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

Phase 2

Recruiting

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

• Registration Number: NCT06706544
• Lead Sponsor: Bernardino Clavo, MD, PhD

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:

1. Can ozone therapy improve patients' self-perceived level of numbness and tingling?

2. Can ozone therapy improve patients' self-perceived health-related quality of life (HRQoL)?

In 42 patients with chronic numbness and tingling secondary to chemotherapy, the researchers will compare:

* 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.

Detailed Description

Rationale Chemotherapy-induced peripheral neuropathy (CIPN) can lead to a decrease and/or interruption of chemotherapy treatment, limiting its efficacy and decreasing patients' quality of life. Therapeutic measures for CIPN are very limited in number and efficacy. Our previous experience has suggested the potential clinical usefulness of adjuvant treatment with ozone in patients with CIPN. The hypothesis of the trial is that ozone treatment will improve numbness and tingling symptoms in patients with CIPN.

Primary objectives:

To evaluate the effect of adding ozone to the usual management of patients with paresthesia (numbness and/or tingling) due to chemotherapy-induced peripheral neuropathy (CIPN), Grade 2 (moderate symptoms and/or limitation in instrumental activities of daily living) or higher, on:

1. patients' self-perceived level of paresthesia

2. patients' self-perceived health-related quality of life (HRQoL).

Secondary objectives:

To evaluate (in patients with numbness and/or tingling secondary to CIPN) the effect of adding ozone to the usual management on:

1. the additional direct costs incurred in the application of ozone and evaluate the cost-effectiveness of the administration of ozone in these patients in comparison with the usual exclusive treatment.

2. the evolution of the sensory neuropathy

3. the evolution of the level of anxiety and depression,

4. the evolution of biochemical parameters related to oxidative stress and chronic inflammation.

5. the evolution of hyperspectral signatures obtained from hands and feet.

6. to evaluate the toxicity of rectal ozone treatment in these patients.

Main trial endpoints.

1. Percentage of 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)

2. Change from baseline in "quality of life" (using the EQ-5D-5L questionnaire) self-perceived by patients at the end of follow-up (week 28 after the commencement of ozone treatment)

Secondary trial endpoints.

To evaluate the percentage of change from baseline in all the secondary objectives:

* at the end of ozone treatment (weeks 16)

* and at the end of follow-up (week 28)

Trial design. Phase II-III randomized triple-blind clinical trial. The duration of each patient in the study will be 28 weeks: 16 weeks of treatment and 12 weeks of follow-up. The planned total duration of the project is 60 months.

Trial population. 42 adult patients (\>= 18 years old), with any tumor, with paresthesias (numbness and/or tingling) due to CIPN, grade of toxicity \>= 2 (according to the Common Toxicity Criteria for Adverse Events (CTCAE) from the National Cancer Institute of EEUU, v.5.0), for \>= 3 months.

Intervention.

All patients will receive the usual management and treatment for their symptoms + "40 sessions of rectal insufflation of O3/O2 gas mixture" in 16 weeks (3 or 2 sessions per week):

* Ozone group, O3/O2 concentration increasing from 10 to 30 µg/mL (µg of O3 by mL of O2).

* Control-placebo group, O3/O2 concentration = 0 µg/mL (this is: only O2).

Study Timeline

• Study First Submitted: 2024-11-22
• Study First Submitted QC: 2024-11-22
• Study First Posted: 2024-11-26
• Status Verified: 2025-02
• Study Start: 2025-02-07
• Last Update Submitted: 2025-02-07
• Last Update Posted: 2025-02-11
• Primary Completion: 2029-12-31
• Study Completion: 2030-03-31

Recruitment & Eligibility

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

Inclusion Criteria

• 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 study-specific informed consent

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 "numbness and tingling" self-perceived by patients at the end of follow-up (week 28 after the commencement of ozone treatment)	28 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).
Change from Baseline in quality of life by the EQ-...	28 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).

Secondary Outcome Measures

Name	Time	Method
Direct hospital costs	28 weeks	The direct expenses incurred by the hospital in providing services (medication, tests, medical visits...) during the 28 weeks for the study (in euros).
Change from baseline in "numbness and tingling" self-perceived by patients at the end of ozone treatment.	16	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 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).
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 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 4 (life-threatening consequences, urgent intervention indicated).
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 that are grouped into 3 dimensions: sensitive, 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 1000, being 0 the best state and 100 the worst.
Change from baseline in "Quality of Life" (using the EQ-5D-5L questionnaire) self-perceived by patients at the end of ozone treatment (week 16 after the commencement 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 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 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 biochemical parameters of inflammation at the end of ozone treatment.	16 weeks	Changes in serum levels of pro-inflammatory cytokines.
Changes from baseline in Hyperspectral signatures and infrared images obtained from hands and feet at then of ozone treatment.	16 weeks	Assessment of the percentage of reflectance for each wavelength of the hyperspectral and infrared images obtained with specific devices.
Changes from baseline in the Grade of toxicity of paresthesias (numbness, tingling) according to the CTCAE v.5.0. scale at the end of follow-up.	28 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).
Changes from baseline in the Grade of toxicity of sensory neuropathy according to the CTCAE v.5.0. scale at the end of follow-up.	28 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 4 (life-threatening consequences, urgent intervention indicated).
Changes from baseline in the degree of neuropathy according to the QLQ-CIPN20 scale at the end of follow-up.	Time frame: 28 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 that are grouped into 3 dimensions: sensitive, 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 1000, being 0 the best state and 100 the worst.
Changes from baseline in the "Quality of Life" according to the QLQ-C30 questionnaire at the end of follow-up.	28 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 levels of anxiety and depression according to the Hospital Anxiety and Depression Scale (HADS) at the end of follow-up.	28 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 oxidative stress at the end of follow-up.	28 weeks.	Changes in serum levels of superoxide dismutase, glutathione, glutathione peroxidase and free radicals.
Changes from baseline in biochemical parameters of inflammation at the end of follow-up.	28 weeks.	Changes in serum levels of pro-inflammatory cytokines.
Changes from baseline in Hyperspectral signatures and infrared images obtained from hands and feet at the end of follow-up.	28 weeks.	Assessment of the percentage of reflectance for each wavelength of the hyperspectral and infrared images obtained with specific devices.
Toxicity of rectal ozone treatment at the end of follow-up.	28 weeks.	Grade of toxicity secondary to the rectal insufflation of the rectal ozone treatment according to the CTCAE v.5.0. scale (from the National Cancer Institute of EEUU).

Trial Locations

Locations (1)

Dr. Negrín University Hospital; 🇪🇸 Las Palmas, Spain