Evaluating Safety and Biological Effect on Wound Healing of ILP100-Topical in Subjects With Diabetic Foot Ulcers

Study Overview
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Brief Summary
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A randomized, double-blind, placebo-controlled, parallel, exploratory phase 2a study to evaluate safety and biologic efficacy on wound healing of ILP100-Topical in subjects with diabetic foot ulcers during 26 weeks with a 5-year long-term follow-up period. A total of 30 subjects will be randomized to low dose of ILP100-Topical (ILP100Lo), high dose of ILP100-Topical (ILP100Hi) or Placebo according to a 1:1:1 randomization schedule. The study will consist of a 3-weeks Screening and Run-in Phase, followed by a 5-week Treatment Phase starting from Baseline and an Assessment Phase from Week 5 to Week 26. Thereafter, the subjects will be followed yearly during 5 years in a Long-Term Safety Follow-up Phase.

Official Title
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A Randomized, Double-Blind, Placebo-controlled, Parallel, Exploratory Phase 2a Study to Evaluate Safety and Biological Effect on Wound Healing of ILP100-Topical in Subjects With Diabetic Foot Ulcers

Conditions
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Wound Heal, Wound Healing Disturbance of, Wound Healing Disorder, Wound Healing Delayed, Diabetic Foot Ulcer, Diabetic Foot Ulcer Mixed

Intervention / Treatment
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* Biological: ILP100-Topical (emilimogene sigulactibac) 5x10^7 CFU/cm^2
* Biological: ILP100-Topical (emilimogene sigulactibac) 1x10^9 CFU/cm^2
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent Males and females aged ≥18 years Diagnosis of diabetes mellitus type 1 or 2 HbA1c ≤ 86 mmol/mol (≤ 10%) at Screening Subjects with at least one first time or recurrent full thickness ulcer (below the ankle) that fulfils all of the following criteria at Screening and at the time of Baseline: A non-interdigital wound Accessible for administration of IMP, wound study assessments and procedures Persistence of the wound for at least 6 weeks at Baseline Minimum full skin ulcer without undermining, with no exposed muscle, tendon or bone A wound area of 1.0 - 5.0 cm^2 after sharp or mechanical debridement at Screening During the 2-weeks between start of Run-in Phase and Baseline the wound size must not decrease by more than 30% or increase by more than 25%, which correspond to wound areas of 0.7 - 6.3 cm^2 Toe pressure ≥30 mm Hg Expected to comply with the study procedures Exclusion Criteria: Has any clinically infected diabetic foot ulcer at Screening and Baseline, confirmed by bacterial wound culture, or ongoing antibiotic treatment The index wound determined as heavily exuding defined as requiring more than 1 dressing change per day or requiring use of super absorbent dressing Wound duration longer than 1 year Active Charcot deformity of the study foot Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m^2 Hemoglobin concentration <100 g/L at Baseline Planned or ongoing treatment with corticosteroids to an equivalent dose of prednisolone >10 mg per day or other immunosuppressive therapy, or such treatment within 4 weeks prior to Baseline Has any major surgery or hospitalization planned up to Week 26 Has changed a treatment for diabetes during the last 3 weeks before Baseline. Dose change is allowed Ongoing treatment with dipeptidyl peptidase 4 (DPP-4) inhibitors Revascularization procedure in the index wound leg planned or undertaken within 8 weeks before Screening, or under investigation Current smokers Participation in other clinical studies or having received any investigational treatment within 1 month or at the earliest five times the half-life prior to Screening Has any disease conditions, including ulcerative dermatological disorders and vasculitis, or comorbidities which is expected to prevent the subject from participating in the study or confounding the evaluation of the safety profile and effect on wound healing of ILP100 Pregnant or lactating woman Male subjects not willing to use a condom and refrain from donating sperm Female subjects of childbearing potential unless they use a contraceptive method with a failure rate of < 1% to prevent pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ILP100Lo<br>During the Treatment Phase, subjects will continue on standard of care according to the protocol and ILP100Lo (ILP100-Topical, 5x10^7 colony forming units (CFU)/cm^2) will be topically administered at two occasions on Day 1 (Baseline and Hour 2), Days 2, 3, and thereafter every second to third day until Day 31. | Biological: ILP100-Topical (emilimogene sigulactibac) 5x10^7 CFU/cm^2<br>* Topical application of ILP100-Topical (emilimogene sigulactibac) at a dose of 5x10^7 CFU/cm^2 wound area.<br>* Other names: ILP100-Topical;|
| Experimental: ILP100Hi<br>During the Treatment Phase, subjects will continue on standard of care according to the protocol and ILP100Hi (ILP100-Topical, 1x10^9 CFU/cm^2) will be topically administered at two occasions on Day 1 (Baseline and Hour 2), Days 2, 3, and thereafter every second to third day until Day 31. | Biological: ILP100-Topical (emilimogene sigulactibac) 1x10^9 CFU/cm^2<br>* Topical application of ILP100-Topical (emilimogene sigulactibac) at a dose of 1x10^9 CFU/cm^2 wound area.<br>* Other names: ILP100-Topical;|
| Placebo Comparator: Placebo<br>During the Treatment Phase, subjects will continue on standard of care according to the protocol and Placebo (ILP100 dilution buffer mixed with the activation peptide SppIP) will be topically administered at two occasions on Day 1 (Baseline and Hour 2), Days 2, 3, and thereafter every second to third day until Day 31. | Biological: Placebo<br>* Topical application of placebo (ILP100 dilution buffer mixed with the activation peptide SppIP).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare incidence of adverse events (AEs) between treatment groups | The incidence of AEs up to Week 26 will be presented for each treatment group and by category, causality, severity and frequency. | Compare between the ILP100-Topical and Placebo treatment arms up to Week 26. | 
| Compare incidence of serious adverse events (SAEs) between treatment groups | The incidence of SAEs up to Week 26 will be presented for each treatment group and by category, causality, severity and frequency. | Compare between the ILP100-Topical and Placebo treatment arms up to Week 26. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local tolerability by Investigator's assessment | Local tolerance to treatment will be assessed by the Investigator. Wound tolerability parameters will be presented in categories of appearance of inflammation, amount of exudate present, hemorrhage, presence of slough/necrotic tissue, presence of granulation tissue and hypergranulation. | Compare Investigator's local tolerability assessments up to Week 26 between the ILP100-Topical and Placebo treatment arms. | 
| Local tolerability by Independent Assessor's assessment | Local tolerance to treatment will be assessed by the Independent Assessor. Wound tolerability parameters will be presented in categories of appearance of inflammation, amount of exudate present, hemorrhage, presence of slough/necrotic tissue, presence of granulation tissue and hypergranulation. | Compare local tolerability up to Week 26 between the ILP100-Topical and Placebo treatment arms. | 
| Proportion of subjects with a local tolerability parameter Grade ≥ 2 per Investigator's Assessment | The proportion of subjects with a local tolerability parameter grade ≥ 2 will be calculated (grading system=0 to 3, where 3 is severe). Local tolerance to treatment, infection and wound healing will be assessed by the Investigator. Wound tolerability parameters include appearance of inflammation, amount of exudate present, hemorrhage, presence of slough/necrotic tissue, presence of granulation tissue and hypergranulation. | Compare the ILP100-Topical and Placebo treatment arms up to Week 26. | 
| Proportion of subjects with a local tolerability parameter Grade ≥ 2 per Independent Assessor's Assessment | The proportion of subjects with a local tolerability parameter grade ≥ 2 will be calculated (grading system=0 to 3, where 3 is severe). Local tolerance to treatment, infection and wound healing will be assessed by the Independent Assessor. Wound tolerability parameters include appearance of inflammation, amount of exudate present, hemorrhage, presence of slough/necrotic tissue, presence of granulation tissue and hypergranulation. | Compare the ILP100-Topical and Placebo treatment arms up to Week 26. | 
| Wound area reduction (percent of Baseline) | Wound area will be measured and calculated as proportion of the wound area at Baseline. Metric analyses of wound area is made on 3D models acquired up to Week 26. | Compare ILP100-Topical and Placebo treatment arms up to Week 26 | 
| Wound healing rate | Wound healing rate will be calculated as change in the wound area per week. Wound healing will be assessed by Investigators and Independent Assessor. | Compare ILP100-Topical and Placebo treatment arms up to Week 26 | 
| Proportion of subjects with ≥50% and 75% partially healed wounds | The proportion of subjects with ≥50% and 75% partially healed wounds will be calculated. | Compare ILP100-Topical and Placebo treatment arms up to Week 26 | 
| Time to partial (≥50% and 75%) and complete healing | Time to event outcomes will be evaluated using Kaplan-Meier curves. Wound healing is defined as full skin re-epithelialization without drainage or dressing requirements confirmed at two consecutive study visits 2 weeks apart. Wound healing will be assessed by Investigators and Independent Assessor. | Compare ILP100-Topical and Placebo treatment arms up to Week 26 | 
| Wound area | Wound area will be measured and calculated (cm^2). Metric analyses of wound healing, including area, are made using 3D models acquired Screening to Week 26. Wound measures will be automatically generated by a computer software and validated by the Independent Assessor. | Compare ILP100-Topical and Placebo treatment arms up to Week 26 | 
| Proportion of subjects with completely healed wounds | The proportion of subjects with completely healed wounds will be calculated. Wound healing is defined as full skin re-epithelialization without drainage or dressing requirements confirmed at two consecutive study visits 2 weeks apart. Wound healing will be assessed by Investigators and the Independent Assessor. | Compare ILP100-Topical and Placebo treatment arms up to Week 26 | 
| Proportion of subjects with recurrence of index wound | The proportion of subjects with recurrence of index wound will be calculated. For wound assessments after each index wound healing visit, it will be documented if the index wound is still healed or if any recurrence of the wound has occurred. | Compare ILP100-Topical and Placebo treatment arms up to Week 26 | 
| Proportion of subjects with new wound infections | The proportion of subjects with new wound infections will be calculated based on the Investigators evaluation of the skin, including assessing whether there are any new wound infections, at each study visit. | Compare ILP100-Topical and Placebo treatment arms up to Week 26 | 
| Days on antibiotic treatment | Days on antibiotic treatment as a percentage of days in the study up to Week 26 will be calculated for each subject. | Compare ILP100-Topical and Placebo treatment arms up to Week 26 | 
| Change in subject-reported wound-related pain | Change in wound-related pain in the area of the index wound, as reported by subjects, using a numeric rating scale (NRS; 0-10, where 10 is the worst possible pain). | Compare ILP100-Topical and Placebo treatment arms up to Week 26 | 
| Long-term incidence of AEs. | AEs and SAEs will be recorded during annual visits from Year 1 through Year 5. | Compare the ILP100-Topical and Placebo treatment arms up to Year 5 after initiation of treatment. | 
| CXCL12 levels in plasma | CXCL12 levels in plasma as measured by enzyme-linked immunosorbent assay (ELISA). | Compare up to Week 16 between the ILP100-Topical and Placebo treatment arms. | 
| Presence of viable L. reuteri containing the pSIP_CXCL12 plasmid in wounds | Bacteria will be collected from the wound and perilesional skin with sterile cotton swabs which will be cultured. | Compare up to Year 5 between the ILP100-Topical and Placebo treatment arms. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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emilimogene sigulactibac, ILP100, ILP100-Topical, Lactobacillus reuteri, Limosilactobacillus reuteri, CXCL12, diabetic foot ulcer, wound healing, Ilya Pharma, live biopharmaceutical product, lactic acid bacteria