Chronic Leg Ulcer, Venous Leg Ulcer
Conditions
Keywords
lower extremities infection biofilm antimicrobial
Brief summary
Single-centre clinical study investigating the safety and tolerability of randomised, double-blinded, placebo-controlled ascending single doses of topically applied SoftOx Biofilm Eradicator (SBE) in patients with chronic leg wounds and of open-label once daily, twice daily, and thrice daily dosing of topically applied SBE for five days in patients with chronic leg wounds. The primary objective of the study is to assess the safety and tolerability of single and multiple doses of topically applied SBE in patients with chronic leg wounds. A secondary objective of the study is to assess changes in bacterial burden in the leg wound after treatment with SBE.
Detailed description
The study enrolled subjects with chronic leg wounds, i.e., the intended target population for SBE. The first part of the study aimed to identify the highest tolerated dose of SBE in a randomised, double-blind, and placebo-controlled manner with sequential evaluation of 4 single ascending doses. As a precaution, sentinel and staggered dosing was applied in the single-dose groups: the safety of two subjects treated on two different days (at least one of whom was treated with SBE) was reviewed before commencing dosing of the remaining subjects in a single-dose group (sentinel dosing), with an interval of at least 1 hour between the dosing of different subjects (staggered dosing). The starting dose of 500 µg/mL HOCl + 1% HAc was based on previous knowledge concerning the MIC and MBC of SBE and the results obtained in a 28-day, repeated-dose toxicology study in minipigs. The latter indicated that up to 1000 µg/mL + 3% HAc (the highest dose tested) was well-tolerated. Choosing 500 µg/mL HOCl + 1% HAc as the starting dose in the current study provided a safety factor of 2 for HOCl and a safety factor of 3 for HAc. The highest well-tolerated dose of SBE in the non-clinical toxicology study was chosen as the highest single dose to be evaluated in the current study. Dose-escalation steps in the single-dose groups were conservatively defined with escalation factors ranging from 1 to 2. Prior to dose escalation, blinded results were evaluated by the Safety Monitoring Committee (SMC). The second part of the study aimed to evaluate the safety and tolerability of multiple dosing of SBE. The multiple-dose groups tested different dosing regimens with formulations determined by the SMC based on the safety and tolerability of the formulations evaluated in the first part of the study. Three multiple-dose groups (once-, twice-, and thrice-daily administrations) were planned.
Interventions
DRUGSoftOx Biofilm Eradicator (Groups 1 to 7)
SBE is a water-based formulation containing hypochlorous acid (HOCl) at concentrations of 500-1000 µg/mL and acetic acid (HAc) at concentrations of 1-3 %. Both active ingredients are naturally occurring molecules and have a long history of safe use in medicinal products and in solutions approved as medical devices. Both molecules, exhibit broad-spectrum antimicrobial activity at the concentrations present in SBE. The antimicrobial effect of HOCl is rapid and powerful by acting on and disrupting the function of key microbial molecules such as proteins, lipids, and nucleic acids, while remaining safe to mammalian cells and not promoting the emergence of new resistant microbes. Moreover, HOCl is active against biofilms, and some studies suggest that HOCl may also increase oxygenation of the wound site leading to improved healing.
DEVICESterile isotonic saline (Groups 1 to 4)
Sterile isotonic saline was used as placebo because it is part of standard of care, used as an irrigation solution at dressing change and has the same appearance as SBE
Sponsors
SoftOx Solutions AS
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
Blinding and unblinding procedures applied only to the single-dose groups, i.e., Groups 1-4, randomized to receive SBE (active) or sterile saline (placebo). The computer-generated randomisation list was kept strictly confidential, accessible only to authorised persons, until the time of unblinding of the study. The following procedures were implemented in the single-dose groups to minimise the risk of unintended unblinding: i. Blinded staff prepared the patient's leg wound for the administration of IMP. ii. Both patient and blinded staff applied a nose clip, prior to and during IMP administration, until all materials used for the treatment (plastic wrapping, gauze, gallipot, etc.) had been removed and the room had been vented for a couple of minutes by opening a window.
Intervention model description
Randomised, double-blinded, placebo-controlled ascending single dose groups (Groups 1 to 4); followed by open-label multiple ascending dose groups (Groups 5 to 7)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
To be eligible for this study, patients must fulfil all of the following criteria: 1. Male and female patients aged 18 and above at time of informed consent. 2. Chronic (present for at least 4 weeks) leg wound, as judged by the Investigator, with a size of at least 1 cm2 and maximally 100 cm2 (measured as the width x length) on the day of the (first) administration of IMP. 3. Patients must have given written informed consent before any study-related activities are carried out and must be able to understand the full nature and purpose of the study, including possible risks and adverse effects.
Exclusion criteria
Patients are not eligible for this study if they fulfil any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Nature, occurrence, and severity of adverse events (AEs) | From the start of the first administration of IMP to 3 to 5 days after the last administration of IMP | Clinically significant abnormal values of vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, body temperature), safety blood and urine parameters, ECG, and physical examination will be reported as AEs. |
| Change from baseline in wound pain assessed by use of visual analogue scale (VAS). | From the start of the first administration of IMP to 3 to 5 days after the last administration of IMP | Change from baseline i.e., the last value before the (first) administration of IMP, in wound pain as assessed by use of a 10 cm VAS, where 0 cm indicated no pain at all, and 10 cm indicated the worst imaginable pain at the time of assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in wound bacterial burden (number of colony-forming units per mL; CFU/mL) | From the start of the first administration of IMP to 3 to 5 days after the last administration of IMP | The bacterial burden of wounds was assessed using surface swabs (collected with the Z technique) at baseline, i.e., before the first administration of IMP, 20 min after the administration of IMP (on the treatment day for the single-dose groups, on each day of treatment for the OD multiple-dose group and after the second administration on each day of treatment for the BID multiple-dose group) and at the Follow-up visit. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in wound area | From the start of the first administration of IMP to 3 to 5 days after the last administration of IMP | The area of the wound in cm2 was calculated by the width x length (both in cm) of the wound. Wound area was estimated at screening, at baseline, i.e., before the (first) administration of IMP, and at the Follow-up visit. |
Countries
Denmark
Outcome results
None listed