Lidocaine for Oxaliplatin-induced Neuropathy

Colorectal Cancer Clinical Trial

Official title:

Intravenous Lidocaine for Preventing Painful Oxaliplatin-induced Peripheral Neuropathy (OIPN)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03254394
• Other study ID #: 201705166
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: September 15, 2017
• Est. completion date: April 1, 2021

Study information

• Verified date: February 2022
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 26
• Est. completion date: April 1, 2021
• Est. primary completion date: September 28, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Chemotherapy-induced Peripheral Neuropathy
• Colorectal Cancer
• Colorectal Neoplasms
• Neuropathy, Painful
• Pain
• Peripheral Nervous System Diseases

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	Washington University School of Medicine/Barnes Jewish Hospital	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Washington University School of Medicine

Country where clinical trial is conducted

United States, 

References & Publications (4)

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. — View Citation

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. — View Citation

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. — View Citation

Ventzel L, Madsen CS, Jensen AB, Jensen AR, Jensen TS, Finnerup NB. Assessment of acute oxaliplatin-induced cold allodynia: a pilot study. Acta Neurol Scand. 2016 Feb;133(2):152-155. doi: 10.1111/ane.12443. Epub 2015 Jun 2. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	14 weeks
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.	12 weeks and 34-36 weeks
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.	6 weeks, 12 weeks, 34-36 weeks
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.	24 weeks