Gut Microbiome Profiles in Patients with Chemotherapy-induced Neuropathy in the RCT OzoParQT (NCT06706544).

NCT06799351 | Recruiting Phase 2

• 4 other identifiers: 2024-385-1PIFIISC24/37PI23/01324CIGC'23/24
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

Brief Summary

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating side effect of chemotherapy (CT), often requiring dose reductions or treatment interruptions, which can compromise efficacy of the planned CT (limiting its efficacy). Additionally, CIPN usually decreases patients' quality of life. Unfortunately, effective treatments for CIPN are limited. Emerging evidence suggests potential benefits of rectal ozone therapy and points to a possible role of the gut microbiome in CIPN development and treatment response. This observational study, ancillary to the randomized clinical trial (RCT) OzoParQT (NCT06706544), investigates the relationship between gut microbiome composition and CIPN severity in patients receiving rectal ozone therapy. Primary Objectives: To evaluate if gut microbiome profiles differ between patients:

• Gut microbiome profile
• Patient-reported numbness and tingling
• Neuropathy severity (QLQ-CIPN20 scale)
• Paresthesia toxicity grade (CTCAE v.5.0) Secondary Trial Endpoints. Changes from baseline at the end of ozone therapy (week 16) in:
• Patient-reported quality of life (EQ-5D-5L questionnaire)
• Quality of life (QLQ-C30 questionnaire)
• Anxiety and depression levels (HADS questionnaire)
• Biochemical markers of oxidative stress
• Biochemical markers of inflammation Trial Design: This observational study will analyze data from patients enrolled in the randomized, triple-blind, placebo-controlled OzoParQT clinical trial (NCT06706544). Trial Population in the OzoParQT trial (NCT06706544): Adults (≥18 years) with any tumor type, experiencing CIPN-related paresthesias (numbness and/or tingling), with a toxicity grade ≥ 2 according to the Common Terminology Criteria for Adverse Events (CTCAE v.5.0) for ≥ 3 months. Intervention in the OzoParQT trial (NCT06706544). All patients will receive standard care for their CIPN symptoms plus 40 sessions of rectal insufflation of an O3/O2 gas mixture over 16 weeks:
• Ozone group: O3/O2 concentration increasing from 10 to 30 µg/mL
• Control-placebo group: O2 only (0 µg/mL O3) Study Duration: Each patient will participate in this study (OzoParQTmicrob) for 16 weeks, concurrent with the ozone therapy intervention. The total planned project duration is 60 months.

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; oxidative stress; gut microbiota

Outcome Measures

Primary Outcomes (4)

• Change from baseline in gut microbiome profile, at the end of ozone therapy.

  Analysis of gut microbiome profile at the end of ozone therapy regarding the basal profile.

  16 weeks.

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

  16 weeks.

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

  Changes from baseline in the degree of neuropathy according to the QLQ-CIPN20 scale at the end of ozone treatment (from the European Organization for Research \& Treatment in Cancer (EORTC)). It is evaluated through 20 items grouped into 3 dimensions: sensory, motor, and autonomic. Range: each item is scored from 1 (nothing) to 4 (a lot). The total score for each dimension is transformed into a score from 0 to 100, with 0 being the best possible state and 100 being the worst.

  16 weeks.

• 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.

  Changes from baseline in the Grade of toxicity of paresthesias (numbness, tingling) according to the CTCAE v.5.0. scale (from the National Cancer Institute of EEUU). Range from: Grade = (asymptomatic or mild symptoms) to Grade 3 (severe symptoms, limiting self-care activities in daily life).

  16 weeks.

Secondary Outcomes (5)

• Change from baseline in "Quality of Life" (using the EQ-5D-5L questionnaire) self-perceived by patients at the end of ozone treatment.

  16 weeks.

• Changes from baseline in the "Quality of Life" according to the QLQ-C30 questionnaire at the end of ozone treatment.

  16 weeks.

• Changes from baseline in levels of anxiety and depression according to the Hospital Anxiety and Depression Scale (HADS), at the end of ozone treatment.

  16 weeks.

• Changes from baseline in biochemical parameters of oxidative stress at the end of ozone treatment.

  16 weeks.

• Changes from baseline in biochemical parameters of inflammation 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/O2 gas mixture, O3

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:

• \. Patients who agree to participate in the randomized clinical trial OzoParQT, and who also agree to participate in this study of gut microbiota by providing stool samples.
• \. 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 specific informed consent of both studies (OzoParQT and OzoParQTmicrob)

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
• Fundacion Canaria Instituto de Investigacion Sanitaria de Canarias: collaborator
• Instituto de Salud Carlos III: collaborator
• Council of Gran Canaria: collaborator
• CIBER (Infectious diseases): collaborator
• Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna: collaborator

Study Sites (1)

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

Las Palmas, Las Palmas, 35019, Spain

RECRUITING

Related Publications (18)

• Ramakrishna C, Corleto J, Ruegger PM, Logan GD, Peacock BB, Mendonca S, Yamaki S, Adamson T, Ermel R, McKemy D, Borneman J, Cantin EM. Dominant Role of the Gut Microbiota in Chemotherapy Induced Neuropathic Pain. Sci Rep. 2019 Dec 30;9(1):20324. doi: 10.1038/s41598-019-56832-x.

  PMID: 31889131 BACKGROUND

• Lin B, Wang Y, Zhang P, Yuan Y, Zhang Y, Chen G. Gut microbiota regulates neuropathic pain: potential mechanisms and therapeutic strategy. J Headache Pain. 2020 Aug 17;21(1):103. doi: 10.1186/s10194-020-01170-x.

  PMID: 32807072 BACKGROUND

• Clavo B, Rodriguez-Abreu D, Galvan-Ruiz S, Federico M, Canovas-Molina A, Ramallo-Farina Y, Antonilli C, Benitez G, Fabelo H, Garcia-Lourve C, Gonzalez-Beltran D, Jorge IJ, Rodriguez-Esparragon F, Callico GM. Long-Term Effects of Ozone Treatment in Patients with Persistent Numbness and Tingling Secondary to Chemotherapy-Induced Peripheral Neuropathy. A Retrospective Study. Integr Cancer Ther. 2025 Jan-Dec;24:15347354241307038. doi: 10.1177/15347354241307038.

  PMID: 39797612 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 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 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

• 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

• 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, 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, 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, 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-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

• 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

• 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

• 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

• 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

• 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

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

• Jacob Lorenzo-Morales, Prof

  Instituto Universitario de Enfermedades Tropicales y Salud Publica de Canarias - Universidad de La Laguna (IUETSPC-ULL)

  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: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: * the oncologists/hematologists who treat and follow the patient regularly, * researchers who carry out biochemical determinations or functional tests, * researchers who carry out the gut microbiome analysis, * statisticians
• Purpose: SCREENING
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Bernardino Clavo, MD, PhD, Dr. Negrin University Hospital

Model Details: This observational study will analyze data from patients enrolled in the randomized, triple-blind, placebo-controlled OzoParQT clinical trial (NCT06706544).

Study Record Dates

• First Submitted: January 23, 2025
• First Posted: January 29, 2025
• Study Start: February 7, 2025
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): March 31, 2030
• Last Updated: February 12, 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)