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Lidocaine for Oxaliplatin-induced Neuropathy

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ClinicalTrials.gov Identifier: NCT03254394
Recruitment Status : Recruiting
First Posted : August 18, 2017
Last Update Posted : January 15, 2019
Sponsor:
Information provided by (Responsible Party):
simon.haroutounian, Washington University School of Medicine

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 38 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Tolerability 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 : September 15, 2017
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : June 1, 2021


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 Name: 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 Name: mFOLFOX6




Primary Outcome Measures :
  1. Intensity of oxaliplatin-induced cold hypersensitivity [ Time Frame: 12 weeks ]
    The intensity of cold hypersensitivity, assessed on a 0-10 scale, upon holding a pre--cooled (~8°C) metal cylinder, will serve as primary outcome measure. Comparison between intervention (lidocaine) and placebo after 6 cycles of oxaliplatin.


Secondary Outcome Measures :
  1. CIPN score on EORTC QLQ-CIPN20 [ Time Frame: 12 weeks and 34-36 weeks ]
    Change in CIPN score (on EORTC QLQ-CIPN20 tool ) over time until last follow-up

  2. Changes in NPSI. [ Time Frame: 6 weeks, 12 weeks, 34-36 weeks ]
    Changes in NPSI descriptors of neuropathic pain over time from baseline to last follow-up.

  3. The cumulative dose of oxaliplatin [ Time Frame: 24 weeks ]
    The cumulative dose of oxaliplatin received over the course (up to 12 cycles) of mFOLFOX6.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03254394


Contacts
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Contact: Simon Haroutounian, PhD 314 286 1715 haroutos@anest.wustl.edu
Contact: Karen Frey, BS 314 454 5980 freyk@anest.wustl.edu

Locations
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United States, Missouri
Washington University School of Medicine/Barnes Jewish Hospital Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Karen Frey, BS    314-454-5980    freyk@anest.wustl.edu   
Principal Investigator: Simon Haroutounian, PhD         
Sub-Investigator: Mathias Leinders, PhD         
Sponsors and Collaborators
Washington University School of Medicine
Investigators
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Principal Investigator: Simon Haroutounian, PhD Washington University School of Medicine

Publications of Results:
Other Publications:
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Responsible Party: simon.haroutounian, Assistant Professor of Anesthesiology, Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT03254394     History of Changes
Other Study ID Numbers: 201705166
First Posted: August 18, 2017    Key Record Dates
Last Update Posted: January 15, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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, Washington University School of Medicine:
Oxaliplatin
Cold hypersensitivity
Neuropathy
Colorectal cancer
CIPN
Neuropathic Pain
Additional relevant MeSH terms:
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Neuromuscular Diseases
Lidocaine
Colorectal Neoplasms
Peripheral Nervous System Diseases
Pain
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Nervous System Diseases
Neurologic Manifestations
Signs and Symptoms
Oxaliplatin
Anesthetics, Local
Anesthetics
Central Nervous System Depressants
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents
Anti-Arrhythmia Agents
Voltage-Gated Sodium Channel Blockers
Sodium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action