Clinical trial NCT02664740: Standard Treatment Associated With Phage Therapy Versus Placebo for Diabetic Foot Ulcers Infected by S. Aureus
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Diabetic Foot
Staphylococcal Infections
Keywords: Phage Therapy
Lead sponsor: Centre Hospitalier Universitaire de Nīmes
Sponsor class: OTHER
Collaborators: name: Phaxiam Therapeutics
First posted: 2016-01-27
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: The relative reduction in wound surface area (%)
timeFrame: 12 weeks
Secondary outcomes:
measure: Immediate Safety
timeFrame: Day 0, 1 hour after application of experimental dressing
measure: Immediate Safety
timeFrame: Day 7, 1 hour after application of experimental dressing
measure: Immediate Safety
timeFrame: Day 14, 1 hour after application of experimental dressing
measure: The number of MedDRA coded Adverse Events per patient
timeFrame: throughout the study; 12 weeks
measure: The presence/absence of abnormal laboratory results
timeFrame: throughout the study; 12 weeks
measure: Wound surface area
timeFrame: 2 weeks
measure: Wound surface area
timeFrame: 4 weeks
measure: Wound surface area
timeFrame: 6 weeks
measure: Wound surface area
timeFrame: 8 weeks
measure: Wound surface area
timeFrame: 10 weeks
measure: Wound surface area
timeFrame: 12 weeks
measure: Wound depth
timeFrame: 2 weeks
measure: Wound depth
timeFrame: 4 weeks
measure: Wound depth
timeFrame: 6 weeks
measure: Wound depth
timeFrame: 8 weeks
measure: Wound depth
timeFrame: 10 weeks
measure: Wound depth
timeFrame: 12 weeks
measure: Time to healing
timeFrame: censored at 12 weeks
measure: The % of completely healed wounds
timeFrame: 12 weeks
measure: Classification of Staphylococcus isolates as MSSA or MRSA resistant
timeFrame: 4 weeks
measure: Classification of Staphylococcus isolates as MSSA or MRSA resistant
timeFrame: at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
measure: Classification of Staphylococcus isolates as MSSA or MRSA resistant
timeFrame: at week 12 if the wound is still not healed
measure: Classification of Staphylococcus isolates according to clonal complexes (virulence classification)
timeFrame: 4 weeks
measure: Classification of Staphylococcus isolates according to clonal complexes (virulence classification)
timeFrame: at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
measure: Classification of Staphylococcus isolates according to clonal complexes (virulence classification)
timeFrame: at week 12 if the wound is still not healed
measure: Presence/absence of non-Staphylococcus aureus bacteria that are antibiotic-resistant
timeFrame: week 0
measure: Presence/absence of non-Staphylococcus aureus bacteria that are antibiotic-resistant
timeFrame: week 4
measure: Presence/absence of non-Staphylococcus aureus bacteria that are antibiotic-resistant
timeFrame: at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
measure: Presence/absence of non-Staphylococcus aureus bacteria that are antibiotic-resistant
timeFrame: at week 12 if the wound is still not healed
measure: Wound microbiota: OTU richness
timeFrame: week 0
measure: Wound microbiota: OTU richness
timeFrame: week 4
measure: Wound microbiota: OTU richness
timeFrame: at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
measure: Wound microbiota: OTU richness
timeFrame: at week 12 if the wound is still not healed
measure: Wound microbiota: Shannon's Diversity
timeFrame: week 0
measure: Wound microbiota: Shannon's Diversity
timeFrame: week 4
measure: Wound microbiota: Shannon's Diversity
timeFrame: at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
measure: Wound microbiota: Shannon's Diversity
timeFrame: at week 12 if the wound is still not healed
measure: Wound microbiota: Functional richness
timeFrame: week 0
measure: Wound microbiota: Functional richness
timeFrame: week 4
measure: Wound microbiota: Functional richness
timeFrame: at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
measure: Wound microbiota: Functional richness
timeFrame: at week 12 if the wound is still not healed
measure: Wound microbiota: Functional diversity
timeFrame: week 0
measure: Wound microbiota: Functional diversity
timeFrame: week 4
measure: Wound microbiota: Functional diversity
timeFrame: at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
measure: Wound microbiota: Functional diversity
timeFrame: at week 12 if the wound is still not healed
measure: Wound microbiota: the relative abundance of Staphylococcus relative to other bacteria in the wound
timeFrame: week 0
measure: Wound microbiota: the relative abundance of Staphylococcus relative to other bacteria in the wound
timeFrame: week 4
measure: Wound microbiota: the relative abundance of Staphylococcus relative to other bacteria in the wound
timeFrame: at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
measure: Wound microbiota: the relative abundance of Staphylococcus relative to other bacteria in the wound
timeFrame: at week 12 if the wound is still not healed
measure: Wound microbiota: the number of Staphylococcus strains in a wound
timeFrame: week 0
measure: Wound microbiota: the number of Staphylococcus strains in a wound
timeFrame: week 4
measure: Wound microbiota: the number of Staphylococcus strains in a wound
timeFrame: at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
measure: Wound microbiota: the number of Staphylococcus strains in a wound
timeFrame: at week 12 if the wound is still not healed
measure: Wound microbiota: the relative abundance of Staphylococcus aureus relative to other bacteria in the wound
timeFrame: week 0
measure: Wound microbiota: the relative abundance of Staphylococcus aureus relative to other bacteria in the wound
timeFrame: week 4
measure: Wound microbiota: the relative abundance of Staphylococcus aureus relative to other bacteria in the wound
timeFrame: at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
measure: Wound microbiota: the relative abundance of Staphylococcus aureus relative to other bacteria in the wound
timeFrame: at week 12 if the wound is still not healed
measure: Wound microbiota: the relative abundance of Staphylococcus aureus relative to other Staphylococcus in the wound
timeFrame: week 0
measure: Wound microbiota: the relative abundance of Staphylococcus aureus relative to other Staphylococcus in the wound
timeFrame: week 4
measure: Wound microbiota: the relative abundance of Staphylococcus aureus relative to other Staphylococcus in the wound
timeFrame: at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
measure: Wound microbiota: the relative abundance of Staphylococcus aureus relative to other Staphylococcus in the wound
timeFrame: at week 12 if the wound is still not healed
measure: Wound microbiota: ordination scores on each of two principal components extracted from UniFrac distances between all bacterial samples taken during the study
timeFrame: week 0
measure: Wound microbiota: ordination scores on each of two principal components extracted from UniFrac distances between all bacterial samples taken during the study
timeFrame: week 4
measure: Wound microbiota: ordination scores on each of two principal components extracted from UniFrac distances between all bacterial samples taken during the study
timeFrame: at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
measure: Wound microbiota: ordination scores on each of two principal components extracted from UniFrac distances between all bacterial samples taken during the study
timeFrame: at week 12 if the wound is still not healed
measure: The presence/absence of anti-phage antibodies in plasma samples
timeFrame: week 0
measure: The presence/absence of anti-phage antibodies in plasma samples
timeFrame: week 4
measure: The presence/absence of anti-phage antibodies in plasma samples
timeFrame: at modification of the first-line treatment or new antibiotic prescription (if any; most likey at 14 days and before 12 weeks)
measure: The presence/absence of anti-phage antibodies in plasma samples
timeFrame: at week 12 if the wound is still not healed
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: CHU de Bordeaux - Hôpital Pellegrin
city: Le Grau du Roi
country: France
facility: CHRU de Nîmes - Hôpital Universitaire de Réadaptation du Grau du Roi
city: Nantes Cedex 1
country: France
facility: CHU de Nantes - Hôtel Dieu
city: Paris Cedex 13
country: France
facility: APHP - Groupe Hospitalier Pitié-Salpetrière
city: Paris
country: France
facility: APHP - Hôpital Lariboisière
city: Toulouse Cedex 9
country: France
facility: CHRU de Toulouse - Hôpital de Rangueil
city: Tourcoing
country: France
facility: CH de Tourcoing
city: Valenton
country: France
facility: Institut Robert Merle d'Aubigné
city: Villeneuve-Saint-Georges
country: France
facility: CH Intercommunal de Villeneuve-Saint-Georges
Study officials:
affiliation: Centre Hospitalier Universitaire de Nîmes
name: Albert Sotto, MD, PhD
role: STUDY_DIRECTOR
References: