Assessing the Efficacy of Anti-staphylococcal Phages in the Management of Infected Foot Ulcers in Diabetes

Study Overview
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Brief Summary
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Work Package 1: Observational cohort pilot safety study Work Package 2: Randomised, double-blind, placebo controlled pilot study Work Package 3: Observer-blind pilot RCT

Detailed Description
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Work Package 1 WP1 is a safety cohort pilot study targeting patients with DFU which are non-infected as determined by the IDSA criteria. 20 participants will be recruited from Diabetic Foot Clinic at the Royal Derby Hospital. Phage gel will be applied to the index ulcer after the first and second sets of measures at baseline, weeks 1, 2 and 3. Samples will be taken at baseline and weekly up to 4 weeks by surface swab and deep tissue sample for determination of bacterial colonisation using both conventional and genotypic (molecular) microbiological methods, prior to any IMP application. Work Package 2 WP2 is a pilot double blind, placebo-controlled, randomised study targeting patients with mild or moderate infection of DFUs and comparing systemic antibiotic therapy plus phage gel against systemic antibiotics therapy plus placebo gel. A total of 50 participants from two centres (foot clinics at Royal Derby Hospital and City Campus, Nottingham University Hospitals NHS Trust) will be recruited. Phage gel or placebo will be applied to the index ulcer after the first and second sets of measures at baseline, weeks 1, 2 and 3. Samples will be taken at baseline and weekly up to 4 weeks by surface swab and deep tissue sample for determination of bacterial colonisation using both conventional and genotypic (molecular) microbiological methods Work Package 3 WP3 is an observer-blind RCT targeting patients with mild diabetic foot infection by IDSA criteria and comparing phage gel with systemic antibiotics. A total of 50 participants from two centres (foot clinics at Royal Derby Hospital and City Campus, Nottingham University Hospitals NHS Trust) will be recruited. Those with moderately severe infections will be withheld from this work package because of the clinical and ethical issues associated with withholding antibiotics in those with a moderately severe infection.

Official Title
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Assessing the Efficacy of Anti-staphylococcal Phages in the Management of Infected Foot Ulcers in Diabetes

Conditions
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Diabetes, Diabetic Foot, Diabetic Foot Infection

Intervention / Treatment
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* Drug: Phage


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diabetes Mellitus according to WHO criteria are aged 18 years or over Additionally, patients must meet one of the following criteria to participate in the described Work Package: Patients are only eligible for WP1 if they also have one or more DFUs (area 25mm2) below the malleoli without infection according to IDSA criteria that have been present for at least 4 weeks Patients are only eligible for WP2 if they also have one or more DFUs (area 25mm2) below the malleoli with mild or moderate infection according to IDSA criteria that have been present for at least 4 weeks Patients are only eligible for WP3 if they also have one or more DFUs (area 25mm2) below the malleoli with mild infection according to IDSA criteria that have been present for at least 4 weeks Exclusion Criteria: We will exclude patients who meet ANY of the following criteria: with mental incapacity to give informed consent, who have other major co-morbidities, which in the opinion of the investigator would mean that the patient would not be able to complete the study with significant peripheral arterial disease (PAD): ABPI (ankle brachial pressure index) <0.7, Who have osteomyelitis defined by agreed clinical criteria who are receiving treatment with systemic glucocorticoids or other immunosuppressants, who have received systemic or topical antibiotics in the preceding 14 days, who are judged to require parenteral administration of antibiotics, Who have been previously recruited to an earlier part of the project who are women of childbearing age who are at risk of conception History of antibiotic hypersensitivity

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phage<br> | Drug: Phage<br>* The studies will be undertaken using a cocktail of at least 2-3 anti-staphylococcal phages produced by Intralytix Inc, Baltimore, Maryland, USA. The phages will be included in a gel designed for application directly to the wound surface and packaged in 5 ml single use tubes.<br>|
| Placebo Comparator: Placebo<br> | Drug: Phage<br>* The studies will be undertaken using a cocktail of at least 2-3 anti-staphylococcal phages produced by Intralytix Inc, Baltimore, Maryland, USA. The phages will be included in a gel designed for application directly to the wound surface and packaged in 5 ml single use tubes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Work Package 1: To assess the safety of the use of anti-staphylococcal phages therapy on the wound bacterial microbiome of uninfected DFU's. | - Safety : Clinically significant change in safety bloods, vital signs, Full Blood Count (FBC), renal function, C-Reactive protein (CRP), Liver function Tests (LFT)s, Adverse events | 7 months | 
| Work Package 2 | To compare the effect on the microbiome of empirical systemic antibiotic therapy alone (ESAT) versus ESAT plus phage therapy in ulcers complicated by mild or moderate infection as assessed by IDSA criteria | 16 months | 
| Work Package 3 | To compare the use of empirical systemic antibiotic therapy versus phage therapy in ulcers complicated by mild infection on the eradication of the infection as assessed by IDSA criteria. | 16 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Work Package 1: Safety of phage gel and overt toxic effect of phage gel. | The following outcomes will be recorded at weekly intervals for 4 weeks from baseline: Incidence of new infection Number of days of antibiotic usage Change in surface microbiome Adverse events Change in safety bloods, vital signs, FBC, renal function, CRP, LFTs Wound status (clinical infection, area, depth, extent of surface slough, pain by VAS, peri ulcer appearance) Patient well-being using a Visual Analogue Scale, 0-100mm. Vital signs (Resting pulse and blood pressure (BP)) | 7 months | 
| Work Package 1: • Impact on the bacterial microbiome of anti-staphylococcal phage gel and systemically chosen antibiotics. | The following outcomes will be recorded at weekly intervals for 4 weeks from baseline: Incidence of new infection Number of days of antibiotic usage Change in surface microbiome Adverse events Change in safety bloods, vital signs, FBC, renal function, CRP, LFTs Wound status (clinical infection, area, depth, extent of surface slough, pain by VAS, peri ulcer appearance) Patient well-being using a Visual Analogue Scale, 0-100mm. Vital signs (Resting pulse and blood pressure (BP)) | 7 months | 
| Work Package 2: Safety of phage gel and overt toxic effect of phage gel. | The following outcomes will be recorded at weekly intervals for 4 weeks from baseline: change in surface microbiome Number of antibiotic-free days Adverse events Change in safety bloods, vital signs, FBC, renal function, CRP, LFTs Wound status (clinical infection, area, depth, extent of surface slough, pain by VAS, peri ulcer appearance) Patient well-being using a Visual Analogue Scale, 0-100mm. Eradication of clinical evidence of the infection in the index ulcer at weeks 1, 2 and 3, and time to eradication Healing of all ulcers and time to healing Resting pulse and blood pressure (BP) | 7 months | 
| Work Package 2: Clinical benefit and patient well-being associated with adding phage gel to systemically chosen antibiotics compared to placebo in the management of mild or moderate infection. | The following outcomes will be recorded at weekly intervals for 4 weeks from baseline: change in surface microbiome Number of antibiotic-free days Adverse events Change in safety bloods, vital signs, FBC, renal function, CRP, LFTs Wound status (clinical infection, area, depth, extent of surface slough, pain by VAS, peri ulcer appearance) Patient well-being using a Visual Analogue Scale, 0-100mm. Eradication of clinical evidence of the infection in the index ulcer at weeks 1, 2 and 3, and time to eradication Healing of all ulcers and time to healing Resting pulse and blood pressure (BP) | 16 months | 
| Work Package 2: Impact on the bacterial microbiome of systemically chosen antibiotics and of anti-staphylococcal phage gel. | The following outcomes will be recorded at weekly intervals for 4 weeks from baseline: change in surface microbiome Number of antibiotic-free days Adverse events Change in safety bloods, vital signs, FBC, renal function, CRP, LFTs Wound status (clinical infection, area, depth, extent of surface slough, pain by VAS, peri ulcer appearance) Patient well-being using a Visual Analogue Scale, 0-100mm. Eradication of clinical evidence of the infection in the index ulcer at weeks 1, 2 and 3, and time to eradication Healing of all ulcers and time to healing Resting pulse and blood pressure (BP) | 16 months | 
| Work Package 3: Safety of phage gel and overt toxic effect of phage gel. | The following outcomes will be recorded at weekly intervals for 4 weeks from baseline: Change in surface microbiome Number of antibiotic-free days Adverse events Change in safety bloods, FBC, renal function, CRP, LFTs Wound status (clinical infection, area, depth, extent of surface slough, pain by VAS, peri ulcer appearance) Patient well-being using a Visual Analogue Scale, 0-100mm. Eradication of clinical evidence of the infection in the index ulcer at weeks 1, 2 and 3, and time to eradication Healing of all ulcers and time to healing Resting pulse and blood pressure (BP) | 16 months | 
| Work Package 3: Clinical benefit and patient well-being associated with phage gel therapy compared to systemically chosen antibiotics in the management of mild infection. | The following outcomes will be recorded at weekly intervals for 4 weeks from baseline: Change in surface microbiome Number of antibiotic-free days Adverse events Change in safety bloods, FBC, renal function, CRP, LFTs Wound status (clinical infection, area, depth, extent of surface slough, pain by VAS, peri ulcer appearance) Patient well-being using a Visual Analogue Scale, 0-100mm. Eradication of clinical evidence of the infection in the index ulcer at weeks 1, 2 and 3, and time to eradication Healing of all ulcers and time to healing Resting pulse and blood pressure (BP) | 16 months | 
| Work Package 3: Impact on the bacterial microbiome of systemically chosen antibiotics and of anti-staphylococcal phage gel. | The following outcomes will be recorded at weekly intervals for 4 weeks from baseline: Change in surface microbiome Number of antibiotic-free days Adverse events Change in safety bloods, FBC, renal function, CRP, LFTs Wound status (clinical infection, area, depth, extent of surface slough, pain by VAS, peri ulcer appearance) Patient well-being using a Visual Analogue Scale, 0-100mm. Eradication of clinical evidence of the infection in the index ulcer at weeks 1, 2 and 3, and time to eradication Healing of all ulcers and time to healing Resting pulse and blood pressure (BP) | 16 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, Diabetic Foot Disease, Diabetic Foot Ulcer