Lidocaine for Oxaliplatin-induced Neuropathy

Sponsor
Washington University School of Medicine (Other)
Overall Status
Completed
CT.gov ID
NCT03254394
Collaborator
(none)
26
1
2
42.5
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
  • 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)

    More Information

    Publications

    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
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    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.

    Results Point of Contact

    Name/Title Simon Haroutounian, PhD. Associate Professor
    Organization Washington University in St Louis
    Phone 3132861715
    Email sharout@wustl.edu
    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