Bacteriophage Therapy TP-102 in Diabetic Foot Ulcers (REVERSE)

A Double-Blind and Randomized Study to Determine the Safety and Tolerability of Multiple Doses of TP-102 in Subjects With Non-Infected and Infected Diabetic Foot Ulcers

This is a Phase I/IIa trial designed to evaluate topical bacteriophage therapy in patients with diabetic foot ulcers.

Study Overview

• Status: Completed
• Conditions: Diabetic Foot Ulcer; Staphylococcus Aureus Infection; Pseudomonas Aeruginosa Infection; Acinetobacter Infection
• Intervention / Treatment: Biological: TP-102

Detailed Description

The primary objective of this study is to evaluate the safety of a topical bacteriophage cocktail in the treatment of non infected and infected diabetic foot ulcers with Pseudomonas aeruginosa, Staphylococcus aureus and/or Acinetobacter baumanni. Patients will also be evaluated for bacterial clearance and wound reduction.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Israel
  • Jerusalem, Israel, 91091
    • Hadassah Medical Center, Ein Kerem
  • Tel Aviv, Israel, 6423906
    • Tel Aviv Sourasky Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Both cohorts:

• Type 1 or type 2 diabetes mellitus with glycated hemoglobin (HbA1c) ≤10, 5%
• Suitable physical and mental health as determined by the investigator based on medical history and general physical examination.
• Subjects must be medically stable based on clinical laboratory tests, medical history and vital signs. Clinical laboratory tests should be within normal values or not clinically significant, unless directly related to the condition of diabetes.

• Female subjects must fulfil one of the following criteria:

  1. At least 1 year post-menopausal (amenorrhea >12 months prior to screening);
  2. Surgically sterile (bilateral oophorectomy or hysterectomy);
  3. If of childbearing potential, must agree to use a highly effective method of birth control from screening until 14 days after the last administration of IP.
• Female subjects of childbearing potential must have a negative pregnancy test at screening.
• Male subjects with a female partner of child-bearing potential or pregnant partner must agree to use a condom from screening until 14 days after the last IP application.
• ICF signed voluntarily before any study-related procedure is performed, indicating that the subject understands the purpose of, and procedures required for the study and is willing to participate in the study.

Part A:

- Non-infected diabetic foot ulcer perfusion grade 1, depth grade 1 and infection grade 1 according to PEDIS classification.

Part B

• Infected diabetic foot ulcer meeting perfusion grade 1 or 2, depth grade 1 or 2 and infection 2 or 3,except if presence of abscess, fasciitis, osteomyelitis, and septic arthritis, according to PEDIS definition.
• Infected with at least one bacterial strain susceptible to bacteriophage cocktail assessed from culture.

Exclusion Criteria:

Both cohorts:

• Study ulcer less than 2 cm away from other ulcers in case of multiple ulcers.
• History in the 5 previous years of any cancer requiring systemic chemotherapy or radiation.
• A condition that, in the opinion of the Investigator, could compromise the well being of the subject or course of the study, or prevent the subject from meeting or performing any study requirements.
• Immunocompromised subjects due to illness, organ transplant, or immune suppressive therapies (e.g. oral or parental corticosteroids, methotrexate, immune modulators) 3 months prior to screening. Ad hoc low dose inhaled corticosteroids or topical corticosteroids are not allowed from 2 weeks prior to randomization.
• Being pregnant or breastfeeding.
• Currently participating in another clinical trial or having participated in a previous clinical trial with receipt of an investigational product within 30 days of the first administration of IP or 5 half-lives, whichever is longer.

• Subjects that, in the opinion of the Investigator or their treating physician, are dependent of the following therapies for their ulcer treatment:

  • Topical antimicrobial treatment (including isobetadine gel/dressing, silver nitrate dressing, topical antibiotic)
  • Enzymatic, autolytic, maggot debridement
  • Any active wound healing products (e.g., Dermagraft, Apligraf, Regranex, or Tegaderm hydrogel or others.)
  • Physical or cleansing modalities, antiseptics, corticosteroids, growth factors, solutions other than sterile normal saline and ulcer treatments.

Part A:

- Clinically infected ulcers

Part B:

• Suspected or confirmed abscess, fasciitis, osteomyelitis or septic arthritis.
• Subjects meeting grade 3 or above PEDIS perfusion criteria
• Planed or anticipated surgery after screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A- Cohort 1; 8 eligible subjects with non-infected DFU will be enrolled (Cohort 1) and receive IP three times weekly (TIW) every other day for up to one week. Of these 8 enrolled subjects, 6 subjects will be randomized to TP-102 and 2 to placebo. Subjects will be followed-up for 7 days.	Biological: TP-102; One mL of IP solution will be applied topically per cm3 of target ulcer. The titer of each bacteriophage in TP 102 is 1x10^9 plaque forming units per milliliter (PFU/mL).
Experimental: Part B- Cohort 2; 18 subjects with a DFU with a grade 2 or 3 infection, as per PEDIS classification, and at least one bacterial strain susceptible to bacteriophage cocktail will be included in Cohort 2. Subjects will receive IP TIW, every other day, up to four weeks and will be randomized at a 2:1 randomization rate to either: TP-102 q.d 3x weekly up to four weeks (n=12); Placebo q.d. 3x weekly up to four weeks (n=6) Subjects will be followed-up for 7 days.	Biological: TP-102; One mL of IP solution will be applied topically per cm3 of target ulcer. The titer of each bacteriophage in TP 102 is 1x10^9 plaque forming units per milliliter (PFU/mL).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
1. Incidence and severity of treatment-emergent solicited local and systemic AEs and relationship to IP from first administration until 1 week after end of treatment (EOT) (end of study -EOS)	Local AEs include erythema/redness, swelling/induration, pain and tenderness Systemic AEs include fatigue, myalgia, fever, headache and gastrointestinal symptoms (nausea, vomiting, diarrhea)	1 week
2. Incidence and severity of treatment-emergent unsolicited AEs and relationship to IP from first administration until EOS.		1 week
3. Incidence and severity of treatment-emergent SAEs and relationship to IP from first administration until EOS.		1 week

Secondary Outcome Measures

Outcome Measure	Time Frame
Proportion of subjects with significant reduction or eradication from baseline in microbiologic data via culture (cfu) at d3, d8, d15, d22, d26 and EOS	35 days
Time (days) to significant reduction or eradication of target bacteria via culture.	35 days
Changes in wound/ulcer healing from to baseline in terms of wound size and depth (cm^3) at EOT.	35 days
Changes in wound/ulcer healing from to baseline in terms of wound complete closure and partial closure (25%, 50% and 75%) at EOT.	35 days

Collaborators and Investigators

• Sponsor: Technophage, SA
• Collaborators: VectorB2B
• Investigators: Principal Investigator: Ran Nir-Paz, MD, Hadassah Medical Organization; Principal Investigator: Ronen Ben Ami, MD, Tel-Aviv Sourasky Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): March 22, 2021
• Primary Completion (Actual): August 7, 2022
• Study Completion (Actual): September 5, 2022

Study Registration Dates

• First Submitted: March 2, 2021
• First Submitted That Met QC Criteria: March 16, 2021
• First Posted (Actual): March 18, 2021

Study Record Updates

• Last Update Posted (Actual): October 4, 2022
• Last Update Submitted That Met QC Criteria: October 3, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Bacteriophage therapy
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Endocrine System Diseases; Disease Attributes; Diabetic Angiopathies; Leg Ulcer; Skin Ulcer; Diabetes Complications; Diabetes Mellitus; Diabetic Neuropathies; Foot Diseases; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Moraxellaceae Infections; Diabetic Foot; Foot Ulcer; Ulcer; Infections; Communicable Diseases; Staphylococcal Infections; Pseudomonas Infections; Acinetobacter Infections
• Other Study ID Numbers: TP-102_101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No