Chronic Wound of the Lower Limb (Leg Ulcer or Foot Ulcer)NCT04561609
Transcutaneous Application of Gaseous CO2
A study testing Transcutaneous CO2 application in people with Chronic Wound of the Lower Limb (Leg Ulcer or Foot Ulcer), run by University Medical Centre Ljubljana at 3 sites in 2 countries.
Trial summary
The research is designed to evaluate influence of transcutaneous application of CO2 (carbon dioxide) on chronic wound healing. Transcutaneous application of CO2 is known to have immediate effect on vasodilatation and elevates oxygen release from Hb via the Bohr effect. Read more about this study
- Who is it for?
- Ages 18 to 90 years
- Conditions the study is for
- Chronic Wound of the Lower Limb (Leg Ulcer or Foot Ulcer)
- What is being tested?
- Transcutaneous CO2 application
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 120 participants
- Where
- 3 sitesin 2 countries
- Study dates
- 15 May 2023to 22 Sep 2025
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 90 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- confirmed diagnosis of DM Type 1 or Type 2,
- confirmed diagnosis of a non-healing DFU without clinical signs of infection,
- being able to provide informed consent for the participation, and
Who cannot join
- patients with severe comorbidities: deep vein thrombosis, chronic kidney diseases grade III and IV, chronic heart diseases NYHA (New York Heart Association) III and IV, patients with known malignant diseases, patients with progressive infection, signs of systemic infection with elevated inflammatory markers or osteomyelitis
Trial locations and contacts
3 sites in 2 countries.
3 sites in 2 countries
Slovenia2 sites
UMCLjubljana
Ljubljana, Ljubljana, 1000
General hospital Novo mesto
Novo Mesto, Slovenia, 8000
Croatia1 site
Clinical Hospital Merkur, University Clinic for Diabetes, Endocrinology, and Metabolic Diseases Vuk Vrhovac, Dugi dol 4a, 10000 Zagreb
Zagreb, Croatia, 10000
About this study
Official title: The Effect of Transcutaneous Application of Gaseous CO2 on Diabetic Chronic Wound Healing
The research is designed to evaluate influence of transcutaneous application of CO2 (carbon dioxide) on chronic wound healing. Transcutaneous application of CO2 is known to have immediate effect on vasodilatation and elevates oxygen release from Hb via the Bohr effect. After repetition of the therapies neoangiogenesis is induced. Impairment of microcirculation is one of the causes of impared wound healing and improvement in circulation could have positive effect on wound healing, reduction of the wound area and granulation of the wound bed (Falanga score).
Read the detailed description
Transcutaneous application of gaseous CO2 showed to be a successful adjuvant therapy in treatment of chronic wounds in diabetic patients (PMID: 32633896). In this intervention technique, therapeutic concentrations of medical-grade CO2 are applied to the skin's surface in a safe, non-invasive manner. The main therapeutic mechanism is derived from the human body's natural response to locally increased CO2 concentration. Because vasodilatory capacity is impaired in diabetic foot, these mechanisms enhance local microvascular perfusion, thereby improving tissue oxygenation in patients with DFUs. Furthermore, although the researchers primarily focus on CO2 therapy as an intervention method, its efficacy is also suggested in preventing DFUs. We plan to enrole 120 patients, 80 into the study arm that will recieve CO2 therapy and 40 for a control group wothout CO2 therapy. All 120 patienrs will receive standard wound care. Aditionally, only study group will receive 20 treatments with CO2 (each workday for 4 weeks). Lower part of the body will be inserted into therapeutic wrap that is filled with 99.9% CO2 gas for 50 minutes. In both groups investigator will evaluate wound status (size, Falanga score of the wound bed) before first and after 4 weeks of treatment. Main outcome measure will be ratio of the completely heald wounds, reduction of the wound size in non healed wounds and status of the wound bed in non healed wounds after 4 weeks of treatment. Possible side effects of the CO2 therapy will be monitored.
- Being tested
- Transcutaneous CO2 application
- Keywords
- transcutaneous CO2 application
- Medical subject headings
- Leg Ulcer, Foot Ulcer
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Transcutaneous CO2 applicationOther
Patients lie on examination tables. Lower extremities of the patients are isolated in a therapeutic wrap (single use, low-density, made from biocompatible polyethylene), sealed at the waist. After this, air is first pumped out of the therapeutic wrap, then the wrap was filled with 99.9% CO2 gas. The therapy lasts for 50 minutes.
Each patient from the study group will receive CO2 therapies - four weeks (meaning 20 CO2 therapies that were performed on workdays only).
| Study group | Role | What they receive |
|---|---|---|
| CO2 treated | Active comparator | Patients receiving treatment with transcutaneous application of gaseous CO2 on lower limbs Receives: Other: Transcutaneous CO2 application |
| control | No intervention | Patients receiving standard of care |
What is being measured
The primary outcome is the main question the study is designed to answer.
Ratio of completely healed wounds
The ratio of the completely healed wounds without exudate on 2 consecutive visits
Measured: after 4 weeks of therapy with CO2 or standard of care
Secondary outcomes (1)
reduction of the wound size of the unhealed wounds
the ratio of the reduction of the wound size in wound that are not completely helaed after 4 weeks of treatment
Measured: after 4 weeks of therapy with CO2 or standard of care
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Sep 2020
- Study start15 May 2023
- Primary completion30 Jun 2025
- Study completion22 Sep 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Chronic Wound of the Lower Limb (Leg Ulcer or Foot Ulcer)Studies of the same condition, open and under way.
- More trials run by University Medical Centre LjubljanaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- The use of transcutaneous application of gaseous CO2 for treatment of diabetic chronic wound. A Control group receives standard of care.
- Masking
- None (open label)
- Enrolment
- 120 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Medical Centre Ljubljana
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Helena Ban Frangez, University Medical Centre Ljubljana
- Investigators
- Igor Frangez, PhD, MD, DDS, Principal investigator, UCMLjubljana
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04561609
- Sponsor's protocol ID
- UMCLjubljana CO2 application
- Status last verified
- Jan 2026
- First submitted
- 6 Sep 2020
- Last updated
- 26 Jan 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Smith AG, Ramachandran P, Tripp S, Singleton JR. Epidermal nerve innervation in impaired glucose tolerance and diabetes-associated neuropathy. Neurology. 2001 Nov 13;57(9):1701-4. doi: 10.1212/wnl.57.9.1701.
PubMed 11706115Sakai Y, Miwa M, Oe K, Ueha T, Koh A, Niikura T, Iwakura T, Lee SY, Tanaka M, Kurosaka M. A novel system for transcutaneous application of carbon dioxide causing an "artificial Bohr effect" in the human body. PLoS One. 2011;6(9):e24137. doi: 10.1371/journal.pone.0024137. Epub 2011 Sep 8.
PubMed 21931656Macura M, Ban Frangez H, Cankar K, Finzgar M, Frangez I. The effect of transcutaneous application of gaseous CO2 on diabetic chronic wound healing-A double-blind randomized clinical trial. Int Wound J. 2020 Dec;17(6):1607-1614. doi: 10.1111/iwj.13436. Epub 2020 Jul 7.
PubMed 32633896Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, Lauria G, Malik RA, Spallone V, Vinik A, Bernardi L, Valensi P; Toronto Diabetic Neuropathy Expert Group. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010 Oct;33(10):2285-93. doi: 10.2337/dc10-1303.
PubMed 20876709
Study at a glance
From the registry record, last updated by the sponsor on 26 Jan 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effect of Transcutaneous Application of Gaseous CO2 on Diabetic Chronic Wound Healing
- ClinicalTrials.gov ID
- NCT04561609
- Acronym / sponsor ID
- UMCLjubljana CO2 application
- Keywords
- transcutaneous CO2 application
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 120 participants (actual)
- Lead sponsor
- University Medical Centre LjubljanaUniversity, hospital or other
- Study start
- 15 May 2023 (actual)
- Primary completion
- 30 Jun 2025 (actual)
- Study completion
- 22 Sep 2025 (actual)
- First posted
- 23 Sep 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The research is designed to evaluate influence of transcutaneous application of CO2 (carbon dioxide) on chronic wound healing. Transcutaneous application of CO2 is known to have immediate effect on vasodilatation and elevates oxygen release from Hb via the Bohr effect. After repetition of the therapies neoangiogenesis is induced. Impairment of microcirculation is one of the causes of impared wound healing and improvement in circulation could have positive effect on wound healing, reduction of the wound area and granulation of the wound bed (Falanga score).
Detailed description
Transcutaneous application of gaseous CO2 showed to be a successful adjuvant therapy in treatment of chronic wounds in diabetic patients (PMID: 32633896). In this intervention technique, therapeutic concentrations of medical-grade CO2 are applied to the skin's surface in a safe, non-invasive manner. The main therapeutic mechanism is derived from the human body's natural response to locally increased CO2 concentration. Because vasodilatory capacity is impaired in diabetic foot, these mechanisms enhance local microvascular perfusion, thereby improving tissue oxygenation in patients with DFUs. Furthermore, although the researchers primarily focus on CO2 therapy as an intervention method, its efficacy is also suggested in preventing DFUs. We plan to enrole 120 patients, 80 into the study arm that will recieve CO2 therapy and 40 for a control group wothout CO2 therapy. All 120 patienrs will receive standard wound care. Aditionally, only study group will receive 20 treatments with CO2 (each workday for 4 weeks). Lower part of the body will be inserted into therapeutic wrap that is filled with 99.9% CO2 gas for 50 minutes. In both groups investigator will evaluate wound status (size, Falanga score of the wound bed) before first and after 4 weeks of treatment. Main outcome measure will be ratio of the completely heald wounds, reduction of the wound size in non healed wounds and status of the wound bed in non healed wounds after 4 weeks of treatment. Possible side effects of the CO2 therapy will be monitored.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- The use of transcutaneous application of gaseous CO2 for treatment of diabetic chronic wound. A Control group receives standard of care.
| Arm | Type | Receives |
|---|---|---|
| CO2 treated | Active comparator | Other: Transcutaneous CO2 applicationPatients receiving treatment with transcutaneous application of gaseous CO2 on lower limbs |
| control | No intervention | –Patients receiving standard of care |
Who may qualify
- Ages
- 18 to 90 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- confirmed diagnosis of DM Type 1 or Type 2,
- confirmed diagnosis of a non-healing DFU without clinical signs of infection,
- being able to provide informed consent for the participation, and
Key exclusion criteria (1 listed)
- patients with severe comorbidities: deep vein thrombosis, chronic kidney diseases grade III and IV, chronic heart diseases NYHA (New York Heart Association) III and IV, patients with known malignant diseases, patients with progressive infection, signs of systemic infection with elevated inflammatory markers or osteomyelitis
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Transcutaneous CO2 applicationPatients lie on examination tables. Lower extremities of the patients are isolated in a therapeutic wrap (single use, low-density, made from biocompatible polyethylene), sealed at the waist. After this, air is first pumped out of the therapeutic wrap, then the wrap was filled with 99.9% CO2 gas. The therapy lasts for 50 minutes. Each patient from the study group will receive CO2 therapies - four weeks (meaning 20 CO2 therapies that were performed on workdays only). | Other | CO2 treated |
Primary outcome
Ratio of completely healed wounds
Time frame: after 4 weeks of therapy with CO2 or standard of care
The ratio of the completely healed wounds without exudate on 2 consecutive visits
1 secondary outcome
reduction of the wound size of the unhealed wounds
Time frame: after 4 weeks of therapy with CO2 or standard of care
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Jan 2026.
- Background: PubMed 11706115Smith AG, Ramachandran P, Tripp S, Singleton JR. Epidermal nerve innervation in impaired glucose tolerance and diabetes-associated neuropathy. Neurology. 2001 Nov 13;57(9):1701-4. doi: 10.1212/wnl.57.9.1701.
- Background: PubMed 21931656Sakai Y, Miwa M, Oe K, Ueha T, Koh A, Niikura T, Iwakura T, Lee SY, Tanaka M, Kurosaka M. A novel system for transcutaneous application of carbon dioxide causing an "artificial Bohr effect" in the human body. PLoS One. 2011;6(9):e24137. doi: 10.1371/journal.pone.0024137. Epub 2011 Sep 8.
- Background: PubMed 32633896Macura M, Ban Frangez H, Cankar K, Finzgar M, Frangez I. The effect of transcutaneous application of gaseous CO2 on diabetic chronic wound healing-A double-blind randomized clinical trial. Int Wound J. 2020 Dec;17(6):1607-1614. doi: 10.1111/iwj.13436. Epub 2020 Jul 7.
- Background: PubMed 20876709Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, Lauria G, Malik RA, Spallone V, Vinik A, Bernardi L, Valensi P; Toronto Diabetic Neuropathy Expert Group. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010 Oct;33(10):2285-93. doi: 10.2337/dc10-1303.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Igor Frangez, PhD, MD, DDS principal investigator
UCMLjubljana
3 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Transcutaneous CO2 application in people with Chronic Wound of the Lower Limb (Leg Ulcer or Foot Ulcer), run by University Medical Centre Ljubljana at 3 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 26 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Slovenia, Croatia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Ratio of completely healed wounds (time frame: after 4 weeks of therapy with CO2 or standard of care). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04561609, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Jan 2026.