Safety, Tolerability, and Efficacy of Caspofungin Versus Amphotericin B Deoxycholate in the Treatment of Invasive Candidiasis in Neonates and Infants (MK-0991-064)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01945281
• Collaborator: (none)
• Enrollment: 51
• Arms: 2
• Actual Duration (Months): 49.4

Study Details

Study Description

Brief Summary

The study will evaluate the safety, tolerability, and efficacy of caspofungin as compared with amphotericin B deoxycholate in the treatment of invasive candidiasis in neonates and infants. The primary hypothesis to be tested in the study is that caspofungin will be superior to amphotericin B deoxycholate with regard to the proportion of participants with fungal-free survival at the 2-week post-therapy follow-up visit.

Condition or Disease	Intervention/Treatment	Phase
Candidiasis, Invasive	Drug: Caspofungin; Drug: Amphotericin B Deoxycholate	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 51 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Double-Blind, Randomized, Comparator-Controlled Study to Evaluate the Safety, Tolerability, and Efficacy of Caspofungin Versus Amphotericin B Deoxycholate in the Treatment of Invasive Candidiasis in Neonates and Infants Less Than 3 Months of Age
• Actual Study Start Date: Jan 15, 2014
• Actual Primary Completion Date: Jan 2, 2018
• Actual Study Completion Date: Feb 28, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Caspofungin Caspofungin 2 mg/kg intravenous once daily for ≥14 days after documented negative culture and improvement of clinical signs and symptoms, for a maximum of 90 days treatment	Drug: Caspofungin
Active Comparator: Amphotericin B Deoxycholate Amphotericin B deoxycholate 1 mg/kg intravenous once daily for ≥14 days after documented negative culture and improvement of clinical signs and symptoms, for a maximum of 90 days treatment	Drug: Amphotericin B Deoxycholate

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Fungal-free Survival Through the 2-week Post-therapy Period [Up to 104 days]

   Fungal-free survival is those participants who survived up to 2 weeks post-therapy, and had documented microbiological eradication of Candida species (sp.) from follow-up cultures collected after the initiation of study therapy. Microbiological eradication denotes negative follow-up cultures for Candida sp. from the site of infection. If a culture is not obtained on the day of assessment, the last culture after study entry may be used to assist in the assessment of microbiological eradication. If the last culture is negative for Candida sp., then microbiological eradication would be considered achieved.

Secondary Outcome Measures

1. Percentage of Participants With Fungal-free Survival Through the End of Study Treatment [Up to 90 days]

   Fungal-free survival is those participants who survived up to end of study treatment, and had documented microbiological eradication of Candida sp. from follow-up cultures collected after the initiation of study therapy. Microbiological eradication denotes negative follow-up cultures for Candida sp. from the site of infection. If a culture is not obtained on the day of assessment, the last culture after study entry may be used to assist in the assessment of microbiological eradication. If the last culture is negative for Candida sp., then microbiological eradication would be considered achieved.

2. Number of Participants With an Adverse Event (AE) [8 weeks after end of study therapy (up to 146 days)]

   An AE is any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product, is also an AE.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 3 Months
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Culture-confirmed invasive Candida infection

Exclusion Criteria:

• Candida disease limited to the oropharynx, esophagus, or other mucosal or superficial skin surfaces

• Positive culture for Candida only from sputum, broncho-alveolar lavage, catheter tip, or previously placed indwelling non-vascular catheters or drains

• Prosthetic device as the suspected site of Candida infection

• Active co-infection with a non-Candida fungal organism

• Received >48 hours of systemic antifungal treatment since the positive Candida index culture was collected as therapy for the present episode of invasive candidiasis

• Failed prior systemic antifungal therapy for the present episode of invasive candidiasis

• Diagnosis of acute hepatitis or cirrhosis

• Scheduled or anticipated to receive rifampin or other systemic antifungal therapy while on study therapy

• History (including participant's mother) of allergy, hypersensitivity, or any serious reaction to caspofungin or other member of the echinocandin class, or to amphotericin B deoxycholate or other member of the polyene class

• Severe congenital disorder known to lower immune response

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 27, 2013

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT01945281
• Other Study ID Numbers: 0991-064; 2013-002084-26; MK-0991-064
• First Posted: Sep 18, 2013
• Last Update Posted: Nov 25, 2019
• Last Verified: Nov 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Candidiasis; Candidiasis, Invasive; Amphotericin B; Liposomal amphotericin B; Caspofungin; Amphotericin B, deoxycholate drug combination; Deoxycholic Acid

Study Results

Participant Flow

Recruitment Details	Participants less than 3 months of age with invasive candidiasis were enrolled in this study.

Arm/Group Title	Caspofungin	Amphotericin B Deoxycholate
Arm/Group Description	Caspofungin 2 mg/kg intravenous once daily for ≥14 days after documented negative culture and improvement of clinical signs and symptoms, for a maximum of 90 days treatment	Amphotericin B deoxycholate 1 mg/kg intravenous once daily for ≥14 days after documented negative culture and improvement of clinical signs and symptoms, for a maximum of 90 days treatment
Period Title: Overall Study
STARTED	34	17
Treated	33	16
COMPLETED	28	13
NOT COMPLETED	6	4

Baseline Characteristics

Arm/Group Title	Caspofungin	Amphotericin B Deoxycholate	Total
Arm/Group Description	Caspofungin 2 mg/kg intravenous once daily for ≥14 days after documented negative culture and improvement of clinical signs and symptoms, for a maximum of 90 days treatment	Amphotericin B deoxycholate 1 mg/kg intravenous once daily for ≥14 days after documented negative culture and improvement of clinical signs and symptoms, for a maximum of 90 days treatment	Total of all reporting groups
Overall Participants	34	17	51
Age (Days) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Days]	31.1 (20.9)	32.8 (23.3)	31.7 (21.5)
Sex: Female, Male (Count of Participants)
Female	14 41.2%	10 58.8%	24 47.1%
Male	20 58.8%	7 41.2%	27 52.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	12 35.3%	7 41.2%	19 37.3%
Not Hispanic or Latino	19 55.9%	9 52.9%	28 54.9%
Unknown or Not Reported	3 8.8%	1 5.9%	4 7.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 8.8%	1 5.9%	4 7.8%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	13 38.2%	6 35.3%	19 37.3%
White	13 38.2%	8 47.1%	21 41.2%
More than one race	5 14.7%	2 11.8%	7 13.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Weight (Grams) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Grams]	1982.1 (980.6)	2160.9 (1513.8)	2042.9 (1175.5)

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Fungal-free Survival Through the 2-week Post-therapy Period
Description	Fungal-free survival is those participants who survived up to 2 weeks post-therapy, and had documented microbiological eradication of Candida species (sp.) from follow-up cultures collected after the initiation of study therapy. Microbiological eradication denotes negative follow-up cultures for Candida sp. from the site of infection. If a culture is not obtained on the day of assessment, the last culture after study entry may be used to assist in the assessment of microbiological eradication. If the last culture is negative for Candida sp., then microbiological eradication would be considered achieved.
Time Frame	Up to 104 days

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 full dose of study therapy and had a documented (culture-confirmed) diagnosis of invasive candidiasis.

Arm/Group Title	Caspofungin	Amphotericin B Deoxycholate
Arm/Group Description	Caspofungin 2 mg/kg intravenous once daily for ≥14 days after documented negative culture and improvement of clinical signs and symptoms, for a maximum of 90 days treatment	Amphotericin B deoxycholate 1 mg/kg intravenous once daily for ≥14 days after documented negative culture and improvement of clinical signs and symptoms, for a maximum of 90 days treatment
Measure Participants	31	16
Number (95% Confidence Interval) [Percentage of Participants]	71.0 208.8%	68.8 404.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Caspofungin, Amphotericin B Deoxycholate
	Comments
	Type of Statistical Test	Other
	Comments	Miettinen & Nurminen method stratified by stratum (Weight category based on weight at study entry) with Cochran Mantel-Haenszel's weights.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Percentage
	Estimated Value	-0.9
	Confidence Interval	(2-Sided) 95%; -24.3 to 27.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Caspofungin minus Amphotericin

2. Secondary Outcome

Title	Percentage of Participants With Fungal-free Survival Through the End of Study Treatment
Description	Fungal-free survival is those participants who survived up to end of study treatment, and had documented microbiological eradication of Candida sp. from follow-up cultures collected after the initiation of study therapy. Microbiological eradication denotes negative follow-up cultures for Candida sp. from the site of infection. If a culture is not obtained on the day of assessment, the last culture after study entry may be used to assist in the assessment of microbiological eradication. If the last culture is negative for Candida sp., then microbiological eradication would be considered achieved.
Time Frame	Up to 90 days

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 full dose of study therapy and had a documented (culture-confirmed) diagnosis of invasive candidiasis.

Arm/Group Title	Caspofungin	Amphotericin B Deoxycholate
Arm/Group Description	Caspofungin 2 mg/kg intravenous once daily for ≥14 days after documented negative culture and improvement of clinical signs and symptoms, for a maximum of 90 days treatment	Amphotericin B deoxycholate 1 mg/kg intravenous once daily for ≥14 days after documented negative culture and improvement of clinical signs and symptoms, for a maximum of 90 days treatment
Measure Participants	31	16
Number (95% Confidence Interval) [Percentage of Participants]	71.0 208.8%	75.0 441.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Caspofungin, Amphotericin B Deoxycholate
	Comments
	Type of Statistical Test	Other
	Comments	Miettinen & Nurminen method stratified by stratum (Weight category based on weight at study entry) with Cochran Mantel-Haenszel's weights.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Percentage
	Estimated Value	-6.3
	Confidence Interval	(2-Sided) 95%; -30.2 to 22.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Caspofungin minus Amphotericin

3. Secondary Outcome

Title	Number of Participants With an Adverse Event (AE)
Description	An AE is any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product, is also an AE.
Time Frame	8 weeks after end of study therapy (up to 146 days)

Outcome Measure Data

Analysis Population Description

All participants as treated

Arm/Group Title	Caspofungin	Amphotericin B Deoxycholate
Arm/Group Description	Caspofungin 2 mg/kg intravenous once daily for ≥14 days after documented negative culture and improvement of clinical signs and symptoms, for a maximum of 90 days treatment	Amphotericin B deoxycholate 1 mg/kg intravenous once daily for ≥14 days after documented negative culture and improvement of clinical signs and symptoms, for a maximum of 90 days treatment
Measure Participants	33	16
Count of Participants [Participants]	28 82.4%	16 94.1%

Adverse Events

Time Frame	8 weeks after end of study therapy (up to 146 days)
Adverse Event Reporting Description	All participants as treated
Arm/Group Title	Caspofungin		Amphotericin B Deoxycholate
Arm/Group Description	Caspofungin 2 mg/kg intravenous once daily for ≥14 days after documented negative culture and improvement of clinical signs and symptoms, for a maximum of 90 days treatment		Amphotericin B deoxycholate 1 mg/kg intravenous once daily for ≥14 days after documented negative culture and improvement of clinical signs and symptoms, for a maximum of 90 days treatment
All Cause Mortality
	Caspofungin		Amphotericin B Deoxycholate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/33 (6.1%)		3/16 (18.8%)
Serious Adverse Events
	Caspofungin		Amphotericin B Deoxycholate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/33 (21.2%)		9/16 (56.3%)
Cardiac disorders
Cardiac arrest	0/33 (0%)	0	1/16 (6.3%)	1
Cardio-respiratory arrest	0/33 (0%)	0	1/16 (6.3%)	1
Gastrointestinal disorders
Intestinal obstruction	1/33 (3%)	1	0/16 (0%)	0
Necrotising colitis	1/33 (3%)	1	0/16 (0%)	0
Necrotising enterocolitis neonatal	1/33 (3%)	1	0/16 (0%)	0
Infections and infestations
Bacterial sepsis	0/33 (0%)	0	1/16 (6.3%)	1
Bronchiolitis	0/33 (0%)	0	1/16 (6.3%)	1
Device related sepsis	0/33 (0%)	0	1/16 (6.3%)	1
Endocarditis	1/33 (3%)	1	0/16 (0%)	0
Escherichia sepsis	1/33 (3%)	1	0/16 (0%)	0
Fungal infection	0/33 (0%)	0	1/16 (6.3%)	1
Meningitis bacterial	0/33 (0%)	0	1/16 (6.3%)	1
Pneumonia	2/33 (6.1%)	2	0/16 (0%)	0
Pneumonia escherichia	0/33 (0%)	0	2/16 (12.5%)	2
Septic shock	1/33 (3%)	1	0/16 (0%)	0
Injury, poisoning and procedural complications
Anastomotic complication	0/33 (0%)	0	1/16 (6.3%)	1
Procedural pneumothorax	0/33 (0%)	0	1/16 (6.3%)	1
Suture rupture	0/33 (0%)	0	1/16 (6.3%)	1
Respiratory, thoracic and mediastinal disorders
Apnoea	1/33 (3%)	1	0/16 (0%)	0
Dyspnoea	0/33 (0%)	0	1/16 (6.3%)	1
Pneumothorax	0/33 (0%)	0	1/16 (6.3%)	1
Pulmonary haemorrhage	0/33 (0%)	0	1/16 (6.3%)	1
Vascular disorders
Superior vena cava syndrome	1/33 (3%)	1	0/16 (0%)	0
Other (Not Including Serious) Adverse Events
	Caspofungin		Amphotericin B Deoxycholate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/33 (69.7%)		15/16 (93.8%)
Blood and lymphatic system disorders
Anaemia	10/33 (30.3%)	16	8/16 (50%)	12
Leukostasis syndrome	0/33 (0%)	0	1/16 (6.3%)	1
Thrombocytopenia	0/33 (0%)	0	1/16 (6.3%)	1
Cardiac disorders
Bradycardia	0/33 (0%)	0	2/16 (12.5%)	3
Tachycardia	2/33 (6.1%)	2	2/16 (12.5%)	2
Eye disorders
Eye discharge	0/33 (0%)	0	1/16 (6.3%)	1
Gastrointestinal disorders
Abdominal distension	1/33 (3%)	2	2/16 (12.5%)	2
Anal fissure	0/33 (0%)	0	1/16 (6.3%)	1
Necrotising enterocolitis neonatal	1/33 (3%)	2	1/16 (6.3%)	1
Vomiting	3/33 (9.1%)	4	1/16 (6.3%)	2
General disorders
Hypothermia	0/33 (0%)	0	1/16 (6.3%)	1
Pyrexia	6/33 (18.2%)	10	3/16 (18.8%)	6
Hepatobiliary disorders
Cholestasis	2/33 (6.1%)	2	0/16 (0%)	0
Hepatic function abnormal	0/33 (0%)	0	1/16 (6.3%)	1
Hyperbilirubinaemia	0/33 (0%)	0	1/16 (6.3%)	1
Jaundice	0/33 (0%)	0	1/16 (6.3%)	1
Infections and infestations
Abscess limb	0/33 (0%)	0	1/16 (6.3%)	1
Postoperative wound infection	1/33 (3%)	1	1/16 (6.3%)	1
Sepsis	3/33 (9.1%)	5	5/16 (31.3%)	6
Septic shock	1/33 (3%)	1	1/16 (6.3%)	1
Staphylococcal sepsis	1/33 (3%)	1	1/16 (6.3%)	1
Injury, poisoning and procedural complications
Accidental overdose	2/33 (6.1%)	2	0/16 (0%)	0
Investigations
Alanine aminotransferase increased	0/33 (0%)	0	2/16 (12.5%)	2
Aspartate aminotransferase increased	0/33 (0%)	0	3/16 (18.8%)	3
Blood alkaline phosphatase increased	0/33 (0%)	0	1/16 (6.3%)	2
Blood bilirubin increased	0/33 (0%)	0	2/16 (12.5%)	2
Blood bilirubin unconjugated increased	0/33 (0%)	0	1/16 (6.3%)	3
Blood lactate dehydrogenase increased	0/33 (0%)	0	1/16 (6.3%)	1
Blood potassium increased	2/33 (6.1%)	2	0/16 (0%)	0
Blood triglycerides increased	0/33 (0%)	0	1/16 (6.3%)	1
Oxygen saturation decreased	0/33 (0%)	0	1/16 (6.3%)	1
Metabolism and nutrition disorders
Feeding intolerance	1/33 (3%)	1	1/16 (6.3%)	1
Hyperglycaemia	2/33 (6.1%)	2	0/16 (0%)	0
Hypernatraemia	0/33 (0%)	0	1/16 (6.3%)	2
Hypertriglyceridaemia	0/33 (0%)	0	1/16 (6.3%)	1
Hypocalcaemia	0/33 (0%)	0	1/16 (6.3%)	1
Hypochloraemia	0/33 (0%)	0	1/16 (6.3%)	1
Hypoglycaemia	2/33 (6.1%)	3	2/16 (12.5%)	5
Hypokalaemia	2/33 (6.1%)	2	1/16 (6.3%)	1
Hyponatraemia	0/33 (0%)	0	1/16 (6.3%)	2
Hypophosphataemia	3/33 (9.1%)	3	1/16 (6.3%)	1
Metabolic alkalosis	0/33 (0%)	0	1/16 (6.3%)	2
Nervous system disorders
Seizure	1/33 (3%)	5	1/16 (6.3%)	1
Renal and urinary disorders
Glycosuria	0/33 (0%)	0	1/16 (6.3%)	1
Renal tubular necrosis	0/33 (0%)	0	1/16 (6.3%)	1
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	0/33 (0%)	0	1/16 (6.3%)	1
Apnoea	1/33 (3%)	1	1/16 (6.3%)	1
Aspiration	0/33 (0%)	0	1/16 (6.3%)	1
Respiratory acidosis	0/33 (0%)	0	1/16 (6.3%)	2
Respiratory failure	0/33 (0%)	0	1/16 (6.3%)	1
Skin and subcutaneous tissue disorders
Decubitus ulcer	0/33 (0%)	0	1/16 (6.3%)	1
Dermatitis	0/33 (0%)	0	1/16 (6.3%)	1
Rash	0/33 (0%)	0	1/16 (6.3%)	2
Skin ulcer	0/33 (0%)	0	1/16 (6.3%)	1

Limitations/Caveats

The trial was terminated early due to operational feasibility with low recruitment due to changing epidemiology of disease.

More Information

Certain Agreements

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

The SPONSOR must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the SPONSOR as confidential must be deleted prior to submission.