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

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.

• Topical anti-Staphylococcus bacteriophage therapy (Drug): 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 (Drug): 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).

Primary outcomes

• The relative reduction in wound surface area (%) [12 weeks]

Secondary outcomes

• Immediate Safety [Day 0, 1 hour after application of experimental dressing]: 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.
• Immediate Safety [Day 7, 1 hour after application of experimental dressing]: 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.
• Immediate Safety [Day 14, 1 hour after application of experimental dressing]: 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.
• 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 [8 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 [4 weeks]: 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"
• Classification of Staphylococcus isolates as MSSA or MRSA resistant [at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)]: 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"
• Classification of Staphylococcus isolates as MSSA or MRSA resistant [at week 12 if the wound is still not healed]: 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"
• 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 [week 0]: OTU: Operational Taxonomic Unit
• Wound microbiota: OTU richness [week 4]: OTU: Operational Taxonomic Unit
• Wound microbiota: OTU richness [at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)]: OTU: Operational Taxonomic Unit
• Wound microbiota: OTU richness [at week 12 if the wound is still not healed]: OTU: Operational Taxonomic Unit
• 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]

Sex: All, ages: 18 Years to any

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 patient has a neuropathic foot wound, classified S (0 or 1), I (0 or 1), N (1), B (1), A (0 or1) and D (1) according to the SINBAD classification,

  * without ischaemia or with non-critical ischaemia defined by: ankle arterial pressure > 50 mm Hg or toe systolic arterial pressure > 30 mm Hg or TcpO2 > 30 mm Hg )
  * with a surface area ≥ 0,5 cm2
  * With IWGDF/IDSA grade 2 or 3 infection without osteomyelitis (normal radiography*)
* Females of childbearing potential or Sexually active males with partner of childbearing potential: commitment to consistently and correctly use an acceptable method of birth control (oral, transdermal, systemic or implant contraception birth control, intrauterine devices) for 1 month after the last study drug administration
* Negative pregnancy test must be obtained before starting any experimental drug
* Females of non-childbearing potential: either surgically sterilized or at least 1 year postmenopausal (amenorrhea duration at least 12 months)

Participant final inclusion criteria:

* The patient has a neuropathic foot wound:

  * Classified S (0 or 1), I (0 or 1), N (1), B (1), A (0 or1) and D (1) according to the SINBAD classification,
* without ischaemia or with non-critical ischaemia defined by: ankle arterial pressure > 50 mm Hg or toe systolic arterial pressure > 30 mm Hg or TcpO2 > 30 mm Hg )
* with a surface area ≥ 0,5 cm2

  * With IWGDF/IDSA grade 2 or 3 infection without osteomyelitis
* The patient's wound is monoinfected by methicillin-resistant or susceptible S. aureus (MSSA or MRSA ), or infected by MSSA or MRSA and other bacteria (a total of 3 bacteria when accounting for MSSA or MRSA)
* The Phagogram of the patient demonstrated that the strains are susceptible to at least one phage(PP1493 and/or PP1815).

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. Patients should not be enrolled if they plan to become pregnant during the treatment period and 1 month after the last administration of study drug
* Women/Men refusing to use an effective contraception during and1 month after the last administration of study drug

Participant final exclusion criteria:

* The patient refuses to participate to the study
* The patient is pregnant, parturient or breastfeeding. Patients should not be enrolled if they plan to become pregnant during the treatment period and 1 month after the last administration of study drug
* Women/Men refusing to use an effective contraception during and1 month after the last administration of study drug
* Patients with diabetic foot wounds associated with clinical or radiographic signs of arthritis or osteomyelitis*
* Patient is not infected by S. aureus or infected by more than 3 bacteria even if the culture isolates a S. aureus.

• Albert Sotto, MD, PhD, Study director, Centre Hospitalier Universitaire de Nīmes