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

Centre Hospitalier Universitaire de Nīmes60 enrolled

Overview

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.

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Diabetic Foot Staphylococcal Infections

Interventions

Topical anti-Staphylococcus bacteriophage therapyDRUG

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).

Topical placebo corresponding to anti-Staphylococcus bacteriophage therapyDRUG

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).

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (9)

CHU de Bordeaux - Hôpital Pellegrin

Bordeaux, France

CHRU de Nîmes - Hôpital Universitaire de Réadaptation du Grau du Roi

Le Grau-du-Roi, France

CHU de Nantes - Hôtel Dieu

Nantes, France

APHP - Hôpital Lariboisière

Outcomes

Primary Outcomes

The relative reduction in wound surface area (%)

Time frame: 12 weeks

Secondary Outcomes

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.

Time frame: Day 0, 1 hour after application of experimental dressing

Immediate Safety

Time frame: Day 7, 1 hour after application of experimental dressing

Immediate Safety

Time frame: Day 14, 1 hour after application of experimental dressing

The number of MedDRA coded Adverse Events per patient

Time frame: throughout the study; 12 weeks

The presence/absence of abnormal laboratory results

Time frame: throughout the study; 12 weeks

Wound surface area

Central Contacts

Albert Sotto, MD, PhD

CONTACT

+33.(0)6.09.56.66.55 albert.sotto@chu-nimes.fr

Carey Suehs, PhD

CONTACT

+33.(0)4.66.68.67.88 carey.suehs@chu-nimes.fr

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

APHP - Groupe Hospitalier Pitié-Salpetrière

Paris, France

CHRU de Toulouse - Hôpital de Rangueil

Toulouse, France

CH de Tourcoing

Tourcoing, France

Institut Robert Merle d'Aubigné

Valenton, France

CH Intercommunal de Villeneuve-Saint-Georges

Villeneuve-Saint-Georges, France

Wound surface area

Time frame: 4 weeks

Wound surface area

Time frame: 6 weeks

Wound surface area

Time frame: 8 weeks

Wound surface area

Time frame: 10 weeks

Wound surface area

Time frame: 12 weeks

Wound depth

Time frame: 2 weeks

Wound depth

Time frame: 4 weeks

Wound depth

Time frame: 6 weeks

Wound depth

Time frame: 8 weeks

Wound depth

Time frame: 10 weeks

Wound depth

Time frame: 12 weeks

Time to healing

Time frame: censored at 12 weeks

The % of completely healed wounds

Time frame: 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"

Time frame: 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"

Time frame: 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"

Time frame: at week 12 if the wound is still not healed

Classification of Staphylococcus isolates according to clonal complexes (virulence classification)

Time frame: 4 weeks

Classification of Staphylococcus isolates according to clonal complexes (virulence classification)

Time frame: 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)

Time frame: at week 12 if the wound is still not healed

Presence/absence of non-Staphylococcus aureus bacteria that are antibiotic-resistant

Time frame: week 0

Presence/absence of non-Staphylococcus aureus bacteria that are antibiotic-resistant

Time frame: week 4

Presence/absence of non-Staphylococcus aureus bacteria that are antibiotic-resistant

Time frame: 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

Time frame: at week 12 if the wound is still not healed

Wound microbiota: OTU richness

OTU: Operational Taxonomic Unit

Time frame: week 0

Wound microbiota: OTU richness

OTU: Operational Taxonomic Unit

Time frame: week 4

Wound microbiota: OTU richness

OTU: Operational Taxonomic Unit

Time frame: 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

Time frame: at week 12 if the wound is still not healed

Wound microbiota: Shannon's Diversity

Time frame: week 0

Wound microbiota: Shannon's Diversity

Time frame: week 4

Wound microbiota: Shannon's Diversity

Time frame: 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

Time frame: at week 12 if the wound is still not healed

Wound microbiota: Functional richness

Time frame: week 0

Wound microbiota: Functional richness

Time frame: week 4

Wound microbiota: Functional richness

Time frame: 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

Time frame: at week 12 if the wound is still not healed

Wound microbiota: Functional diversity

Time frame: week 0

Wound microbiota: Functional diversity

Time frame: week 4

Wound microbiota: Functional diversity

Time frame: 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

Time frame: at week 12 if the wound is still not healed

Wound microbiota: the relative abundance of Staphylococcus relative to other bacteria in the wound

Time frame: week 0

Wound microbiota: the relative abundance of Staphylococcus relative to other bacteria in the wound

Time frame: week 4

Wound microbiota: the relative abundance of Staphylococcus relative to other bacteria in the wound

Time frame: 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

Time frame: at week 12 if the wound is still not healed

Wound microbiota: the number of Staphylococcus strains in a wound

Time frame: week 0

Wound microbiota: the number of Staphylococcus strains in a wound

Time frame: week 4

Wound microbiota: the number of Staphylococcus strains in a wound

Time frame: 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

Time frame: 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

Time frame: week 0

Wound microbiota: the relative abundance of Staphylococcus aureus relative to other bacteria in the wound

Time frame: week 4

Wound microbiota: the relative abundance of Staphylococcus aureus relative to other bacteria in the wound

Time frame: 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

Time frame: 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

Time frame: week 0

Wound microbiota: the relative abundance of Staphylococcus aureus relative to other Staphylococcus in the wound

Time frame: week 4

Wound microbiota: the relative abundance of Staphylococcus aureus relative to other Staphylococcus in the wound

Time frame: 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

Time frame: 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

Time frame: week 0

Wound microbiota: ordination scores on each of two principal components extracted from UniFrac distances between all bacterial samples taken during the study

Time frame: week 4

Wound microbiota: ordination scores on each of two principal components extracted from UniFrac distances between all bacterial samples taken during the study

Time frame: 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

Time frame: at week 12 if the wound is still not healed

The presence/absence of anti-phage antibodies in plasma samples

Time frame: week 0

The presence/absence of anti-phage antibodies in plasma samples

Time frame: week 4

The presence/absence of anti-phage antibodies in plasma samples

Time frame: 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

Time frame: at week 12 if the wound is still not healed