Evaluation of the Safety and Efficacy of Topical Bacteriophage Therapy TP-102 in Diabetic Foot Ulcers Infected by Acinetobacter baumannii, Pseudomonas aeruginosa, or Staphylococcus aureus

The primary objective of this Phase 2b clinical study is to evaluate the **safety** and tolerability of the topical administration of TP-102, a bacteriophage therapy, in patients with diabetic foot infection. This is assessed by comparing TP-102 to a placebo, in addition to the standard of care (SoC). The study also aims to determine the efficacy of TP-102 by measuring clinical improvement in diabetic foot infection classification according to IWGDF/IDSA guidelines, and its effects on wound healing, both compared to placebo alongside SoC. These objectives are clinically relevant as they address the need for effective and safe treatments for diabetic foot ulcers, which are often complicated by infections from pathogens such as **Acinetobacter baumannii**, **Pseudomonas aeruginosa**, and **Staphylococcus aureus**.

Secondary objectives include: - Improvement in DFI-related laboratory biomarkers; - Efficacy as measured by eradication of TP-102 susceptible strains; - Percentage of patients with target strain not-susceptible to TP-102 at the end of treatment; - Changes in wound/ulcer healing from baseline; - Clinical improvement in wound infection scores (DFUWI) of TP-102 as compared to placebo, in addition to SoC. These secondary objectives provide further insights into the potential benefits of TP-102 in managing diabetic foot infections, which can significantly impact patient outcomes and healthcare resources.

The clinical trial involves a total of **54 participants** diagnosed with **diabetic foot ulcers** infected by **Acinetobacter baumannii**, **Pseudomonas aeruginosa**, and/or **Staphylococcus aureus**. The study population includes both male and female subjects aged 18 years and older, with an established diagnosis of **Diabetes Mellitus** (type I or II). Participants were selected based on specific criteria, including a glycosylated hemoglobin (HbA1c) value of 12.0% or less and a designated foot infection present for at least three weeks. The trial does not include a vulnerable population. Participants are required to have suitable physical and mental health as determined by the investigator. Women of childbearing potential must have a negative serum pregnancy test at screening and agree to use effective birth control methods during the study and for four weeks after stopping study medications. The trial population was selected to ensure that the participants' diabetic foot infections are susceptible to the TP-102 bacteriophage cocktail, as assessed from wound cultures. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **safety** and efficacy of a topical bacteriophage therapy, TP-102, in patients with diabetic foot infections. This study is a Phase 2b, randomized, double-blind, placebo-controlled trial. The trial will involve the administration of TP-102, a suspension containing a bacteriophage cocktail, and a placebo, both applied topically on wounds. The trial is expected to last until May 31, 2024, with recruitment starting on October 31, 2023. The maximum treatment period for participants is 31 days.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, diabetes diagnosis, and specific characteristics of the foot infection. The primary inclusion criteria include being 18 years or older, having a diagnosis of Diabetes Mellitus (type I or II), and a glycosylated hemoglobin (HbA1c) value of ≤12.0%. The designated foot infection must meet specific criteria, including being present for at least three weeks and having a wound area of ≤20.0 cm². The infection must be caused by at least one target bacterial strain susceptible to TP-102.

Following the screening, participants will be randomized to receive either TP-102 or placebo, in addition to the standard of care. The study will include multiple follow-up visits to monitor safety and efficacy outcomes, such as the number and percentage of treatment-emergent adverse events (TEAEs) and changes in wound healing. The primary endpoints include the clinical improvement in diabetic foot infection classification and the percentage of patients achieving at least a 50% reduction in wound surface area by week 4. Secondary endpoints will assess changes in inflammatory markers and the eradication of susceptible bacterial strains.

The end-of-study visit will conclude the participant's involvement, which is expected to last up to 31 days. Conditions that may lead to early termination from the study include the occurrence of significant adverse events or the participant's decision to withdraw consent. The trial aims to provide valuable insights into the potential benefits of TP-102 in managing diabetic foot infections, contributing to the development of new therapeutic options for this condition.

The clinical trial involves the evaluation of two treatments for patients with **diabetic foot infection**. The first treatment is an experimental medication, TP-102, which is a **suspension** containing a bacteriophage cocktail. This cocktail comprises five bacteriophages: F44/10, F125/10, F770/05, F510/08, and F1245/05. The pharmaceutical form of TP-102 is a suspension, and it is administered via **topical application on the wound**. The maximum daily dose and total dose amount are both set at 1 unit, with a maximum treatment period of 31 days. The product is developed by Technophage Investigacao e Desenvolvimento em Biotecnologia S.A. and is not a pediatric formulation.

The second treatment used in the study is a non-experimental comparator, **Cloreto de Sódio 0.9% Labesfal**, which is a **solution for injection** containing **sodium chloride**. This solution is also applied topically on the wound. The maximum daily dose and total dose amount are similarly set at 1 unit, with a treatment period of up to 31 days. This product is manufactured by Labesfal Laboratorios Almiro, S.A. and serves as a placebo in the trial. Both treatments are administered in addition to the standard of care therapy for diabetic foot infections, ensuring comprehensive management of the condition. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

Efficacy in this clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints include the number and percentage of Treatment Emergent Adverse Events (TEAEs) from Day 1 (Baseline) to the end of treatment (EOT), a statistically significant change in the percentage of patients in the respective IWGDF/IDSA classes for TP-102 versus Placebo, in addition to Standard of Care (SoC) from Day 1 to EOT, and the percentage of patients achieving at least a 50% reduction in wound surface area by week 4 for TP-102 versus Placebo, in addition to SoC.

Secondary endpoints will evaluate changes in mean C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), procalcitonin (PCT), and white blood cell (WBC) count values for TP-102 versus Placebo, in addition to SoC from Day 1 to EOT. The percentage of patients with values over the clinical diagnostic cut-off for diabetic foot infection (DFI) for CRP/ESR/PCT/WBC count, the percentage eradication of TP-102 susceptible strains, and the percentage of patients with target strains not susceptible to TP-102 at EOT will also be assessed. Additionally, changes in wound size, depth, granulation, and closure (25%, 50%, 75%) from baseline will be measured at Day 3, 8, 15, EOT, and end of study (EOS). The percentage of patients achieving complete wound closure by EOS and the total Area Under the Curve (AUC) of the mean Diabetic Foot Ulcer Wound Index (DFUWI) score for TP-102 versus Placebo, in addition to SoC from Day 1 to EOT, will be evaluated.