Caspofungin Maximum Tolerated Dose in Patients With Invasive Aspergillosis

• Sponsor: University of Cologne (Other)
• Overall Status: Completed
• CT.gov ID: NCT00404092
• Collaborator: (none)
• Enrollment: 46
• Locations: 4
• Arms: 4
• Duration (Months): 36
• Patients Per Site: 11.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This study investigates the safety and tolerability as well as the efficacy and pharmacokinetics of caspofungin in four escalating dosages in adult patients with hematologic malignancies and proven or probable invasive aspergillosis.

Condition or Disease	Intervention/Treatment	Phase
Invasive Aspergillosis	Drug: caspofungin	Phase 2

Detailed Description

Due to its efficacy and a broad antifungal spectrum against relevant fungal pathogens, lack of cross-resistance to azoles and amphotericin B, documented efficacy against human Aspergillus infections, favorable pharmacokinetic properties, and excellent tolerability according to the current data, caspofungin is a highly promising candidate for improving the results of treatment of invasive fungal infections.

Preclinical and clinical data indicate a dose dependent antifungal efficacy of caspofungin as well as of other echinocandins such as micafungin and anidulafungin. Thus it appears reasonable to investigate the impact of higher doses of caspofungin to improve the results already achieved with this component so far.

The maximum tolerated dose (MTD) of caspofungin and the distribution of the drug in patients following administration of doses of 70 mg or more are not yet known. We therefore investigate the safety, tolerability and pharmacokinetics of caspofungin in rising doses in a dose escalation study in adult patients with proven or probable invasive aspergillosis.

Study Design

• Study Type: Interventional
• Actual Enrollment: 46 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Dose Escalation Study of Caspofungin in Patients With Invasive Aspergillosis
• Study Start Date: Oct 1, 2006
• Actual Primary Completion Date: Oct 1, 2009
• Actual Study Completion Date: Oct 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1st cohort 70mg caspofungin 1x/day	Drug: caspofungin; i.v.; Other Names: cancidas
Experimental: 2nd cohort 100mg caspofungin 1x/day	Drug: caspofungin; i.v.; Other Names: cancidas
Experimental: 3rd cohort 150mg caspofungin 1x/day	Drug: caspofungin; i.v.; Other Names: cancidas
Experimental: 4th cohort 200mg caspofungin 1x/day	Drug: caspofungin; i.v.; Other Names: cancidas

Outcome Measures

Primary Outcome Measures

1. Safety and Tolerability of Caspofungin in Four Escalating Dosages in Adult Patients With Hematologic Malignancies and Proven or Probable Invasive Aspergillosis [End of caspofungin treatment, treatment duration varied between 3 and 29 days (mean: 20.5; median: 24.5)]

   Endpoints of safety and tolerability are the number of toxicity-related study therapy discontinuations and grade III and IV clinical and laboratory events, as evaluated on the basis of current NCI criteria.

Secondary Outcome Measures

1. Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis. [End of caspofungin treatment; 4 weeks follow-up; 12 weeks follow-up]

   Numbers of patients in each dose cohort according to invasive aspergillosis (IA) outcome at end of protocol treatment (EOT), 4 weeks follow-up (4w FU) and 12 weeks follow-up (12w FU), respectively. 12w FU was only required for patients with a CR or PR at the 4w FU. Definitions: CR: resolution of all attributable symptoms, signs, and radiographic or bronchoscopic abnormalities. PR: clinically meaningful improvement in attributable symptoms, signs, and radiographic (min. 50% decrease) or bronchoscopic abnormalities. Stable disease (SD): no improvement in attributable symptoms, signs, and radiographic or bronchoscopic abnormalities. Failure: deterioration in attributable clinical or radiographic abnormalities necessitating alternative antifungal therapy or resulting in death. Relapse: reemergence of IA after EOT following CR, PR or SD or early withdrawal.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Immunocompromised due to hematologic malignancies, bone marrow failure syndromes, hematopoietic stem cell transplantation, solid organ transplantation, other conditions resulting in severe neutropenia, HIV infection, prolonged corticosteroid therapy, treatment with other immunosuppressive medications, or other immunocompromising conditions that place patients at risk for invasive fungal infections.

• Evidence of proven or probable invasive aspergillosis, by modified EORTC criteria

Exclusion Criteria:

• Concomitant other systemic antifungal agents are not permitted on study.

• Chronic invasive fungal infection, defined as signs/symptoms of invasive fungal infection present for > 4 weeks preceding entry into study

• Prior systemic therapy of ≥ 4 days with any polyene anti-fungal agent within 14 days of study enrollment

• Prior systemic therapy of ≥ 4 days with non-polyenes for the current, documented IFI.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Hospital Gasthuisberg	Leuven		Belgium	3000
2	Charité - Campus Benjamin Franklin	Berlin		Germany	12200
3	Klinikum der Universität zu Köln	Köln		Germany	50924
4	Universitätsklinikum Münster	Münster		Germany	48149

Sponsors and Collaborators

• University of Cologne

Investigators

• Principal Investigator: Oliver A. Cornely, MD, Klinikum der Universität zu Köln

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Oliver Cornely, MD, Prof. Dr. Oliver Cornely, University of Cologne
• ClinicalTrials.gov Identifier: NCT00404092
• Other Study ID Numbers: Uni-Koeln-687; 2006-001936-30
• First Posted: Nov 27, 2006
• Last Update Posted: Jul 31, 2013
• Last Verified: Jul 1, 2013

• Keywords provided by Oliver Cornely, MD, Prof. Dr. Oliver Cornely, University of Cologne: aspergillosis; caspofungin; maximum tolerated dose
• Additional relevant MeSH terms: Aspergillosis; Caspofungin

Study Results

Participant Flow

Arm/Group Title	1st Cohort	2nd Cohort	3rd Cohort	4th Cohort
Arm/Group Description	70mg 1x/day caspofungin : i.v.	100mg 1x/day caspofungin : i.v.	150mg 1x/day caspofungin : i.v.	200mg 1x/day caspofungin : i.v.
Period Title: Overall Study
STARTED	9	8	9	20
COMPLETED	8	8	8	20
NOT COMPLETED	1	0	1	0

Baseline Characteristics

Arm/Group Title	1st Cohort	2nd Cohort	3rd Cohort	4th Cohort	Total
Arm/Group Description	70mg 1x/day caspofungin : i.v.	100mg 1x/day caspofungin : i.v.	150mg 1x/day caspofungin : i.v.	200mg 1x/day caspofungin : i.v.	Total of all reporting groups
Overall Participants	9	8	9	20	46
Age, Customized (participants) [Number]
<=30 years	0 0%	1 12.5%	0 0%	1 5%	2 4.3%
Between 30 and 40 years	2 22.2%	1 12.5%	1 11.1%	2 10%	6 13%
Between 40 and 50 years	1 11.1%	1 12.5%	2 22.2%	2 10%	6 13%
Between 50 and 60 years	3 33.3%	0 0%	1 11.1%	3 15%	7 15.2%
Between 60 and 70 years	2 22.2%	4 50%	4 44.4%	7 35%	17 37%
> 70 years	1 11.1%	1 12.5%	1 11.1%	5 25%	8 17.4%
Sex: Female, Male (Count of Participants)
Female	2 22.2%	5 62.5%	4 44.4%	10 50%	21 45.7%
Male	7 77.8%	3 37.5%	5 55.6%	10 50%	25 54.3%
Region of Enrollment (participants) [Number]
Germany	9 100%	8 100%	9 100%	20 100%	46 100%

Outcome Measures

1. Secondary Outcome

Title	Efficacy of Caspofungin in Four Escalating Dosages in the Treatment of Proven or Probable Invasive Aspergillosis.
Description	Numbers of patients in each dose cohort according to invasive aspergillosis (IA) outcome at end of protocol treatment (EOT), 4 weeks follow-up (4w FU) and 12 weeks follow-up (12w FU), respectively. 12w FU was only required for patients with a CR or PR at the 4w FU. Definitions: CR: resolution of all attributable symptoms, signs, and radiographic or bronchoscopic abnormalities. PR: clinically meaningful improvement in attributable symptoms, signs, and radiographic (min. 50% decrease) or bronchoscopic abnormalities. Stable disease (SD): no improvement in attributable symptoms, signs, and radiographic or bronchoscopic abnormalities. Failure: deterioration in attributable clinical or radiographic abnormalities necessitating alternative antifungal therapy or resulting in death. Relapse: reemergence of IA after EOT following CR, PR or SD or early withdrawal.
Time Frame	End of caspofungin treatment; 4 weeks follow-up; 12 weeks follow-up

Outcome Measure Data

Analysis Population Description

All 46 recruited patients were included in the analysis. 2 (EOT), 16 (4w FU) and 23 (12w FU) outcomes out of 46 were not recorded.

Arm/Group Title	1st Cohort	2nd Cohort	3rd Cohort	4th Cohort
Arm/Group Description	70mg 1x/day caspofungin : i.v.	100mg 1x/day caspofungin : i.v.	150mg 1x/day caspofungin : i.v.	200mg 1x/day caspofungin : i.v.
Measure Participants	9	8	9	20
Favorable Response (CR&PR)	4 44.4%	3 37.5%	6 66.7%	12 60%
Complete Response (CR)	0 0%	0 0%	1 11.1%	0 0%
Partial Response (PR)	4 44.4%	3 37.5%	5 55.6%	12 60%
Stable Disease	2 22.2%	0 0%	2 22.2%	0 0%
Failure	3 33.3%	4 50%	0 0%	8 40%
Relapse (from Favorable Response) 4w post EOT	0 0%	0 0%	2 22.2%	3 15%
Relapse (from Favorable Response) 12w post EOT	1 11.1%	0 0%	2 22.2%	3 15%

2. Primary Outcome

Title	Safety and Tolerability of Caspofungin in Four Escalating Dosages in Adult Patients With Hematologic Malignancies and Proven or Probable Invasive Aspergillosis
Description	Endpoints of safety and tolerability are the number of toxicity-related study therapy discontinuations and grade III and IV clinical and laboratory events, as evaluated on the basis of current NCI criteria.
Time Frame	End of caspofungin treatment, treatment duration varied between 3 and 29 days (mean: 20.5; median: 24.5)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	1st Cohort	2nd Cohort	3rd Cohort	4th Cohort
Arm/Group Description	70mg 1x/day caspofungin : i.v.	100mg 1x/day caspofungin : i.v.	150mg 1x/day caspofungin : i.v.	200mg 1x/day caspofungin : i.v.
Measure Participants	9	7	8	20
Treatment-emergent AEs (grade 3 to 5)	11	12	9	73
At least possibly related AEs (grade 3 to 5)	0	0	0	6
At least probably related AEs (grade 3 to 5)	0	0	0	1

Adverse Events

Arm/Group Title	1st Cohort		2nd Cohort		3rd Cohort		4th Cohort
Arm/Group Description	70mg 1x/day caspofungin : i.v.		100mg 1x/day caspofungin : i.v.		150mg 1x/day caspofungin : i.v.		200mg 1x/day caspofungin : i.v.
All Cause Mortality
	1st Cohort		2nd Cohort		3rd Cohort		4th Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	1st Cohort		2nd Cohort		3rd Cohort		4th Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/9 (11.1%)		5/8 (62.5%)		7/9 (77.8%)		12/20 (60%)
Blood and lymphatic system disorders
Anemia	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
Hypotension	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
Syncope	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
Lymphadenitis	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
Cardiac disorders
Bradycardia	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
Ventricular tachycardia	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
Gastrointestinal disorders
Enterocolitis	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
General disorders
Fever	0/9 (0%)		0/8 (0%)		4/9 (44.4%)		3/20 (15%)
Worsening of general condition	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
Death	1/9 (11.1%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
Persistence or progression of underlying disease	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		4/20 (20%)
Hepatobiliary disorders
Liver failure	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
Infections and infestations
Sepsis	0/9 (0%)		0/8 (0%)		0/9 (0%)		3/20 (15%)
Musculoskeletal and connective tissue disorders
Osteonecrosis	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
Psychiatric disorders
Psychosis	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/9 (0%)		3/8 (37.5%)		1/9 (11.1%)		3/20 (15%)
Hemoptysis	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
Pneumonia	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		2/20 (10%)
Pulmonary hemorrhage	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
Surgical and medical procedures
Urinary bladder tamponade	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	1st Cohort		2nd Cohort		3rd Cohort		4th Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/9 (100%)		8/8 (100%)		9/9 (100%)		20/20 (100%)
Blood and lymphatic system disorders
anemia	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		11/20 (55%)
intermittend leukopenia	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
intermittend thrombocytopenia	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
leukopenia	2/9 (22.2%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
neutropenia	3/9 (33.3%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
persistence of blast cells	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
persistence of blasts	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
thrombopenia	0/9 (0%)		1/8 (12.5%)		1/9 (11.1%)		3/20 (15%)
hematoma	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
hematoma at the neck	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
hematoma left arm	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
nosebleed	1/9 (11.1%)		2/8 (25%)		2/9 (22.2%)		2/20 (10%)
petechiae	2/9 (22.2%)		0/8 (0%)		4/9 (44.4%)		2/20 (10%)
red spots at the lower abdominal area	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
red spots, pustules	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
Cardiac disorders
arterial hypertension	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
cardiac dysrrhthmias	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
circulatory discomfort	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
collaps	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		1/20 (5%)
cyanosis	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
edema	5/9 (55.6%)		1/8 (12.5%)		2/9 (22.2%)		4/20 (20%)
fall, knocked head	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
heart-trouble	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
hypertension	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		3/20 (15%)
hypotension	2/9 (22.2%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
hypotension with dizziness	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
hypotonia	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
tachycardia	0/9 (0%)		1/8 (12.5%)		1/9 (11.1%)		0/20 (0%)
tightness in the chest	0/9 (0%)		1/8 (12.5%)		1/9 (11.1%)		0/20 (0%)
vertigo	1/9 (11.1%)		1/8 (12.5%)		2/9 (22.2%)		1/20 (5%)
Ear and labyrinth disorders
intermittant ear pressure	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
pressure on the ears	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
hearing loss	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
Eye disorders
reddened eyes	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
Gastrointestinal disorders
frequent dejection	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
aphtha	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
brown coated tongue	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
coated tongue	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
constipation	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		1/20 (5%)
diarrhea	1/9 (11.1%)		1/8 (12.5%)		4/9 (44.4%)		6/20 (30%)
discomfort over the liver area	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
dry lips	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
dry mucosa mouth	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
flatulence	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		1/20 (5%)
heartburn	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
inappetance	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		1/20 (5%)
inappetence	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
mucositis	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
nausea	2/9 (22.2%)		3/8 (37.5%)		1/9 (11.1%)		5/20 (25%)
obstipation	2/9 (22.2%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
oral lesions due to dental prosthesis	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
pain during swallowing	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
red-brown coated tongue	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
sialorrhea	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
sore throat	0/9 (0%)		0/8 (0%)		2/9 (22.2%)		0/20 (0%)
swallow pain	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
vomiting	2/9 (22.2%)		3/8 (37.5%)		0/9 (0%)		2/20 (10%)
xerostomia	0/9 (0%)		0/8 (0%)		0/9 (0%)		2/20 (10%)
yellow coated tongue	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
hemorrhoids bleeding	0/9 (0%)		1/8 (12.5%)		1/9 (11.1%)		0/20 (0%)
redness and bleeding of anus	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
abdominal pain	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
pain in thorax and abdomen	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
General disorders
fatigue	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
fatique	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		1/20 (5%)
loss of weight	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
night sweat	0/9 (0%)		0/8 (0%)		0/9 (0%)		2/20 (10%)
perspiration	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
sweating	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
weakness	0/9 (0%)		0/8 (0%)		0/9 (0%)		2/20 (10%)
gain of weight	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
hair loss	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
flank pain	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
pain stomach left site	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
Hepatobiliary disorders
high gammaglobuline/alpha-1-globuline	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
high LDH	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		1/20 (5%)
elevated bilirubin	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
elevated liver test (alt)	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
high ALT	2/9 (22.2%)		0/8 (0%)		0/9 (0%)		2/20 (10%)
high AP	2/9 (22.2%)		0/8 (0%)		1/9 (11.1%)		6/20 (30%)
high AST	2/9 (22.2%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
high billirubin	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
high direct bilirubin	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
high gGT	4/9 (44.4%)		0/8 (0%)		0/9 (0%)		5/20 (25%)
high GPT	2/9 (22.2%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
high total bilirubin	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
hyperbilirubinemia	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
intermittant elevated alt	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
low cholinesterase	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
low pancreas amylase	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
alkaline phophatase increase	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
Infections and infestations
flu-like symptoms	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
febrile neutropenia	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
fever	2/9 (22.2%)		3/8 (37.5%)		1/9 (11.1%)		3/20 (15%)
fever in neutropenia	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
herpes infection	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
herpes simplex infection lips	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
high procalcitonin	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
infection at the puncture of central ven	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
infection of puncture at central venous	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
infection with staphylococcus	0/9 (0%)		0/8 (0%)		3/9 (33.3%)		0/20 (0%)
infection with streptococcus mitis	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
klebsiella detection in sputum	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
rhinitis	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
swelling of the mucosa at the bottom of	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
thrombophlebitis	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
urethritis	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
urinary tract infection	0/9 (0%)		0/8 (0%)		0/9 (0%)		3/20 (15%)
ague	2/9 (22.2%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
Injury, poisoning and procedural complications
aching of the intravenuos line	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
bleeding at puncture	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		3/20 (15%)
bleeding operation wound left shoulder	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
hematoma due to blood sampling	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
pain at puncture of the central venous c	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
pain on central venous catheder punction	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
painful peripheral catheter punktion pla	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
Metabolism and nutrition disorders
hypalbuminemia	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
hypercalcelmia	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
hyperchloridemia	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
hyperglykemia	0/9 (0%)		0/8 (0%)		0/9 (0%)		4/20 (20%)
hyperkalemia	2/9 (22.2%)		0/8 (0%)		1/9 (11.1%)		5/20 (25%)
hypernatremia	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
hypoalbuminemia	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
hypocalcemia	0/9 (0%)		3/8 (37.5%)		0/9 (0%)		5/20 (25%)
hypokalemia	1/9 (11.1%)		2/8 (25%)		2/9 (22.2%)		6/20 (30%)
hyponatremia	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		2/20 (10%)
intermittant hypoalbuminia	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
intermittent hyponatremia	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
low albumin	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
low albumine	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
low protein	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		1/20 (5%)
Musculoskeletal and connective tissue disorders
hardening of arm/leg	1/9 (11.1%)		0/8 (0%)		2/9 (22.2%)		0/20 (0%)
calf cramps	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
swelling of arm/leg	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
back pain	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
backache	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		1/20 (5%)
bonepain	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
joint pain	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
kneepain	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
muscle pain	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		1/20 (5%)
neck aches	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
neck ache	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
neck pain (osteoporosis)	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
neck stiffness	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
pain at the costal arch	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
pain in the left arm	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
pain left calf	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
pain left upper arm	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
painful shoulder	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
slight backpain	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
Nervous system disorders
cavernoma left occipital cerebrum	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
confusion	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
hallucination	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
intermittant sleep disturbance	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
intermittend sleeping disorder	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
neuropathia aboth arms	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
paraesthesia (fingers)	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
paraesthesia (limbs, lips, fingers)	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
patient not addressable	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
prickle and numbness in both feet	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
restlessness	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
sleep disturbance	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
slight drowsiness during caspofungin inf	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
small pupils	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
tremor	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
viewing of colours	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
worsening of visual acuity	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
headache	2/9 (22.2%)		2/8 (25%)		2/9 (22.2%)		2/20 (10%)
Psychiatric disorders
amentia	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
Renal and urinary disorders
haemorrhagic cystitis	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
urinary bleeding	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
elevated uric acid	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
high creatinine	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		2/20 (10%)
high urea	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
high uric acid	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
hyperuricemia	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
acute renal failure	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
pollakisuria	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
polyuria	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
reduced urine production	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
Respiratory, thoracic and mediastinal disorders
croakiness	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
dry nose	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
bloody sputum	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
haemoptysen	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
hemoptysis	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
hyperventilation	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		1/20 (5%)
thoracic pain	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
bronchospasms	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
cold	2/9 (22.2%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
cough	3/9 (33.3%)		1/8 (12.5%)		1/9 (11.1%)		3/20 (15%)
cough, bloody sputum	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
dyspnea	1/9 (11.1%)		3/8 (37.5%)		0/9 (0%)		0/20 (0%)
hoarse voice	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
local pneumothorax	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
nasal discharge	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
pain int the lungs	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
pain while breathing	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
patients feels like he has a common cold	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
pleural effusion	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
stridor	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
worsening of breathing	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
yellow expectoration	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
Skin and subcutaneous tissue disorders
decubitus ulcer both ears	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/20 (5%)
itching	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
pruritus	0/9 (0%)		1/8 (12.5%)		1/9 (11.1%)		0/20 (0%)
pruritus at the eyelids	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
rash	3/9 (33.3%)		0/8 (0%)		2/9 (22.2%)		2/20 (10%)
reddened hands	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
redness at puncture	1/9 (11.1%)		1/8 (12.5%)		2/9 (22.2%)		5/20 (25%)
redness of eyelid	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/20 (0%)
redness on backside	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)
swelling of arm/leg	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		1/20 (5%)
pressure pain on the fingernails	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/20 (0%)
Vascular disorders
thrombosis left leg	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/20 (0%)

Limitations/Caveats

[Not Specified]

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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.