MSG-01: Randomized Study of Caspofungin Prophylaxis Followed by Pre-emptive Therapy for Invasive Candidiasis in the Intensive Care Unit (ICU)

• Sponsor: Mycoses Study Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00520234
• Collaborator: Merck Sharp & Dohme LLC (Industry)
• Enrollment: 222
• Locations: 12
• Arms: 2
• Duration (Months): 31
• Patients Per Site: 18.5
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

Adults admitted to intensive care units are at risk for a variety of complications. Infections due to the fungus called candida are of particular concern. The study will test the possibility that caspofungin, a new therapy for fungal infections, can successfully reduce the rate of candida infections in subjects at risk. It will also test if caspofungin is useful in treating subjects for this disease when diagnosed using a new blood test that is performed twice weekly, permitting earlier diagnosis than current practice standards.

Condition or Disease	Intervention/Treatment	Phase
Invasive Candidiasis	Drug: Caspofungin; Drug: Normal Saline	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 222 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: A Randomized, Double-blind, Placebo Controlled Trial of Caspofungin Prophylaxis Followed by Pre-emptive Therapy for Invasive Candidiasis in High-risk Adults in the Critical Care Setting
• Study Start Date: Aug 1, 2007
• Actual Primary Completion Date: Mar 1, 2010
• Actual Study Completion Date: Mar 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1 prophylaxis Caspofungin 50 mg Intravenous (IV) daily up to 28 days of therapy	Drug: Caspofungin; 50 mg IV daily
Placebo Comparator: 2 placebo Normal Saline 100 cc IV daily	Drug: Normal Saline; 100 cc IV daily; Other Names: placebo

Outcome Measures

Primary Outcome Measures

1. Proven and Probable Invasive Candidiasis Based on Modified Mycoses Study Group/European Organization for Research and Treatment of Cancer (MSG/EORTC) Criteria. [Within 7 days after end of therapy]

   Modified MSG/EORTC criteria for the diagnosis of fungal infections: Proven invasive candidiasis is defined as candidemia, Candida cultured from a sterile site, or histopathological evidence of candida infection. Probable invasive candidiasis is defined as 2 consecutive positive beta glucan levels in the presence of signs and symptoms of infection.

Secondary Outcome Measures

1. Incidence of Proven Invasive Candidiasis by MSG/ EORTC Criteria. [Within 7 days of end of therapy]

2. All Cause Mortality [Within 7 days of end of therapy]

3. Initiation of Other Antifungals [Within 7 days after end of therapy]

4. Time to Development of Proven or Probable Invasive Candidiasis [Within 7 days after end of therapy]

5. Incidence of Proven and Probable Invasive Fungal Infections Other Than Invasive Candidiasis. [Within 7 days after end of therapy]

6. Time to Beta Glucan Negativity in Pre-emptive Phase. [Within 14 days after end of therapy]

7. Incidence of Complete and Partial Response by Clinical and Microbiological or Serological Evidence for Subjects on the Pre-emptive Therapy Phase. [Within 14 days after end of therapy]

8. Hospital Metrics (to be Evaluated Separately for Prophylaxis and Pre-emptive Therapy Phases); Length of Stay in the Hospital, Length of Stay in the ICU, and the Costs Data for the ICU Stay and the Hospitalization, if Available. [Hospital discharge]

9. Subjects Who Discontinue Study Therapy Due to a Drug-related Adverse Event [Up to 14 days after end of therapy]

10. Subjects With 1 or More Serious Drug-related Adverse Event(s) [Up to 14 days after end of therapy]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Non-pregnant >18 yrs of age

• Subjects admitted to ICU during the preceding 3 days and expected to stay in the ICU for at least another 48 hours.Subjects can be enrolled on days 3-5 of ICU admission.

• Subjects meeting the clinical prediction rule

Exclusion Criteria:

• Subjects with an allergy/intolerance to caspofungin or echinocandin analog

• absolute neutrophil count <500/mm3 at study entry or likely to develop such a count during therapy

• acquired immunodeficiency syndrome, aplastic anemia or chronic granulomatous disease

• moderate or severe hepatic insufficiency

• subjects who are pregnant or lactating

• unlikely to survive < 24 hours

• subjects who have received systemic antifungal therapy within 10 days prior to study entry

• Documented active proven or probable invasive fungal infection upon enrollment

• previously enrolled in this study

• Currently on another investigational agent or have received an investigational agent within 10 days prior to study entry.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35124
2	University of Southern California	Los Angeles	California	United States	29425
3	University of Colorado	Denver	Colorado	United States	80262
4	Washington Hospital Center	Washington	District of Columbia	United States	20010
5	Tulane University	New Orleans	Louisiana	United States	70112
6	Harper University Hospital/ Wayne State	Detroit	Michigan	United States	48201
7	Henry Ford Hospital	Detroit	Michigan	United States	48202
8	St. Patrick's Hospital	Missoula	Montana	United States	59802
9	Cooper University Hospital	Camden	New Jersey	United States	08103
10	The Ohio State University	Columbus	Ohio	United States	43210
11	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
12	Medical Center of South Carolina	Charleston	South Carolina	United States	29425

Sponsors and Collaborators

• Mycoses Study Group
• Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Luis Ostrosky-Zeichner, MD, The University of Texas Health Science Center, Houston
• Principal Investigator: Peter G Pappas, MD, Mycoses Study Group

Study Documents (Full-Text)

None provided.

More Information

Publications

• Denning DW. Echinocandins: a new class of antifungal. J Antimicrob Chemother. 2002 Jun;49(6):889-91. Review.
• Diekema DJ, Messer SA, Brueggemann AB, Coffman SL, Doern GV, Herwaldt LA, Pfaller MA. Epidemiology of candidemia: 3-year results from the emerging infections and the epidemiology of Iowa organisms study. J Clin Microbiol. 2002 Apr;40(4):1298-302.
• Goodman JL, Winston DJ, Greenfield RA, Chandrasekar PH, Fox B, Kaizer H, Shadduck RK, Shea TC, Stiff P, Friedman DJ, et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med. 1992 Mar 26;326(13):845-51.
• Jarvis WR. Epidemiology of nosocomial fungal infections, with emphasis on Candida species. Clin Infect Dis. 1995 Jun;20(6):1526-30. Review.

• ClinicalTrials.gov Identifier: NCT00520234
• Other Study ID Numbers: MSG-01
• First Posted: Aug 23, 2007
• Last Update Posted: May 9, 2011
• Last Verified: Apr 1, 2011

• Keywords provided by , ,: Candida; Prophylaxis; High risk adults; Intensive care unit (ICU)
• Additional relevant MeSH terms: Candidiasis; Candidiasis, Invasive; Caspofungin

Study Results

Participant Flow

Arm/Group Title	Prophylaxis	Placebo
Arm/Group Description	Caspofungin 50 mg IV daily up to 28 days of therapy	Normal Saline 100 cc IV daily
Period Title: Overall Study
STARTED	118	104
COMPLETED	117	102
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	Prophylaxis	Placebo	Total
Arm/Group Description	Caspofungin 50 mg IV daily up to 28 days of therapy	Normal Saline 100 cc IV daily	Total of all reporting groups
Overall Participants	117	102	219
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.2 (17.5)	56.7 (16.6)	57.5 (17.1)
Sex: Female, Male (Count of Participants)
Female	46 39.3%	41 40.2%	87 39.7%
Male	71 60.7%	61 59.8%	132 60.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	7 6%	8 7.8%	15 6.8%
Not Hispanic or Latino	109 93.2%	94 92.2%	203 92.7%
Unknown or Not Reported	1 0.9%	0 0%	1 0.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	2 2%	2 0.9%
Asian	1 0.9%	0 0%	1 0.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	35 29.9%	35 34.3%	70 32%
White	78 66.7%	60 58.8%	138 63%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	3 2.6%	5 4.9%	8 3.7%
Acute Physiology And Chronic Health Evaluation (APACHE) II score (minimum 0, maximum 71) (Score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Score on a scale]	25.3 (8.0)	25.1 (8.7)	25.2 (8.3)

Outcome Measures

1. Primary Outcome

Title	Proven and Probable Invasive Candidiasis Based on Modified Mycoses Study Group/European Organization for Research and Treatment of Cancer (MSG/EORTC) Criteria.
Description	Modified MSG/EORTC criteria for the diagnosis of fungal infections: Proven invasive candidiasis is defined as candidemia, Candida cultured from a sterile site, or histopathological evidence of candida infection. Probable invasive candidiasis is defined as 2 consecutive positive beta glucan levels in the presence of signs and symptoms of infection.
Time Frame	Within 7 days after end of therapy

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population, defined as subjects who received at least one dose of study drug and did not have baseline invasive candidiasis.

Arm/Group Title	Prophylaxis	Placebo
Arm/Group Description	Caspofungin 50mg IV daily	Normal Saline 100 cc IV daily
Measure Participants	102	84
Number [percent of participants]	9.8 8.4%	16.6 16.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Prophylaxis, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.14
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	APACHE II Stratified

2. Secondary Outcome

Title	Incidence of Proven Invasive Candidiasis by MSG/ EORTC Criteria.
Time Frame	Within 7 days of end of therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	All Cause Mortality
Time Frame	Within 7 days of end of therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Initiation of Other Antifungals
Time Frame	Within 7 days after end of therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Time to Development of Proven or Probable Invasive Candidiasis
Time Frame	Within 7 days after end of therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Incidence of Proven and Probable Invasive Fungal Infections Other Than Invasive Candidiasis.
Time Frame	Within 7 days after end of therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Time to Beta Glucan Negativity in Pre-emptive Phase.
Time Frame	Within 14 days after end of therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Incidence of Complete and Partial Response by Clinical and Microbiological or Serological Evidence for Subjects on the Pre-emptive Therapy Phase.
Time Frame	Within 14 days after end of therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Hospital Metrics (to be Evaluated Separately for Prophylaxis and Pre-emptive Therapy Phases); Length of Stay in the Hospital, Length of Stay in the ICU, and the Costs Data for the ICU Stay and the Hospitalization, if Available.
Time Frame	Hospital discharge

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	Subjects Who Discontinue Study Therapy Due to a Drug-related Adverse Event
Time Frame	Up to 14 days after end of therapy

Outcome Measure Data

Analysis Population Description

Safety population, defined as all subjects who received at least one dose of study drug.

Arm/Group Title	Prophylaxis	Placebo
Arm/Group Description	Caspofungin 50 mg IV daily up to 28 days of therapy	Normal Saline 100 cc IV daily
Measure Participants	117	102
Number [participants]	2 1.7%	2 2%

11. Secondary Outcome

Title	Subjects With 1 or More Serious Drug-related Adverse Event(s)
Time Frame	Up to 14 days after end of therapy

Outcome Measure Data

Analysis Population Description

Safety population, defined as all subjects who received at least one dose of study drug.

Arm/Group Title	Prophylaxis	Placebo
Arm/Group Description	Caspofungin 50 mg IV daily up to 28 days of therapy	Normal Saline 100 cc IV daily
Measure Participants	117	102
Number [participants]	1 0.9%	0 0%

Adverse Events

Time Frame	Within 14 days of completion of study therapy.
Arm/Group Title	Prophylaxis		Placebo
Arm/Group Description	Caspofungin 50 mg IV daily up to 28 days of therapy		Normal Saline 100 cc IV daily
All Cause Mortality
	Prophylaxis		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Prophylaxis		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/117 (28.2%)		28/102 (27.5%)
Cardiac disorders
Atrioventricular extrasystoles	1/117 (0.9%)		0/102 (0%)
Bradycardia	0/117 (0%)		1/102 (1%)
Cardiac arrest	3/117 (2.6%)		3/102 (2.9%)
Cardiac failure congestive	0/117 (0%)		1/102 (1%)
Cardiomyopathy acute	0/117 (0%)		1/102 (1%)
Cardio-respiratory arrest	4/117 (3.4%)		1/102 (1%)
Electromechanical dissociation	0/117 (0%)		1/102 (1%)
Congenital, familial and genetic disorders
Bradyarrhythmia	0/117 (0%)		1/102 (1%)
Gastrointestinal disorders
Chronic gastrointestinal bleeding	2/117 (1.7%)		0/102 (0%)
Gastrointestinal haemorrhage	0/117 (0%)		1/102 (1%)
Intestinal haemorrhage	1/117 (0.9%)		0/102 (0%)
Pneumoperitoneum	1/117 (0.9%)		0/102 (0%)
General disorders
Multi-organ failure	0/117 (0%)		2/102 (2%)
Sudden death	0/117 (0%)		1/102 (1%)
Infections and infestations
Abdominal sepsis	1/117 (0.9%)		0/102 (0%)
Sepsis	8/117 (6.8%)		3/102 (2.9%)
Septic shock	7/117 (6%)		0/102 (0%)
Investigations
Transaminases increased	0/117 (0%)		1/102 (1%)
Metabolism and nutrition disorders
Hyperkalaemia	1/117 (0.9%)		0/102 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma	0/117 (0%)		1/102 (1%)
Nervous system disorders
Brain stem infarction	1/117 (0.9%)		0/102 (0%)
Grand mal convulsion	1/117 (0.9%)		0/102 (0%)
Haemorrhage intracranial	1/117 (0.9%)		0/102 (0%)
Haemorrhagic stroke	0/117 (0%)		1/102 (1%)
Ischaemic stroke	0/117 (0%)		1/102 (1%)
Metabolic encephalopathy	1/117 (0.9%)		0/102 (0%)
Spinal cord infarction	0/117 (0%)		1/102 (1%)
Renal and urinary disorders
Renal failure	0/117 (0%)		1/102 (1%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	1/117 (0.9%)		1/102 (1%)
Dyspnoea	0/117 (0%)		1/102 (1%)
Pulmonary embolism	1/117 (0.9%)		0/102 (0%)
Pulmonary fibrosis	0/117 (0%)		1/102 (1%)
Pulmonary hypertension	0/117 (0%)		1/102 (1%)
Respiratory arrest	0/117 (0%)		2/102 (2%)
Respiratory distress	3/117 (2.6%)		1/102 (1%)
Respiratory failure	4/117 (3.4%)		2/102 (2%)
Vascular disorders
Deep vein thrombosis	1/117 (0.9%)		0/102 (0%)
Flushing	1/117 (0.9%)		0/102 (0%)
Hypotension	1/117 (0.9%)		0/102 (0%)
Peripheral ischaemia	0/117 (0%)		1/102 (1%)
Shock	0/117 (0%)		1/102 (1%)
Other (Not Including Serious) Adverse Events
	Prophylaxis		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	106/117 (90.6%)		87/102 (85.3%)
Blood and lymphatic system disorders
Anaemia	14/117 (12%)		13/102 (12.7%)
Leukocytosis	14/117 (12%)		7/102 (6.9%)
Thrombocytopenia	7/117 (6%)		4/102 (3.9%)
Gastrointestinal disorders
Diarrhoea	6/117 (5.1%)		6/102 (5.9%)
General disorders
Pyrexia	18/117 (15.4%)		6/102 (5.9%)
Infections and infestations
Bacteraemia	5/117 (4.3%)		7/102 (6.9%)
Sepsis	9/117 (7.7%)		5/102 (4.9%)
Septic shock	8/117 (6.8%)		0/102 (0%)
Investigations
Blood urea increased	6/117 (5.1%)		3/102 (2.9%)
Hepatic enzyme increased	13/117 (11.1%)		3/102 (2.9%)
Metabolism and nutrition disorders
Hyperkalaemia	3/117 (2.6%)		6/102 (5.9%)
Hypoglycaemia	9/117 (7.7%)		7/102 (6.9%)
Hypokalaemia	11/117 (9.4%)		3/102 (2.9%)
Hyponatraemia	4/117 (3.4%)		6/102 (5.9%)
Hypophosphataemia	8/117 (6.8%)		3/102 (2.9%)
Musculoskeletal and connective tissue disorders
Hyperglycaemia	6/117 (5.1%)		4/102 (3.9%)
Psychiatric disorders
Agitation	7/117 (6%)		4/102 (3.9%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	11/117 (9.4%)		4/102 (3.9%)
Respiratory distress	7/117 (6%)		3/102 (2.9%)
Respiratory failure	7/117 (6%)		4/102 (3.9%)
Skin and subcutaneous tissue disorders
Decubitus ulcer	3/117 (2.6%)		6/102 (5.9%)
Vascular disorders
Deep vein thrombosis	10/117 (8.5%)		1/102 (1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.