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

Official title

Evaluation of the Gut Microbiome Profiles in Patients with Chemotherapy-induced Peripheral Neuropathy Treated in the Randomized Clinical Trial with Ozone OzoParQT (NCT06706544).

Overview

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: 1. with and without symptomatic improvement of CIPN. 2. receiving rectal ozone therapy and those receiving placebo. Secondary Objectives: To evaluate the relationship between gut microbiome composition and: 1. Health-related quality of life, 2. Anxiety and depression, 3. Biochemical markers of oxidative stress and inflammation. Main Trial Endpoints. Changes from baseline at the end of ozone therapy (week 16) in: * 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.

Detailed description

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:

1. with and without symptomatic improvement of CIPN. 2. receiving rectal ozone therapy and those receiving placebo.

Secondary Objectives:

To evaluate the relationship between gut microbiome composition and:

1. Health-related quality of life, 2. Anxiety and depression, 3. Biochemical markers of oxidative stress and inflammation.

Main Trial Endpoints.

Changes from baseline at the end of ozone therapy (week 16) in:

* 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.

Interventions

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

Primary outcome measures

• Change from baseline in gut microbiome profile, at the end of ozone therapy. [Time frame: 16 weeks.]
• Change from baseline in "numbness and tingling" self-perceived by patients at the end of ozone treatment. [Time frame: 16 weeks.]
• Changes from baseline in the degree of neuropathy according to the QLQ-CIPN20 scale at the end of ozone treatment. [Time frame: 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. [Time frame: 16 weeks.]

Secondary outcome measures (5)

• Change from baseline in "Quality of Life" (using the EQ-5D-5L questionnaire) self-perceived by patients at the end of ozone treatment. [Time frame: 16 weeks.]
• Changes from baseline in the "Quality of Life" according to the QLQ-C30 questionnaire at the end of ozone treatment. [Time frame: 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. [Time frame: 16 weeks.]
• Changes from baseline in biochemical parameters of oxidative stress at the end of ozone treatment. [Time frame: 16 weeks.]
• Changes from baseline in biochemical parameters of inflammation at the end of ozone treatment. [Time frame: 16 weeks.]

Eligibility criteria

Inclusion criteria

• 0\. 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.
• 1\. Adults > = 18 years old.
• 2\. Previous treatment with any chemotherapy because of any tumor.
• 3\. 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.
• 4\. Without neurotoxic chemotherapy > = 3 months.
• 5\. Cancer disease is stable or in remission.
• 6\. Life expectancy > = 6 months.
• 7\. 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.
• 8\. To sign and date the specific informed consent of both studies (OzoParQT and OzoParQTmicrob)

Exclusion criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Screening

Study locations

Spain · 1 center

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

Publications

• 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
• 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
• 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 PMID 39797612
• 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
• 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
• 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
• 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: PMID 37599784
• 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 PMID 36674232

Identifiers

NCT: NCT06799351 · 2024-385-1 · PIFIISC24/37 · PI23/01324 · CIGC'23/24

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗