Candida in the Respiratory Tract Secretions of Critically Ill Patients and The Efficacy of Antifungal Treatment

Study Overview
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Brief Summary
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The purpose of the study is to determine whether the effect of treating Candida spp. isolated in the respiratory tract secretions of patients with a clinical suspicion of ventilator associated pneumonia (VAP) on clinical outcomes will be feasible and supported by biomarker data obtained.

Detailed Description
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Candida spp. is commonly retrieved from microbiologic specimens of ICU patients with suspected VAP. It has been associated with increased systemic inflammation and worse clinical outcomes. This association may be due to the propensity for Candida to colonize those who are sicker, who have increased levels of systemic inflammation and worse clinical outcomes. However, an alternate possibility is that Candida is more than a colonizer and is responsible for the clinical and biochemical features observed. The only way to clarify the pathogenic role of Candida from this patient population is to treat the organism and see if patients improve compared to an untreated group. The purpose of this research program is to conduct such a study to determine if Candida in respiratory tract secretions should be routinely treated in critically ill patients. Since a definitive randomized controlled trial designed to demonstrate a reduction in mortality would be large, require the commitment of large amount of resources including both time and money, the investigators propose to first conduct a small pilot feasibility study. Eligible patients will be randomized to receive antifungal treatment with anidulafungin or placebo. Following enrollment, study treatment (or placebo) will be started as soon as possible. When the Candida or yeast organisms have been speciated and/or a susceptibility profile is known, the study medication will be adjusted based on susceptibility patterns. The investigators propose to treat with antifungal therapy for a total of 14 days. Patients will be followed daily for their entire stay in ICU or till day 28, whichever comes first. For patients discharged from the ICU to the ward, they will be followed until study treatment is complete (i.e. day 14). Mortality will be determined for the ICU stay, hospital stay and at 90 days. The investigators will record admission and discharge dates to ICU, step down units, and to hospital. All patients will have 13 mL of blood/day drawn at baseline, day 3, day 8 and at the end of the treatment period on day 14 (or last day of treatment). The samples will be prepared on site and shipped to a central lab for processing. The investigators will use the blood specimens to measure markers of inflammation (C-reactive protein, Procalcitonin, and Interleukin-6 and others as determined by the investigators), markers of candida presence (b-glucan and other potential future markers) and markers of immune dysfunction (to be determined by investigators).

Official Title
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Candida in the Respiratory Tract Secretions of Critically Ill Patients and The Efficacy of Antifungal Treatment (The CANTREAT Study): A Prospective, Randomized, Double Blind, Placebo Controlled Pilot Study

Conditions
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Ventilator Associated Pneumonia, Respiratory Tract Infection

Intervention / Treatment
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* Other: Normal Saline
* Drug: anidulafungin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients (>18 years old) In the ICU > 48 hours Mechanically ventilated (>48 hours) Grow a Candida spp. on respiratory tract secretion culture (either by Bronchoalveolar Lavage or Endotracheal Aspirate) taken on or between 48 hours before or after the day of their suspicion of respiratory tract infection. Develop a clinical suspicion of respiratory tract infection while ventilated as defined by the following criteria (as defined previously in our VAP trial)5: The presence of new, worsening or persistent radiographic features suggestive of pneumonia without another obvious cause AND The presence of any two of the following: Fever > 38C (core temperature) Leukocytosis (>11.0 x109/L) or neutropenia (<3.5 x109/L) Purulent endotracheal aspirates or change in character of aspirates Isolation of pathogenic bacteria from endotracheal aspirates Increasing oxygen requirements Exclusion Criteria: Patients not expected to be in ICU for more than 72 hours (due to imminent death, withdrawal of aggressive care or discharge). Patients with Candida spp. in the blood or another sterile body site. Patients colonized at other non-pulmonary body site(s) with Candida. Already being treated with antifungal drugs (because of documented fungal infection, pre-emptive therapy, or prophylaxis). Allergy to study drugs (Fluconazole or the Echinocandin on formulary at treating institution). Immunocompromised patients (post-organ transplantation, Acquired Immunodeficiency Syndrome [AIDS], neutropenia [<1000 absolute neutrophils], corticosteroids [>20 mgs/day of prednisone or equivalent for more than 6 months]). These patients are excluded since Candida may be more invasive and these patients are much more likely to require systemic antifungal therapy. Patients with fulminant liver failure or end stage liver disease (Child's Class C). Women who are pregnant or lactating. Enrollment in industry sponsored interventional trial (co-enrollment in other academic studies would be allowed with the proviso that there was no potential interaction between the protocols). Prior randomization in this study.

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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Saline will serve as the placebo solution since the active comparator is clear and colourless. | Other: Normal Saline<br>* Normal Saline<br>|
| Active Comparator: Antifungal<br>Patient will receive a dose daily for a total of 14 days | Drug: anidulafungin<br>* TBA<br>* Other names: TBA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Recruitment Rate | Overall recruitment rate per site | 32 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Stay in ICU | Measure of the duration of participant stay in the ICU | 28 days | 
| Ventilator Free Days | Number of days in ICU free of ventilation | 28 days | 
| ICU Free Days | Number of days free of ICU | 28 days | 
| Antibiotic Free Days 28-day Post Randomization | Number of days free of antibiotic use within the first 28 days | 28 days | 
| Hospital Length of Stay | Measure of the duration of the participant's hospital stay | 90 days | 
| (SOFA) Post Randomization | Sequential organ failure assessment. 0-24 The higher the number the more severe organ failure | post randomization | 
| Sequential Procalcitonin |  | 28 days | 
| C-reactive Protein |  | 28 days | 
| Interleukin-6 |  | 28 days | 
| B-glucan Levels |  | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Candida, ventilator associated pneumonia, respiratory tract infection, antifungal, biomarker