Ozone Treatment in Paresthesia (Numbness, Tingling) Secondary to Chemotherapy-induced Peripheral Neuropathy

NCT06706544 | Recruiting Phase 2

• 5 other identifiers: OzoParQTPI23/01324CIGC'23/242024-517196-20-002023-210-1
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this phase II/III randomized clinical trial is to evaluate the effect of adding rectal ozone therapy to the usual management of patients with paresthesia (numbness and/or tingling) due to chemotherapy-induced peripheral neuropathy (CIPN). Ozone treatment consists of the rectal insufflation of 180 - 300 milliliters of an ozone/oxygen gas mixture. The main questions to answer are:

• the addition of rectal ozone insufflations
• versus the addition of rectal oxygen insufflations (placebo). Participants will receive 40 rectal gas (ozone versus oxygen) insufflations in 16 weeks and will continue other symptomatic or cancer treatments prescribed by their oncologists. Before treatment, after treatment, and 12 weeks after treatment, they will be evaluated:
• Several questionnaires about neuropathy, quality of life, and anxiety and depression.
• Biochemical parameters of oxidative stress and inflammation
• Hyperspectral images of hands and feet
• Toxicity of procedure.

Conditions

Chemotherapy Induced Peripheral Neuropathy (CIPN); Paresthesia; Numbness; Tingling

Keywords

Chemotherapy induced peripheral neuropathy; paresthesia; numbness and tingling; side effect of cancer treatment; toxicity of chemotherapy; ozone therapy; quality of life; anxiety; depression; hyperspectral imaging; oxidative stress

Outcome Measures

Primary Outcomes (2)

• Change from baseline in "numbness and tingling" self-perceived by patients at the end of follow-up (week 28 after the commencement of ozone treatment)

  Self-reported evaluation of the percentage of "numbness and/or tingling" regarding the basal level. From 100% (basal level, 0% improvement) to 0% (no numbness and tingling, 100% improvement).

  28 weeks

• Change from Baseline in quality of life by the EQ-...

  Self-reported evaluation of: a) 5 physical and emotional items scored in five levels, from 1 (Best: I have no problem) to 5 (worst: I have an extreme problem or I am unable to…) and b) additional self-assessment of health by a visual analog scale (0 = worst health patient can imagine, 100 = best health patient can imagine).

  28 weeks

Secondary Outcomes (20)

• Direct hospital costs

  28 weeks

• Change from baseline in "numbness and tingling" self-perceived by patients at the end of ozone treatment.

  16

• Changes from baseline in the Grade of toxicity of parestesias (numbness, tingling) according to the CTCAE v.5.0. scale at the end of ozone treatment.

  16 weeks

• Changes from baseline in the Grade of toxicity of sensory neuropathy according to the CTCAE v.5.0. scale at the end of ozone treatment.

  16 weeks.

• Changes from baseline in the degree of neuropathy according to the QLQ-CIPN20 scale at the end of ozone treatment.

  16 weeks.

Study Arms (2)

Ozone Group

EXPERIMENTAL

Drug: Ozone (O3/O2). Treatment: Usual treatment + Ozone therapy by rectal insufflation. O3/O2 concentration progressively increased from 10 to 30 μg/ml; 40 sessions in 16 weeks.

Drug: Ozone therapy

Oxygen Group (Placebo)

PLACEBO COMPARATOR

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

Drug: Oxygen (placebo)

Interventions

Ozone therapy DRUG

Usual treatment (by their oncologist or hematologist) + Ozone therapy by rectal insufflation. O3/O2 concentration progressively increased from 10 to 30 μg/ml; 40 sessions in 16 weeks.

Also known as: Ozone treatment, O3, O3/O2 gas mixture

Ozone Group

Oxygen (placebo) DRUG

Usual treatment (by their oncologist or hematologist) + Oxygen by rectal insufflation. O3/O2 concentration = 0 μg/ml (only O2); 40 sessions in 16 weeks.

Also known as: O2

Oxygen Group (Placebo)

Eligibility Criteria

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

You may qualify if:

• \. Adults \> = 18 years old.
• \. Previous treatment with any chemotherapy because of any tumor.
• \. Clinical diagnosis of paresthesia (numbness, tingling) secondary to CIPN, with toxicity Grade \> = 2 (according to the Common Toxicity Criteria for Adverse Events (CTCAE) from the National Cancer Institute of EEUU, v.5.0) for \> = 3 months.
• \. Without neurotoxic chemotherapy \> = 3 months.
• \. Cancer disease is stable or in remission.
• \. Life expectancy \> = 6 months.
• \. 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 14 days before the first ozone therapy session up to 14 days after the last one.
• \. To sign and date the study-specific informed consent

You may not qualify if:

• \. Age \< 18 years.
• \. A woman who is lactating, pregnant, suspected of being pregnant, or a woman of childbearing potential who does not use adequate contraceptive methods.
• \. Suspected symptoms are due to diabetic or compressive neuropathy.
• \. Severe psychiatric disorders.
• \. Inability to complete the quality of life questionnaires.
• \. Elevation above 5 times the maximum limit of normal creatinine.
• \. Patient who is hemodynamic or clinically unstable or who requires urgent or short-term interventional measures.
• \. Neoplasia in progression requiring recent initiation of systemic treatment or maintenance with neurotoxic chemotherapy.
• \. Life expectancy (for any reason) \< 6 months.
• \. Known allergy to ozone, known glucose 6 phosphate dehydrogenase (G6PD) deficiency, or hemochromatosis.
• \. Contraindications or impossibility for rectal ozone treatment or to attend regularly to the treatment.

Sponsors & Collaborators

• Bernardino Clavo, MD, PhD: lead
• Council of Gran Canaria: collaborator
• CIBER (Infectious diseases): collaborator
• Fundacion Canaria Instituto de Investigacion Sanitaria de Canarias: collaborator
• Complejo Hospitalario Universitario Insular Materno Infantil: collaborator
• Servicio de Evaluacion del Servicio Canario de Salud.: collaborator
• Institute for Applied Microelectronics, University of Las Palmas de Gran Canaria, Spain: collaborator
• Instituto de Salud Carlos III: collaborator

Study Sites (1)

Dr. Negrín University Hospital

Las Palmas, Las Palmas, 35019, Spain

RECRUITING

Related Publications (19)

• Viebahn-Haensler R, Leon Fernandez OS. Ozone in Medicine. The Low-Dose Ozone Concept and Its Basic Biochemical Mechanisms of Action in Chronic Inflammatory Diseases. Int J Mol Sci. 2021 Jul 23;22(15):7890. doi: 10.3390/ijms22157890.

  PMID: 34360655 BACKGROUND

• Tricarico G, Travagli V. The Relationship between Ozone and Human Blood in the Course of a Well-Controlled, Mild, and Transitory Oxidative Eustress. Antioxidants (Basel). 2021 Dec 4;10(12):1946. doi: 10.3390/antiox10121946.

  PMID: 34943049 BACKGROUND

• Szklener K, Rudzinska A, Juchaniuk P, Kabala Z, Mandziuk S. Ozone in Chemotherapy-Induced Peripheral Neuropathy-Current State of Art, Possibilities, and Perspectives. Int J Mol Sci. 2023 Mar 9;24(6):5279. doi: 10.3390/ijms24065279.

  PMID: 36982352 BACKGROUND

• 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

• Hidalgo-Tallon J, Menendez-Cepero S, Vilchez JS, Rodriguez-Lopez CM, Calandre EP. Ozone therapy as add-on treatment in fibromyalgia management by rectal insufflation: an open-label pilot study. J Altern Complement Med. 2013 Mar;19(3):238-42. doi: 10.1089/acm.2011.0739. Epub 2012 Oct 9.

  PMID: 23046293 BACKGROUND

• Hidalgo-Tallon FJ, Torres-Morera LM, Baeza-Noci J, Carrillo-Izquierdo MD, Pinto-Bonilla R. Updated Review on Ozone Therapy in Pain Medicine. Front Physiol. 2022 Feb 23;13:840623. doi: 10.3389/fphys.2022.840623. eCollection 2022.

  PMID: 35283802 BACKGROUND

• Galie M, Covi V, Tabaracci G, Malatesta M. The Role of Nrf2 in the Antioxidant Cellular Response to Medical Ozone Exposure. Int J Mol Sci. 2019 Aug 17;20(16):4009. doi: 10.3390/ijms20164009.

  PMID: 31426459 BACKGROUND

• Clavo B, Suarez G, Aguilar Y, Gutierrez D, Ponce P, Cubero A, Robaina F, Carreras JL. Brain ischemia and hypometabolism treated by ozone therapy. Forsch Komplementmed. 2011;18(5):283-7. doi: 10.1159/000333795. Epub 2011 Oct 13.

  PMID: 22105041 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, 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, 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, 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

• 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, 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, Canovas-Molina A, Ramallo-Farina Y, Federico M, Rodriguez-Abreu D, Galvan S, Ribeiro I, Marques da Silva SC, Navarro M, Gonzalez-Beltran D, Diaz-Garrido JA, Cazorla-Rivero S, Rodriguez-Esparragon F, Serrano-Aguilar P. Effects of Ozone Treatment on Health-Related Quality of Life and Toxicity Induced by Radiotherapy and Chemotherapy in Symptomatic Cancer Survivors. Int J Environ Res Public Health. 2023 Jan 13;20(2):1479. doi: 10.3390/ijerph20021479.

  PMID: 36674232 BACKGROUND

• Clavo B, Canovas-Molina A, Diaz-Garrido JA, Canas S, Ramallo-Farina Y, Laffite H, Federico M, Rodriguez-Abreu D, Galvan S, Garcia-Lourve C, Gonzalez-Beltran D, Carames MA, Hernandez-Fleta JL, Serrano-Aguilar P, Rodriguez-Esparragon F. Effects of ozone therapy on anxiety and depression in patients with refractory symptoms of severe diseases: a pilot study. Front Psychol. 2023 Aug 4;14:1176204. doi: 10.3389/fpsyg.2023.1176204. eCollection 2023.

  PMID: 37599784 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

• 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

MeSH Terms

Conditions

Paresthesia; Hypesthesia; Anxiety Disorders; Depression

Interventions

Oxygen

Condition Hierarchy (Ancestors)

Somatosensory Disorders; Sensation Disorders; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Mental Disorders; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Chalcogens; Elements; Inorganic Chemicals; Gases

Study Officials

• Bernardino Clavo, MD, PhD

  Hospital Universitario de Gran Canaria Dr. Negrín, (FIISC), Las Palmas, Spain

  STUDY CHAIR

• Francisco Rodríguez-Esparragón, BSc, PhD

  Hospital Universitario de Gran Canaria Dr. Negrín, (FIISC), Las Palmas, Spain

  STUDY DIRECTOR

• Himar Fabelo, BSc, PhD

  Hospital Universitario de Gran Canaria Dr. Negrín, (FIISC), Las Palmas, Spain

  PRINCIPAL INVESTIGATOR

• Gustavo M Callicó, Prof, PhD

  Institute for Applied Microelectronics, University of Las Palmas de Gran Canaria, Spain

  PRINCIPAL INVESTIGATOR

• Francisco Rodríguez-Esparragón, BSc, PhD

  Hospital Universitario de Gran Canaria Dr. Negrín, (FIISC), Las Palmas, Spain

  PRINCIPAL INVESTIGATOR

• Bernardino Clavo, MD, PhD

  Hospital Universitario de Gran Canaria Dr. Negrín, (FIISC), Las Palmas, Spain

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Bernardino Clavo, MD, PhD

CONTACT

34928449278; bernardinoclavo@gmail.com

Francisco Rodríguez-Esparragón, BSc, PhD

CONTACT

34928449288; afrodesp@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Masking Details: * the oncologists/hematologists who treat and follow the patient regularly, * researchers who carry out biochemical determinations or functional tests, * the staff who obtain the economic data, * statisticians
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Bernardino Clavo, MD, PhD, Dr. Negrin University Hospital

Model Details: Randomized, triple-blind clinical trial

Study Record Dates

• First Submitted: November 22, 2024
• First Posted: November 26, 2024
• Study Start: February 7, 2025
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): March 31, 2030
• Last Updated: February 11, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Data will be available after publication, ending 36 months following article publication.
• Access Criteria: Data will be available for investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose. \- Study protocol Proposals should be directed to: bernardinoclavo@gmail.com To gain access, data requestors will need to sign a data access agreement.

Locations

ES (1)