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

Diabetic Foot Clinical Trial

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Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT02664740
• Other study ID #: PHRC-N/2015/AS-01
• Status: Not yet recruiting
• Phase: Phase 1/Phase 2
• Start date: June 1, 2022
• Est. completion date: August 2024

Study information

• Verified date: February 2022
• Source: Centre Hospitalier Universitaire de Nimes
• Contact: Albert Sotto, MD, PhD
• Phone: +33.(0)6.09.56.66.55
• Email: albert.sotto[@]chu-nimes.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 60
• Est. completion date: August 2024
• Est. primary completion date: August 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Diabetic Foot
• Foot Ulcer
• Staphylococcal Infections

Intervention

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).
• 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).

Locations

Country	Name	City	State
France	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 Cedex 1
France	APHP - Hôpital Lariboisière	Paris
France	APHP - Groupe Hospitalier Pitié-Salpetrière	Paris Cedex 13
France	CHRU de Toulouse - Hôpital de Rangueil	Toulouse Cedex 9
France	CH de Tourcoing	Tourcoing
France	Institut Robert Merle d'Aubigné	Valenton
France	CH Intercommunal de Villeneuve-Saint-Georges	Villeneuve-Saint-Georges

Sponsors (2)

Lead Sponsor	Collaborator
Centre Hospitalier Universitaire de Nimes	Pherecydes Pharma

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The relative reduction in wound surface area (%)		12 weeks
Secondary	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
Secondary	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
Secondary	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
Secondary	The number of MedDRA coded Adverse Events per patient		throughout the study; 12 weeks
Secondary	The presence/absence of abnormal laboratory results		throughout the study; 12 weeks
Secondary	Wound surface area		2 weeks
Secondary	Wound surface area		4 weeks
Secondary	Wound surface area		6 weeks
Secondary	Wound surface area		8 weeks
Secondary	Wound surface area		10 weeks
Secondary	Wound surface area		12 weeks
Secondary	Wound depth		2 weeks
Secondary	Wound depth		4 weeks
Secondary	Wound depth		6 weeks
Secondary	Wound depth		8 weeks
Secondary	Wound depth		10 weeks
Secondary	Wound depth		12 weeks
Secondary	Time to healing		censored at 12 weeks
Secondary	The % of completely healed wounds		12 weeks
Secondary	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
Secondary	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)
Secondary	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
Secondary	Classification of Staphylococcus isolates according to clonal complexes (virulence classification)		4 weeks
Secondary	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)
Secondary	Classification of Staphylococcus isolates according to clonal complexes (virulence classification)		at week 12 if the wound is still not healed
Secondary	Presence/absence of non-Staphylococcus aureus bacteria that are antibiotic-resistant		week 0
Secondary	Presence/absence of non-Staphylococcus aureus bacteria that are antibiotic-resistant		week 4
Secondary	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)
Secondary	Presence/absence of non-Staphylococcus aureus bacteria that are antibiotic-resistant		at week 12 if the wound is still not healed
Secondary	Wound microbiota: OTU richness	OTU: Operational Taxonomic Unit	week 0
Secondary	Wound microbiota: OTU richness	OTU: Operational Taxonomic Unit	week 4
Secondary	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)
Secondary	Wound microbiota: OTU richness	OTU: Operational Taxonomic Unit	at week 12 if the wound is still not healed
Secondary	Wound microbiota: Shannon's Diversity		week 0
Secondary	Wound microbiota: Shannon's Diversity		week 4
Secondary	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)
Secondary	Wound microbiota: Shannon's Diversity		at week 12 if the wound is still not healed
Secondary	Wound microbiota: Functional richness		week 0
Secondary	Wound microbiota: Functional richness		week 4
Secondary	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)
Secondary	Wound microbiota: Functional richness		at week 12 if the wound is still not healed
Secondary	Wound microbiota: Functional diversity		week 0
Secondary	Wound microbiota: Functional diversity		week 4
Secondary	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)
Secondary	Wound microbiota: Functional diversity		at week 12 if the wound is still not healed
Secondary	Wound microbiota: the relative abundance of Staphylococcus relative to other bacteria in the wound		week 0
Secondary	Wound microbiota: the relative abundance of Staphylococcus relative to other bacteria in the wound		week 4
Secondary	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)
Secondary	Wound microbiota: the relative abundance of Staphylococcus relative to other bacteria in the wound		at week 12 if the wound is still not healed
Secondary	Wound microbiota: the number of Staphylococcus strains in a wound		week 0
Secondary	Wound microbiota: the number of Staphylococcus strains in a wound		week 4
Secondary	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)
Secondary	Wound microbiota: the number of Staphylococcus strains in a wound		at week 12 if the wound is still not healed
Secondary	Wound microbiota: the relative abundance of Staphylococcus aureus relative to other bacteria in the wound		week 0
Secondary	Wound microbiota: the relative abundance of Staphylococcus aureus relative to other bacteria in the wound		week 4
Secondary	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)
Secondary	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
Secondary	Wound microbiota: the relative abundance of Staphylococcus aureus relative to other Staphylococcus in the wound		week 0
Secondary	Wound microbiota: the relative abundance of Staphylococcus aureus relative to other Staphylococcus in the wound		week 4
Secondary	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)
Secondary	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
Secondary	Wound microbiota: ordination scores on each of two principal components extracted from UniFrac distances between all bacterial samples taken during the study		week 0
Secondary	Wound microbiota: ordination scores on each of two principal components extracted from UniFrac distances between all bacterial samples taken during the study		week 4
Secondary	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)
Secondary	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
Secondary	The presence/absence of anti-phage antibodies in plasma samples		week 0
Secondary	The presence/absence of anti-phage antibodies in plasma samples		week 4
Secondary	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)
Secondary	The presence/absence of anti-phage antibodies in plasma samples		at week 12 if the wound is still not healed