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

Official title

Effectiveness and Cost-effectiveness of Ozone Treatment in Patients With Paresthesia (Numbness, Tingling) Secondary to Chemotherapy-induced Peripheral Neuropathy. Randomized, Triple-blind Clinical Trial (OzoParQT)

Overview

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).

Interventions

• Drug Ozone therapy
  Usual treatment (by their oncologist or hematologist) + Ozone therapy by rectal insufflation. O3/O2 concentration progressively increased from 10 to 30 μg/ml; 40 sessions in 16 weeks.
• Drug Oxygen (placebo)
  Usual treatment (by their oncologist or hematologist) + Oxygen by rectal insufflation. O3/O2 concentration = 0 μg/ml (only O2); 40 sessions in 16 weeks.

Primary outcome measures

• 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) [Time frame: 28 weeks]
• Change from Baseline in quality of life by the EQ-... [Time frame: 28 weeks]

Secondary outcome measures (12)

• Direct hospital costs [Time frame: 28 weeks]
• Change from baseline in "numbness and tingling" self-perceived by patients at the end of ozone treatment. [Time frame: 16]
• 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. [Time frame: 16 weeks]
• 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. [Time frame: 16 weeks.]
• Changes from baseline in the degree of neuropathy according to the QLQ-CIPN20 scale at the end of ozone treatment. [Time frame: 16 weeks.]
• 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). [Time frame: 16 weeks.]
• Changes from baseline in the "Quality of Life" according to the QLQ-C30 questionnaire at the end of ozone treatment. [Time frame: 16 weeks.]
• Changes from baseline in levels of anxiety and depression according to the Hospital Anxiety and Depression Scale (HADS), at the end of ozone treatment. [Time frame: 16 weeks]
• Changes from baseline in biochemical parameters of oxidative stress at the end of ozone treatment. [Time frame: 16 weeks.]
• Changes from baseline in biochemical parameters of inflammation at the end of ozone treatment. [Time frame: 16 weeks]
• Changes from baseline in Hyperspectral signatures and infrared images obtained from hands and feet at then of ozone treatment. [Time frame: 16 weeks]
• 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. [Time frame: 28 weeks.]

Eligibility criteria

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

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

Triple blind

Primary purpose

Treatment

Study locations

Spain · 1 center

• Dr. Negrín University Hospital — Las Palmas

Publications

• Viebahn-Haensler R, Leon Fernandez OS. Ozone in Medicine. The Low-Dose Ozone Concept and Its Basic Biochemical Mechanisms of Action in Chronic Inflammatory Diseases. Int J Mol Sci. 2021 Jul 23;22(15):7890. doi: 10.3390/ijms22157890. PMID 34360655
• Tricarico G, Travagli V. The Relationship between Ozone and Human Blood in the Course of a Well-Controlled, Mild, and Transitory Oxidative Eustress. Antioxidants (Basel). 2021 Dec 4;10(12):1946. doi: 10.3390/antiox10121946. PMID 34943049
• Szklener K, Rudzinska A, Juchaniuk P, Kabala Z, Mandziuk S. Ozone in Chemotherapy-Induced Peripheral Neuropathy-Current State of Art, Possibilities, and Perspectives. Int J Mol Sci. 2023 Mar 9;24(6):5279. doi: 10.3390/ijms24065279. PMID 36982352
• 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
• Hidalgo-Tallon J, Menendez-Cepero S, Vilchez JS, Rodriguez-Lopez CM, Calandre EP. Ozone therapy as add-on treatment in fibromyalgia management by rectal insufflation: an open-label pilot study. J Altern Complement Med. 2013 Mar;19(3):238-42. doi: 10.1089/acm.2011.0739. Epub 2012 Oct 9. PMID 23046293
• Hidalgo-Tallon FJ, Torres-Morera LM, Baeza-Noci J, Carrillo-Izquierdo MD, Pinto-Bonilla R. Updated Review on Ozone Therapy in Pain Medicine. Front Physiol. 2022 Feb 23;13:840623. doi: 10.3389/fphys.2022.840623. eCollection 2022. PMID 35283802
• Galie M, Covi V, Tabaracci G, Malatesta M. The Role of Nrf2 in the Antioxidant Cellular Response to Medical Ozone Exposure. Int J Mol Sci. 2019 Aug 17;20(16):4009. doi: 10.3390/ijms20164009. PMID 31426459
• Clavo B, Suarez G, Aguilar Y, Gutierrez D, Ponce P, Cubero A, Robaina F, Carreras JL. Brain ischemia and hypometabolism treated by ozone therapy. Forsch Komplementmed. 2011;18(5):283-7. doi: 10.1159/000333795. Epub 2011 Oct 13. PMID 22105041

Identifiers

NCT: NCT06706544 · OzoParQT · PI23/01324 · CIGC'23/24 · 2024-517196-20-00 · 2023-210-1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗