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

Phase 2

Recruiting

• Conditions: Chemotherapy Induced Peripheral Neuropathy (CIPN); Paresthesia; Numbness; Tingling
• Interventions: Drug: Ozone therapy; Drug: Oxygen (placebo)

• Registration Number: NCT06799351
• Lead Sponsor: Bernardino Clavo, MD, PhD

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:

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.

Study Timeline

• Study First Submitted: 2025-01-23
• Study First Submitted QC: 2025-01-23
• Study First Posted: 2025-01-29
• Status Verified: 2025-02
• Study Start: 2025-02-07
• Last Update Submitted: 2025-02-10
• Last Update Posted: 2025-02-12
• Primary Completion: 2029-12-31
• Study Completion: 2030-03-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 42

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
Change from baseline in gut microbiome profile, at the end of ozone therapy.	16 weeks.	Analysis of gut microbiome profile at the end of ozone therapy regarding the basal profile.
Change from baseline in "numbness and tingling" self-perceived by patients at the end of ozone treatment.	16 weeks.	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).
Changes from baseline in the degree of neuropathy according to the QLQ-CIPN20 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 (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.
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 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).

Secondary Outcome Measures

Name	Time	Method
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.	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).
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 the "Quality of Life" according to the QLQ-C30 questionnaire (from the European Organization for Research \& Treatment in Cancer (EORTC)). Self-reported evaluation of 30 items that measure several scales and symptoms. Range (after standardization): from 0 (worst for overall health and function, best for symptoms) to 100 (best for overall health and functions, worst for symptoms).
Changes from baseline in biochemical parameters of oxidative stress at the end of ozone treatment.	16 weeks.	Changes in serum levels of superoxide dismutase, glutathione, glutathione peroxidase and free radicals.
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 levels of anxiety and depression according to the Hospital Anxiety and Depression Scale (HADS). HADS is a self-administered questionnaire that assesses 14 items/symptoms of anxiety (7) and depression (7) experienced by patients. Each item is scored from 0 (better, no alteration) to 3 (worse level of alteration). For each symptom (anxiety or depression), the overall score is from 0 (better, no anxiety or depression) to 21 (worse, very severe anxiety or depression).
Changes from baseline in biochemical parameters of inflammation at the end of ozone treatment.	16 weeks.	Changes in serum levels of pro-inflammatory cytokines.

Trial Locations

Locations (1)

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