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

Phase 2

Terminated

• Conditions: Ventilator Associated Pneumonia; Respiratory Tract Infection
• Interventions: Other: Normal Saline; Drug: anidulafungin

• Registration Number: NCT00934934
• Lead Sponsor: Daren K. Heyland

Brief Summary

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

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).

Study Timeline

• Study First Submitted: 2009-07-07
• Study First Submitted QC: 2009-07-07
• Study First Posted: 2009-07-08
• Study Start: 2010-04
• Primary Completion: 2012-08
• Study Completion: 2012-08
• Results First Submitted: 2020-08-19
• Status Verified: 2021-01
• Results First Submitted QC: 2021-01-28
• Last Update Submitted: 2021-01-28
• Results First Posted: 2021-02-01
• Last Update Posted: 2021-02-01

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 61

Inclusion Criteria

1. Adult patients (>18 years old)

2. In the ICU > 48 hours

3. Mechanically ventilated (>48 hours)

4. 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.

5. 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

Read More

Exclusion Criteria

1. Patients not expected to be in ICU for more than 72 hours (due to imminent death, withdrawal of aggressive care or discharge).
2. Patients with Candida spp. in the blood or another sterile body site.
3. Patients colonized at other non-pulmonary body site(s) with Candida.
4. Already being treated with antifungal drugs (because of documented fungal infection, pre-emptive therapy, or prophylaxis).
5. Allergy to study drugs (Fluconazole or the Echinocandin on formulary at treating institution).
6. 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.
7. Patients with fulminant liver failure or end stage liver disease (Child's Class C).
8. Women who are pregnant or lactating.
9. 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).
10. Prior randomization in this study.

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Normal Saline	Saline will serve as the placebo solution since the active comparator is clear and colourless.
Antifungal	anidulafungin	Patient will receive a dose daily for a total of 14 days

Primary Outcome Measures

Name	Time	Method
Overall Recruitment Rate	32 months	Overall recruitment rate per site

Secondary Outcome Measures

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

Trial Locations

Locations (6)

Hopital Maisonneuve-Rosemont; 🇨🇦 Montreal, Quebec, Canada

Hopital du Sacre-Coeur do Montreal; 🇨🇦 Montreal, Quebec, Canada

Hamilton Health Sciences Centre; 🇨🇦 Hamilton, Ontario, Canada

Kingston General Hospital; 🇨🇦 Kingston, Ontario, Canada

Hopital l'Enfant-Jesus; 🇨🇦 Quebec, Canada

Ottawa General Hospital; 🇨🇦 Ottawa, Ontario, Canada