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CompletedNCT06071611Updated Dec 26, 2023

Cognitive Frailty and Oxygen-ozone Therapy

An interventional study of Experimental: Oxygen-Ozone (O2-O3) and Active Comparator: Oxygen (O2) in Cognitive Frailty, sponsored by IRCCS Centro San Giovanni di Dio Fatebenefratelli. Completed at 1 site in Italy. Open to participants aged 60 Years to 85 Years. Per ClinicalTrials.gov, last updated 2023-12-26.

Sponsored by IRCCS Centro San Giovanni di Dio Fatebenefratelli · Not applicable, Interventional, and Treatment

From the registry’s dates

  • Registered 4 years 2 months after the study started (first participant enrolled Jul 2019, registered Sep 2023).
Phase
Not applicable
Study type
Interventional
Enrollment
75
Allocation
Randomized
Ages
60 Years to 85 Years
Sex
All
01

Study summary

As the world's population age, frailty is moving to the forefront of health and medical research and may become one of the world's most serious health issues. Understanding frailty prevention and treatment becomes even more crucial in order to reduce national healthcare costs. Oxygen-Ozone (O2-O3) therapy is a no-invasive/no-pharmacological and low cost procedure based on the therapeutic effects of low O3 concentrations, already used in medicine as an alternative/adjuvant treatment for different diseases and in the elderly. This project is the first pilot double blind randomized controlled trial where a group of elderly frail subjects are stratified as untreated (air), treated with pure O2 and treated with a mixture of O2-O3. The biological corollary will be transcriptomics, proteomics and also cognitive impairment assessment at baseline and after treatment. An algorithm combining these data will identify biomarkers of the response to O2-O3 therapy.

Read the detailed description

Background: Although frailty does not yet have an internationally recognized standard definition, the general premise is that it may be considered a geriatric syndrome reflecting multi-system dysfunction, in which individuals are able to dynamically transition between severity states. The World Health Organization and The International Association of Geriatrics and Gerontology are working on an internationally accepted frailty definition. Accumulating evidence supports the existence of a close relation between frailty and cognitive impairment in subjects with/without dementia. To date specific treatments for the cognitive frailty are not still available. Oxygen-Ozone (O2-O3) therapy is a no-invasive/no-pharmacological low cost procedure based on therapeutic effects of low O3 concentrations and used in medicine as an alternative/adjuvant treatment for different diseases and for improving metabolic activities in elderly. Molecular evidence shows that low O3 concentrations dissolve in the biological fluids and induce a mild oxidative stress, which stimulates antioxidant defences thus preventing the inflammatory response and cell damage. Inflammatory processes, altered release of the main reactive O2 species and mitochondrial/cytoskeletal modifications have been hypothesized to influence significantly the frailty state as well as the neurodevelopmental network on cognitive impairment.

Aims

  1. To characterize clinical and neuropsychological-cognitive impairment profiles in elderly frail subjects at baseline and after treatment.
  2. To identify in vivo peripheral biomarkers associated to O2-O3 therapy through transcriptomic and proteomic analyses at baseline and after treatment.
  3. To correlate clinical/cognitive improvement with transcriptomic and proteomic profiles to identify biomarkers associated to treatment response.
02

Conditions studied

  • Cognitive Frailty

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03

In context

Frailty

1,199 studies on the registry are indexed under Frailty; 430 are open to participants now.

This study's enrollment of 75 is close to the median of 80 across 681 interventional studies indexed under Frailty.

Browse Frailty studies →

Lead sponsor

IRCCS Centro San Giovanni di Dio Fatebenefratelli is the lead sponsor of 36 studies on the registry; 15 are open to participants now.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
60 Years to 85 Years
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  1. subjects between the ages of 60 and 85, referring to the diagnosis of amnesic or non-amnesic cognitive disorder, reported by the subject himself or by family members;
  2. MMSE score > 24/30;
  3. exclusion of dementia, even in the presence of ascertained Alzheimer's disease detected by the most advanced diagnostic techniques;
  4. function intact, or functional reduction not related to the cognitive problem;
  5. pharmacological therapy for the treatment of stable cognitive or behavioral disorders for at least 3 months at the time of enrolment;
  6. specific assessments/tools for frailty: "Italian frailty index (IFi)" and for "Frailty Instrument (FIt) based on the Survey of Health, Ageing and Retirement in Europe (SHARE-FIt)".

Exclusion criteria

Exclusion Criteria:

  1. subjects affected by disabling vision or hearing impairments;
  2. subjects affected by known psychosis or psychiatric illness, alcohol or drug abuse;
  3. subjects affected by uncontrolled hyperthyroidism or by Glucose-6-Phostate Dehydrogenase Deficiency (G6PD)-Favism (according to S.I.O.O.T Guidelines, http://www.ossiozono.it);
  4. subjects who considered invasive the methodology for rectal insufflation.
05

Study design

Phase
Not applicable
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Double (Participant, Investigator)
Enrollment
75 participants (actual)

Study arms

  • Experimental
    Oxygen-Ozone (O2-O3)

    A small catheter is inserted into the rectum and a total amount of 150cc of O2-O3 mixture at the concentration of 30ug of O3 per cc of O2 over a 5-10 min period is administered.

    Other: Experimental: Oxygen-Ozone (O2-O3)

  • Active comparator
    Oxygen (O2)

    A small catheter is inserted into the rectum and a total amount of 150cc of O2 over a 5-10 min period is administered.

    Other: Active Comparator: Oxygen (O2)

  • Placebo comparator
    Placebo (Air)

    A small catheter is inserted into the rectum and a total amount of 150cc of air over a 5-10 min period is administered.

    Other: Placebo Comparator: Placebo (Air)

Interventions

  • OtherExperimental: Oxygen-Ozone (O2-O3)

    Oxygen-Ozone (O2-O3) treatment by rectal insufflations for 5 weeks (3 sessions for week).

  • OtherActive Comparator: Oxygen (O2)

    Oxygen (O2) treatment by rectal insufflations for 5 weeks (3 sessions for week).

  • OtherPlacebo Comparator: Placebo (Air)

    Air treatment by rectal insufflations for 5 weeks (3 sessions for week).

06

What researchers measure

Primary outcomes

  1. Change from baseline and post-intervention in Italian frailty index (IFi)

    Italian frailty index (IFi) is an Italian version of the "frailty index" based on accumulation of age-related deficits. IFi has been expressed as a ratio of deficits present/deficits considered after a comprehensive geriatric assessment. Change = month 3rd after treatment - baseline score / Change = month 9th after treatment - baseline score / Change = month 15th after treatment - baseline score

    Time frame: Baseline (pre-intervention), post-intervention (3, 9 and 15 months)

  2. Change from baseline and post-intervention in Frailty Instrument (FIt) based on the Survey of Health, Ageing and Retirement in Europe (SHARE-FIt)

    SHARE-FIt is based on 5-item (i.e. grip strength and four self-reported items: fatigue, loss of appetite and/or eating less than usual, difficulties climbing stairs and/or walking 100 metres, and low level of physical activity). For each gender, a discreet factor (DFactor) model was estimated based on the five SHARE frailty variables. Change = month 3rd after treatment - baseline score / Change = month 9th after treatment - baseline score / Change = month 15th after treatment - baseline score

    Time frame: Baseline (pre-intervention), post-intervention (3, 9 and 15 months)

  3. Change from baseline and post-intervention in Everyday Memory Questionnaire (EMQ)

    Everyday Memory Questionnaire (EMQ) is a subjective measure of memory failure in everyday life, lower scores indicating better memory function. Change = month 3rd after treatment - baseline score / Change = month 9th after treatment - baseline score / Change = month 15th after treatment - baseline score

    Time frame: Baseline (pre-intervention), post-intervention (3, 9 and 15 months)

  4. Change from baseline and post-intervention in Raven's Progressive Matrices (RPM)

    Raven's Progressive Matrices (RPM) is used to measure fluid intelligence, with higher scores indicating better function. Change = month 3rd after treatment - baseline score / Change = month 9th after treatment - baseline score / Change = month 15th after treatment - baseline score

    Time frame: Baseline (pre-intervention), post-intervention (3, 9 and 15 months)

  5. Change from baseline and post-intervention in Free and Cued Selective Reminding Test (FCSRT)

    Free and Cued Selective Reminding Test (FCSRT) is a test used to assess episodic memory, with higher scores indicating better function. Change = month 3rd after treatment - baseline score / Change = month 9th after treatment - baseline score / Change = month 15th after treatment - baseline score

    Time frame: Baseline (pre-intervention), post-intervention (3, 9 and 15 months)

  6. Change from baseline and post-intervention in Rey-Osterrieth Complex Figure A Test (ROCF-A)

    ROCF-A is used to explore visuo-constructional ability and visuo-spatial memory, with higher scores indicating better function. Change = month 3rd after treatment - baseline score / Change = month 9th after treatment - baseline score / Change = month 15th after treatment - baseline score

    Time frame: Baseline (pre-intervention), post-intervention (3, 9 and 15 months)

  7. Change from baseline and post-intervention in Face-name association task (FNAT)

    FNAT is used to assess the patient's associative memory and is composed of encoding and retrieval phases, with higher scores indicating better function. Change = month 3rd after treatment - baseline score / Change = month 9th after treatment - baseline score / Change = month 15th after treatment - baseline score

    Time frame: Baseline (pre-intervention), post-intervention (3, 9 and 15 months)

  8. Change from baseline and post-intervention in Picture naming task (PNT)

    The PNT is designed to explore lexical access, with higher scores indicating better function. Change = month 3rd after treatment - baseline score / Change = month 9th after treatment - baseline score / Change = month 15th after treatment - baseline score

    Time frame: Baseline (pre-intervention), post-intervention (3, 9 and 15 months)

  9. Change from baseline and post-intervention in Trail Making Tests A (TMT-A)

    Trail Making Tests A (TMT-A) is used to assess visual attention and motor speed skills, with lower scores indicating better attention. Change = month 3rd after treatment - baseline score / Change = month 9th after treatment - baseline score / Change = month 15th after treatment - baseline score

    Time frame: Baseline (pre-intervention), post-intervention (3, 9 and 15 months)

  10. Change from baseline and post-intervention in Trail Making Tests B (TMT-B)

    Trail Making Tests B (TMT-B) is used to assess executive functions, with lower scores indicating good performance in executive function. Change = month 3rd after treatment - baseline score / Change = month 9th after treatment - baseline score / Change = month 15th after treatment - baseline score

    Time frame: Baseline (pre-intervention), post-intervention (3, 9 and 15 months)

Secondary outcomes

  1. Change from baseline and post-intervention in peripheral mRNAs levels in subjects stratified according to IFi or SHARE-FIt scores

    The mRNAs peripheral signatures compared before and after treatments. To identify the list of differentially expressed mRNAs we filter ANOVA results using both fold change \|FC\| ≥ 1.5 and p-value ≤0.05. Change = month 3rd after treatment - baseline score / Change = month 9th after treatment - baseline score / Change = month 15th after treatment - baseline score

    Time frame: Baseline (pre-intervention), post-intervention (3, 9 and 15 months)

  2. Change from baseline and post-intervention in peripheral NGFb (beta-Nerve Growth Factor) levels in subjects stratified according to IFi or SHARE-FIt scores

    Peripheral concentrations (pg/ml) of NGFb compared before and after treatments. Change = month 3rd after treatment - baseline score / Change = month 9th after treatment - baseline score / Change = month 15th after treatment - baseline score

    Time frame: Baseline (pre-intervention), post-intervention (3, 9 and 15 months)

  3. Change from baseline and post-intervention in peripheral BDNF (Brain Derived Neurotrophic Factor) levels in subjects stratified according to IFi or SHARE-FIt scores

    Peripheral concentrations (pg/ml) of BDNF compared before and after treatments. Change = month 3rd after treatment - baseline score / Change = month 9th after treatment - baseline score / Change = month 15th after treatment - baseline score

    Time frame: Baseline (pre-intervention), post-intervention (3, 9 and 15 months)

  4. Change from baseline and post-intervention in peripheral VEGF (Vascular Endothelial Growth Factor) levels in subjects stratified according to IFi or SHARE-FIt scores

    Peripheral concentrations (pg/ml) of VEGF compared before and after treatments. Change = month 3rd after treatment - baseline score / Change = month 9th after treatment - baseline score / Change = month 15th after treatment - baseline score

    Time frame: Baseline (pre-intervention), post-intervention (3, 9 and 15 months)

  5. Change from baseline and post-intervention in peripheral IL, Interleukin-1b levels in subjects stratified according to IFi or SHARE-FIt scores

    Peripheral concentrations (pg/ml) of IL-1b compared before and after treatments. Change = month 3rd after treatment - baseline score / Change = month 9th after treatment - baseline score / Change = month 15th after treatment - baseline score

    Time frame: Baseline (pre-intervention), post-intervention (3, 9 and 15 months)

  6. Change from baseline and post-intervention in peripheral IL, Interleukin-4 levels in subjects stratified according to IFi or SHARE-FIt scores

    Peripheral concentrations (pg/ml) of IL-4 compared before and after treatments. Change = month 3rd after treatment - baseline score / Change = month 9th after treatment - baseline score / Change = month 15th after treatment - baseline score

    Time frame: Baseline (pre-intervention), post-intervention (3, 9 and 15 months)

  7. Change from baseline and post-intervention in peripheral IL, Interleukin-6 levels in subjects stratified according to IFi or SHARE-FIt scores

    Peripheral concentrations (pg/ml) of IL-6 compared before and after treatments. Change = month 3rd after treatment - baseline score / Change = month 9th after treatment - baseline score / Change = month 15th after treatment - baseline score

    Time frame: Baseline (pre-intervention), post-intervention (3, 9 and 15 months)

  8. Change from baseline and post-intervention in peripheral IL, Interleukin-8 levels in subjects stratified according to IFi or SHARE-FIt scores

    Peripheral concentrations (pg/ml) of IL-8 compared before and after treatments. Change = month 3rd after treatment - baseline score / Change = month 9th after treatment - baseline score / Change = month 15th after treatment - baseline score

    Time frame: Baseline (pre-intervention), post-intervention (3, 9 and 15 months)

  9. Change from baseline and post-intervention in peripheral IL, Interleukin-9 levels in subjects stratified according to IFi or SHARE-FIt scores

    Peripheral concentrations (pg/ml) of IL-9 compared before and after treatments. Change = month 3rd after treatment - baseline score / Change = month 9th after treatment - baseline score / Change = month 15th after treatment - baseline score

    Time frame: Baseline (pre-intervention), post-intervention (3, 9 and 15 months)

  10. Change from baseline and post-intervention in peripheral IL, Interleukin-10 levels in subjects stratified according to IFi or SHARE-FIt scores

    Peripheral concentrations (pg/ml) of IL-10 compared before and after treatments. Change = month 3rd after treatment - baseline score / Change = month 9th after treatment - baseline score / Change = month 15th after treatment - baseline score

    Time frame: Baseline (pre-intervention), post-intervention (3, 9 and 15 months)

  11. Change from baseline and post-intervention in peripheral IL, Interleukin-13 levels in subjects stratified according to IFi or SHARE-FIt scores

    Peripheral concentrations (pg/ml) of IL-13 compared before and after treatments. Change = month 3rd after treatment - baseline score / Change = month 9th after treatment - baseline score / Change = month 15th after treatment - baseline score

    Time frame: Baseline (pre-intervention), post-intervention (3, 9 and 15 months)

  12. Change from baseline and post-intervention in peripheral TNF-a (Tumor Necrosis Factor) levels in subjects stratified according to IFi or SHARE-FIt scores

    Peripheral concentrations (pg/ml) of TNF-a compared before and after treatments. Change = month 3rd after treatment - baseline score / Change = month 9th after treatment - baseline score / Change = month 15th after treatment - baseline score

    Time frame: Baseline (pre-intervention), post-intervention (3, 9 and 15 months)

  13. Change from baseline and post-intervention in peripheral IFN-g (Interferon-gamma) levels in subjects stratified according to IFi or SHARE-FIt scores

    Peripheral concentrations (pg/ml) of IFN-g compared before and after treatments. Change = month 3rd after treatment - baseline score / Change = month 9th after treatment - baseline score / Change = month 15th after treatment - baseline score

    Time frame: Baseline (pre-intervention), post-intervention (3, 9 and 15 months)

07

Study locations

1 site
  • IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli
    Brescia, 25125, Italy
08

References and documents

Publications

  • Scassellati C, Ciani M, Galoforo AC, Zanardini R, Bonvicini C, Geroldi C. Molecular mechanisms in cognitive frailty: potential therapeutic targets for oxygen-ozone treatment. Mech Ageing Dev. 2020 Mar;186:111210. doi: 10.1016/j.mad.2020.111210. Epub 2020 Jan 23. Erratum In: Mech Ageing Dev. 2022 Oct;207:111729. doi: 10.1016/j.mad.2022.111729. PubMed 31982474 ↗
  • Scassellati C, Galoforo AC, Bonvicini C, Esposito C, Ricevuti G. Ozone: a natural bioactive molecule with antioxidant property as potential new strategy in aging and in neurodegenerative disorders. Ageing Res Rev. 2020 Nov;63:101138. doi: 10.1016/j.arr.2020.101138. Epub 2020 Aug 15. PubMed 32810649 ↗
  • Scassellati C, Galoforo AC, Esposito C, Ciani M, Ricevuti G, Bonvicini C. Promising Intervention Approaches to Potentially Resolve Neuroinflammation And Steroid Hormones Alterations in Alzheimer's Disease and Its Neuropsychiatric Symptoms. Aging Dis. 2021 Aug 1;12(5):1337-1357. doi: 10.14336/AD.2021.0122. eCollection 2021 Aug. PubMed 34341712 ↗
  • Varesi A, Chirumbolo S, Campagnoli LIM, Pierella E, Piccini GB, Carrara A, Ricevuti G, Scassellati C, Bonvicini C, Pascale A. The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence. Antioxidants (Basel). 2022 Jun 22;11(7):1224. doi: 10.3390/antiox11071224. PubMed 35883714 ↗
  • Scassellati C, Costanzo M, Cisterna B, Nodari A, Galie M, Cattaneo A, Covi V, Tabaracci G, Bonvicini C, Malatesta M. Effects of mild ozonisation on gene expression and nuclear domains organization in vitro. Toxicol In Vitro. 2017 Oct;44:100-110. doi: 10.1016/j.tiv.2017.06.021. Epub 2017 Jun 23. PubMed 28652203 ↗

Individual participant data

Plan to share: Undecided

09

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Dec 26, 2023, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
10

Registry details

Key details

Study ID
NCT06071611
Lead sponsor
IRCCS Centro San Giovanni di Dio Fatebenefratelli
Responsible party
Cristian Bonvicini (Co-Principal Investigator (CoPI), IRCCS Centro San Giovanni di Dio Fatebenefratelli) — Principal investigator
First posted
Oct 6, 2023
Start date
Jul 2, 2019
Primary completion
Nov 2, 2022
Completion
Nov 17, 2023
Last update
Dec 26, 2023

Study contacts

Cristina Geroldi, MD
principal investigator · IRCCS Centro San Giovanni di Dio Fatebenefratelli

Oversight

Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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