Transcript Slide 1
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.
Background
• • •
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
Summary
• •
Causal relationship vs innocent bystander Benefit from therapy?
Need an RCT to move forward
Does Clinical Equipoise Exist?
Objectives
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
20% Base Event Rate and Power 25%^ 30%# 35%* Relative Risk Reduction (RRR) @
ARR
80% 90%
ARR
80% 90%
ARR
80% 90%
ARR
80% 90% 25%
5.00%
906 1213
6.25%
687
30% 35%
6.00% 7.00%
615 441 823
7.50%
467 590
8.75%
335 918
7.50%
540 624
9.00%
368 448
10.50%
265 722
8.75%
435 582 492
10.50%
297 397 354
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 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.
The CANTREAT Pilot Study Overall Design
Phase 2 Proof of Principle Study Antifungal Therapy For 14 days 120 ICU patients Candida in RT secretions only R placebo Primary Outcome Feasibility IL-6 CRP PCT SOFA
Overview of Study
ICU Admission
Duration of Study
Patient Eligibility
Consent Obtained
RANDOMIZATION Study Treatment Initiated 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 ICU Discharge or Day 28 90 day survival follow-up
Anidulafungin or Placebo
Organism speciation & susceptibility profile known If applicable, treatment Adjustments
Study Treatment is 14 days
Anidulafungin changed to
fluconazole
If applicable, route adjustment from IV to PO
Study Population
Inclusion 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 x10 9 /L) or neutropenia (<3.5 x10 9 /L) - Purulent endotracheal aspirates or change in character of aspirates - Isolation of pathogenic bacteria from endotracheal aspirates - Increasing oxygen requirements Note: date and time when 2 nd criteria met -Must occur >48 hr of mech vent - no CXR requirement 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.
Communication with the Local Micro lab
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 missed if >96 hrs
Exclusion criteria:
Study Population
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 failure
The study treatment arms are:
Study Treatment Arms
Intervention
•
Antifungal Therapy
(anidulafungin initially, potentially switching to fluconazole following speciation and susceptibility results)
OR Placebo
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.
The study treatment arms are:
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
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 Centres
Site
Kingston General
Investigator
Dr. John Muscedere St. Michael’s Hospital Dr. Jan Friedrich University Health Network Dr. Coleman Rotstein Hamilton HSC Ottawa General Sacre-Coeur Dr. Shariq Haider Salmann Kanji Dr. Martin Albert Montreal General Laval Enfant-Jesus Charles-Lemoyne Dr. Kosar Khwaja Dr. Francois Lellouche Dr. Alexis Turgeon Dr. Germain Poirier
Status
Activated Status Unknown REB Submitted, Contract under review REB Submitted, Contract under review REB Submitted, Contract under review Central REB Submitted, Contract under review REB Submitted Contract status unknown REB Submitted, Fully Executed Contract REB Submitted, Contract under review REB status unknown Contract circulating for signature