EORTC QLQ-CIPN20 tool is a quality of life questionnaire (QLQ) from the European Organization for Research and Treatment of Cancer (EORTC) for evaluation of CIPN.
Time Frame	12 weeks and 34-36 weeks

Outcome Measure Data

Analysis Population Description

Patients in each group who had corresponding visit data

Arm/Group Title	Placebo + FOLFOX	Lidocaine + FOLFOX
Arm/Group Description	Intravenous infusion of D5W solution over a 130 minute period. FOLFOX: Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days. Placebo: Dextrose 5% in water will be administered as active comparator. FOLFOX regimen: Each cycle (repeated every 14 days): Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.	Intravenous infusion of lidocaine hydrochloride solution in D5W over a 130 minute period. FOLFOX: Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days. Lidocaine Hydrochloride: Intravenous lidocaine will be dosed as a brief 1 mg/kg infusion (based on Ideal Body Weight (IBW)) over 10 minutes, followed by a 0.04 mg/kg/min infusion over additional 120 minutes, resulting in a total dose of 5.8 mg/kg IBW. If this dose is tolerable in four consecutive sessions of mFOLFOX6 in six or more of the eight patients in the tolerability phase, we will initiate the randomized efficacy pilot study. FOLFOX regimen: Each cycle (repeated every 14 days): Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.
Measure Participants	12	12
12	2	4
34-36 weeks	17.0	37.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + FOLFOX, Lidocaine + FOLFOX
	Comments	the null hypothesis is EORTC QLQ-CIPN20 sensory score change in the Control group is equal to or less than that of the experimental group for the last follow-up study visit.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.338
	Comments	p-value was not adjusted for any parameter.
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	20
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + FOLFOX, Lidocaine + FOLFOX
	Comments	The null hypothesis is EORTC QLQ-CIPN20 sensory score change in the Control group is equal to or less than that of the experimental group for the cycle 6 (12 weeks) follow-up study visit.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.759
	Comments	p-value was not adjusted for any parameter.
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	2
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Changes in NPSI Score.
Description	Changes in Neuropathic Pain Symptom Inventory (NPSI) descriptors of neuropathic pain over time from baseline to cycle 3(6 weeks), cycle 6 (12 weeks), and the last follow-up (34-36 weeks). The total NPSI score ranges from 0 to 100; a higher NPSI total score represents a worse neuropathy outcome. The changes in scores from baseline are compared between study arms.
Time Frame	6 weeks, 12 weeks, 34-36 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo + FOLFOX	Lidocaine + FOLFOX
Arm/Group Description	Intravenous infusion of D5W solution over a 130 minute period. FOLFOX: Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days. Placebo: Dextrose 5% in water will be administered as active comparator. FOLFOX regimen: Each cycle (repeated every 14 days): Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.	Intravenous infusion of lidocaine hydrochloride solution in D5W over a 130 minute period. FOLFOX: Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days. Lidocaine Hydrochloride: Intravenous lidocaine will be dosed as a brief 1 mg/kg infusion (based on Ideal Body Weight (IBW)) over 10 minutes, followed by a 0.04 mg/kg/min infusion over additional 120 minutes, resulting in a total dose of 5.8 mg/kg IBW. If this dose is tolerable in four consecutive sessions of mFOLFOX6 in six or more of the eight patients in the tolerability phase, we will initiate the randomized efficacy pilot study. FOLFOX regimen: Each cycle (repeated every 14 days): Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.
Measure Participants	12	12
6 weeks visit	0	0
12 weeks visit	0	0
last follow-up visit	3.0	13.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + FOLFOX, Lidocaine + FOLFOX
	Comments	The null hypothesis is NPSI total score in the Control group is equal to or less than that of the experimental group for the C3 (6 weeks) study visit.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.581
	Comments	p-value was not adjusted for any parameter.
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo + FOLFOX, Lidocaine + FOLFOX
	Comments	The null hypothesis is NPSI total score in the Control group is equal to or less than that of the experimental group for the C6 (12 weeks) study visit.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.962
	Comments	p-value was not adjusted for any parameter.
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo + FOLFOX, Lidocaine + FOLFOX
	Comments	The null hypothesis is NPSI total score in the Control group is equal to or less than that of the experimental group for the last follow-up study visit.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.365
	Comments	p-value was not adjusted for any parameter.
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	10.50
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	The Cumulative Dose of Oxaliplatin
Description	The cumulative dose of oxaliplatin received over the course (up to 12 cycles) of mFOLFOX6 treatment regimen. It corresponds to the absolute summed up quantity of Oxaliplatin administered to the patient over time. There is no range for this measure. Since this is a dose-limiting neuropathy prevention study, the higher value can be interpreted as better outcome.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo + FOLFOX	Lidocaine + FOLFOX
Arm/Group Description	Intravenous infusion of D5W solution over a 130 minute period. FOLFOX: Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days. Placebo: Dextrose 5% in water will be administered as active comparator. FOLFOX regimen: Each cycle (repeated every 14 days): Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.	Intravenous infusion of lidocaine hydrochloride solution in D5W over a 130 minute period. FOLFOX: Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days. Lidocaine Hydrochloride: Intravenous lidocaine will be dosed as a brief 1 mg/kg infusion (based on Ideal Body Weight (IBW)) over 10 minutes, followed by a 0.04 mg/kg/min infusion over additional 120 minutes, resulting in a total dose of 5.8 mg/kg IBW. If this dose is tolerable in four consecutive sessions of mFOLFOX6 in six or more of the eight patients in the tolerability phase, we will initiate the randomized efficacy pilot study. FOLFOX regimen: Each cycle (repeated every 14 days): Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.
Measure Participants	12	12
Mean (Standard Deviation) [mg]	1161.8 (300.2)	1294.8 (221.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + FOLFOX, Lidocaine + FOLFOX
	Comments	The null hypothesis is Oxaliplatin cumulative dose in the Control group is equal to or higher than that of the experimental group.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.730
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	57.68
	Confidence Interval	(2-Sided) 95%; -1771 to 1886
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	16 weeks
Adverse Event Reporting Description	Adverse Event: any unfavorable medical occurrence in a human subject including any abnormal sign, symptom, or disease. For the purposes of this protocol, all adverse events will be collected and documented on CRFs by questionnaire.
Arm/Group Title	Placebo + FOLFOX		Lidocaine + FOLFOX
Arm/Group Description	Intravenous infusion of D5W solution over a 130 minute period. FOLFOX: Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days. Placebo: Dextrose 5% in water will be administered as active comparator. FOLFOX regimen: Each cycle (repeated every 14 days): Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.		Intravenous infusion of lidocaine hydrochloride solution in D5W over a 130 minute period. FOLFOX: Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days. Lidocaine Hydrochloride: Intravenous lidocaine will be dosed as a brief 1 mg/kg infusion (based on Ideal Body Weight (IBW)) over 10 minutes, followed by a 0.04 mg/kg/min infusion over additional 120 minutes, resulting in a total dose of 5.8 mg/kg IBW. If this dose is tolerable in four consecutive sessions of mFOLFOX6 in six or more of the eight patients in the tolerability phase, we will initiate the randomized efficacy pilot study. FOLFOX regimen: Each cycle (repeated every 14 days): Oxaliplatin 85mg/m2 IV over 2h, Leucovorin 400 mg/m2 IV over 2h, 5-FU 400mg/m2 IV bolus, followed by a 1200mg/m2/day continuous infusion for 2 days.
All Cause Mortality
	Placebo + FOLFOX		Lidocaine + FOLFOX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/14 (0%)
Serious Adverse Events
	Placebo + FOLFOX		Lidocaine + FOLFOX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	Placebo + FOLFOX		Lidocaine + FOLFOX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/12 (50%)		12/14 (85.7%)
Cardiac disorders
Arrhythmia	2/12 (16.7%)	2	1/14 (7.1%)	1
Eye disorders
Blurred vision	1/12 (8.3%)	1	1/14 (7.1%)	1
Gastrointestinal disorders
Nausea	2/12 (16.7%)	3	6/14 (42.9%)	12
Nervous system disorders
Dizziness	4/12 (33.3%)	14	4/14 (28.6%)	14
Somnolence	0/12 (0%)	0	1/14 (7.1%)	1
Paresthesia	1/12 (8.3%)	1	2/14 (14.3%)	5
Lightheadedness	1/12 (8.3%)	1	2/14 (14.3%)	4
Headache	0/12 (0%)	0	3/14 (21.4%)	3
Skin and subcutaneous tissue disorders
Itching	2/12 (16.7%)	2	1/14 (7.1%)	1

Limitations/Caveats

Due to the COVID-19 pandemic, the study finished earlier than planned. The total number of patients enrolled was 26 instead of 30.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT 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.