Ozone Therapy in Chemotherapy-induced Peripheral Neuropathy: RCT (O3NPIQ)
NCT ID: NCT04299893
Last Updated: 2025-09-02
Study Results
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Basic Information
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RECRUITING
PHASE2/PHASE3
42 participants
INTERVENTIONAL
2020-11-30
2027-12-31
Brief Summary
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Detailed Description
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Main Objectives: 1) To evaluate the clinical effect on the health-related quality of life (HRQOL) of adding ozone to the usual patient´s treatment with persistent pain because of CIPN. 2) Estimate the additional costs and evaluate the cost-effectiveness ratio.
Secondary Objectives: To evaluate the evolution of 3) oxidative stress and chronic inflammation through biochemical measurements; 4) anxiety and depression of patients; 5) the diagnostic and predictive value of hyperspectral imaging in the assessment of pain; 6) the acceptability of patients to a shared decision-making (SDM) tool.
METHODOLOGY: Randomized controlled trial (RCT) phase II-III, randomized, triple-blind; 42 patients with any kind of cancer treated with any kind of chemotherapy, with CIPN of grade \> = 2 for \> = 3 months.
TREATMENT: All patients will receive: usual treatment + 40 rectal insufflation sessions of O3/O2 in 16 weeks:
* Ozone-Arm (n = 21): concentration of O3/O2 increasing from 10 to 30 μg/ml.
* Control-placebo- Arm (n = 21): concentration of O3/O2 = 0 μg/ml.
Main Variables: At the end of treatment with O3/O2 the following variables will be analyzed: 1) "average pain" secondary to CIPN following the Brief Pain Inventory-Short Form (BPI-SF); 2) health-related quality of life (HRQOL) and utilities using EQ-5D-5L and SF-36 quality of life questionnaires; 3) Direct costs.
Secondary Variables: 3) biochemical parameters of oxidative stress and inflammation; 4) Hamilton scale for anxiety and depression; 5) hyperspectral images; 6) acceptability of patients to a shared decision-making (SDM) tool.
Assessments at weeks: 0 (baseline), 16 (end of O3/O2 insufflations, objective), and 28 (end of follow-up, control).
Length of treatment: 16 weeks.
Follow-up: 12 weeks after finishing O3/O2 insufflation.
Planned length of the clinical trial: 36 months.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Ozone Group
Drug: Ozone Ozone Group: Usual treatment + Ozone therapy (O3/O2) by rectal insufflation. O3/O2 concentration progressively increased from 10 to 30 μg/ml; 40 sessions in 16 weeks.
Other Names: O3
Ozone
Ozone Group: Standard treatment + Ozone therapy (O3/O2) by rectal insufflation. O3/O2 concentration progressively increased from 10 to 30 μg/ml; 40 sessions in 16 weeks.
Control Group
Drug: Oxygen Control Group: Standard treatment + Oxygen (O2) by rectal insufflation. O3/O2 concentration = 0 μg/ml (only O2); 40 sessions in 16 weeks.
Other Names: O2
Oxygen
Control Group: Standard treatment + Oxygen (O2) by rectal insufflation. O3/O2 concentration = 0 μg/ml (only O2); 40 sessions in 16 weeks.
Interventions
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Oxygen
Control Group: Standard treatment + Oxygen (O2) by rectal insufflation. O3/O2 concentration = 0 μg/ml (only O2); 40 sessions in 16 weeks.
Ozone
Ozone Group: Standard treatment + Ozone therapy (O3/O2) by rectal insufflation. O3/O2 concentration progressively increased from 10 to 30 μg/ml; 40 sessions in 16 weeks.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 2\. Any kind of cancer in any stage, treated with any kind of chemotherapy, and life expectancy \> = 6 months.
* 3\. Clinical diagnosis of painful chemotherapy-induced peripheral neuropathy, toxicity Grade 2 or higher according to the Common Toxicity Criteria for Adverse Events (CTCAE) from the National Cancer Institute of EEUU, v.5.0, for \> = 3 months and without the inclusion of new treatments for pain and/or neuropathy for \> = 1 month.
* 4\. "Average pain" \> = 3/10 according to the Brief Pain Inventory-Short Form (BPI-SF) \> = 3 months beyond chemotherapy completion.
* 5\. Pregnant women cannot participate in the clinical trial.
* 6\. Before enrollment, women of childbearing potential should obtain a negative result in the serum or urine pregnancy test at the screening visit and accept the use of appropriate contraceptive methods at least from the 14 days prior to the first ozone therapy session up to 14 days after the last one.
* 7\. Patients who have signed and dated the study 's specific informed consent
Exclusion Criteria
* 2\. Pregnancy at the time of enrollment.
* 3\. Women with childbearing potential who are unwilling to perform a pregnancy test and/or employ adequate contraception from the 14 days prior to the first ozone therapy session up to 14 days after the last one.
* 4\. Clinical suspicion that peripheral neuropathy (compressive or diabetic neuropathy) in the same area prior to receiving neurotoxic chemotherapy.
* 5\. Psychiatric illness or social situations that would limit compliance with study requirements.
* 6\. Those who are unable to fill in the scales used to measure quality of life variables
* 7\. Specific liver enzymes \[Aspartate Aminotransferase (AST), and Alanine Aminotransferase (ALT) \> 5 times the upper limit of normal
* 8\. Increased creatinine \> 3 times the upper limit of normal.
* 9\. Hemodynamically or clinically unstable patients or uncontrolled severe illness.
* 10\. Uncontrolled cancer disease.
* 11\. Leptomeningeal carcinomatosis.
* 12\. Life expectancy \< 6 months
* 13\. Contraindication or disability for rectal ozone administration or to attend scheduled treatments.
* 14\. Known allergy to ozone.
18 Years
100 Years
ALL
No
Sponsors
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Servicio Canario de Salud
OTHER
Instituto de Salud Carlos III
OTHER_GOV
Red de Investigación en Servicios de Salud en Enfermedades Crónicas
OTHER
Fundación DISA, Spain
UNKNOWN
Fundación Española del Dolor (FED)
UNKNOWN
Bernardino Clavo, MD, PhD
OTHER
Responsible Party
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Bernardino Clavo, MD, PhD
MD, PhD, Head of Research Unit
Principal Investigators
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Bernardino Clavo, MD, PhD
Role: STUDY_CHAIR
Dr. Negrín University Hospital, Las Palmas, Spain
Pedro G Serrano-Aguilar, MD, PhD
Role: STUDY_DIRECTOR
Servicio de Evaluación. Servicio Canario de Salud. Spain
Delvys Rodríguez-Abreu, MD
Role: PRINCIPAL_INVESTIGATOR
Complejo Hospitalario Universitario Insular Materno Infantil, Las Palmas, Spain
Gustavo M Callico, Prof, PhD
Role: PRINCIPAL_INVESTIGATOR
Institute for Applied Microelectronics, University of Las Palmas de G. C., Spain
Francisco Rodríguez-Esparragón, BSc, PhD
Role: PRINCIPAL_INVESTIGATOR
Dr. Negrín University Hospital, Las Palmas, Spain
Bernardino Clavo, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Dr. Negrín University Hospital, Las Palmas, Spain
Locations
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Complejo Hospitalario Materno Insular
Las Palmas de Gran Canaria, Las Palmas, Spain
Hospital Universitario de Gran Canaria Dr. Negrín
Las Palmas de Gran Canaria, Las Palmas, Spain
Countries
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Central Contacts
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Facility Contacts
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References
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Smith EM, Pang H, Cirrincione C, Fleishman S, Paskett ED, Ahles T, Bressler LR, Fadul CE, Knox C, Le-Lindqwister N, Gilman PB, Shapiro CL; Alliance for Clinical Trials in Oncology. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA. 2013 Apr 3;309(13):1359-67. doi: 10.1001/jama.2013.2813.
Durand JP, Deplanque G, Montheil V, Gornet JM, Scotte F, Mir O, Cessot A, Coriat R, Raymond E, Mitry E, Herait P, Yataghene Y, Goldwasser F. Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity: results of EFFOX, a randomized, double-blind, placebo-controlled phase III trial. Ann Oncol. 2012 Jan;23(1):200-205. doi: 10.1093/annonc/mdr045. Epub 2011 Mar 22.
Albers JW, Chaudhry V, Cavaletti G, Donehower RC. Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database Syst Rev. 2014 Mar 31;2014(3):CD005228. doi: 10.1002/14651858.CD005228.pub4.
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.
Bocci V, Borrelli E, Travagli V, Zanardi I. The ozone paradox: ozone is a strong oxidant as well as a medical drug. Med Res Rev. 2009 Jul;29(4):646-82. doi: 10.1002/med.20150.
Bocci VA, Zanardi I, Travagli V. Ozone acting on human blood yields a hormetic dose-response relationship. J Transl Med. 2011 May 17;9:66. doi: 10.1186/1479-5876-9-66.
Bocci V, Valacchi G. Nrf2 activation as target to implement therapeutic treatments. Front Chem. 2015 Feb 2;3:4. doi: 10.3389/fchem.2015.00004. eCollection 2015.
Clavo B, Ceballos D, Gutierrez D, Rovira G, Suarez G, Lopez L, Pinar B, Cabezon A, Morales V, Oliva E, Fiuza D, Santana-Rodriguez N. Long-term control of refractory hemorrhagic radiation proctitis with ozone therapy. J Pain Symptom Manage. 2013 Jul;46(1):106-12. doi: 10.1016/j.jpainsymman.2012.06.017. Epub 2012 Oct 26.
Clavo B, Rodriguez-Esparragon F, Rodriguez-Abreu D, Martinez-Sanchez G, Llontop P, Aguiar-Bujanda D, Fernandez-Perez L, Santana-Rodriguez N. Modulation of Oxidative Stress by Ozone Therapy in the Prevention and Treatment of Chemotherapy-Induced Toxicity: Review and Prospects. Antioxidants (Basel). 2019 Nov 26;8(12):588. doi: 10.3390/antiox8120588.
Clavo B, Martinez-Sanchez G, Rodriguez-Esparragon F, Rodriguez-Abreu D, Galvan S, Aguiar-Bujanda D, Diaz-Garrido JA, Canas S, Torres-Mata LB, Fabelo H, Tellez T, Santana-Rodriguez N, Fernandez-Perez L, Marrero-Callico G. Modulation by Ozone Therapy of Oxidative Stress in Chemotherapy-Induced Peripheral Neuropathy: The Background for a Randomized Clinical Trial. Int J Mol Sci. 2021 Mar 10;22(6):2802. doi: 10.3390/ijms22062802.
Clavo B, Navarro M, Federico M, Borrelli E, Jorge IJ, Ribeiro I, Rodriguez-Melcon JI, Carames MA, Santana-Rodriguez N, Rodriguez-Esparragon F. Ozone Therapy in Refractory Pelvic Pain Syndromes Secondary to Cancer Treatment: A New Approach Warranting Exploration. J Palliat Med. 2021 Jan;24(1):97-102. doi: 10.1089/jpm.2019.0597. Epub 2020 May 5.
Clavo B, Navarro M, Federico M, Borrelli E, Jorge IJ, Ribeiro I, Rodriguez-Melcon JI, Carames MA, Santana-Rodriguez N, Rodriguez-Esparragon F. Long-Term Results with Adjuvant Ozone Therapy in the Management of Chronic Pelvic Pain Secondary to Cancer Treatment. Pain Med. 2021 Sep 8;22(9):2138-2141. doi: 10.1093/pm/pnaa459. No abstract available.
Clavo B, Rodriguez-Abreu D, Galvan S, Federico M, Martinez-Sanchez G, Ramallo-Farina Y, Antonelli C, Benitez G, Rey-Baltar D, Jorge IJ, Rodriguez-Esparragon F, Serrano-Aguilar P. Long-term improvement by ozone treatment in chronic pain secondary to chemotherapy-induced peripheral neuropathy: A preliminary report. Front Physiol. 2022 Aug 30;13:935269. doi: 10.3389/fphys.2022.935269. eCollection 2022.
Other Identifiers
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PI 19/00458
Identifier Type: OTHER_GRANT
Identifier Source: secondary_id
016/2019
Identifier Type: OTHER_GRANT
Identifier Source: secondary_id
BF1-19-03
Identifier Type: OTHER_GRANT
Identifier Source: secondary_id
2019-000821-37
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
2018-156-1
Identifier Type: -
Identifier Source: org_study_id
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