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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Effectiveness and Cost-effectiveness of Ozone Therapy in Patients With Pain Secondary to Chemotherapy-induced Peripheral Neuropathy. Randomized, Triple-blind Clinical Trial (O3NPIQ)

Conditions
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Pain, Neuropathic, Chemotherapy-induced Peripheral Neuropathy, Pain Syndrome

Intervention / Treatment
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* Drug: Ozone
* Drug: Oxygen


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Standard treatment + ozone therapy (O3/O2) versus Standard treatment + oxygen (O2) as placebo
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ozone Group<br>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 | Drug: Ozone<br>* Ozone Group: Standard treatment + Ozone therapy (O3/O2) by rectal insufflation. O3/O2 concentration progressively increased from 10 to 30 μg/ml; 40 sessions in 16 weeks.<br>* Other names: O3;|
| Placebo Comparator: Control Group<br>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 | Drug: Oxygen<br>* Control Group: Standard treatment + Oxygen (O2) by rectal insufflation. O3/O2 concentration = 0 μg/ml (only O2); 40 sessions in 16 weeks.<br>* Other names: O2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Average pain according to the Brief Pain Inventory-Short Form (BPI-SF) (at the end of ozone therapy) | 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). | 16 weeks | 
| Direct Hospital Cost (at the end of ozone therapy) | The direct expenses incurred by the hospital in providing services (medication, tests, medical visits...) during the 16 weeks of ozone therapy (in euros). | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in quality of life by the 5-level, 5-dimension EuroQol (EQ-5D-5L) questionnaire (at the end of ozone therapy) | 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) | 16 weeks | 
| Change from Baseline in quality of life by the Short Form 36-item health survey (SF-36v2) questionnaire (at the end of ozone therapy) | Self-reported evaluation of 36 items (0 = worst, 100 = best). Final accumulated total range from 0 (worst) to 100 (best) | 16 weeks | 
| Change from Baseline in Biochemical parameters of oxidative stress (at the end of ozone therapy) | Serum levels of superoxide dismutase, glutathione, glutathione peroxidase and free radicals | 16 weeks | 
| Change from Baseline in Biochemical parameters of inflammation (at the end of ozone therapy) | Serum levels of pro-inflammatory interleukins and TNFalpha | 16 weeks | 
| Change from Baseline in Hyperspectral image of painful area (at the end of ozone therapy) | Assessment of the percentage of reflectance for each wavelength | 16 weeks | 
| Change from Baseline in Levels of anxiety and depression according to the Hamilton scale (at the end of ozone therapy) | 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). | 16 weeks | 
| Change from Baseline in Nerve conduction studies in the painful area (at the end of ozone therapy) | Assessment of nerve conduction velocity (in m/s) | 16 weeks | 
| 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) | Number of events that are fatal, life threatening, leading to or prolonging a stay in hospital, or resulting in severe disability | 16 weeks | 
| 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) | 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) | 28 weeks | 
| Direct Hospital Cost (at 12 weeks after the end of ozone therapy) | The direct expenses incurred by the hospital in providing services (medication, tests, medical visits...) during the 16 weeks of ozone therapy (in euros) | 28 weeks | 
| 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) | 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) | 28 weeks | 
| 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) | Self-reported evaluation of 36 items (0 = worst, 100 = best). Final accumulated total range from 0 (worst) to 100 (best) | 28 weeks | 
| Change from Baseline in Biochemical parameters of oxidative stress (at 12 weeks after the end of ozone therapy) | Serum levels of superoxide dismutase, glutathione, glutathione peroxidase and free radicals | 28 weeks | 
| Change from Baseline in Biochemical parameters of inflammation (at 12 weeks after the end of ozone therapy) | Serum levels of pro-inflammatory interleukins and TNFalpha | 28 weeks | 
| Change from Baseline in Hyperspectral image of painful area (at 12 weeks after the end of ozone therapy) | Assessment of the percentage of reflectance for each wavelength | 28 weeks | 
| Change from Baseline in Levels of anxiety and depression according to the Hamilton scale (at 12 weeks after the end of ozone therapy) | 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) | 28 weeks | 
| Change from Baseline in Nerve conduction studies in the painful area (at 12 weeks after the end of ozone therapy) | Assessment of nerve conduction velocity (in m/s) | 28 weeks | 
| 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) | Number of events that are fatal, life threatening, leading to or prolonging a stay in hospital, or resulting in severe disability | 28 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pain, complementary and integrative medicine, cost-effectiveness ratio, chemotherapy-induced peripheral neuropathy, ozone therapy, quality of life related to health, shared decision-making tool, randomized controlled trial