Chemotherapy-induced Peripheral Neuropathy, Colorectal Cancer, Neuropathy, Painful
Conditions
Keywords
Oxaliplatin, Cold hypersensitivity, Neuropathy, Colorectal cancer, CIPN, Neuropathic Pain
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.
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.
Interventions
DRUGLidocaine 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.
DRUGPlacebo
Dextrose 5% in water will be administered as active comparator.
DRUGFOLFOX 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.
Sponsors
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, 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.
Intervention model description
Tolerability phase: prospective, open-label Efficacy pilot study: randomized, parallel, double blind, placebo controlled
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
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. | 12 |
| 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.
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. | 14 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Lidocaine + FOLFOX | Total | Placebo + FOLFOX |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 6 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 20 Participants | 10 Participants |
| Age, Continuous | 50.9 years STANDARD_DEVIATION 13.2 | 51.5 years STANDARD_DEVIATION 14.5 | 52.3 years STANDARD_DEVIATION 16.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 25 Participants | 12 Participants |
| Region of Enrollment United States | 14 participants | 26 participants | 12 participants |
| Sex: Female, Male Female | 11 Participants | 17 Participants | 6 Participants |
| Sex: Female, Male Male | 3 Participants | 9 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 14 |
| other Total, other adverse events | 6 / 12 | 12 / 14 |
| serious Total, serious adverse events | 0 / 12 | 0 / 14 |
Outcome results
Primary
Area Under the Curve (AUC) of Intensity of Oxaliplatin-induced Cold Pain/Unpleasantness vs Time
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
Population: data for 14 days following the 6th cycle was collected and analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo + FOLFOX | Area Under the Curve (AUC) of Intensity of Oxaliplatin-induced Cold Pain/Unpleasantness vs Time | pain AUC | 16.4 score on a scale*days | Standard Deviation 18.3 |
| Placebo + FOLFOX | Area Under the Curve (AUC) of Intensity of Oxaliplatin-induced Cold Pain/Unpleasantness vs Time | unpleasantness AUC | 33.1 score on a scale*days | Standard Deviation 27.8 |
| Lidocaine + FOLFOX | Area Under the Curve (AUC) of Intensity of Oxaliplatin-induced Cold Pain/Unpleasantness vs Time | pain AUC | 9.5 score on a scale*days | Standard Deviation 14.4 |
| Lidocaine + FOLFOX | Area Under the Curve (AUC) of Intensity of Oxaliplatin-induced Cold Pain/Unpleasantness vs Time | unpleasantness AUC | 25.4 score on a scale*days | Standard Deviation 22.6 |
Comparison: 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 patientp-value: 0.31895% CI: [-7.09, 20.85]t-test, 2 sided
Comparison: 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.p-value: 0.46695% CI: [-13.76, 29.1]t-test, 2 sided
Secondary
Changes in NPSI Score.
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
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo + FOLFOX | Changes in NPSI Score. | 6 weeks visit | 0 score on a scale |
| Placebo + FOLFOX | Changes in NPSI Score. | 12 weeks visit | 0 score on a scale |
| Placebo + FOLFOX | Changes in NPSI Score. | last follow-up visit | 3.0 score on a scale |
| Lidocaine + FOLFOX | Changes in NPSI Score. | 6 weeks visit | 0 score on a scale |
| Lidocaine + FOLFOX | Changes in NPSI Score. | 12 weeks visit | 0 score on a scale |
| Lidocaine + FOLFOX | Changes in NPSI Score. | last follow-up visit | 13.5 score on a scale |
Comparison: 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.p-value: 0.581Wilcoxon (Mann-Whitney)
Comparison: 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.p-value: 0.962Wilcoxon (Mann-Whitney)
Comparison: 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.p-value: 0.365Wilcoxon (Mann-Whitney)
Secondary
CIPN Score on EORTC QLQ-CIPN20
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
Population: Patients in each group who had corresponding visit data
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo + FOLFOX | CIPN Score on EORTC QLQ-CIPN20 | 12 | 2 score on a scale |
| Placebo + FOLFOX | CIPN Score on EORTC QLQ-CIPN20 | 34-36 weeks | 17.0 score on a scale |
| Lidocaine + FOLFOX | CIPN Score on EORTC QLQ-CIPN20 | 12 | 4 score on a scale |
| Lidocaine + FOLFOX | CIPN Score on EORTC QLQ-CIPN20 | 34-36 weeks | 37.0 score on a scale |
Comparison: 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.p-value: 0.338Wilcoxon (Mann-Whitney)
Comparison: 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.p-value: 0.759Wilcoxon (Mann-Whitney)
Secondary
The Cumulative Dose of Oxaliplatin
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + FOLFOX | The Cumulative Dose of Oxaliplatin | 1161.8 mg | Standard Deviation 300.2 |
| Lidocaine + FOLFOX | The Cumulative Dose of Oxaliplatin | 1294.8 mg | Standard Deviation 221.6 |
Comparison: The null hypothesis is Oxaliplatin cumulative dose in the Control group is equal to or higher than that of the experimental group.p-value: 0.7395% CI: [-1771, 1886]t-test, 2 sided