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

(The CANTREAT Study):A prospective, randomized, double blind, A prospective, randomized, double blind,

placebo controlled pilot study.placebo controlled pilot study.

BackgroundBackground

• In critically ill patients, Candida in the RT secretions (only) associated with:– Increased length of stay– Increased mortality– High levels of systematic inflammation

• Plausible mechanism related to ß-glucan • In animal models, C. albicans causes immune

dysfunction and local inflammation predisposing patients to pneumonia

SummarySummary

• Causal relationship vs innocent bystander• Benefit from therapy?

Does Clinical Equipoise Does Clinical Equipoise Exist?Exist?

Need an RCT to Need an RCT to move forwardmove forward

ObjectivesObjectives

Definitive Objective :

Compare the effect of antifungal therapy on mortality in patients with suspected VAP and Candida in the airway specimen

Sample size required per arm to achieve stated power using a two-sided Mantel-Haenszel test at alpha=0.05

Relative Risk Reduction (RRR) @

Base Event Rate and Power

20% 25%^ 30%# 35%*

ARR 80% 90% ARR 80% 90% ARR 80% 90% ARR 80% 90%

25% 5.00% 906 1213 6.25% 687 918 7.50% 540 722 8.75% 435 582

30% 6.00% 615 823 7.50% 467 624 9.00% 368 492 10.50% 297 397

35% 7.00% 441 590 8.75% 335 448 10.50% 265 354 12.25% 215 287

ARR=Absolute risk reduction from base event rate.

Mantel-Haenszel test may be stratified for >=2 comorbidities which may increase power slightly assuming similar

Objectives of the Pilot StudyObjectives of the Pilot Study

• The primary objective will be to determine the feasibility of conducting a large scale RCT evaluating effect mortality:– Determine recruitment rates– Acceptability of the treatment protocol (rate of open

label use of antifungal therapy)– Workload and compliance related to study

implementation and data capture

• The secondary objective of this pilot study is to effect of treatment for Candida on inflammatory biomarkers and ß-glucan levels.

120 ICU patientsCandida in

RT secretions onlyR

Antifungal Therapy For 14 days

placebo

Phase 2 Proof of Principle StudyPhase 2 Proof of Principle Study

The CANTREAT Pilot StudyThe CANTREAT Pilot StudyOverall DesignOverall Design

Primary Outcome

FeasibilityFeasibilityIL-6IL-6CRPCRPPCTPCT

SOFASOFA

Overview of Study Overview of Study ICU Admission

ICU Discharge or Day 28

Patient EligibilityConsent Obtained

RANDOMIZATION

Study Treatment Initiated

Organism speciation & susceptibility profile known

If applicable, treatment Adjustments

90 day survival follow-up

Anidulafungin or Placebo

Anidulafungin changed

to fluconazole

Study Treatment

is 14 days

Laboratory Samples

•Blood draws at baseline, day 3, 8, 14 (last day of treatment)

•Blood, urine, respiratory tract secretions, drains, wounds, and other sources as per clinical routine

If applicable, route adjustment from IV to PO

Duration of Study

Study PopulationInclusion criteria:1) Adult patients (>18 years old)

2) In the ICU >48 hours

(if transfer in, clock starts with ICU admission at st. elsewhere)

3) Mechanically ventilated >48 hours (invasively only)

4) Develop a clinical suspicion of respiratory tract infection (RTI) while ventilated as defined by the presence of any two of the following: - Fever > 38ºC (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

5) Grow a Candida spp. on respiratory tract secretion culture (either by BAL or ETA) taken on or between 48 hours before or after the day of their suspicion of respiratory tract infection.

Note: date and time when Note: date and time when 22ndnd criteria met criteria met

-Must occur >48 hr of mech -Must occur >48 hr of mech ventvent

- no CXR requirement- no CXR requirement

Communication with the Local Micro labCommunication with the Local Micro lab

Important Rules!Important Rules!If Candida is isolated < 48 hrs after the start of mechanical ventilation but the patient has a CSRTI after 48 hours then the patient would still be eligible as long as the Candida was isolated within 48 hours of RTI.

Patients must be randomized into the study < 96 hours from the time of the Candida positive respiratory sample (or should this be from time of CSRTI).

Log as Log as missed if missed if >96 hrs>96 hrs

Study PopulationExclusion criteria: 1) Patients not expected to be in ICU for more than 72 hours due to imminent death,

withdrawal of aggressive care or discharge.(physician determination)

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 (Swabs OK).

4) Already being treated with antifungal drugs (because of documented fungal infection, pre-emptive therapy, or prophylaxis).

[one dose OK but if physician wants to treat continuously, must be excluded]

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.

Study Population

Exclusion criteria cont’d: 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.

No exclusion re: renal failureNo exclusion re: renal failure

Intervention

• Rationale for this:– Anidulafungin proven superiority in bloodstream infections; may have nothing to do with

susceptibility profiles but more to do with clearance from blood– Anidulafungin requires no dosing for hepatic or renal dysfunction– Delays to ‘adequate’ therapy associated with increased mortality– Canadian and IDSA guidelines recommend echinocandin for first line therapy in seriously

ill patients.

Antifungal Therapy(anidulafungin initially, potentially switching to fluconazole following

speciation and susceptibility results)

OR Placebo

The study treatment arms are:

Study Treatment Arms

Intervention

• The study therapy should be initiated as soon as possible following randomization but no later than 2 hours.

• The investigational product will initially be administered via the IV route (for at least 72 hours).

• Yeast organism speciation and susceptibility results (from the respiratory tract specimen used to qualify the patient for the study) should be reported to the Pharmacy once available.

• If susceptible to Fluconazole, switch to Fluconazole after at least 72 hrs of anidulafungin– loading dose via IV route, then can switch to oral if

appropriate

The study treatment arms are:

Intervention

• If the gastro-intestinal tract is functional based on tolerance to feeds or diet, the route of administration will be converted to oral.

• Each randomized patient should receive study treatment for a total of 14 days.

• If the patient is discharged to the ward before 14 days of study treatment, study treatment should continue on the ward until a total 14 days has been given.

• For patients discharged from the hospital before 14 days of study treatment has been administered, hospital discharge day will be the last day of study treatment.

Blinding

• The treating clinician will remain blinded during the study but pharmacy will be unblinded to allow antifungal treatment modifications according to the susceptibility patterns and renal function.

• Blinding for the fluconazole and echinocandin intravenously will be maintained by transferring the commercial formulations to IV minibags by the pharmacy. The solutions of these drugs are clear, colourless and normal saline will serve as the placebo solution.

• For the oral fluconazole, we will be using a suspension which will be packaged in an amber oral syringe. An oral suspending vehicle (OraPlus®) will serve as the placebo.

Cointerventions• All patients will be managed according to the

– Canadian VAP treatment guidelines• Choice of antibiotics will be left to the treating team; the Canadian VAP treatment

guidelines recommend the prescription of empiric antibiotics at the time of CSVAP

– Canadian nutrition guidelines– Standardized weaning protocol (trial of spontaneous breathing daily).

• If during the study, a patient is felt to require systemic antifungal agents for a systemic fungal infection, the administration of study drugs will be discontinued and the patient will be treated with open label antifungal agents as per the attending physicians. Rate of this occurrence will be monitored in the context of this pilot study.

• Topical antifungal therapy is allowed.

Outcomes (1)

• Feasibility Outcomes– Enrolment rates– Compliance with study medication (Contamination or drop out

rates)– Acceptability of lab procedures– Time and compliance with data collection

Outcomes (2)

• Biochemical outcomes:– CRP, PCT, IL-6– ß-glucan, – Ex vivo LPS stimulation of TNF from monocytes– blood samples drawn at baseline, day 3, day 8 and at the

end of the treatment period on day 14

Outcomes (3)

• Usual Clinical Outcomes– SOFA daily– Modified CPIS daily (without CXR)– Duration of mechanical ventilation, stay in ICU and Hospital– Mortality at 28, ICU, hospital and 90 days– Adjudicated diagnosis of infection after 72 hours

• Do we want to adjudicate the enrollment infection?

– Acquired resistance to antifungal therapy based on samples collected for clinical reasons

• RT samples should go to central lab for susceptibility testing• No protocolized sampling

Significance• This program of research represents a significant change in the

way mechanically ventilated critically ill patients are managed. • The isolation of Candida in respiratory tract secretions has been

traditionally felt to not require treatment. Yet our recent observations suggest that patients with Candida present in their respiratory tract have elevated biochemical markers of systemic inflammation and experience considerable excess morbidity and mortality.

• It is expected that the results of this study will suggest a potential therapeutic benefit to antifungal therapy in this study population.

• This program of research has the potential to change practice and may improve the survival of critically ill patients.

Participating CentresSite Investigator Status

Kingston General Dr. John Muscedere Activated

St. Michael’s Hospital Dr. Jan Friedrich Status Unknown

University Health Network

Dr. Coleman Rotstein REB Submitted, Contract under review

Hamilton HSC Dr. Shariq Haider REB Submitted, Contract under review

Ottawa General Salmann Kanji REB Submitted, Contract under review

Sacre-Coeur Dr. Martin Albert Central REB Submitted, Contract under review

Montreal General Dr. Kosar Khwaja REB Submitted Contract status unknown

Laval Dr. Francois Lellouche REB Submitted, Fully Executed Contract

Enfant-Jesus Dr. Alexis Turgeon REB Submitted, Contract under review

Charles-Lemoyne Dr. Germain Poirier REB status unknown Contract circulating for signature

Time Lines • Protocol finalized• Initiating sites now• Start-up meeting Mar 25 2010• First patient on study in Kingston April 2010• Remaining sites initiated from April to June 2010.