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

• Sponsor: Daren K. Heyland (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00934934
• Collaborator: The Physicians' Services Incorporated Foundation (Other), Queen's University (Other), Pfizer (Industry)
• Enrollment: 61
• Locations: 6
• Arms: 2
• Duration (Months): 28
• Patients Per Site: 10.2
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Ventilator Associated Pneumonia; Respiratory Tract Infection	Other: Normal Saline; Drug: anidulafungin	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 61 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: 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
• Study Start Date: Apr 1, 2010
• Actual Primary Completion Date: Aug 1, 2012
• Actual Study Completion Date: Aug 1, 2012

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Overall Recruitment Rate [32 months]

   Overall recruitment rate per site

Secondary Outcome Measures

1. Duration of Stay in ICU [28 days]

   Measure of the duration of participant stay in the ICU

2. Ventilator Free Days [28 days]

   Number of days in ICU free of ventilation

3. ICU Free Days [28 days]

   Number of days free of ICU

4. Antibiotic Free Days 28-day Post Randomization [28 days]

   Number of days free of antibiotic use within the first 28 days

5. Hospital Length of Stay [90 days]

   Measure of the duration of the participant's hospital stay

6. (SOFA) Post Randomization [post randomization]

   Sequential organ failure assessment. 0-24 The higher the number the more severe organ failure

7. Sequential Procalcitonin [28 days]

8. C-reactive Protein [28 days]

9. Interleukin-6 [28 days]

10. B-glucan Levels [28 days]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hamilton Health Sciences Centre	Hamilton	Ontario	Canada
2	Kingston General Hospital	Kingston	Ontario	Canada	K7L 2V7
3	Ottawa General Hospital	Ottawa	Ontario	Canada
4	Hopital Maisonneuve-Rosemont	Montreal	Quebec	Canada	H1T 2M4
5	Hopital du Sacre-Coeur do Montreal	Montreal	Quebec	Canada	H4J 1C5
6	Hopital l'Enfant-Jesus	Quebec		Canada	G1J 1Z4

Sponsors and Collaborators

• Daren K. Heyland
• The Physicians' Services Incorporated Foundation
• Queen's University
• Pfizer

Investigators

• Study Chair: Daren Heyland, MD, Clinical Evaluation Research Unit

Study Documents (Full-Text)

None provided.

More Information

Publications

• Arnold DM, Burns KE, Adhikari NK, Kho ME, Meade MO, Cook DJ; McMaster Critical Care Interest Group. The design and interpretation of pilot trials in clinical research in critical care. Crit Care Med. 2009 Jan;37(1 Suppl):S69-74. doi: 10.1097/CCM.0b013e3181920e33. Review.
• Azoulay E, Timsit JF, Tafflet M, de Lassence A, Darmon M, Zahar JR, Adrie C, Garrouste-Orgeas M, Cohen Y, Mourvillier B, Schlemmer B; Outcomerea Study Group. Candida colonization of the respiratory tract and subsequent pseudomonas ventilator-associated pneumonia. Chest. 2006 Jan;129(1):110-7.
• Canadian Critical Care Trials Group. A randomized trial of diagnostic techniques for ventilator-associated pneumonia. N Engl J Med. 2006 Dec 21;355(25):2619-30.
• Canadian Institutes of Health Research. Available at: www.cihr.ca Accessed February 9, 2009.
• Chastre J, Fagon JY. Ventilator-associated pneumonia. Am J Respir Crit Care Med. 2002 Apr 1;165(7):867-903. Review.
• Christofilopoulou S, Charvalos E, Petrikkos G. Could procalcitonin be a predictive biological marker in systemic fungal infections?. Study of 14 cases. Eur J Intern Med. 2002 Dec;13(8):493-495.
• Delisle MS, Williamson DR, Perreault MM, Albert M, Jiang X, Heyland DK. The clinical significance of Candida colonization of respiratory tract secretions in critically ill patients. J Crit Care. 2008 Mar;23(1):11-7. doi: 10.1016/j.jcrc.2008.01.005.
• el-Ebiary M, Torres A, Fàbregas N, de la Bellacasa JP, González J, Ramirez J, del Baño D, Hernández C, Jiménez de Anta MT. Significance of the isolation of Candida species from respiratory samples in critically ill, non-neutropenic patients. An immediate postmortem histologic study. Am J Respir Crit Care Med. 1997 Aug;156(2 Pt 1):583-90.
• Heyland DK, Dodek P, Muscedere J, Day A, Cook D; Canadian Critical Care Trials Group. Randomized trial of combination versus monotherapy for the empiric treatment of suspected ventilator-associated pneumonia. Crit Care Med. 2008 Mar;36(3):737-44.
• Heyland et al, WATTCH database. Observational study of the clinical characteristics and biomarker profiles of 569 critically ill patients. Analysis ongoing.
• Inoue K, Takano H, Oda T, Yanagisawa R, Tamura H, Ohno N, Adachi Y, Ishibashi K, Yoshikawa T. Candida soluble cell wall beta-D-glucan induces lung inflammation in mice. Int J Immunopathol Pharmacol. 2007 Jul-Sep;20(3):499-508.
• Magill SS, Swoboda SM, Johnson EA, Merz WG, Pelz RK, Lipsett PA, Hendrix CW. The association between anatomic site of Candida colonization, invasive candidiasis, and mortality in critically ill surgical patients. Diagn Microbiol Infect Dis. 2006 Aug;55(4):293-301. Epub 2006 May 15. Erratum in: Diagn Microbiol Infect Dis. 2007 Mar;57(3):351.
• Müller V, Viemann D, Schmidt M, Endres N, Ludwig S, Leverkus M, Roth J, Goebeler M. Candida albicans triggers activation of distinct signaling pathways to establish a proinflammatory gene expression program in primary human endothelial cells. J Immunol. 2007 Dec 15;179(12):8435-45.
• Muscedere J, Dodek P, Keenan S, Fowler R, Cook D, Heyland D; VAP Guidelines Committee and the Canadian Critical Care Trials Group. Comprehensive evidence-based clinical practice guidelines for ventilator-associated pneumonia: diagnosis and treatment. J Crit Care. 2008 Mar;23(1):138-47. doi: 10.1016/j.jcrc.2007.12.008.
• Muscedere J, Dodek P, Keenan S, Fowler R, Cook D, Heyland D; VAP Guidelines Committee and the Canadian Critical Care Trials Group. Comprehensive evidence-based clinical practice guidelines for ventilator-associated pneumonia: prevention. J Crit Care. 2008 Mar;23(1):126-37. doi: 10.1016/j.jcrc.2007.11.014.
• Muscedere JG, Martin CM, Heyland DK. The impact of ventilator-associated pneumonia on the Canadian health care system. J Crit Care. 2008 Mar;23(1):5-10. doi: 10.1016/j.jcrc.2007.11.012. Review.
• Muscedere JG, McColl C, Shorr A, Jiang X, Marshall J, Heyland DK; Canadian Critical Care Trials Group. Determinants of outcome in patients with a clinical suspicion of ventilator-associated pneumonia. J Crit Care. 2008 Mar;23(1):41-9. doi: 10.1016/j.jcrc.2007.12.007.
• Nseir S, Jozefowicz E, Cavestri B, Sendid B, Di Pompeo C, Dewavrin F, Favory R, Roussel-Delvallez M, Durocher A. Impact of antifungal treatment on Candida-Pseudomonas interaction: a preliminary retrospective case-control study. Intensive Care Med. 2007 Jan;33(1):137-42. Epub 2006 Nov 8.
• Odabasi Z, Mattiuzzi G, Estey E, Kantarjian H, Saeki F, Ridge RJ, Ketchum PA, Finkelman MA, Rex JH, Ostrosky-Zeichner L. Beta-D-glucan as a diagnostic adjunct for invasive fungal infections: validation, cutoff development, and performance in patients with acute myelogenous leukemia and myelodysplastic syndrome. Clin Infect Dis. 2004 Jul 15;39(2):199-205. Epub 2004 Jun 28.
• Presterl E, Lassnigg A, Mueller-Uri P, El-Menyawi I, Graninger W. Cytokines in sepsis due to Candida albicans and in bacterial sepsis. Eur Cytokine Netw. 1999 Sep;10(3):423-30.
• Reade MC, Angus DC. The clinical research enterprise in critical care: what's right, what's wrong, and what's ahead? Crit Care Med. 2009 Jan;37(1 Suppl):S1-9. doi: 10.1097/CCM.0b013e318192074c.
• Rello J, Esandi ME, Díaz E, Mariscal D, Gallego M, Vallès J. The role of Candida sp isolated from bronchoscopic samples in nonneutropenic patients. Chest. 1998 Jul;114(1):146-9.
• Safdar N, Dezfulian C, Collard HR, Saint S. Clinical and economic consequences of ventilator-associated pneumonia: a systematic review. Crit Care Med. 2005 Oct;33(10):2184-93. Review.
• Sakurai T, Ohno N, Yadomae T. Effects of fungal beta-glucan and interferon-gamma on the secretory functions of murine alveolar macrophages. J Leukoc Biol. 1996 Jul;60(1):118-24.
• Senn L, Robinson JO, Schmidt S, Knaup M, Asahi N, Satomura S, Matsuura S, Duvoisin B, Bille J, Calandra T, Marchetti O. 1,3-Beta-D-glucan antigenemia for early diagnosis of invasive fungal infections in neutropenic patients with acute leukemia. Clin Infect Dis. 2008 Mar 15;46(6):878-85. doi: 10.1086/527382.
• Tschaikowsky K, Hedwig-Geissing M, Schiele A, Bremer F, Schywalsky M, Schüttler J. Coincidence of pro- and anti-inflammatory responses in the early phase of severe sepsis: Longitudinal study of mononuclear histocompatibility leukocyte antigen-DR expression, procalcitonin, C-reactive protein, and changes in T-cell subsets in septic and postoperative patients. Crit Care Med. 2002 May;30(5):1015-23.
• Van Saene H., Peric M., De La Cal M., Silvestri L.: Pneumonia during Mechanical Ventilation. Anestiologie a Intenzivni Medicina 2004; 15: 89-100.
• van Teijlingen E, Hundley V. The importance of pilot studies. Nurs Stand. 2002 Jun 19-25;16(40):33-6. Review.
• Wheeler RT, Fink GR. A drug-sensitive genetic network masks fungi from the immune system. PLoS Pathog. 2006 Apr;2(4):e35. Epub 2006 Apr 28.
• Williamson D., Albert M., Perreault M., Delisle M., Muscedere J., Rotstein C.Jiang X., Day A. ,Heyland D. Effect of Candida spp. in respiratory tract secretions on systemic inflammation. Submitted to SCCM for Feb. 2009
• Williamson D., Martin A., Perreault M., Delisle M., Muscedere J., Rotstein C., Jiang X., Heyland D. Impact of pulmonary Candida colonization on systemic inflammation in the critically ill. Manuscript in preparation.

• Responsible Party: Daren K. Heyland, Director, Clinical Evaluation Research Unit, Clinical Evaluation Research Unit at Kingston General Hospital
• ClinicalTrials.gov Identifier: NCT00934934
• Other Study ID Numbers: CANTREAT
• First Posted: Jul 8, 2009
• Last Update Posted: Feb 1, 2021
• Last Verified: Jan 1, 2021

• Keywords provided by Daren K. Heyland, Director, Clinical Evaluation Research Unit, Clinical Evaluation Research Unit at Kingston General Hospital: Candida; ventilator associated pneumonia; respiratory tract infection; antifungal; biomarker
• Additional relevant MeSH terms: Pneumonia; Respiratory Tract Infections; Pneumonia, Ventilator-Associated; Anidulafungin

Study Results

Participant Flow

Pre-assignment Detail	One pt was mistakenly randomized to intervention without Candida, so was moved to observational group prior to starting treatment

Arm/Group Title	Placebo	Antifungal
Arm/Group Description	Saline will serve as the placebo solution since the active comparator is clear and colourless. Normal Saline: Normal Saline	Patient will receive a dose daily for a total of 14 days anidulafungin: TBA
Period Title: Overall Study
STARTED	30	31
COMPLETED	29	31
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Placebo	Antifungal	Total
Arm/Group Description	Saline will serve as the placebo solution since the active comparator is clear and colourless. Normal Saline: Normal Saline	Patient will receive a dose daily for a total of 14 days anidulafungin: TBA	Total of all reporting groups
Overall Participants	29	31	60
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.0 (13.8)	57.6 (17.1)	60.3 (15.5)
Sex: Female, Male (Count of Participants)
Female	6 20.7%	10 32.3%	16 26.7%
Male	23 79.3%	21 67.7%	44 73.3%
Region of Enrollment (participants) [Number]
Canada	29 100%	31 100%	60 100%

Outcome Measures

1. Primary Outcome

Title	Overall Recruitment Rate
Description	Overall recruitment rate per site
Time Frame	32 months

Outcome Measure Data

Analysis Population Description

This outcome measure was pre-specified to be for overall participants not by group. It was a reflection of how recruitment went for this protocol overall not by group.

Arm/Group Title	Overall
Arm/Group Description
Measure Participants	61
Measure sites	5
Number [participants per site /month]	0.6 2.1%

2. Secondary Outcome

Title	Duration of Stay in ICU
Description	Measure of the duration of participant stay in the ICU
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Antifungal
Arm/Group Description
Measure Participants	29	31
Median (Inter-Quartile Range) [days]	11.5	13

3. Secondary Outcome

Title	Ventilator Free Days
Description	Number of days in ICU free of ventilation
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Antifungal
Arm/Group Description
Measure Participants	29	31
Median (Inter-Quartile Range) [days]	8	9

4. Secondary Outcome

Title	ICU Free Days
Description	Number of days free of ICU
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Antifungal
Arm/Group Description
Measure Participants	29	31
Median (Inter-Quartile Range) [days]	14	4

5. Secondary Outcome

Title	Antibiotic Free Days 28-day Post Randomization
Description	Number of days free of antibiotic use within the first 28 days
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Antifungal
Arm/Group Description
Measure Participants	29	31
Median (Inter-Quartile Range) [days]	16	10

6. Secondary Outcome

Title	Hospital Length of Stay
Description	Measure of the duration of the participant's hospital stay
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Antifungal
Arm/Group Description
Measure Participants	29	31
Median (Inter-Quartile Range) [days]	29	28

7. Secondary Outcome

Title	(SOFA) Post Randomization
Description	Sequential organ failure assessment. 0-24 The higher the number the more severe organ failure
Time Frame	post randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Antifungal
Arm/Group Description
Measure Participants	29	31
Mean (Standard Deviation) [score on a scale]	5.9 (3.3)	5.9 (3.6)

8. Secondary Outcome

Title	Sequential Procalcitonin
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	VAP withCandida	VAP Without Candida
Arm/Group Description
Measure Participants	56	21
Mean (Standard Deviation) [ng/ml]	3.0 (8.8)	22.5 (89.4)

9. Secondary Outcome

Title	C-reactive Protein
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	VAP withCandida	VAP Without Candida
Arm/Group Description
Measure Participants	56	21
Mean (Standard Deviation) [mg/l]	133 (115)	145.7 (104)

10. Secondary Outcome

Title	Interleukin-6
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	VAP withCandida	VAP Without Candida
Arm/Group Description
Measure Participants	56	21
Mean (Standard Deviation) [pg/ml]	97.5 (183)	3 (10.3)

11. Secondary Outcome

Title	B-glucan Levels
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	VAP withCandida	VAP Without Candida
Arm/Group Description
Measure Participants	56	21
Mean (Standard Deviation) [pg/ml]	116 (171)	129.1 (190.5)

Adverse Events

Adverse Event Reporting Description	"0" Total Number of Participants at Risk (e.g.., serious and other [non-serious] adverse events were not collected or assessed as part of the study).
Arm/Group Title	Placebo		Antifungal
Arm/Group Description	Saline will serve as the placebo solution since the active comparator is clear and colourless. Normal Saline: Normal Saline		Patient will receive a dose daily for a total of 14 days anidulafungin: TBA
All Cause Mortality
	Placebo		Antifungal
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Serious Adverse Events
	Placebo		Antifungal
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Placebo		Antifungal
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

We had an overall enrolment rate/month of 0.6 patients/site for the randomized trial. Consequently, recruitment was halted prematurely despite efforts to optimize enrolment because of difficulty in recruiting patients and diminishing study resources.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.