Ozone Therapy in Chemotherapy-induced Peripheral Neuropathy: RCT (O3NPIQ)

Phase 2

Recruiting

• Conditions: Pain, Neuropathic; Chemotherapy-induced Peripheral Neuropathy; Pain Syndrome
• Interventions: Drug: Oxygen; Drug: Ozone

• Registration Number: NCT04299893
• Lead Sponsor: Bernardino Clavo, MD, PhD

Brief Summary

The main objective of this clinical trial is to evaluate the effectiveness and cost-effectiveness of adding ozone therapy to the clinical management of patients with pain secondary to chemotherapy-induced peripheral neuropathy

Detailed Description

Chemotherapy-induced peripheral neuropathy (CIPN) decreases the quality of life of patients and can lead to a decrease and/or interruption of the chemotherapy treatment-limiting its effectiveness. The therapeutic measures for the CIPN are very limited in their number and efficacy.

Main Objectives: 1) To evaluate the clinical effect on the health-related quality of life (HRQOL) of adding ozone to the usual patient´s treatment with persistent pain because of CIPN. 2) Estimate the additional costs and evaluate the cost-effectiveness ratio.

Secondary Objectives: To evaluate the evolution of 3) oxidative stress and chronic inflammation through biochemical measurements; 4) anxiety and depression of patients; 5) the diagnostic and predictive value of hyperspectral imaging in the assessment of pain; 6) the acceptability of patients to a shared decision-making (SDM) tool.

METHODOLOGY: Randomized controlled trial (RCT) phase II-III, randomized, triple-blind; 42 patients with any kind of cancer treated with any kind of chemotherapy, with CIPN of grade \> = 2 for \> = 3 months.

TREATMENT: All patients will receive: usual treatment + 40 rectal insufflation sessions of O3/O2 in 16 weeks:

* Ozone-Arm (n = 21): concentration of O3/O2 increasing from 10 to 30 μg/ml.

* Control-placebo- Arm (n = 21): concentration of O3/O2 = 0 μg/ml.

Main Variables: At the end of treatment with O3/O2 the following variables will be analyzed: 1) "average pain" secondary to CIPN following the Brief Pain Inventory-Short Form (BPI-SF); 2) health-related quality of life (HRQOL) and utilities using EQ-5D-5L and SF-36 quality of life questionnaires; 3) Direct costs.

Secondary Variables: 3) biochemical parameters of oxidative stress and inflammation; 4) Hamilton scale for anxiety and depression; 5) hyperspectral images; 6) acceptability of patients to a shared decision-making (SDM) tool.

Assessments at weeks: 0 (baseline), 16 (end of O3/O2 insufflations, objective), and 28 (end of follow-up, control).

Length of treatment: 16 weeks.

Follow-up: 12 weeks after finishing O3/O2 insufflation.

Planned length of the clinical trial: 36 months.

Study Timeline

• Study First Submitted: 2020-03-05
• Study First Submitted QC: 2020-03-06
• Study First Posted: 2020-03-09
• Study Start: 2020-11-30
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-01
• Last Update Posted: 2024-03-04
• Primary Completion: 2026-12-31
• Study Completion: 2026-12-31

Recruitment & Eligibility

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

Inclusion Criteria

• 1. Adults > = 18 years old.
• 2. Any kind of cancer in any stage, treated with any kind of chemotherapy, and life expectancy > = 6 months.
• 3. Clinical diagnosis of painful chemotherapy-induced peripheral neuropathy, toxicity Grade 2 or higher according to the Common Toxicity Criteria for Adverse Events (CTCAE) from the National Cancer Institute of EEUU, v.5.0, for > = 3 months and without the inclusion of new treatments for pain and/or neuropathy for > = 1 month.
• 4. "Average pain" > = 3/10 according to the Brief Pain Inventory-Short Form (BPI-SF) > = 3 months beyond chemotherapy completion.
• 5. Pregnant women cannot participate in the clinical trial.
• 6. 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 the 14 days prior to the first ozone therapy session up to 14 days after the last one.
• 7. Patients who have signed and dated the study 's specific informed consent

Exclusion Criteria

• 1. Age < 18 years old.
• 2. Pregnancy at the time of enrollment.
• 3. Women with childbearing potential who are unwilling to perform a pregnancy test and/or employ adequate contraception from the 14 days prior to the first ozone therapy session up to 14 days after the last one.
• 4. Clinical suspicion that peripheral neuropathy (compressive or diabetic neuropathy) in the same area prior to receiving neurotoxic chemotherapy.
• 5. Psychiatric illness or social situations that would limit compliance with study requirements.
• 6. Those who are unable to fill in the scales used to measure quality of life variables
• 7. Specific liver enzymes [Aspartate Aminotransferase (AST), and Alanine Aminotransferase (ALT) > 5 times the upper limit of normal
• 8. Increased creatinine > 3 times the upper limit of normal.
• 9. Hemodynamically or clinically unstable patients or uncontrolled severe illness.
• 10. Uncontrolled cancer disease.
• 11. Leptomeningeal carcinomatosis.
• 12. Life expectancy < 6 months
• 13. Contraindication or disability for rectal ozone administration or to attend scheduled treatments.
• 14. Known allergy to ozone.
• 15.Patients who do not meet all the inclusion criteria.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Control Group	Oxygen	Drug: Oxygen Control Group: Standard treatment + Oxygen (O2) by rectal insufflation. O3/O2 concentration = 0 μg/ml (only O2); 40 sessions in 16 weeks. Other Names: O2
Ozone Group	Ozone	Drug: Ozone Ozone Group: Usual treatment + Ozone therapy (O3/O2) by rectal insufflation. O3/O2 concentration progressively increased from 10 to 30 μg/ml; 40 sessions in 16 weeks. Other Names: O3

Primary Outcome Measures

Name	Time	Method
Direct Hospital Cost (at the end of ozone therapy)	16 weeks	The direct expenses incurred by the hospital in providing services (medication, tests, medical visits...) during the 16 weeks of ozone therapy (in euros).
Change from Baseline in "Average pain" according to the Brief Pain Inventory-Short Form (BPI-SF) (at the end of ozone therapy)	16 weeks	Self-reported evaluation of 15 items to assess the severity of pain on daily functions in seven interference areas. From the 15 items, 11 items are scored from 0 ("No pain" or "Does not no interfere") to 10 ("Pain as bad as you can imagine" or "Completely interferes").

Secondary Outcome Measures

Name	Time	Method
Change from Baseline in quality of life by the "5-level, 5-dimension EuroQol" (EQ-5D-5L) questionnaire (at the end of ozone therapy)	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 extreme problem or I am unable to...) and b) additional self-assessment of health by a visual analogue scale (0 = worst health patient can imagine, 100 = best health patient can imagine)
Change from Baseline in Biochemical parameters of oxidative stress (at the end of ozone therapy)	16 weeks	Serum levels of superoxide dismutase, glutathione, glutathione peroxidase and free radicals
Change from Baseline in Nerve conduction studies in the painful area (at the end of ozone therapy)	16 weeks	Assessment of nerve conduction velocity (in m/s)
Incidence of severe adverse events in accordance with the definition of the Council for International Organizations of Medical Sciences (at the end of ozone therapy)	16 weeks	Number of events that are fatal, life threatening, leading to or prolonging a stay in hospital, or resulting in severe disability
Change from Baseline in quality of life by the "Short Form 36-item health survey" (SF-36v2) questionnaire (at the end of ozone therapy)	16 weeks	Self-reported evaluation of 36 items (0 = worst, 100 = best). Final accumulated total range from 0 (worst) to 100 (best)
Change from Baseline in Biochemical parameters of inflammation (at the end of ozone therapy)	16 weeks	Serum levels of pro-inflammatory interleukins and TNFalpha
Change from Baseline in Hyperspectral image of painful area (at the end of ozone therapy)	16 weeks	Assessment of the percentage of reflectance for each wavelength
Change from Baseline in Levels of anxiety and depression according to the Hamilton scale (at the end of ozone therapy)	16 weeks	Clinician-administered depression assessment scale with 17 items pertaining to symptoms of depression experienced over the past week. Each item is scored from 0 (better, no alteration) to 2 (worse level of alteration) for items with three options, or from or from 0 (better, no alteration) to 4 (worse level of alteration) for items with five options. Overall score is from 0 (better, no anxiety/depression) to 52 (worse, very severe anxiety/depression).
Change from Baseline in Biochemical parameters of inflammation (at 12 weeks after the end of ozone therapy)	28 weeks	Serum levels of pro-inflammatory interleukins and TNFalpha
Change from Baseline in Nerve conduction studies in the painful area (at 12 weeks after the end of ozone therapy)	28 weeks	Assessment of nerve conduction velocity (in m/s)
Incidence of severe adverse events in accordance with the definition of the Council for International Organizations of Medical Sciences (at 12 weeks after the end of ozone therapy)	28 weeks	Number of events that are fatal, life threatening, leading to or prolonging a stay in hospital, or resulting in severe disability
Change from Baseline in Biochemical parameters of oxidative stress (at 12 weeks after the end of ozone therapy)	28 weeks	Serum levels of superoxide dismutase, glutathione, glutathione peroxidase and free radicals
Change from Baseline in Hyperspectral image of painful area (at 12 weeks after the end of ozone therapy)	28 weeks	Assessment of the percentage of reflectance for each wavelength
Change from Baseline in "Average pain" according to the Brief Pain Inventory-Short Form (BPI-SF) (at 12 weeks after the end of ozone therapy)	28 weeks	Self-reported evaluation of 15 items to assess the severity of pain on daily functions in seven interference areas. From the 15 items, 11 items are scored from 0 ("No pain" or "Does not no interfere") to 10 ("Pain as bad as you can imagine" or "Completely interferes")
Change from Baseline in quality of life by the "5-level, 5-dimension EuroQol" (EQ-5D-5L) questionnaire (at 12 weeks after the end of ozone therapy)	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 extreme problem or I am unable to...) and b) additional self-assessment of health by a visual analogue scale (0 = worst health patient can imagine, 100 = best health patient can imagine)
Direct Hospital Cost (at 12 weeks after the end of ozone therapy)	28 weeks	The direct expenses incurred by the hospital in providing services (medication, tests, medical visits...) during the 16 weeks of ozone therapy (in euros)
Change from Baseline in quality of life by the "Short Form 36-item health survey" (SF-36v2) questionnaire (at 12 weeks after the end of ozone therapy)	28 weeks	Self-reported evaluation of 36 items (0 = worst, 100 = best). Final accumulated total range from 0 (worst) to 100 (best)
Change from Baseline in Levels of anxiety and depression according to the Hamilton scale (at 12 weeks after the end of ozone therapy)	28 weeks	Clinician-administered depression assessment scale with 17 items pertaining to symptoms of depression experienced over the past week. Each item is scored from 0 (better, no alteration) to 2 (worse level of alteration) for items with three options, or from or from 0 (better, no alteration) to 4 (worse level of alteration) for items with five options. Overall score is from 0 (better, no anxiety/depression) to 52 (worse, very severe anxiety/depression)

Trial Locations

Locations (2)

Hospital Universitario de Gran Canaria Dr. Negrín; 🇪🇸 Las Palmas De Gran Canaria, Las Palmas, Spain

Complejo Hospitalario Materno Insular; 🇪🇸 Las Palmas De Gran Canaria, Las Palmas, Spain