Standard Treatment Associated With Phage Therapy Versus Placebo for Diabetic Foot Ulcers Infected by S. Aureus (PhagoPied)

Comparison of the Efficacy of Standard Treatment Associated With Phage Therapy Versus Standard Treatment Plus Placebo for Diabetic Foot Ulcers Monoinfected by Staphylococcus Aureus: a Randomized, Multi-centre, Controlled, 2-parallel-group, Double-blind, Superiority Trial

The primary objective of this study is to compare the efficacy of standard treatment associated with a topical anti-staphylococcal bacteriophage cocktail versus standard treatment plus placebo for diabetic foot ulcers monoinfected by methicillin-resistant or susceptible S. aureus (MRSA or MSSA) as measured by the relative reduction in wound surface area (%) at 12 weeks.

Study Overview

• Status: Not yet recruiting
• Conditions: Diabetic Foot; Staphylococcal Infections
• Intervention / Treatment: Drug: Topical anti-Staphylococcus bacteriophage therapy; Drug: Topical placebo corresponding to anti-Staphylococcus bacteriophage therapy

Detailed Description

The secondary objectives of this study are:

A. To compare the two study arms in terms of treatment safety and tolerance throughout the study.

B. To compare the two study arms in terms of further changes in wound healing at weeks 2, 4, 6, 8, 10, 12.

C. To describe the changes in the resistance and virulence of S. aureus (if present in the wound) from baseline to week 4, at modification of the first-line treatment or new antibiotic prescription (if any) and at week 12 if the wound is still not healed.

D. To describe in the two study arms the antibiotic resistance status of other bacteria isolated from wounds at week 4, at modification of the first-line treatment or new antibiotic prescription (if any) and at week 12 if the wound is still not healed.

E. To describe in the two study arms changes in wound microbiota from baseline to week 4, at modification of the first-line treatment or new antibiotic prescription (if any) and at week 12 if the wound is still not healed.

F. To describe the production of anti-phage antibodies during the topical treatment: baseline and week 4, at modification of the first-line treatment or new antibiotic prescription (if any), and at week 12.

G. Creation of a biobank for future ancillary studies (including, but not limited to, cytokine levels and cellular immune responses): days 0 and week 4, as well as week 12.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Albert Sotto, MD, PhD; Phone Number: +33.(0)6.09.56.66.55; Email: albert.sotto@chu-nimes.fr

Study Locations

• France
  • Bordeaux, France, 33000
    • CHU de Bordeaux - Hôpital Pellegrin
    • Principal Investigator: Michel Dupon, MD, PhD
  • Le Grau du Roi, France, 30240
    • CHRU de Nîmes - Hôpital Universitaire de Réadaptation du Grau du Roi
    • Principal Investigator: Sophie Schuldiner, MD
  • Nantes Cedex 1, France, 44093
    • CHU de Nantes - Hotel Dieu
    • Principal Investigator: David Boutoille, MD, PhD
  • Paris, France, 75010
    • APHP - Hôpital Lariboisière
    • Principal Investigator: Jean-François Gautier, MD,PhD
  • Paris Cedex 13, France, 75651
    • APHP - Groupe Hospitalier Pitié-Salpetrière
    • Principal Investigator: Agnès Hartemann, MD, PhD
  • Toulouse Cedex 9, France, 31059
    • CHRU de Toulouse - Hôpital de Rangueil
    • Principal Investigator: Jacques Martini, MD
  • Tourcoing, France, 59200
    • CH de Tourcoing
    • Principal Investigator: Eric Senneville, MD, PhD
  • Valenton, France, 94460
    • Institut Robert Merle d'Aubigné
    • Principal Investigator: Gérard Chiesa, MD
  • Villeneuve-Saint-Georges, France, 94195
    • CH Intercommunal de Villeneuve-Saint-Georges
    • Principal Investigator: Olivier Patey, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Participant pre-inclusion criteria:

• The patient must have given his/her informed and signed consent
• The patient must be insured or beneficiary of a health insurance plan
• The patient is at least 18 years old
• The patient has type 1 or type 2 diabetes
• The patient is hospitalized/consulting in a participating centre
• The patient has a wound below the ankle that has be evolving for >2 weeks
• The target wound is classified as P (1 or 2), E (1-30 cm^2), D (2), I (2) and S (1 or 2) according to the PEDIS classification

Participant final inclusion criteria:

• The patient must have given his/her informed and signed consent
• The patient must be insured or beneficiary of a health insurance plan
• The patient is at least 18 years old
• The patient has type 1 or type 2 diabetes
• The patient is hospitalized/consulting in a participating centre
• The patient has a wound below the ankle that has be evolving for >2 weeks
• The target wound is classified as P (1 or 2), E (1-30 cm^2), D (2), I (2) and S (1 or 2) according to the PEDIS classification
• The patient's wound is mono-infected with Staphylococcus aureus (MRSA or MSSA)

Participant pre-exclusion criteria:

• The patient is participating in, or has participated in over the past three months, another trial
• The patient is participating in, or has participated in over the past three months, another study that may interfere with the results or conclusions of this study
• The patient is in an exclusion period determined by a previous study
• The patient is under judicial protection, or is an adult under guardianship
• It is impossible to correctly inform the patient
• The patient refuses to sign the consent
• The patient is pregnant, parturient or breastfeeding

Participant final exclusion criteria:

• The patient is participating in, or has participated in over the past three months, another trial
• The patient is participating in, or has participated in over the past three months, another study that may interfere with the results or conclusions of this study
• The patient is in an exclusion period determined by a previous study
• The patient is under judicial protection, or is an adult under guardianship
• It is impossible to correctly inform the patient
• The patient refuses to sign the consent
• The patient is pregnant, parturient or breastfeeding
• Patients who have received antibiotics within the 7 days preceding inclusion
• Patients with diabetic foot wounds associated with clinical or radiographic signs of arthritis or osteomyelitis*
• Patients with diabetic foot wounds associated with critical limb ischemia according to P = grade 3 in the PEDIS classification
• Patients whose wound is infected by a pathogen other than S. aureus (includes multi-infections) according to bacteriological sampling performed at the pre-inclusion visit

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: Phage therapy; Patients randomized to this arm will have phage therapy. Intervention: Topical anti-Staphylococcus bacteriophage therapy	Drug: Topical anti-Staphylococcus bacteriophage therapy; Patients randomized to the experimental arm will receive sterile compress dressings impregnated with a phage solution of 10^7 PFU/ml on days 0, 7 and 14 (unless the wound is already healed, i.e. phage solutions are not applied to healed wounds).
Placebo Comparator: Placebo; Patients randomized to this arm will have placebo therapy anologous to that of the experimental arm. Intervention: Topical placebo corresponding to anti-Staphylococcus bacteriophage therapy	Drug: Topical placebo corresponding to anti-Staphylococcus bacteriophage therapy; Patients randomized to the placebo arm will receive sterile compress dressings impregnated with a placebo solution on days 0, 7 and 14 (unless the wound is already healed, i.e. placebo solutions are not applied to healed wounds).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The relative reduction in wound surface area (%)	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Wound surface area		8 weeks
Immediate Safety	The presence/absence of the following symptoms during each 1 hour observation periods following the application of each experimental wound dressing: local side effects (local rash onset or worsening of local inflammatory signs) and general symptoms (vital signs, fever, rash, arthralgia, gastro-intestinal symptoms...) will be performed.	Day 0, 1 hour after application of experimental dressing
Immediate Safety	The presence/absence of the following symptoms during each 1 hour observation periods following the application of each experimental wound dressing: local side effects (local rash onset or worsening of local inflammatory signs) and general symptoms (vital signs, fever, rash, arthralgia, gastro-intestinal symptoms...) will be performed.	Day 7, 1 hour after application of experimental dressing
Immediate Safety	The presence/absence of the following symptoms during each 1 hour observation periods following the application of each experimental wound dressing: local side effects (local rash onset or worsening of local inflammatory signs) and general symptoms (vital signs, fever, rash, arthralgia, gastro-intestinal symptoms...) will be performed.	Day 14, 1 hour after application of experimental dressing
The number of MedDRA coded Adverse Events per patient		throughout the study; 12 weeks
The presence/absence of abnormal laboratory results		throughout the study; 12 weeks
Wound surface area		2 weeks
Wound surface area		4 weeks
Wound surface area		6 weeks
Wound surface area		10 weeks
Wound surface area		12 weeks
Wound depth		2 weeks
Wound depth		4 weeks
Wound depth		6 weeks
Wound depth		8 weeks
Wound depth		10 weeks
Wound depth		12 weeks
Time to healing		censored at 12 weeks
The % of completely healed wounds		12 weeks
Classification of Staphylococcus isolates as MSSA or MRSA resistant	MSSA: Methicillin-susceptible Staphylococcus aureus MRSA: Methicillin-resistant Staphylococcus aureus What is reported is a binary result: isolates are classified as either "MSSA" or "MRSA"	4 weeks
Classification of Staphylococcus isolates as MSSA or MRSA resistant	MSSA: Methicillin-susceptible Staphylococcus aureus MRSA: Methicillin-resistant Staphylococcus aureus What is reported is a binary result: isolates are classified as either "MSSA" or "MRSA"	at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
Classification of Staphylococcus isolates as MSSA or MRSA resistant	MSSA: Methicillin-susceptible Staphylococcus aureus MRSA: Methicillin-resistant Staphylococcus aureus What is reported is a binary result: isolates are classified as either "MSSA" or "MRSA"	at week 12 if the wound is still not healed
Classification of Staphylococcus isolates according to clonal complexes (virulence classification)		4 weeks
Classification of Staphylococcus isolates according to clonal complexes (virulence classification)		at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
Classification of Staphylococcus isolates according to clonal complexes (virulence classification)		at week 12 if the wound is still not healed
Presence/absence of non-Staphylococcus aureus bacteria that are antibiotic-resistant		week 0
Presence/absence of non-Staphylococcus aureus bacteria that are antibiotic-resistant		week 4
Presence/absence of non-Staphylococcus aureus bacteria that are antibiotic-resistant		at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
Presence/absence of non-Staphylococcus aureus bacteria that are antibiotic-resistant		at week 12 if the wound is still not healed
Wound microbiota: OTU richness	OTU: Operational Taxonomic Unit	week 0
Wound microbiota: OTU richness	OTU: Operational Taxonomic Unit	week 4
Wound microbiota: OTU richness	OTU: Operational Taxonomic Unit	at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
Wound microbiota: OTU richness	OTU: Operational Taxonomic Unit	at week 12 if the wound is still not healed
Wound microbiota: Shannon's Diversity		week 0
Wound microbiota: Shannon's Diversity		week 4
Wound microbiota: Shannon's Diversity		at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
Wound microbiota: Shannon's Diversity		at week 12 if the wound is still not healed
Wound microbiota: Functional richness		week 0
Wound microbiota: Functional richness		week 4
Wound microbiota: Functional richness		at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
Wound microbiota: Functional richness		at week 12 if the wound is still not healed
Wound microbiota: Functional diversity		week 0
Wound microbiota: Functional diversity		week 4
Wound microbiota: Functional diversity		at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
Wound microbiota: Functional diversity		at week 12 if the wound is still not healed
Wound microbiota: the relative abundance of Staphylococcus relative to other bacteria in the wound		week 0
Wound microbiota: the relative abundance of Staphylococcus relative to other bacteria in the wound		week 4
Wound microbiota: the relative abundance of Staphylococcus relative to other bacteria in the wound		at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
Wound microbiota: the relative abundance of Staphylococcus relative to other bacteria in the wound		at week 12 if the wound is still not healed
Wound microbiota: the number of Staphylococcus strains in a wound		week 0
Wound microbiota: the number of Staphylococcus strains in a wound		week 4
Wound microbiota: the number of Staphylococcus strains in a wound		at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
Wound microbiota: the number of Staphylococcus strains in a wound		at week 12 if the wound is still not healed
Wound microbiota: the relative abundance of Staphylococcus aureus relative to other bacteria in the wound		week 0
Wound microbiota: the relative abundance of Staphylococcus aureus relative to other bacteria in the wound		week 4
Wound microbiota: the relative abundance of Staphylococcus aureus relative to other bacteria in the wound		at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
Wound microbiota: the relative abundance of Staphylococcus aureus relative to other bacteria in the wound		at week 12 if the wound is still not healed
Wound microbiota: the relative abundance of Staphylococcus aureus relative to other Staphylococcus in the wound		week 0
Wound microbiota: the relative abundance of Staphylococcus aureus relative to other Staphylococcus in the wound		week 4
Wound microbiota: the relative abundance of Staphylococcus aureus relative to other Staphylococcus in the wound		at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
Wound microbiota: the relative abundance of Staphylococcus aureus relative to other Staphylococcus in the wound		at week 12 if the wound is still not healed
Wound microbiota: ordination scores on each of two principal components extracted from UniFrac distances between all bacterial samples taken during the study		week 0
Wound microbiota: ordination scores on each of two principal components extracted from UniFrac distances between all bacterial samples taken during the study		week 4
Wound microbiota: ordination scores on each of two principal components extracted from UniFrac distances between all bacterial samples taken during the study		at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
Wound microbiota: ordination scores on each of two principal components extracted from UniFrac distances between all bacterial samples taken during the study		at week 12 if the wound is still not healed
The presence/absence of anti-phage antibodies in plasma samples		week 0
The presence/absence of anti-phage antibodies in plasma samples		week 4
The presence/absence of anti-phage antibodies in plasma samples		at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
The presence/absence of anti-phage antibodies in plasma samples		at week 12 if the wound is still not healed

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Nīmes
• Collaborators: Pherecydes Pharma
• Investigators: Study Director: Albert Sotto, MD, PhD, Centre Hospitalier Universitaire de Nîmes

Study record dates

Study Major Dates

• Study Start (Anticipated): June 1, 2022
• Primary Completion (Anticipated): August 1, 2024
• Study Completion (Anticipated): August 1, 2024

Study Registration Dates

• First Submitted: January 19, 2016
• First Submitted That Met QC Criteria: January 22, 2016
• First Posted (Estimate): January 27, 2016

Study Record Updates

• Last Update Posted (Actual): February 3, 2022
• Last Update Submitted That Met QC Criteria: February 2, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Phage Therapy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Infections; Endocrine System Diseases; Diabetic Angiopathies; Leg Ulcer; Skin Ulcer; Diabetes Complications; Diabetes Mellitus; Diabetic Neuropathies; Foot Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Diabetic Foot; Foot Ulcer; Staphylococcal Infections
• Other Study ID Numbers: PHRC-N/2015/AS-01

Drug and device information, study documents

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