Ozone Therapy in Chemotherapy-induced Peripheral Neuropathy: RCT (O3NPIQ)

NCT04299893 | Recruiting Phase 2 DMC

• 5 other identifiers: 2018-156-1PI 19/00458016/2019BF1-19-032019-000821-37
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 2

Brief Summary

The main objective of this clinical trial is to evaluate the effectiveness and cost-effectiveness of adding ozone therapy to the clinical management of patients with pain secondary to chemotherapy-induced peripheral neuropathy

Conditions

Chemotherapy-induced Peripheral Neuropathy; Pain, Neuropathic; Pain Syndrome

Keywords

complementary and integrative medicine; cost-effectiveness ratio; chemotherapy-induced peripheral neuropathy; pain; ozone therapy; quality of life related to health; shared decision-making tool; randomized controlled trial

Outcome Measures

Primary Outcomes (2)

• Change from Baseline in "Average pain" according to the Brief Pain Inventory-Short Form (BPI-SF) (at the end of ozone therapy)

  Self-reported evaluation of 15 items to assess the severity of pain on daily functions in seven interference areas. From the 15 items, 11 items are scored from 0 ("No pain" or "Does not no interfere") to 10 ("Pain as bad as you can imagine" or "Completely interferes").

  16 weeks

• Direct Hospital Cost (at the end of ozone therapy)

  The direct expenses incurred by the hospital in providing services (medication, tests, medical visits...) during the 16 weeks of ozone therapy (in euros).

  16 weeks

Secondary Outcomes (18)

• Change from Baseline in quality of life by the "5-level, 5-dimension EuroQol" (EQ-5D-5L) questionnaire (at the end of ozone therapy)

  16 weeks

• Change from Baseline in quality of life by the "Short Form 36-item health survey" (SF-36v2) questionnaire (at the end of ozone therapy)

  16 weeks

• Change from Baseline in Biochemical parameters of oxidative stress (at the end of ozone therapy)

  16 weeks

• Change from Baseline in Biochemical parameters of inflammation (at the end of ozone therapy)

  16 weeks

• Change from Baseline in Hyperspectral image of painful area (at the end of ozone therapy)

  16 weeks

Study Arms (2)

Ozone Group

EXPERIMENTAL

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

Drug: Ozone

Control Group

PLACEBO COMPARATOR

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

Drug: Oxygen

Interventions

Ozone DRUG

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.

Also known as: O3

Ozone Group

Oxygen DRUG

Control Group: Standard treatment + Oxygen (O2) by rectal insufflation. O3/O2 concentration = 0 μg/ml (only O2); 40 sessions in 16 weeks.

Also known as: O2

Control Group

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. Adults \> = 18 years old.
• \. Any kind of cancer in any stage, treated with any kind of chemotherapy, and life expectancy \> = 6 months.
• \. "Average pain" \> = 3/10 according to the Brief Pain Inventory-Short Form (BPI-SF) \> = 3 months beyond chemotherapy completion.
• \. Pregnant women cannot participate in the clinical trial.
• \. 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.
• \. Patients who have signed and dated the study 's specific informed consent

You may not qualify if:

• \. Age \< 18 years old.
• \. Pregnancy at the time of enrollment.
• \. 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.
• \. Clinical suspicion that peripheral neuropathy (compressive or diabetic neuropathy) in the same area prior to receiving neurotoxic chemotherapy.
• \. Psychiatric illness or social situations that would limit compliance with study requirements.
• \. Those who are unable to fill in the scales used to measure quality of life variables
• \. Specific liver enzymes \[Aspartate Aminotransferase (AST), and Alanine Aminotransferase (ALT) \> 5 times the upper limit of normal
• \. Increased creatinine \> 3 times the upper limit of normal.
• \. Hemodynamically or clinically unstable patients or uncontrolled severe illness.
• \. Uncontrolled cancer disease.
• \. Leptomeningeal carcinomatosis.
• \. Life expectancy \< 6 months
• \. Contraindication or disability for rectal ozone administration or to attend scheduled treatments.
• \. Known allergy to ozone.

Sponsors & Collaborators

• Bernardino Clavo, MD, PhD: lead
• Servicio Canario de Salud: collaborator
• Instituto de Salud Carlos III: collaborator
• Red de Investigación en Servicios de Salud en Enfermedades Crónicas: collaborator
• Fundación DISA, Spain: collaborator
• Fundación Española del Dolor (FED): collaborator

Study Sites (2)

Complejo Hospitalario Materno Insular

Las Palmas de Gran Canaria, Las Palmas, 35016, Spain

RECRUITING

Hospital Universitario de Gran Canaria Dr. Negrín

Las Palmas de Gran Canaria, Las Palmas, 35019, Spain

RECRUITING

Related Publications (13)

• 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.

  PMID: 23549581 BACKGROUND

• 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.

  PMID: 21427067 BACKGROUND

• 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.

  PMID: 24687190 BACKGROUND

• 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.

  PMID: 24733808 BACKGROUND

• 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.

  PMID: 19260079 BACKGROUND

• 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.

  PMID: 21575276 BACKGROUND

• 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.

  PMID: 25699252 BACKGROUND

• 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.

  PMID: 23102757 BACKGROUND

• 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.

  PMID: 31779159 BACKGROUND

• 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.

  PMID: 33802143 BACKGROUND

• 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.

  PMID: 32379556 BACKGROUND

• 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.

  PMID: 33738491 BACKGROUND

• 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.

  PMID: 36111149 BACKGROUND

MeSH Terms

Conditions

Neuralgia; Somatoform Disorders; Pain

Interventions

Ozone; Oxygen

Condition Hierarchy (Ancestors)

Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Mental Disorders

Intervention Hierarchy (Ancestors)

Gases; Inorganic Chemicals; Chalcogens; Elements

Study Officials

• Bernardino Clavo, MD, PhD

  Dr. Negrín University Hospital, Las Palmas, Spain

  STUDY CHAIR

• Pedro G Serrano-Aguilar, MD, PhD

  Servicio de Evaluación. Servicio Canario de Salud. Spain

  STUDY DIRECTOR

• Delvys Rodríguez-Abreu, MD

  Complejo Hospitalario Universitario Insular Materno Infantil, Las Palmas, Spain

  PRINCIPAL INVESTIGATOR

• Gustavo M Callico, Prof, PhD

  Institute for Applied Microelectronics, University of Las Palmas de G. C., Spain

  PRINCIPAL INVESTIGATOR

• Francisco Rodríguez-Esparragón, BSc, PhD

  Dr. Negrín University Hospital, Las Palmas, Spain

  PRINCIPAL INVESTIGATOR

• Bernardino Clavo, MD, PhD

  Dr. Negrín University Hospital, Las Palmas, Spain

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Bernardino Clavo, MD, PhD

CONTACT

(34)928449278; bernardinoclavo@gmail.com

Delvys Rodríguez-Abreu, MD

CONTACT

(34)928441779; drodabr@gobiernodecanarias.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) Masking of: patients, Medical Oncologists (clinical assessment), investigators obtaining other parameters (quality of life, biochemical and clinical parameters, hyperspectral images), investigators for statistical analysis
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD, PhD, Head of Research Unit

Model Details: Standard treatment + ozone therapy (O3/O2) versus Standard treatment + oxygen (O2) as placebo

Study Record Dates

• First Submitted: March 5, 2020
• First Posted: March 9, 2020
• Study Start: November 30, 2020
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: September 2, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

ES (2)