Lidocaine Versus Duloxetine for the Prevention of Taxane-Induced Peripheral Neuropathy In Breast Cancer Patients

Breast Cancer Clinical Trial

— TIPN  

Official title:

Intravenous Lidocaine Infusion Versus Oral Duloxetine For The Prevention And Treatment Of Chemotherapy Induced Peripheral Neuropathy Among Breast Cancer Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04732455
• Other study ID #: 1216-4-011
• Status: Completed
• Phase: N/A
• Start date: January 15, 2021
• Est. completion date: July 5, 2022

Study information

• Verified date: July 2022
• Source: Alexandria University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The aim of the study is to evaluate the effect of intravenous (IV) lidocaine versus oral duloxetine on the onset and severity of TIPN in patient with breast cancer as well as evaluation of Patients' quality of life and estimation the cell mediated immunity.

The current study is a single blinded randomized controlled study, assumed that lidocaine could prevent and reduce TIPN similar to duloxetine in patient with breast cancer.

Method of randomization: The allocation sequence was generated using permuted block randomization technique and the block size was variable. Allocation sequence/code was concealed from the person allocating the participants to the intervention arms using sealed opaque envelopes.

Primary outcome: Degree of neuropathic pain measured by neuropathy pain scale (NPS) among breast cancer patients on Taxane chemotherapy after the pretreatment with either lidocaine or duloxetine.

Secondary outcomes are: The incidence of TIPN using DN4 questionnaire and nerve conduction study and Patients' quality of life using The European Organization for Research and Treatment of Cancer (EORTC) QLQ-CIPN20 as well as the Change in serum level natural killer cell to estimate cell mediated immunity.

Description:

Patients' assessment:

• Medical history (Previous diseases and medications)

• Clinical examination and laboratory investigations (according to patient' condition).

• Each patient will be informed with the study, its expected result and its possible side effects. The patients will be trained to use neuropathic pain scale (NPS). Additionally, DN4 questionnaire will be explained to all participants. IV line will be inserted for all participants. Vital signs including heart rate and mean arterial blood pressure will be measured.

The participants will be randomly allocated into three groups as follows:

• Group control (C): 20 adult breast cancer patients on Taxane chemo protocol will receive 200 ml normal saline over forty minutes pre each chemotherapy session until end of the cycle.

• Group lidocaine infusion (L): 20 adult breast cancer patients on Taxane chemo protocol will receive lidocaine IV infusion (2 mg/kg) in 200ml saline over forty minutes with a maximum upper limit of 200 mg pre each chemotherapy session until end of the cycle. If any selected patient reported neuropathic pain (DN4 > 4) during the course of chemotherapy lidocaine (2 mg/kg) re-infused after each session. If lidocaine side effects such as circumoral numbness, twitches, metal test, tachy or bradycardia recorded at any time, lidocaine infusion will be reduced to 1mg/kg, if side effects persist, the patients will be managed accordingly as well as lidocaine infusion will be stopped and patient will be excluded from the study.

• Group duloxetine (D): 20 adult breast cancer patients on chemotherapy will take oral duloxetine tablet 30 mg once per day starting from the night pre chemotherapy session until the end of cycle. If any selected patient reported neuropathic pain (DN4 > 4) during the course of chemotherapy the duloxetine dose will be adjusted to 60 mg daily till the end of the cycle. They also will receive 200 ml normal saline over forty minutes before each chemotherapy session until end of the cycle.

Measurements

Demographic features of the patients

-Age (years), Weight (kg).

Neuropathic pain characters and severity

-Intensity and characters of neuropathic pain will be measured by neuropathic pain scale (0-10cm) after each chemotherapy session which is expected to be one session every week for 12 weeks

Chemotherapy induced peripheral neuropathy

• Nerve conduction study will be performed to detect sensory peripheral neuropathy pre and immediately after the end of chemo protocol cycle.

• Detection of TIPN will be measured using DN4 questionnaire before starting chemotherapy protocol and after each chemotherapy session which is expected to be one session every week for 12 weeks

Patients' quality of life -The European Organization for Research and Treatment of Cancer (EORTC) QLQ-CIPN20 questionnaire for quality of life will be taken from patient before starting chemotherapy protocol ,one month ,two month after the treatment and at the end of treatment .

Cell mediated immunity: Natural killer cell isolation and cytotoxicity assay.

-Sample of 1ml of patients' peripheral blood will be collected on EDTA for flow cytometry to enumerate for both cytotoxic lymphocytes population (NK cells, and cytotoxic lymphocytes (ctls)). CD 56 will be used as a market for NK cells while CD8 will be used as a marker for Ctls. Cytotoxic assay will be done by measuring the release of lactate dehydrogenase (LDH) from non-viable cells (Cytotoxicity Detection kit, 630117; Clontech laboratories, Mountain View, California) according to manufacturer's instructions. Then ratio of LDH released specifically from NK cells will be carried according to the result of flow cytometry . Blood Sample will be collected at the start and the end of chemo protocol cycle of breast cancer patients.

Complications

-Any complications will occur during or after the treatment with lidocaine or duloxetine will be reported and managed accordingly.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: July 5, 2022
• Est. primary completion date: June 8, 2022
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• breast cancer

• at any stage,

• Taxane chemo-protocol.

Exclusion Criteria:

• Documented history of gloves and stock neuropathy.

• Alcohol abuse.

• Abnormal renal or liver function tests.

• Allergy to local anesthetics.

• Myocardial infarction within 6 months

• Profound high-grade arrhythmias.

• Patients with neurological or psychological problems.

• Diabetes Mellitus.

• History of previous chemotherapy treatment

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms
• Chemotherapy-induced Peripheral Neuropathy
• Peripheral Nervous System Diseases
• Peripheral Neuropathy

Intervention

Drug:
• Lidocaine in Saline
Lidocaine IV infusion (2 mg/kg) in 200 ml saline over forty minutes with a maximum upper limit of 200 mg pre each chemotherapy session until end of the cycle.
• Duloxetine 30 MG
Oral Duloxetine tablet 30 mg once per day starting from the night pre chemotherapy during the whole period of chemotherapy cycle which expected to be three month
• Normal saline
200 ml normal saline over forty minutes pre each chemotherapy session until end of the cycle.

Locations

Country	Name	City	State
Egypt	Egypt Medical Research Institute	Alexandria

Sponsors (1)

Lead Sponsor	Collaborator
Gamal Mohamed Taha Abouelmagd

Country where clinical trial is conducted

Egypt, 

References & Publications (27)

Areti A, Yerra VG, Naidu V, Kumar A. Oxidative stress and nerve damage: role in chemotherapy induced peripheral neuropathy. Redox Biol. 2014 Jan 18;2:289-95. doi: 10.1016/j.redox.2014.01.006. eCollection 2014. Review. — View Citation

Argyriou AA, Bruna J, Marmiroli P, Cavaletti G. Chemotherapy-induced peripheral neurotoxicity (CIPN): an update. Crit Rev Oncol Hematol. 2012 Apr;82(1):51-77. doi: 10.1016/j.critrevonc.2011.04.012. Epub 2011 Sep 10. Review. — View Citation

Bril V, England JD, Franklin GM, Backonja M, Cohen JA, Del Toro DR, Feldman EL, Iverson DJ, Perkins B, Russell JW, Zochodne DW; American Academy of Neurology; American Asociation of Neuromuscular and Electrodiagnostic Medicine; American Academy of Physical Medicine and Rehabilitation. Evidence-based guideline: treatment of painful diabetic neuropathy--report of the American Association of Neuromuscular and Electrodiagnostic Medicine, the American Academy of Neurology, and the American Academy of Physical Medicine & Rehabilitation. Muscle Nerve. 2011 Jun;43(6):910-7. doi: 10.1002/mus.22092. Epub 2011 Apr 11. — View Citation

Charan J, Biswas T. How to calculate sample size for different study designs in medical research? Indian J Psychol Med. 2013 Apr;35(2):121-6. doi: 10.4103/0253-7176.116232. Review. — View Citation

Chatila N, Pereira B, Maarrawi J, Dallel R. Validation of a New Arabic Version of the Neuropathic Pain Diagnostic Questionnaire (DN4). Pain Pract. 2017 Jan;17(1):78-87. doi: 10.1111/papr.12419. Epub 2016 Feb 20. — View Citation

DeMarco GJ, Nunamaker EA. A Review of the Effects of Pain and Analgesia on Immune System Function and Inflammation: Relevance for Preclinical Studies. Comp Med. 2019 Dec 1;69(6):520-534. doi: 10.30802/AALAS-CM-19-000041. Epub 2019 Dec 20. Review. — View Citation

Ewertz M, Qvortrup C, Eckhoff L. Chemotherapy-induced peripheral neuropathy in patients treated with taxanes and platinum derivatives. Acta Oncol. 2015 May;54(5):587-91. doi: 10.3109/0284186X.2014.995775. Epub 2015 Mar 9. Review. — View Citation

Fallon MT. Neuropathic pain in cancer. Br J Anaesth. 2013 Jul;111(1):105-11. doi: 10.1093/bja/aet208. Review. — View Citation

Galer BS, Jensen MP. Development and preliminary validation of a pain measure specific to neuropathic pain: the Neuropathic Pain Scale. Neurology. 1997 Feb;48(2):332-8. — View Citation

Hershman DL, Lacchetti C, Dworkin RH, Lavoie Smith EM, Bleeker J, Cavaletti G, Chauhan C, Gavin P, Lavino A, Lustberg MB, Paice J, Schneider B, Smith ML, Smith T, Terstriep S, Wagner-Johnston N, Bak K, Loprinzi CL; American Society of Clinical Oncology. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014 Jun 20;32(18):1941-67. doi: 10.1200/JCO.2013.54.0914. Epub 2014 Apr 14. Review. — View Citation

Kosharskyy B, Almonte W, Shaparin N, Pappagallo M, Smith H. Intravenous infusions in chronic pain management. Pain Physician. 2013 May-Jun;16(3):231-49. Review. — View Citation

Meng J, Zhang Q, Yang C, Xiao L, Xue Z, Zhu J. Duloxetine, a Balanced Serotonin-Norepinephrine Reuptake Inhibitor, Improves Painful Chemotherapy-Induced Peripheral Neuropathy by Inhibiting Activation of p38 MAPK and NF-?B. Front Pharmacol. 2019 Apr 9;10:365. doi: 10.3389/fphar.2019.00365. eCollection 2019. — View Citation

Mols F, Beijers T, Vreugdenhil G, van de Poll-Franse L. Chemotherapy-induced peripheral neuropathy and its association with quality of life: a systematic review. Support Care Cancer. 2014 Aug;22(8):2261-9. doi: 10.1007/s00520-014-2255-7. Epub 2014 May 1. Review. — View Citation

Pannucci CJ, Wilkins EG. Identifying and avoiding bias in research. Plast Reconstr Surg. 2010 Aug;126(2):619-625. doi: 10.1097/PRS.0b013e3181de24bc. Review. — View Citation

Perez C, Galvez R, Huelbes S, Insausti J, Bouhassira D, Diaz S, Rejas J. Validity and reliability of the Spanish version of the DN4 (Douleur Neuropathique 4 questions) questionnaire for differential diagnosis of pain syndromes associated to a neuropathic or somatic component. Health Qual Life Outcomes. 2007 Dec 4;5:66. — View Citation

Rivera DR, Ganz PA, Weyrich MS, Bandos H, Melnikow J. Chemotherapy-Associated Peripheral Neuropathy in Patients With Early-Stage Breast Cancer: A Systematic Review. J Natl Cancer Inst. 2018 Feb 1;110(2). doi: 10.1093/jnci/djx140. Review. — View Citation

Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD005454. Review. — View Citation

Schulz KF, Grimes DA. Allocation concealment in randomised trials: defending against deciphering. Lancet. 2002 Feb 16;359(9306):614-8. Review. — View Citation

Schulz KF, Grimes DA. Generation of allocation sequences in randomised trials: chance, not choice. Lancet. 2002 Feb 9;359(9305):515-9. Review. — View Citation

Shimozuma K, Ohashi Y, Takeuchi A, Aranishi T, Morita S, Kuroi K, Ohsumi S, Makino H, Katsumata N, Kuranami M, Suemasu K, Watanabe T, Hausheer FH. Taxane-induced peripheral neuropathy and health-related quality of life in postoperative breast cancer patients undergoing adjuvant chemotherapy: N-SAS BC 02, a randomized clinical trial. Support Care Cancer. 2012 Dec;20(12):3355-64. doi: 10.1007/s00520-012-1492-x. Epub 2012 May 15. — View Citation

Skljarevski V, Desaiah D, Liu-Seifert H, Zhang Q, Chappell AS, Detke MJ, Iyengar S, Atkinson JH, Backonja M. Efficacy and safety of duloxetine in patients with chronic low back pain. Spine (Phila Pa 1976). 2010 Jun 1;35(13):E578-85. doi: 10.1097/BRS.0b013e3181d3cef6. — View Citation

Starobova H, Vetter I. Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy. Front Mol Neurosci. 2017 May 31;10:174. doi: 10.3389/fnmol.2017.00174. eCollection 2017. Review. — View Citation

van Haren F, van den Heuvel S, Radema S, van Erp N, van den Bersselaar L, Vissers K, Steegers M. Intravenous lidocaine affects oxaliplatin pharmacokinetics in simultaneous infusion. J Oncol Pharm Pract. 2020 Dec;26(8):1850-1856. doi: 10.1177/1078155220905011. Epub 2020 Feb 19. — View Citation

Wang YJ, Chan YN, Jheng YW, Wu CJ, Lin MW, Tseng LM, Tsai YF, Liu LC. Chemotherapy-induced peripheral neuropathy in newly diagnosed breast cancer survivors treated with taxane: a prospective longitudinal study. Support Care Cancer. 2021 Jun;29(6):2959-2971. doi: 10.1007/s00520-020-05796-0. Epub 2020 Oct 6. — View Citation

Westbom C, Thompson JK, Leggett A, MacPherson M, Beuschel S, Pass H, Vacek P, Shukla A. Inflammasome Modulation by Chemotherapeutics in Malignant Mesothelioma. PLoS One. 2015 Dec 21;10(12):e0145404. doi: 10.1371/journal.pone.0145404. eCollection 2015. — View Citation

Willison HJ, Winer JB. Clinical evaluation and investigation of neuropathy. J Neurol Neurosurg Psychiatry. 2003 Jun;74 Suppl 2:ii3-ii8. — View Citation

Zhi WI, Chen P, Kwon A, Chen C, Harte SE, Piulson L, Li S, Patil S, Mao JJ, Bao T. Chemotherapy-induced peripheral neuropathy (CIPN) in breast cancer survivors: a comparison of patient-reported outcomes and quantitative sensory testing. Breast Cancer Res Treat. 2019 Dec;178(3):587-595. doi: 10.1007/s10549-019-05416-4. Epub 2019 Aug 27. — View Citation

* Note: There are 27 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Neuropathic pain characters and severity	The change in intensity and characters of neuropathic pain will be measured using Neuropathy Pain Scale (NPS). It quantifies severity of neuropathic pain (0 indicates no pain, 10 indicates the most pain imaginable).	every week for 12 weeks (after each chemotherapy session)
Secondary	Quality of life assessment using the European Organization for Research and Treatment of Cancer - Quality of life questioner - Chemotherapy induced peripheral neuropathy twenty-item scale(EORTC - QLQ - CIPN20 ).	The European Organization for Research and Treatment of Cancer (EORTC - QLQ - CIPN20) will be used to elicit patients' experience of symptoms and functional limitations related to chemotherapy induced peripheral neuropathy . It consists of 20 items with scores ranging from 1 to 4 for each item . Not at All (1), A Little (2), Quite a Bit (3), and Very much(4).	Baseline (before starting chemotherapy protocol), one month ,two month and at 12 weeks ( end of chemotherapy cycle)
Secondary	Detection of Chemotherapy induced peripheral neuropathy using sensory nerve conduction latency study .	Sensory nerve conduction latency study will be performed on bilateral sural and radial nerves. It test peak latency (millisecond).	Baseline (before starting chemotherapy protocol) then 12 weeks later ( end of chemotherapy cycle)
Secondary	Detection of Chemotherapy induced peripheral neuropathy using sensory nerve conduction amplitude study .	Sensory nerve conduction amplitude study will be performed on bilateral sural and radial nerves. It test amplitude (microvolt) .	Baseline (before starting chemotherapy protocol) then 12 weeks later ( end of chemotherapy cycle)
Secondary	Detection of Chemotherapy induced peripheral neuropathy using sensory nerve conduction velocity study .	Sensory nerve conduction velocity study will be performed on bilateral sural and radial nerves. It test nerve conduction velocity (meter/second).	Baseline (before starting chemotherapy protocol) then 12 weeks later ( end of chemotherapy cycle)
Secondary	Incidence of Taxane induced peripheral neuropathy (TIPN) using Douleur Neuropathique 4 questionnaire (DN4)	Detection of TIPN will be measured by DN4 questionnaire .It is a clinician-administered questionnaire consisting of 10 items. Seven items related to pain quality (i.e. subjective sensory and pain descriptors) and 3 items based on the clinical examination. Scores = 4/10 indicate neuropathic pain.	Baseline (before starting chemotherapy protocol), then every week for 12 weeks (after each chemotherapy session)
Secondary	Change in serum level of natural killer cell to estimate cell mediated immunity	CD 56 will be used as a marker for NK cells while CD8 will be used as a marker for cytotoxic lymphocytes (CtLS).	Baseline (before starting chemotherapy protocol) then 12 weeks later ( end of chemotherapy cycle)