Methods

Prospective, Phase IIA, randomised, parallel‐group, placebo‐controlled, double‐blinded study

Multicentric (6 centres) in the USA

Period of Inclusion: December 2011 to August 2012

Participants

Inclusion criteria

• A clinical diagnosis of NSTI due to bacterial infection (e.g. necrotizing fasciitis, group A Streptococcus toxic shock, Fournier gangrene, clostridial gangrene or myonecrosis, and synergistic necrotizing cellulitis)

• A decision to perform urgent surgical exploration and debridement

Exclusion criteria

• Age less than 18 years

• Weight greater than 150 kg

• Diabetes mellitus with below‐ankle infection

• Overt peripheral vascular disease in the involved area refractory

• Refractory haemodynamic instability

• Coagulopathy or hypoxia

• Burn wounds

• Cardiac arrest within the past 30 days

• Expected survival less than 30 days because of underlying medical condition

• Human immunodeficiency virus infection (CD4 count < 200 cells/mm³ or < 14% of lymphocytes)

• Pregnancy or lactation

• Prior curative tissue debridement

• Immunosuppression

Baseline characteristics

N = 43, mean age of 50.7 years and 65% of men

Interventions

Each participant was treated with standardised empiric antibiotic therapy, and underwent surgical debridement of necrotic tissue

Intervention 1 (n = 17)

AB103, one dose intravenous (IV), 0.5 mg/kg, < 6 hours after diagnosis (infusion before, during or after the surgery)

Intervention 2 (n = 15)

AB103, one dose IV 0.25 mg/kg, < 6 hours after diagnosis (infusion before, during or after the surgery)

Intervention 3 (n = 11)

Placebo IV, < 6 hours after diagnosis (infusion before during or after the surgery)

Outcomes

Primary outcome

• Change in the SOFA score from baseline within 28 days. The SOFA scores were calculated on days 0 (before drug administration), D1, D2, D4, D28 in modified ITT population

Secondary outcomes

• Intensive care unit‐free, vasopressor‐free and ventilator‐free days within the first 28 days in modified ITT population

• Number of debridements through day 7 in modified ITT population

• Hospital length of stay in modified ITT population

• Plasma and tissue cytokine levels at 0 to 72 hours in modified ITT population

• Adverse events *including death* in ITT population

Notes

Financial support and the drug for this trial was provided by the manufacturer Atox Bio Ltd.

Authors declared conflict of interest for Bayer HealthCare, BayerSchering Pharma, Novartis, GlaxoSmith Kline and Wyeth.

* outcomes reported that were of interest in the review

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “Patients were randomised by a computer‐generated system to receive placebo or a low or high dose of AB103 in a 10:15:15 ratio.”

Comment: computer‐generated random sequence is adequate

Allocation concealment (selection bias)

Unclear risk

Comment: there was no description of the method used to guarantee allocation concealment

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote “double blinded”

Comment: placebo‐controlled with similar adverse‐effect profile reported. However, concerning the risk of performance bias, 2/43 (4.6%) patients randomised had received co‐treatment IVIG and HBO and the group of these two patients was not indicated. Authors did not specify the method of blinding of physicians and participants but they assess that all investigators and care providers remained masked throughout the study.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote “double blinded" "investigators remained blinded throughout the study"

Comment: there was no clear description of the process used to guarantee blinding of the assessor but it was a placebo‐controlled study with similar adverse‐effect profile reported and assessment of outcome was objective: death. Then we considered there was a low risk of detection bias for investigator‐reported outcomes for the same reasons.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Quote “Because drug administration may have started before definitive surgical diagnosis of NSTI, a modified ITT population was defined as patients in the ITT analysis who were properly randomised, treated (received AB103 or placebo), and assessable (definitive surgical diagnosis of NSTI).”

Comment: three patients were excluded from the ITT population; 1/11 (9%) in the placebo group who did not meet the clinical diagnosis of NSTI and 2/15 (13.3%) in the high‐dose group.

Selective reporting (reporting bias)

Low risk

Comment: in accordance with the protocol available in clinical trials.gov (NCT01417780)

Other bias

Low risk

No other bias identified

Methods

Randomised, blinded, parallel‐group, placebo‐controlled trial

Monocentric at Copenhagen University Hospital, where the management of patients with NSTI in Denmark is centralised

Period of inclusion: 7 April 2014 to 1 March 2016

Participants

Inclusion criteria

• 18 years of age or older

• Patients with confirmed NSTI at surgical exploration who were admitted to, or planned to be admitted to, the ICU

Exclusion criteria

• Patients who had received more than one dose of IVIG before randomisation

• Hypersensitivity to IVIG

• Known hyperprolinaemia

• Women who were pregnant or breast‐feeding

• Diagnosis of NSTI for more than 48 hours

Baseline characteristics

N = 100, Mean age of 60 years and 60% of men

Interventions

Each patient was treated in accordance with the clinical protocols in place at Copenhagen University Hospital with standardised empiric antibiotic therapy (meropenem, clindamycin and ciprofloxacin), repeated surgical revisions, three sessions of hyperbaric oxygenation; sepsis, and supportive intensive care.

Intervention 1 (N = 50)

IVIG (Privigen, CSL Behring, Bern,Switzerland), 25 g/day for three consecutive days. The first dose of trial medicine was given immediately after arrival to the ICU or in the operating room before admission to ICU.

Intervention 2 (N = 50)

Equivalent amount of intravenous 0.9% saline for three consecutive days (placebo)

Outcomes

Primary outcome

• Patient‐reported physical function as the physical component summary (PCS) score of the Medical Outcomes Study 36‐item short form health survey version 2 (SF‐36) at day 180 after randomisation*

Secondary outcomes

• Mortality at 28*, 90 and180 days

• Time to resolution of shock defined as maintenance of a systolic blood pressure of at least 90 mmHg without vasopressor agents for 24 hours

• Severe bleeding defined as clinical bleeding and use of 3 units of red blood cells (RBC) within 24 hours of the episode in the ICU after randomisation

• Bleeding in the ICU after randomisation

• Total volumes of blood products used in the ICU after randomisation

• Sepsis‐related organ failure assessment (SOFA) scores at days 1–7 after randomisation

• Use of renal replacement therapy (RRT)

• Ventilation and vasopressor in the ICU after randomisation

• Serious adverse reactions observed in the ICU after randomisation*

• Days alive off life support in the 90 days after randomisation

• Days alive and out of hospital in the 180‐day follow‐up period

• Amputation (yes/no) within the 180 days

Notes

* outcomes reported that were of interest in the review

Authors declared conflict of interest for CSL Behring.

Financial support from Fresenius Kabi, Germany, and Ferring Pharmaceuticals, Denmark, was declared.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were randomised 1:1 to IVIG or placebo. Two allocation lists with variable block sizes of 2, 4 and 6 were computer generated."

Comment: computer‐generated random sequence is adequate

Allocation concealment (selection bias)

Low risk

Quote: "Two allocation lists with variable block sizes of 2, 4 and 6 were computer generated to form two separate boxes that contained sequentially numbered, opaque and sealed envelopes" "Patients were randomised by dedicated personnel who drew the next envelope from the box according to the site of NSTI. The randomisation note was handed to an ICU nurse not otherwise involved in the care of the patient who placed both IVIG and 0.9% saline in a black, opaque plastic bag, inserted an orange‐coloured infusion set into the allocated intervention (IVIG or saline) and sealed the bag with a plastic strip (more details are given in the Electronic Supplementary Material (ESM)."

Comment: the method used to guarantee allocation concealment seems to be adequate

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The randomisation note was handed to an ICU nurse not otherwise involved in the care of the patient who placed both IVIG and 0.9% saline in a black, opaque plastic bag, inserted an orange‐coloured infusion set into the allocated intervention (IVIG or saline) and sealed the bag with a plastic strip."

"Patients, clinical staff caring for the patients, research staff, the statistician and the authors when writing the first draft for the abstract (supplementary results in the ESM) were all blinded to the intervention."

Comment: the method used to guarantee blinding of participants and personnel was adequate and well described

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Patients, clinical staff caring for the patients, research staff, the statistician and the authors when writing the first draft for the abstract (supplementary results in the ESM) were all blinded to the intervention" "The statistician (TL) did the analyses while still blinded to the intervention according to the statistical analysis plan."

Comment: the method used to guarantee blinding of outcome assessment was well described and primary outcome is a patient‐reported outcome.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Quote: "129 patients were screened, of whom 100 were enrolled; 50 patients were assigned to the IVIG group and 50 patients to the placebo group" "Of the 100 patients randomised, 87 were included in the intention‐to‐treat analysis."

Comment: 100 patients were randomised but the SF‐36 could not be obtained from 13 patients, thus analysis of primary outcome was based on 87patients. For the primary outcome, there were no data available for 38% of patients in each group with 25% of death and 13% of missing data.

Selective reporting (reporting bias)

Low risk

Comment: in accordance with the protocol available in clinical trials.gov NCT02111161

Other bias

High risk

Comment: There was baseline imbalance: number of patients who had received IVIG before randomisation was higher in placebo group 20 (40%) than in IVIG group 8 (16%) and number of patients with acute kidney injury was higher in IVIG group 5 (10%) than in placebo group 1 (2%). This is a placebo‐controlled trial, however nearly half of patients in placebo group had received one dose of IVIG before randomisation.

Methods

Prospective, non‐inferiority randomised controlled, open‐label, parallel‐group trial

Multicentric, 74 centres, worldwide

Period of inclusion: April 2001 to April 2002

Participants

Inclusion criteria

• Patients ≥ 18 years

• Patients with a complicated skin and soft tissue infection (cSSSI) at one site only (cSSSI diagnoses were prospectively defined: diabetic foot infection, necrotizing fasciitis, post‐surgical wound infection, complicated cellulitis, complicated erysipelas, major abscess of the skin, infection of traumatic lesion, and infected Ischaemic ulcer)

• If it was anticipated that participants required systemic antimicrobial therapy

• If they had a sample culture taken within 24 hours prior to being included

• Patients had to had one of the following signs and symptoms: fever ≥ 38.0 C axillary or ≥ 38.5 C orally; leukocytosis (absolute white blood cell (WBC) count > 10,000 cells/mL) with neutrophilia (> 80% neutrophils), tachycardia (> 90 beats per minute), increased respiratory rate (> 20 breaths per minute), or elevated C‐reactive protein (CRP) – plus two or more of the following signs and symptoms within 24 hours preceding enrolment: local pain or tenderness, anaesthesia or hypoaesthesia of the affected area, swelling of the presumed affected area, purulent, serosanguinous, ‘dishwater’ or foul‐smelling discharge, gas formation detected under the skin, and changes in the appearance of the involved area, such as discolouration of skin, presence of black necrotic areas, red‐brown or haemorrhagic bullae, or skin colour changes from red‐blue to patches of blue‐grey.

Exclusion criteria

• Patients with a diagnoses of uncomplicated mild‐to‐moderate SSSIs and of secondary infected burns, atopic dermatitis, or eczema

• Pregnant or nursing patients

• Patients with severe life‐threatening diseases with a life expectancy < 2 months

• End‐stage liver cirrhosis

• Severe renal impairment requiring dialysis,

• Hypersensitivity to fluoroquinolones, and beta‐lactams

• A congenital or sporadic syndromes of QTc prolongation or patients taking concomitant medication reported to increase the QTc

• Patients with hypersensitivity to fluoroquinolones, and beta‐lactams

• History of tendinopathy with quinolones

• Severe renal impairment requiring dialysis

• Septic shock

• Patients receiving chronic immunosuppressant treatment

• Patients with neutropenia (neutrophil absolute count < 1000 cells/mL) or at AIDS stage 1 or 2 (CD4+ absolute count < 200 cells/µL)

• HIV‐seropositive individuals receiving highly‐activated antiretroviral treatment

• SSSI secondary to prosthetic materials

• 18% of the skin and soft tissue affected

• Suspected underlying osteomyelitis not related to diabetic foot infection

• Requirement for systemic concomitant antibacterial agents

• fFilure to respond to previous antibacterial treatment only if previous treatment contained a fluoroquinolone, amoxicillin or a beta‐lactam/beta‐lactamase inhibitor combination

• Patients who had received systemic antibacterial treatment (orally or parenteral) for > 24 hours within the 24 hours immediately prior to enrolment in the study

Baseline characteristics ITT population

Subgroup of NSTI (n = 54): 57.4% of male; mean age 52.2 years (provided upon a request to the authors)

Interventions

Intervention 1 (Per protocol (PP), n = 315); abscess n = 98; necrotizing fasciitis, n = 22; surgical wound infection n = 9; diabetic foot n = 49; complicated erysipelas n = 101; infected traumatic lesion n = 21; infected ischaemic ulcers n = 6; complicated cellulitis n = 9.

moxifloxacin 400 mg per day intravenous (IV), for at least 3 days, followed by moxifloxacin 400 mg orally, once daily, for 7–21 days

Intervention 2 (PP, n = 317): abscess n = 93, necrotizing fasciitis, n = 13, surgical wound infection n = 13, diabetic foot n = 63, complicated erysipelas n = 95, infected traumatic lesion n = 19, infected ischaemic ulcers n = 4, complicated cellulitis n = 17

amoxicillin‐clavulanate, IV 1000 mg/200 mg three times daily for at least 3 days, followed by amoxicillin‐clavulanate 500 mg/125 mg orally, three times daily, for 7–21 days

Outcomes

Primary outcome

• Clinical response (CR) at test of cure (TOC) for the PP population

CR at the TOC, days 14‐28, visit was defined as: cure (total resolution or marked improvement of all cSSSI signs and symptoms; no additional or alternative antimicrobial treatment necessary). Evaluations (both the visual description of the lesion and the assessment of clinical outcome) were performed by investigators.

Secondary outcomes

• Clinical response at TOC days 14‐28 for the intention to treat (ITT) population

• Clinical response at TOC days14‐28 by indication in the PP and ITT population

• Bacteriological success (eradication/presumed eradication) at TOC days 14‐28 for the PP/microbiologically evaluable population

• Adverse events in ITT population*. Assessments for safety were based on physical examination and routine laboratory tests throughout the study

Notes

This study was sponsored by Bayer HealthCare AG.

Authors declared conflict of interest for Atox Bio Ltd and Biomedical Statistical Consulting, Wynnewood, Pennsylvania.

* outcomes reported that were of interest in the review

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: “randomised into two groups in a 1:1 ratio”

Comment: the method used to generate the allocation sequence was not reported

Allocation concealment (selection bias)

Unclear risk

Quote: "Patients were randomised into two groups in a 1:1 ratio to receive either moxifloxacin or the control regimen."

Comment: there was no mention of how allocation concealment was guaranteed

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: “open label”

Comment: both participants and study personnel were aware of the assigned treatment

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: “open‐label”, “Clinical outcomes were assessed bimodally as cure or failure, such that patients with only limited improvement in clinical status and partial resolution of symptoms would conservatively be considered as failures."

Comment: assessment was performed by investigators who were not blinded

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: number of randomly assigned participants: 804

Number of analysed participants for the main outcome per protocol: 632

Patients withdrawn: 172

The main reasons for withdrawal after randomisation (moxifloxacin vs amoxicillin‐clavulanate) were adverse events (6.2% vs 3.8%), insufficient therapeutic effect (4.2% vs 5.3%), patient lost to follow‐up (3.9% vs 5.3%), and protocol violation (3.4% vs 2.8%) (P > 0.1 in all cases). There was a high rate of withdrawal mainly due to serious adverse events and insufficient therapeutic effect.

Selective reporting (reporting bias)

Unclear risk

Comment: no protocol was available, however, the outcomes predefined in the methods were well reported in the results section.

Other bias

High risk

Comment: there was baseline imbalance; number of patients in the NSTI subgroup was two‐fold higher in the moxifloxacin group (36/54) treatment than in the amoxicillin‐clavulanate group (18/54) treatment