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

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.

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.

Interventions

• 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).
• 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).

Primary outcome measures

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

Secondary outcome measures (12)

• Immediate Safety [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 [Time frame: 2 weeks]
• 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]

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 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

France · 6 centers

• CHU de Bordeaux - Hôpital Pellegrin — Bordeaux
• CHRU de Nîmes - Hôpital Universitaire de Réadaptation du Grau du Roi — Le Grau-du-Roi
• Hopital européen — Marseille
• CHRU de Toulouse - Hôpital de Rangueil — Toulouse
• CH de Tourcoing — Tourcoing
• CH Intercommunal de Villeneuve-Saint-Georges — Villeneuve-Saint-Georges

Identifiers

NCT: NCT02664740 · PHRC-N/2015/AS-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗