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

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ClinicalTrials.gov Identifier: NCT01945281
Recruitment Status : Terminated (Operational feasibility with low recruitment due to changing epidemiology of disease)
First Posted : September 18, 2013
Results First Posted : August 28, 2018
Last Update Posted : November 25, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Candidiasis, Invasive
Interventions Drug: Caspofungin
Drug: Amphotericin B Deoxycholate
Enrollment 51
Recruitment Details Participants less than 3 months of age with invasive candidiasis were enrolled in this study.
Pre-assignment Details  
Arm/Group Title Caspofungin Amphotericin B Deoxycholate
Hide 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
Reason Not Completed
Adverse Event             1             0
Death             3             3
Physician Decision             1             1
Technical Problems             1             0
Arm/Group Title Caspofungin Amphotericin B Deoxycholate Total
Hide 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 Number of Baseline Participants 34 17 51
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Days
Number Analyzed 34 participants 17 participants 51 participants
31.1  (20.9) 32.8  (23.3) 31.7  (21.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 34 participants 17 participants 51 participants
Female
14
  41.2%
10
  58.8%
24
  47.1%
Male
20
  58.8%
7
  41.2%
27
  52.9%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 34 participants 17 participants 51 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)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 34 participants 17 participants 51 participants
American Indian or Alaska Native
3
   8.8%
1
   5.9%
4
   7.8%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
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%
0
   0.0%
Weight   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Grams
Number Analyzed 31 participants 16 participants 47 participants
1982.1  (980.6) 2160.9  (1513.8) 2042.9  (1175.5)
[1]
Measure Description: Weight at Baseline Measurement
[2]
Measure Analysis Population Description: Participants who received at least 1 full dose of study therapy and had a documented (culture-confirmed) diagnosis of invasive candidiasis.
1.Primary Outcome
Title Percentage of Participants With Fungal-free Survival Through the 2-week Post-therapy Period
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 31 16
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
71.0
(52.0 to 85.8)
68.8
(41.3 to 89.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Caspofungin, Amphotericin B Deoxycholate
Comments [Not Specified]
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.
Method of Estimation Estimation Parameter Difference in Percentage
Estimated Value -0.9
Confidence Interval (2-Sided) 95%
-24.3 to 27.7
Estimation Comments Caspofungin minus Amphotericin
2.Secondary Outcome
Title Percentage of Participants With Fungal-free Survival Through the End of Study Treatment
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 31 16
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
71.0
(52.0 to 85.8)
75.0
(47.6 to 92.7)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Caspofungin, Amphotericin B Deoxycholate
Comments [Not Specified]
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.
Method of Estimation Estimation Parameter Difference in Percentage
Estimated Value -6.3
Confidence Interval (2-Sided) 95%
-30.2 to 22.6
Estimation Comments Caspofungin minus Amphotericin
3.Secondary Outcome
Title Number of Participants With an Adverse Event (AE)
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants as treated
Arm/Group Title Caspofungin Amphotericin B Deoxycholate
Hide 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
Overall Number of Participants Analyzed 33 16
Measure Type: Count of Participants
Unit of Measure: Participants
28
  84.8%
16
 100.0%
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
Hide 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 (%) Affected / at Risk (%)
Total   2/33 (6.06%)      3/16 (18.75%)    
Hide Serious Adverse Events
Caspofungin Amphotericin B Deoxycholate
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   7/33 (21.21%)      9/16 (56.25%)    
Cardiac disorders     
Cardiac arrest  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Cardio-respiratory arrest  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Gastrointestinal disorders     
Intestinal obstruction  1  1/33 (3.03%)  1 0/16 (0.00%)  0
Necrotising colitis  1  1/33 (3.03%)  1 0/16 (0.00%)  0
Necrotising enterocolitis neonatal  1  1/33 (3.03%)  1 0/16 (0.00%)  0
Infections and infestations     
Bacterial sepsis  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Bronchiolitis  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Device related sepsis  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Endocarditis  1  1/33 (3.03%)  1 0/16 (0.00%)  0
Escherichia sepsis  1  1/33 (3.03%)  1 0/16 (0.00%)  0
Fungal infection  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Meningitis bacterial  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Pneumonia  1  2/33 (6.06%)  2 0/16 (0.00%)  0
Pneumonia escherichia  1  0/33 (0.00%)  0 2/16 (12.50%)  2
Septic shock  1  1/33 (3.03%)  1 0/16 (0.00%)  0
Injury, poisoning and procedural complications     
Anastomotic complication  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Procedural pneumothorax  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Suture rupture  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Respiratory, thoracic and mediastinal disorders     
Apnoea  1  1/33 (3.03%)  1 0/16 (0.00%)  0
Dyspnoea  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Pneumothorax  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Pulmonary haemorrhage  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Vascular disorders     
Superior vena cava syndrome  1  1/33 (3.03%)  1 0/16 (0.00%)  0
1
Term from vocabulary, MedDRA 20.1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Caspofungin Amphotericin B Deoxycholate
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   23/33 (69.70%)      15/16 (93.75%)    
Blood and lymphatic system disorders     
Anaemia  1  10/33 (30.30%)  16 8/16 (50.00%)  12
Leukostasis syndrome  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Thrombocytopenia  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Cardiac disorders     
Bradycardia  1  0/33 (0.00%)  0 2/16 (12.50%)  3
Tachycardia  1  2/33 (6.06%)  2 2/16 (12.50%)  2
Eye disorders     
Eye discharge  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Gastrointestinal disorders     
Abdominal distension  1  1/33 (3.03%)  2 2/16 (12.50%)  2
Anal fissure  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Necrotising enterocolitis neonatal  1  1/33 (3.03%)  2 1/16 (6.25%)  1
Vomiting  1  3/33 (9.09%)  4 1/16 (6.25%)  2
General disorders     
Hypothermia  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Pyrexia  1  6/33 (18.18%)  10 3/16 (18.75%)  6
Hepatobiliary disorders     
Cholestasis  1  2/33 (6.06%)  2 0/16 (0.00%)  0
Hepatic function abnormal  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Hyperbilirubinaemia  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Jaundice  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Infections and infestations     
Abscess limb  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Postoperative wound infection  1  1/33 (3.03%)  1 1/16 (6.25%)  1
Sepsis  1  3/33 (9.09%)  5 5/16 (31.25%)  6
Septic shock  1  1/33 (3.03%)  1 1/16 (6.25%)  1
Staphylococcal sepsis  1  1/33 (3.03%)  1 1/16 (6.25%)  1
Injury, poisoning and procedural complications     
Accidental overdose  1  2/33 (6.06%)  2 0/16 (0.00%)  0
Investigations     
Alanine aminotransferase increased  1  0/33 (0.00%)  0 2/16 (12.50%)  2
Aspartate aminotransferase increased  1  0/33 (0.00%)  0 3/16 (18.75%)  3
Blood alkaline phosphatase increased  1  0/33 (0.00%)  0 1/16 (6.25%)  2
Blood bilirubin increased  1  0/33 (0.00%)  0 2/16 (12.50%)  2
Blood bilirubin unconjugated increased  1  0/33 (0.00%)  0 1/16 (6.25%)  3
Blood lactate dehydrogenase increased  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Blood potassium increased  1  2/33 (6.06%)  2 0/16 (0.00%)  0
Blood triglycerides increased  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Oxygen saturation decreased  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Metabolism and nutrition disorders     
Feeding intolerance  1  1/33 (3.03%)  1 1/16 (6.25%)  1
Hyperglycaemia  1  2/33 (6.06%)  2 0/16 (0.00%)  0
Hypernatraemia  1  0/33 (0.00%)  0 1/16 (6.25%)  2
Hypertriglyceridaemia  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Hypocalcaemia  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Hypochloraemia  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Hypoglycaemia  1  2/33 (6.06%)  3 2/16 (12.50%)  5
Hypokalaemia  1  2/33 (6.06%)  2 1/16 (6.25%)  1
Hyponatraemia  1  0/33 (0.00%)  0 1/16 (6.25%)  2
Hypophosphataemia  1  3/33 (9.09%)  3 1/16 (6.25%)  1
Metabolic alkalosis  1  0/33 (0.00%)  0 1/16 (6.25%)  2
Nervous system disorders     
Seizure  1  1/33 (3.03%)  5 1/16 (6.25%)  1
Renal and urinary disorders     
Glycosuria  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Renal tubular necrosis  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Respiratory, thoracic and mediastinal disorders     
Acute respiratory distress syndrome  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Apnoea  1  1/33 (3.03%)  1 1/16 (6.25%)  1
Aspiration  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Respiratory acidosis  1  0/33 (0.00%)  0 1/16 (6.25%)  2
Respiratory failure  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Skin and subcutaneous tissue disorders     
Decubitus ulcer  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Dermatitis  1  0/33 (0.00%)  0 1/16 (6.25%)  1
Rash  1  0/33 (0.00%)  0 1/16 (6.25%)  2
Skin ulcer  1  0/33 (0.00%)  0 1/16 (6.25%)  1
1
Term from vocabulary, MedDRA 20.1
Indicates events were collected by systematic assessment
The trial was terminated early due to operational feasibility with low recruitment due to changing epidemiology of disease.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Senior Vice President, Global Clinical Development
Organization: Merck Sharp & Dohme Corp.
Phone: 1-800-672-6372
EMail: ClinicalTrialsDisclosure@merck.com
Layout table for additonal information
Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT01945281    
Other Study ID Numbers: 0991-064
2013-002084-26 ( EudraCT Number )
MK-0991-064 ( Other Identifier: Merck Protocol Number )
First Submitted: September 13, 2013
First Posted: September 18, 2013
Results First Submitted: July 30, 2018
Results First Posted: August 28, 2018
Last Update Posted: November 25, 2019