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

Official title

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

Overview

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.

Interventions

• Drug Ozone
  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.
• Drug Oxygen
  Control Group: Standard treatment + Oxygen (O2) by rectal insufflation. O3/O2 concentration = 0 μg/ml (only O2); 40 sessions in 16 weeks.

Primary outcome measures

• Change from Baseline in "Average pain" according to the Brief Pain Inventory-Short Form (BPI-SF) (at the end of ozone therapy) [Time frame: 16 weeks]
• Direct Hospital Cost (at the end of ozone therapy) [Time frame: 16 weeks]

Secondary outcome measures (12)

• Change from Baseline in quality of life by the "5-level, 5-dimension EuroQol" (EQ-5D-5L) questionnaire (at the end of ozone therapy) [Time frame: 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) [Time frame: 16 weeks]
• Change from Baseline in Biochemical parameters of oxidative stress (at the end of ozone therapy) [Time frame: 16 weeks]
• Change from Baseline in Biochemical parameters of inflammation (at the end of ozone therapy) [Time frame: 16 weeks]
• Change from Baseline in Hyperspectral image of painful area (at the end of ozone therapy) [Time frame: 16 weeks]
• Change from Baseline in Levels of anxiety and depression according to the Hamilton scale (at the end of ozone therapy) [Time frame: 16 weeks]
• Change from Baseline in Nerve conduction studies in the painful area (at the end of ozone therapy) [Time frame: 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) [Time frame: 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) [Time frame: 28 weeks]
• Direct Hospital Cost (at 12 weeks after the end of ozone therapy) [Time frame: 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) [Time frame: 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) [Time frame: 28 weeks]

Eligibility criteria

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.

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

Treatment

Study locations

Spain · 2 centers

• Complejo Hospitalario Materno Insular — Las Palmas de Gran Canaria
• Hospital Universitario de Gran Canaria Dr. Negrín — Las Palmas de Gran Canaria

Publications

• Clavo B, Martinez-Sanchez G, Rodriguez-Esparragon F, Rodriguez-Abreu D, Galvan S, Aguiar-Bujanda D, Diaz-Garrido JA, Canas S, Torres-Mata LB, Fabelo H, Tellez T, Santana-Rodriguez N, Fernandez-Perez L, Marrero-Callico G. Modulation by Ozone Therapy of Oxidative Stress in Chemotherapy-Induced Peripheral Neuropathy: The Background for a Randomized Clinical Trial. Int J Mol Sci. 2021 Mar 10;22(6):280 PMID 33802143
• Clavo B, Rodriguez-Abreu D, Galvan S, Federico M, Martinez-Sanchez G, Ramallo-Farina Y, Antonelli C, Benitez G, Rey-Baltar D, Jorge IJ, Rodriguez-Esparragon F, Serrano-Aguilar P. Long-term improvement by ozone treatment in chronic pain secondary to chemotherapy-induced peripheral neuropathy: A preliminary report. Front Physiol. 2022 Aug 30;13:935269. doi: 10.3389/fphys.2022.935269. eCollection 202 PMID 36111149
• Smith EM, Pang H, Cirrincione C, Fleishman S, Paskett ED, Ahles T, Bressler LR, Fadul CE, Knox C, Le-Lindqwister N, Gilman PB, Shapiro CL; Alliance for Clinical Trials in Oncology. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA. 2013 Apr 3;309(13):1359-67. doi: 10.1001/jama.2013.2 PMID 23549581
• Durand JP, Deplanque G, Montheil V, Gornet JM, Scotte F, Mir O, Cessot A, Coriat R, Raymond E, Mitry E, Herait P, Yataghene Y, Goldwasser F. Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity: results of EFFOX, a randomized, double-blind, placebo-controlled phase III trial. Ann Oncol. 2012 Jan;23(1):200-205. doi: 10.1093/annonc/mdr045. Epub 2011 Mar 22 PMID 21427067
• Albers JW, Chaudhry V, Cavaletti G, Donehower RC. Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database Syst Rev. 2014 Mar 31;2014(3):CD005228. doi: 10.1002/14651858.CD005228.pub4. PMID 24687190
• Hershman DL, Lacchetti C, Dworkin RH, Lavoie Smith EM, Bleeker J, Cavaletti G, Chauhan C, Gavin P, Lavino A, Lustberg MB, Paice J, Schneider B, Smith ML, Smith T, Terstriep S, Wagner-Johnston N, Bak K, Loprinzi CL; American Society of Clinical Oncology. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clini PMID 24733808
• 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 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

Identifiers

NCT: NCT04299893 · 2018-156-1 · PI 19/00458 · 016/2019 · BF1-19-03 · 2019-000821-37

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗