Clinical trial NCT01945281
Conditions: Candidiasis, Invasive
Sponsor: Merck Sharp & Dohme LLC
Start date: 2014-01-15; Completion date: 2018-02-28
Enrollment: 51 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Detailed description:

Arms: arm 1: 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 arm 2: 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
Interventions: intervention 1: Caspofungin intervention 2: Amphotericin B Deoxycholate
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol 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
NCT number: 
NCT01945281 
Document Date: 
27-Aug-2013


Product:  MK-0991
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THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION 
RELATING TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY 
OF MERCK SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., 
INC., WHITEHOUSE STATION, NJ, U.S.A.
THIS PROTOCOL AMENDMENT IS APPLICABLE ONLY TO BRAZIL.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (hereafter referred to as 
the SPONSOR or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Administrative 
Binder.
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
INVESTIGATOR:
PRIMARY:
CLINICAL PHASE: IIA
US IND NUMBER:
48,484
SITE:
INSTITUTIONAL REVIEW BOARD/ETHICS REVIEW COMMITTEE:
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES...............................................................................................5
PRIMARY REASON(S) FOR THIS AMENDMENT.....................................................5
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT .............................................5
1. SUMMARY...................................................................................................................6
1.1
TITLE ......................................................................................................................6
1.2
INDICATION..........................................................................................................6
1.3
SUMMARY OF RATIONALE...............................................................................6
1.4
SUMMARY OF STUDY DESIGN ........................................................................7
1.5
SAMPLE ...............................................................................................................10
1.6
DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN.........................10
1.7
STUDY FLOW CHART.......................................................................................12
2. CORE PROTOCOL.....................................................................................................14
2.1
OBJECTIVES AND HYPOTHESES ...................................................................14
2.1.1
Primary Objective...........................................................................................14
2.1.2
Secondary Objectives .....................................................................................14
2.1.2.1
Efficacy...................................................................................................14
2.1.2.2
Safety ......................................................................................................14
2.1.3
Exploratory Objectives...................................................................................14
2.2
SUBJECT/PATIENT INCLUSION CRITERIA...................................................15
2.3
SUBJECT/PATIENT EXCLUSION CRITERIA .................................................15
2.4
STUDY DESIGN AND DURATION...................................................................17
2.4.1
Summary of Study Design..............................................................................17
2.4.2
Treatment Plan................................................................................................18
2.5
LIST OF EFFICACY MEASUREMENTS...........................................................22
2.6
LIST OF SAFETY MEASUREMENTS...............................................................22
2.7
PHARMACOKINETIC MEASUREMENTS.......................................................23
2.8
STATISTICAL ANALYSIS PLAN SUMMARY................................................23
2.8.1
Efficacy Analyses...........................................................................................23
2.8.2
Safety Analyses ..............................................................................................25
2.8.3
Power and Sample Size ..................................................................................26
3. PROTOCOL DETAILS...............................................................................................27
3.1
RATIONALE ........................................................................................................27
3.1.1
Rationale for This Study.................................................................................27
3.1.2
Rationale for Dose and Regimen....................................................................34
3.1.3
Rationale for Study Design ............................................................................36
3.2
STUDY PROCEDURES.......................................................................................37
3.2.1
Concomitant Medication(s)/Treatment(s) ......................................................37
3.2.2
Diet/Activity/Other.........................................................................................37
3.2.3
Procedures ......................................................................................................37
3.2.3.1
Informed Consent....................................................................................37
3.2.3.1.1
General Informed Consent ..............................................................37
 
 
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3.2.3.2
Assignment of Baseline Number ............................................................38
3.2.3.3
Screening Procedures..............................................................................38
3.2.3.4
Randomization and Stratification............................................................40
3.2.3.5
Treatment Evaluation/Follow-Up ...........................................................40
3.2.3.5.1
Procedures Performed During the Treatment Phase .......................40
3.2.3.5.2
Procedures Performed During the Posttherapy 
Follow-up Visits..............................................................................43
3.2.3.6
Blinding/Unblinding ...............................................................................44
3.2.3.7
Discontinuation/Withdrawal from Study................................................44
3.2.3.7.1
Discontinuation/Withdrawal Criteria ..............................................45
3.3
EFFICACY/PHARMACOKINETIC MEASUREMENTS ..................................46
3.3.1
Clinical and Laboratory Measurements for Efficacy .....................................46
3.3.2
Measurements for Pharmacokinetics..............................................................47
3.3.3
Microbiological Measurements......................................................................48
3.3.4
Data Monitoring Committee...........................................................................48
3.4
SAFETY MEASUREMENTS ..............................................................................49
3.4.1
Clinical and Laboratory Measurements for Safety.........................................49
3.4.2
Management of Adverse Events.....................................................................50
3.4.3
Recording Adverse Experiences.....................................................................50
3.4.4
Definition of an Overdose for This Protocol..................................................51
3.4.4.1
Reporting of Overdose to SPONSOR.....................................................51
3.4.5
Immediate Reporting of Adverse Experiences to the 
SPONSOR......................................................................................................51
3.4.5.1
Serious Adverse Experiences..................................................................51
3.4.5.2
Selected Nonserious Adverse Experiences.............................................52
3.4.6
Evaluating Adverse Experiences....................................................................52
3.4.7
SPONSOR Responsibility for Reporting Adverse Experiences ....................55
3.5
STATISTICAL ANALYSIS PLAN (SAP)...........................................................55
3.5.1
Responsibility for Analysis ............................................................................55
3.5.2
Responsibility for Analyses/In-House Blinding.............................................55
3.5.3
Hypotheses/Estimation...................................................................................55
3.5.4
Analysis Endpoints.........................................................................................55
3.5.4.1
Efficacy/Pharmacokinetic Endpoints......................................................55
3.5.4.1.1
Pharmacokinetic Endpoints.............................................................55
3.5.4.1.2
Efficacy Endpoints ..........................................................................56
3.5.4.2
Safety Endpoints .....................................................................................56
3.5.5
Analysis Populations ......................................................................................57
3.5.5.1
Efficacy Analysis Populations ................................................................57
3.5.5.2
Safety Analysis Population.....................................................................58
3.5.6
Statistical Methods .........................................................................................58
3.5.6.1
Statistical Methods for Efficacy Analyses..............................................58
3.5.6.2
Statistical Methods for Safety Analyses .................................................60
3.5.6.3
Summaries of Baseline Characteristics and Demographics....................62
3.5.7
Multiplicity.....................................................................................................62
3.5.8
Sample Size and Power Calculations .............................................................62
3.5.8.1
Sample Size and Power for Efficacy.......................................................62
 
 
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3.5.8.2
Sample Size and Power for Safety..........................................................63
3.5.8.3
Subgroup Analysis ..................................................................................66
3.5.9
Interim Analyses.............................................................................................66
3.5.10 Compliance (Medication Adherence).............................................................66
3.5.11 Extent of Exposure .........................................................................................66
3.6
LABELING, PACKAGING, STORAGE, DISPENSING, AND 
RETURN OF CLINICAL SUPPLIES...................................................................66
3.6.1
Product Descriptions ......................................................................................66
3.6.2
Primary Packaging..........................................................................................66
3.6.3
Clinical Supplies Disclosure...........................................................................67
3.6.4
Storage and Handling Requirements..............................................................67
3.6.5
Standard Policies / Return of Clinical Supplies .............................................68
3.6.6
Distributing to Sites and Dispensing to Subjects/Patients..............................68
3.7
DATA MANAGEMENT ......................................................................................68
3.8
BIOLOGICAL SPECIMENS................................................................................69
4. ADMINISTRATIVE AND REGULATORY DETAILS............................................70
4.1
CONFIDENTIALITY ...........................................................................................70
4.1.1
Confidentiality of Data...................................................................................70
4.1.2
Confidentiality of Subject/Patient Records ....................................................70
4.1.3
Confidentiality of Investigator Information ...................................................70
4.2
COMPLIANCE WITH LAW, AUDIT, AND DEBARMENT.............................71
4.3
COMPLIANCE WITH FINANCIAL DISCLOSURE 
REQUIREMENTS ................................................................................................72
4.4
QUALITY CONTROL AND QUALITY ASSURANCE ....................................73
4.5
COMPLIANCE WITH INFORMATION PROGRAM ON 
CLINICAL TRIALS FOR SERIOUS OR LIFE THREATENING 
CONDITIONS.......................................................................................................73
4.6
PUBLICATIONS ..................................................................................................73
5. LIST OF REFERENCES.............................................................................................75
6. APPENDICES .............................................................................................................78
6.1
LABORATORY SAFETY STUDIES ..................................................................78
6.2
RISK FACTORS OF INVASIVE CANDIDIASIS IN 
NEONATES AND INFANTS LESS THAN 3 MONTHS OF AGE....................79
6.3
GENERAL GUIDELINES FOR THE MANAGEMENT OF
INVASIVE CANDIDA INFECTIONS..................................................................80
7. ATTACHMENTS........................................................................................................84
8. SIGNATURES.............................................................................................................87
8.1
SPONSOR’S REPRESENTATIVE ......................................................................87
8.2
INVESTIGATOR..................................................................................................87
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT
Section 
Num-ber(s)
Section Title(s)
Description of Change(s)
1.7
2.2
3.1.4
3.2.3.1.2
3.2.3.1.3
3.2.3.8
6.4
7.
Study Flow Chart
Inclusion Criterion 
#4: removed 2nd and 
3rd sentences
Rationale for Future 
Biomedical 
Research
Consent and 
Collection of 
Specimens for 
Future Biomedical 
Research
Future Biomedical 
Research
Withdrawal From 
Future Biomedical 
Research
Collection and 
Management of 
Specimens for 
Future
Biomedical 
Research
Attachments:  
Pharmacogenomics 
Informational 
Brochure for 
IRBs/IECs & 
Investigational Site 
Staff
Removal of Future Biomedical Research sample 
collection and any associated protocol language
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT
Section 
Num-bers
Section Titles
Description of Change
There are no additional changes.
 
 
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1. SUMMARY
1.1
TITLE
A Multicenter, Double-blind, Randomized, Comparator-Controlled Study to Evaluate the 
Safety, Tolerability, and Efficacy of Caspofungin Verses Amphotericin B Deoxycholate 
in the Treatment of Invasive Candidiasis in Neonates and Infants Less Than 3 Months of 
Age
1.2
INDICATION
A prior clinical study has evaluated the pharmacokinetics and tolerability of single- and 
multiple-dose therapy with caspofungin in the neonatal and infant population (i.e., 
children <3 months of age).  The current study will investigate the safety, tolerability, and 
efficacy of caspofungin versus amphotericin B deoxycholate for the treatment of invasive 
candidiasis in this same pediatric patient population.
1.3
SUMMARY OF RATIONALE
Caspofungin acetate (MK-0991, CANCIDAS™; herein referred to as caspofungin) is a 
parenteral echinocandin antifungal agent that has received approval in the United States, 
the European Union (EU), and over 80 other countries for the treatment of adult patients 
(≥18 years of age) for one or more of the following: (1) invasive aspergillosis in patients 
who are refractory to or intolerant of other therapies (i.e., amphotericin B deoxycholate, 
lipid formulations of amphotericin B, and/or itraconazole); (2) esophageal candidiasis; 
(3) candidemia and other Candida infections, including intra-abdominal abscesses, 
peritonitis, and pleural space infection; and (4) empirical therapy of suspected invasive 
fungal infections in febrile, neutropenic patients [1-2].  Furthermore, caspofungin has 
been approved for use in pediatric patients (>3 months of age) in over 60 countries 
worldwide for the same indications as in adults. 
In the neonatal and infant population, candidemia and other forms of invasive candidiasis 
are a major medical concern and are associated with excess mortality, increased length of 
hospital stay and health-care costs [3, 4].  Candida species represent the second most 
common pathogen among all nosocomial blood stream infections and the most common 
fungal infection in infants less than 1 year of age [5].  Furthermore, in the United States 
in 2003, the overall incidence of invasive candidiasis among neonates was 15 cases per 
10,000 neonatal admissions [3].  However incidence has been shown to vary widely 
between clinical centers [4, 6-7]. Notably, the current antifungal regimens administered 
in the neonatal population are associated with significant toxicity, multiple drug-drug 
interactions, or limitations in spectrum of activity.   With caspofungin approved for use as 
primary treatment of older pediatric patients (3 months to 17 years of age), the use of this 
agent in the neonatal population will be further investigated in this study.  
The pharmacokinetics and safety of caspofungin in the neonatal patient population were 
evaluated in a prospective pharmacokinetic trial (Protocol 058).  In this study, the 
pharmacokinetics in 18 neonates and infants receiving single or multiple once-daily 
caspofungin doses of 25 mg/m2 were generally similar to that in adults receiving a 50-mg 
 
 
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once-daily maintenance dose.  Caspofungin was well tolerated in the 18 patients included 
in this study; in fact, no drug-related adverse experiences were noted in any of the 18 
caspofungin recipients [8].  However, measurements of height are not routinely 
performed in the neonatal/infant population, so a dosing regimen based on body surface 
area (BSA) is not preferred in this patient population.  Simulations for weight-based 
dosing, using a 2 mg/kg dose, performed for the 12 patients who received multiple doses 
of caspofungin in Protocol 058 showed similar C1hr and C24hr values to the 25 mg/m2 daily 
dose.  Based on this analysis, a weight-based dose of 2 mg/kg of caspofungin is deemed 
roughly equivalent to 25 mg/m2.
The efficacy of caspofungin in the treatment of invasive candidiasis and other Candida 
infections in neonates and infants was recently demonstrated in a randomized, double-
blind, prospective clinical trial in 32 patients comparing caspofungin to amphotericin B 
deoxycholate [9]. In this study conducted at a single site in Saudi Arabia, newborn infants 
received either caspofungin (2 mg/kg/day, n=15) or amphotericin B deoxycholate 
(1 mg/kg/day, n=17).  A favorable response at the end of intravenous therapy, the 
primary timepoint for efficacy, was observed at a greater rate in patients who received 
caspofungin (86.7%) than those who received amphotericin B deoxycholate (41.7%) 
(p=0.04).  Importantly, caspofungin was effective in all sites of Candida infection, 
including all 3 cases with Candida meningitis and 4 of 5 patients with Candida 
endocarditis.
Furthermore, published data from several case series in neonates with invasive 
candidiasis (two from Costa Rica, one from Italy, and one from the United States) 
provide additional evidence of efficacy in this age group [10-13].  In these studies, 
caspofungin therapy was begun only after initial therapy with conventional antifungals 
(amphotericin B deoxycholate, fluconazole, and/or flucytosine) had failed; in other 
words, the Candida infection was resistant to, or the patient was intolerant of, the initial 
therapy.  Collectively, 53 of 75 neonates received either a caspofungin dose of 2 mg/kg 
or 25 mg/m2 and the favorable response rate across these series was in excess of 80%.  
Caspofungin was well tolerated, with few drug-related adverse events reported. 
With the approval of the use of caspofungin in many countries in children and 
adolescents between the ages of 3 months to 17 years, this study will prospectively 
evaluate the safety and efficacy of caspofungin in the treatment of invasive candidiasis in 
the youngest pediatric group, the neonatal and infant population less than 3 months of 
age.  The recommended dose for caspofungin for this study is 2 mg/kg daily.  This dose 
is based on the published data referenced above as well as the simulated results from the 
prior pharmacokinetic and safety study for caspofungin in neonates and infants <3 
months of age (Protocol 058).
1.4
SUMMARY OF STUDY DESIGN
This is a double-blind, randomized, comparative study to evaluate the safety, tolerability, 
and efficacy of caspofungin versus amphotericin B deoxycholate in the treatment of 
neonatal candidiasis.  Neonates and infants less than 3 months of age will be eligible for 
enrollment provided they have documented (culture-confirmed) invasive Candida
infections within the 96 hours prior to study entry.  Diagnosis of invasive candidiasis in a 
 
 
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symptomatic or at-risk patient would require either (a) a positive culture for Candida spp. 
from a normally sterile body fluid, or (b) a positive culture for Candida spp. from a 
newly-placed drain at a normally sterile body site.  For this study, patients with a 
Candida urinary tract infection (UTI) are considered to have invasive candidiasis, as such 
infections are associated with high mortality (~30%) and morbidity in the neonatal 
patient population [14-16]; these patients are eligible for enrollment, provided there is a 
positive urine culture of >10,000 colony-forming units (CFUs) per milliliter of a Candida
spp. from a newly placed urinary catheter.  Patients with a positive culture from sputum 
or nonsterile sites are not eligible for enrollment.  
A detailed description and evaluation of the Candida infection will be performed at 
screening, daily while on study therapy, on the last day of study therapy, and at the 2-
week and 8-week posttherapy follow-up visits.  Resolution or progression of the Candida
infection will be documented by assessment of signs and symptoms, radiographic studies 
(when clinically indicated), and follow-up blood cultures or, as appropriate, other follow-
up cultures (including urine or cerebrospinal fluid [CSF]).  Based on available data, an 
efficacy assessment will be made at the end of study therapy and at the 2-week 
posttherapy follow-up visit.  The efficacy endpoint will be based on fungal-free survival 
(i.e., patient survival in the setting of documented microbiological eradication of Candida
sp. from follow-up cultures).  Although fungal-free survival will be assessed at 2 
different time points, the primary efficacy time point will be at the 2-week posttherapy 
follow-up visit.   
All patients who receive 1 or more doses of study therapy will be evaluated for the 
presence of adverse experiences while on study therapy and through the 2-week 
posttherapy follow-up visit.
The overall design of the study is in Figure 1-1.
 
 
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Figure 1-1
MK-0991 Protocol 064 Trial Design
 
 
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1.5
SAMPLE
Approximately 90 patients with documented invasive candidiasis will be randomized in a 
2:1 ratio (caspofungin: amphotericin B deoxycholate), as specified in Table 1-1 below.  
All doses of study drug will be administered intravenously as a single once-daily dose. 
Table 1-1
Protocol 064 Treatment Groups
Treatment 
Group
Regimen
Number of Patients
Group 1
Caspofungin at 2 mg/kg (per body weight) 
once daily
~60
Group 2
Amphotericin B deoxycholate at 1 mg/kg 
(per body weight) once daily
~30
In an effort to strive for adequate representation of patients from different weight groups 
(reflective of patient gestational age) in both treatment arms, randomization will be 
stratified into 3 weight categories (based on weight at study entry): <1000 grams, 1000 to 
1500 grams, and >1500 grams.  Patients will be stratified into each of the weight 
categories in a manner consistent with the 2:1 randomization of caspofungin to 
amphotericin B deoxycholate.
1.6
DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN
Caspofungin will be administered at 2 mg/kg once daily (with no loading dose).  
Amphotericin B deoxycholate will be administered at 1 mg/kg once daily.  
Initial dosing with the study medications will be based on the patient's actual body weight 
(in kg) at the time of study entry.  The patient is to be weighed at least weekly during the 
treatment period.  The study medication dose (mg) should be adjusted as the patient's 
weight increases to maintain the mg/kg dose of the assigned treatment throughout the 
study treatment period. 
Caspofungin and amphotericin B deoxycholate will both be administered intravenously 
over approximately 2 hours.  As these 2 products differ in color, opaque masking will be 
used over the infusion materials (e.g., infusion syringe and tubing) to ensure adequate 
blinding of the treatment group. 
The duration of study therapy with caspofungin or amphotericin B deoxycholate is 
variable and dependent on a variety of factors, including (1) the rapidity of a patient’s 
clinical and microbiological response, (2) the patient’s general medical condition, and (3) 
 
 
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the underlying site of Candida infection.  In general, patients should be treated with study 
therapy for a minimum of 14 days following the time of documented negative cultures 
from the site of infection and improvement of any clinical signs and symptoms of 
invasive candidiasis.  Certain sites of infection, including Candida endocarditis, 
meningitis, osteomyelitis/septic arthritis, and endophthalmitis, may warrant a longer 
treatment course based on the consideration of a variety of relevant factors (see Table 2-1
in Section 2.4.2, Treatment Plan).
 
 
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1.7
STUDY FLOW CHART
Screening
Study Therapy
a
Follow-up Assessments
Activity
Prestudy
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Continuing 
Study Therapy 
Past Day 7
Last Day of 
Study 
Therapy
2 Weeks 
after the End 
of Study 
Therapy
8 Weeks 
after the End 
of Study 
Therapy
Informed Consent from Parent/Guardian
X
Provide Participant Identification Card
X
Review Inclusion/Exclusion Criteria
X
Medical History
X
Chest X-ray
b
X
Assessment of signs and symptoms 
pertaining to Candida infection
X
X
X
X
X
X
X
X
Daily
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Daily
X
X
X
Physical examination
X
X
X
Twice weekly
X
X
X
Weight
X
X
c
X
c
Weekly
Blood culture
X
d, e
X
d
X
d
X
d
X
f
X
f
Other cultures or biopsies
X
e
X
f
X
f
X
f
X
f
X
f
Other radiographic studies
X
g
X
h
X
h
X
h
X
h
X
h
Administer study therapy 
X
X
X
X
X
X
X
Once daily
X
Blood for safety
X
X
i
X
Twice weekly
X
X
Plasma (and CSF, if available) for drug 
level
Xj
Xj
Monitor for adverse experiences
X
X
X
X
X
X
X
X
Daily
X
X
Efficacy assessment (fungal-free 
survival)
X
X
Efficacy assessment (development of 
complicated candidiasis)
X
 
 
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a
Duration of study therapy should be according to criteria specified in Table 2-1 of the protocol.  In general, patients should be treated with study therapy for a minimum of 14 days following the 
time of documented negative cultures from the site of infection and improvement of any clinical signs and symptoms of invasive candidiasis.  
b
Prior chest X-ray may be used, provided the chest X-ray was performed within 10 days prior to initiation of study therapy.
c
In addition to at least weekly measurements of weight, weight is to be measured on either Day 4 or Day 7 based on the assigned day of PK blood sampling (see Section 3.3.2).
d
Two sets of blood cultures must be obtained at screening in all patients.  Patients with candidemia should have periodic blood cultures collected while on therapy until cultures are negative for 
Candida (on at least 2 consecutive occasions). 
e
The blood cultures or cultures from the non-blood site(s), which confirm the evidence of invasive Candida infection during the screening phase, must be obtained within 96 hours prior to study 
entry.
f
Follow-up culture samples to be collected from the site(s) of Candida infection, as clinically indicated (see Section 3.2, Study Procedures).  Specifically, follow-up CSF cultures should be 
collected until negative follow-up CSF cultures are documented.  
g
When appropriate, a radiographic study from the site of infection (e.g., echocardiogram, chest/abdominal ultrasound) should be performed within 96 hours prior to study entry.
h
Follow-up radiographs are to be performed from the site(s) of infection (e.g., echocardiogram, chest/abdominal ultrasound, CT, MRI) as clinically indicated, based on the site of infection (see 
Section 3.2, Study Procedures).  If a radiographic study that helped confirm the diagnosis of invasive candidiasis is deemed necessary to assess the outcome of study therapy, a follow-up 
radiographic study must be obtained within 72 hours (3 days) prior to completion of study therapy.
i
The first laboratory safety sample following initiation of study therapy should be performed on Day 4.  If collection of a Day 4 sample is not possible, the laboratory sample may be obtained on 
Day 3 or Day 5 of study therapy.  The selected chemistry and hematology laboratory tests for safety are included in Appendix 6.1.
j
Three blood samples (350 μL each) are to be collected on either Day 4 or Day 7 (according to the assigned schedule as described in Section 3.3.2).  Plasma will be separated from blood and sent 
to a central laboratory for pharmacokinetic testing.  If sampling cannot be performed on the assigned day, blood samples can be drawn at comparable timepoints on the following day.  If a 
patient undergoes any procedure at baseline or during study therapy that involves collecting CSF, a CSF sample (350 μL) should be retained at each timepoint and sent to a central laboratory for 
pharmacokinetic testing.
 
 
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2. CORE PROTOCOL
2.1
OBJECTIVES AND HYPOTHESES
2.1.1
Primary Objective
Efficacy:  To compare caspofungin to amphotericin B deoxycholate with respect to the 
efficacy endpoint of fungal-free survival at the 2-week posttherapy follow-up visit (i.e., 
the proportion of patients who survived through the 2-week posttherapy follow-up period 
and had documented microbiological eradication of Candida sp. from follow-up cultures 
collected after the initiation of study therapy).
Hypothesis:  In neonates and infants with invasive candidiasis, caspofungin will be 
superior to amphotericin B deoxycholate, with regard to the proportion of patients with 
fungal-free survival at the 2-week posttherapy follow-up visit.
2.1.2
Secondary Objectives
2.1.2.1
Efficacy
To assess in neonates and infants who are treated with caspofungin or amphotericin B 
deoxycholate for documented invasive candidiasis, fungal-free survival at the end of 
study therapy (i.e., the proportion of patients who survived through the end of study 
therapy visit period and had documented microbiological eradication of Candida sp. from 
follow-up cultures collected after the initiation of study therapy).
2.1.2.2
Safety 
To assess the safety in neonates and infants who are treated with caspofungin or 
amphotericin B deoxycholate for documented invasive candidiasis.
2.1.3
Exploratory Objectives
 
 
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2.2
SUBJECT/PATIENT INCLUSION CRITERIA
1. Patient is <3 months (90 days) of age on day of informed consent.  
NOTE: Age is based on chronological assessment from the time of birth.
2. Patient (either symptomatic or at-risk) has a documented (culture-confirmed), 
invasive Candida infection, as defined by the presence of (a) a positive culture for 
Candida spp. collected from a normally sterile body fluid within 96 hours of study 
entry or (b) a positive culture for Candida spp. collected within 96 hours of study 
entry from a newly-placed drain inserted into a normally sterile body site.  "At-risk" 
is defined by the presence of one or more of the risk factors included in Appendix 6.2.
NOTE: A symptomatic or at-risk patient with a Candida UTI, as defined by a 
positive urine culture of >10,000 colony-forming units (CFUs) per milliliter of 
Candida spp. from a newly placed catheter, will also be eligible for enrollment.  
3. Parent (or guardian) understands the study procedures, alternative treatments 
available, and risks involved with the study and voluntarily agree to the patient’s 
participation by giving written informed consent.
4. Parent (or guardian) provides written informed consent for the trial.  
2.3
SUBJECT/PATIENT EXCLUSION CRITERIA
1. Patient is ≥3 months (≥90 days) of age at the time of informed consent.
2. Patient has Candida disease limited to the oropharynx, esophagus, or other mucosal 
or superficial skin surfaces (e.g., vagina or other genitalia, colonic tract, skin folds, 
nail beds, etc.).
3. Patient has evidence of infection limited to a positive culture for Candida spp. from 
the sputum, broncho-alveolar lavage (BAL), catheter tip, or previously placed 
indwelling non-vascular catheters/drains. 
NOTE: Patients with a positive Candida culture sample obtained at the time of the 
sterile placement of a non-vascular catheter or drain are eligible. 
4. Patient has a prosthetic device (e.g., prosthetic heart valve) at a suspected site of 
Candida infection.
NOTE: Patients may be eligible for enrollment if the device is surgically removed at 
study entry or within 72 hours after randomization.
5. Patient is actively co-infected with a non-Candida fungal organism. 
 
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6. Patient has received more than 48 hours of systemic (IV or oral) antifungal treatment 
since the time the positive Candida index culture was collected as therapy for this 
episode of invasive candidiasis.  
NOTE: Prior antifungal prophylaxis with a triazole [e.g., fluconazole] is permitted.
7. Patient has failed prior systemic (IV or oral) antifungal therapy for this episode of 
invasive candidiasis.
8. Patient has exclusionary laboratory values (obtained within 48 hours of study therapy 
initiation) as listed below:  

Aspartate aminotransferase (AST, also referred to as SGOT) >3 times the upper 
limit of normal, for age. 

Alanine aminotransferase (ALT, also referred to as SGPT) >3 times the upper 
limit of normal, for age.
NOTE:  Patients with screening values/findings outside the ranges described may, at 
the discretion of the investigator, have one repeat determination performed and if the 
repeat value satisfies the criterion, the investigator may continue in the screening 
process for this particular patient.  Only the specific out of range values/findings 
should be repeated (not the entire panel).
9. Patient is not expected to survive at least 5 days.
10. Patient has a diagnosis of acute hepatitis or cirrhosis due to any cause.
11. Patient is currently participating or has participated in a study with an investigational 
compound or device.
12. Patient has previously participated in this study.
13. Patient is scheduled or anticipated to receive rifampin or other systemic (IV or oral) 
antifungal therapy (i.e., an intravenous or oral formulation of the member of the 
polyene, triazole, or echinocandin class) while on study therapy.  
NOTE: Patients who were on rifampin or other systemic antifungal therapy prior to 
study entry are eligible for enrollment, provided these are discontinued prior to the 
initiation of study therapy.
14. Patient has known renal insufficiency, which, in the investigator's assessment, has the 
potential to worsen as a result of subsequent study therapy with amphotericin B 
deoxycholate.
15. Patient or the patient’s mother has a history of allergy, hypersensitivity, or any 
serious reaction to caspofungin or another member of the echinocandin class (e.g., 
micafungin, anidulafungin, or aminocandin).
 
 
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16. Patient or the patient’s mother has a history of allergy, hypersensitivity, or any 
serious reaction to amphotericin B deoxycholate or other members of the polyene 
class (e.g., amphotericin B lipid complex, liposomal amphotericin B, or amphotericin 
B colloidal dispersion).
17. Patient has a severe congenital disorder known to lower immune response.
18. Patient has a history or current evidence of any condition, therapy, lab abnormality or 
other circumstance that might confound the results of the study, or interfere with the 
patient’s participation for the full duration of the study, such that it is not in the best 
interest of the patient to participate.
2.4
STUDY DESIGN AND DURATION
2.4.1
Summary of Study Design
This is a multicenter, double-blind, randomized, comparative study to evaluate the safety, 
tolerability, and efficacy of caspofungin versus amphotericin B deoxycholate in the 
treatment of neonatal candidiasis.  Approximately 90 neonates and infants less than 3 
months of age with documented (culture-confirmed) invasive Candida infections within 
96 hours prior to study entry will be enrolled and randomized in a 2:1 ratio to receive 
intravenous caspofungin 2 mg/kg (per body weight) once daily (~60 patients) or
intravenous amphotericin B deoxycholate 1 mg/kg (per body weight) once daily (~30 
patients).  
The duration of study therapy with caspofungin or amphotericin B deoxycholate is 
variable and dependent on a variety of factors, including (1) the rapidity of a patient’s 
clinical and microbiological response, (2) the patient’s general medical condition, and (3) 
the underlying site of Candida infection.  In general, patients should be treated with study 
therapy for a minimum of 14 days following the time of documented negative cultures 
from the site of infection and improvement of any clinical signs and symptoms of 
invasive candidiasis (see Section 2.4.2, Treatment Plan).  
Patients will be monitored for adverse experiences while on study therapy and during the 
2-week posttherapy follow-up period. Selected laboratory safety tests will be performed 
from blood collected at screening, on Day 4 (or Day 3 or Day 5) and Day 7 of study 
therapy, twice weekly thereafter while on study therapy, on the last day of study therapy, 
and at the 2-week posttherapy follow-up visit. A physical examination will be performed 
at prestudy, twice weekly throughout the study therapy period (including Day 4 and Day 
7), on the last day of study therapy, and at each of the 2 posttherapy follow-up visits (2 
and 8 weeks posttherapy).  
A detailed description and evaluation of the Candida infection will be performed at 
screening, daily while on study therapy, on the last day of study therapy, and at the 2- and 
8-week posttherapy follow-up visits.  Resolution or progression of the Candida infection 
should be documented by assessment of signs and symptoms, radiographic studies (when 
clinically indicated), and follow-up blood cultures or, as appropriate, other follow-up 
cultures (including urine or CSF).  Based on all available data, an efficacy assessment 
will be made at the end of study therapy and at the 2-week posttherapy follow-up visit.  
 
 
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2.4.2
Treatment Plan
Neonates and infants <3 months of age with documented (culture-confirmed) Candida
infections will be randomized in a 2:1 ratio to receive caspofungin (~60 patients) or 
amphotericin B deoxycholate (~30 patients). 
In an effort to strive for adequate representation of patients from different weight groups 
(reflective of patient gestational age) in both treatment arms, randomization will be 
stratified into 3 weight categories (based on weight at study entry): <1000 grams, 1000 to 
1500 grams, and >1500 grams. Patients will be stratified into each of the weight 
categories in a manner consistent with the 2:1 randomization of caspofungin to 
amphotericin B deoxycholate.
Study Drug Preparation
Caspofungin will be administered at 2 mg/kg once daily (with no loading dose).  Dosing 
with caspofungin will be based on the patient's actual weight at the time of study entry.    
Caspofungin will be reconstituted/prepared by an unblinded study pharmacist.  
Appropriate quantities of caspofungin will be diluted with normal (0.9%) saline to 
achieve a final concentration not to exceed 0.5 mg/mL.  For example, for a 1-kg neonate, 
the daily caspofungin dose is 2 mg, and should be diluted in at least 4 mL.  NOTE: 
Dilution of caspofungin in dextrose-containing solutions is contraindicated.   The 
final total volume of infusate is at the discretion of the unblinded pharmacist and should 
be based on the patient’s ability to tolerate the fluid load.  However, the final caspofungin 
concentration should not exceed 0.5 mg/mL.  Full guidelines for the preparation of 
caspofungin study therapy for infusion are provided in the Pharmacy Binder.  
Amphotericin B deoxycholate will be administered at 1 mg/kg (per body weight) once 
daily. Amphotericin B deoxycholate will be reconstituted/prepared by an unblinded study 
pharmacist. Dosing with amphotericin B deoxycholate will be based on the patient's 
actual weight at the time of study entry.  The amphotericin preparation will also be 
administered as a single daily infusion.  Full guidelines for the preparation of 
amphotericin B deoxycholate study therapy for infusion are provided in the Pharmacy 
Binder.
In order to verify the patient is receiving the correct dose of either caspofungin or 
amphotericin B deoxycholate, weight should be measured at least once weekly while the 
patient is on study therapy, and the dose of caspofungin or amphotericin B deoxycholate 
should be adjusted accordingly.  
All study therapy (caspofungin or amphotericin B deoxycholate) will be administered 
intravenously as a single daily dose.  Each infusion should be administered over 
approximately 2 hours.  The IV line should be flushed thoroughly after each study 
therapy infusion.  Infusion of study therapy may be given through either a pediatric 
syringe pump or ambulatory pump if this will help ensure that the patient receives the 
complete dose.  
As these 2 products differ in color, opaque masking will be used over the infusion 
materials (e.g., infusion syringe and tubing) to ensure adequate blinding of the treatment 
 
 
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group.  The unblinded pharmacist will be responsible to cover the materials (e.g., 
infusion syringe and tubing) with opaque masking.  Importantly, the unblinded 
pharmacist will be uninvolved in any of the postinfusion evaluations for the patient.  All 
study personnel involved with the postinfusion evaluations of safety and efficacy 
outcomes, including the study coordinator(s), investigator, or subinvestigator(s), must 
have no access to the treatment group assignment or the preparation of the study infusion.
Duration of Study Therapy
The duration of study therapy with caspofungin or amphotericin B deoxycholate is 
variable and dependent on a variety of factors, including (1) the rapidity of a patient’s 
clinical and microbiological response, (2) the patient’s general medical condition, and (3) 
the underlying site of Candida infection.  In general, patients should be treated with 
intravenous study therapy for a minimum of 14 days following the time of documented 
negative cultures from the site of infection and improvement of any clinical signs and 
symptoms of invasive candidiasis.  Certain sites of infection, including Candida
endocarditis, meningitis, osteomyelitis/septic arthritis, and endophthalmitis, may warrant 
a longer treatment course based on the consideration of a variety of relevant factors (see 
Table 2-1).  
The maximum duration of study therapy permitted is 90 days.  If longer duration of 
therapy is warranted, a written request for continuation of therapy, including a written 
summary of the case, should be provided to the SPONSOR Clinical Monitor (or 
designee) before Day 85 of therapy.
 
 
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Table 2-1
General Guidelines for the Duration of Total Antifungal Therapya for Various
Non-fungemic Forms of Invasive Candidiasis
Candida Infection
Recommended Duration of 
Therapy
Other Considerations or Guidelines 
for Managementb
Peritonitis
2 to 4 weeks of therapy 
(minimum of at least 14 days 
following both clinical 
resolution and microbiological 
eradication)

Patients on peritoneal dialysis:  
Removal of peritoneal dialysate catheter 
likely required 

Surgical patients:  Surgical repair and 
drainage of perforation or leak likely 
required. 
Abscess involving 
intraabdominal cavity 
or organ
2 to 4 weeks of therapy 
(minimum of at least 14 days 
following both clinical 
resolution and microbiological 
eradication)

Surgical drainage or aspiration drainage 
of abscess collection likely required

Follow-up radiography (ultrasound, CT, 
or MRI) should be used to gauge 
response and determine treatment 
duration
Abscess involving 
other cavity or organ
2 to 4 weeks of therapy 
(minimum of at least 14 days 
following both clinical 
resolution and microbiological 
eradication)

Surgical drainage or aspiration drainage 
of abscess collection likely  required

Follow-up radiography (ultrasound, CT, 
or MRI) should be used to gauge 
response and determine treatment 
duration
Pleural space infection 
(empyema)
2 to 4 weeks of therapy 
(minimum of at least 14 days 
following both clinical 
resolution and microbiological 
eradication)

Ongoing chest tube drainage likely 
required

Follow-up radiography (chest 
ultrasound, x-ray, or CT) should be used 
to gauge response and determine 
treatment duration
Pneumonia
2 to 4 weeks of therapy 
(minimum of at least 14 days 
following both clinical 
resolution and microbiological 
eradication)

Follow-up radiography (chest 
ultrasound, x-ray, or CT) should gauge 
response and determine treatment 
duration

In general, consider 2 weeks of therapy 
for  non-necrotizing pneumonia and 4 
weeks of therapy for necrotizing 
pneumonia 
Endophthalmitis
Generally 6 to 12 weeks of 
therapy (until complete 
resolution of lesions or 
stabilization)
Not Applicable
 
 
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General Guidelines for the Duration of Total Antifungal Therapya for Various Non-fungemic Forms 
of Invasive Candidiasis (Cont.)
Candida Infection
Recommended 
Duration of Therapy
Other Considerations or Guidelines 
for Managementb
Osteomyelitis 
At least 4 weeks of therapy 

Initial surgical debridement may be 
required. 

Repeat follow-up debridements may also 
be necessary, based on response (follow-
up cultures encouraged during repeated 
debridements)

Follow-up radiography should be used to 
gauge response and determine treatment 
duration
Septic arthritis
At least 4 weeks of therapy 

Initial, adequate drainage of joint fluid 
may be required.  

Repeated drainage (with assessments of 
fluid cell count and repeat culture) may 
also be necessary, based on response
Meningitis
3 to 6 weeks of therapy

Meningitis associated with neurosurgical 
procedures:  Consideration for removal of 
any prosthetic material and shunts 
Consider 3 weeks of therapy for  patients 
with meningitis without associated 
abscess

Consider 6 weeks of therapy (or longer) 
for complicated meningitis. In such cases 
consider continuation of treatment until 
normalization of all CSF analyses 
(including negative follow-up CSF 
cultures), normalization of radiologic 
findings, and stabilization of neurological 
function 
Endocarditis
At least 6 weeks of therapy 

Combined medical and surgical treatment 
may be needed.  Removal of all infected 
valves and debridement of abscessed 
cardiac/pericardial tissue may be required

Document follow-up blood cultures are 
negative for Candida species 

Careful follow-up of cardiac function to 
assure no relapse of infection
a These general guidelines for treatment duration are based, in part, on Infectious Diseases Society of 
America (IDSA) Treatment Guidelines for the treatment of invasive candidiasis.  As there are no 
dedicated guidelines for neonatal candidiasis, most of the dosing duration recommendations are based 
on adult experience, and, hence, may require some modification in the neonatal/infant population on a 
case-by-case basis.
b The general IDSA guidelines for treatment management of each site of Candida infection are included 
in Appendix 6.3.
 
 
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2.5
LIST OF EFFICACY MEASUREMENTS
Based on all available data, an efficacy assessment will be made at the end of study 
therapy and at the 2-week posttherapy follow-up visit.  The efficacy endpoint will be 
based on fungal-free survival (i.e., the proportion of patients who survived at the 
timepoint of interest 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 
at the time of evaluation.  If a culture is not obtained on the day of assessment, then 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 microbiologic eradication 
would be considered achieved.   Although fungal-free survival will be assessed at 2 
different time points (end of study therapy and the 2-week posttherapy follow-up visit), 
the primary efficacy time point will be at the 2-week posttherapy follow-up visit.  
NOTE:  Fungal-free survival assumes no additional antifungal therapy is required for the 
treatment of the underlying Candida infection once study therapy has ended; however, 
once study therapy has ended, prophylaxis with an antifungal agent (e.g., fluconazole) 
may be administered, if this is deemed appropriate by the investigator. 
 
 
 
 
 
 
 
 
 
Finally, the efficacy with caspofungin in neonates and infants (less than 3 months of age) 
enrolled in this study will be compared descriptively to the efficacy in caspofungin-
treated patients enrolled with invasive candidiasis in the prior Phase II pediatric 
documented infection study (Protocol 043, children and adolescents [3 months to 
17 years]) and prior Phase III adult studies (Protocols 014 and 801).
2.6
LIST OF SAFETY MEASUREMENTS
All patients who receive one or more doses of study therapy will be evaluated for the 
presence of adverse experiences while on study therapy and through the 2-week 
posttherapy follow-up visit.  To assist with these safety assessments, a physical 
examination will be performed at prestudy, twice weekly throughout the study therapy 
period (including Day 4 and Day 7), on the last day of study therapy, and at each of the 2 
posttherapy follow-up visits (2 and 8 weeks posttherapy).  In addition, selected laboratory 
safety tests will be performed at screening, on Day 4 (or Day 3 or Day 5) and Day 7 of 
study therapy, twice weekly thereafter while on study therapy, on the last day of study 
therapy, and at the 2-week posttherapy follow-up visit (see Appendix 6.1). 
 
 
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To address the secondary safety objective, the following safety endpoints will be 
evaluated: (1) the development of adverse experience(s) during the study therapy period 
or during the 2-week posttherapy follow-up period; (2) the development of drug-related 
adverse experience(s) during the study therapy period or during the 2-week posttherapy 
follow-up period; (3) the development of serious adverse experience(s) during study 
therapy period or during the 2-week posttherapy follow-up period; (4) the development of 
drug-related, serious adverse experience(s) during study therapy period or during the 
2-week posttherapy follow-up period; (5) the development of adverse experiences that 
necessitate discontinuation of study therapy; and (6) the development of drug-related 
adverse experiences that necessitate discontinuation of study therapy.
2.7
PHARMACOKINETIC MEASUREMENTS
Three blood samples (each 350 μL) for pharmacokinetic assessments will be collected 
from all patients.  Each patient will be randomly assigned to one of 8 sampling schedules; 
all 3 samples are to be taken on the same study day.  Half of the patients will have 
samples taken on Study Day 4 and the other half will have samples taken on Study Day 7.  
If it is not possible to take samples on the assigned Study Day, it is recommended that 
samples be taken on the following Study Day.
Blood samples will be collected from all patients at the time of peak concentration 
(within 5 minutes after the end of study therapy infusion) and time of trough 
concentration (approximately 24 hours after the start of study therapy infusion but prior 
to the next day’s dose).  In addition, a blood sample will be collected at an intermediate 
time between peak and trough times as shown in Table 3-4, in Section 3.3.2.  
Weight should be measured within 12 hours prior to the infusion of study therapy on the 
assigned day of pharmacokinetic blood sampling, and the study therapy dose given on the 
pharmacokinetic sample day should be adjusted to reflect the most recently measured 
weight.
If a patient undergoes any procedure that involves collecting CSF while on study therapy, 
approximately 350-μL of CSF should be retained for pharmacokinetic assessments.  If 
available, a baseline (or prestudy) CSF sample should also be retained.
Plasma will be separated from blood and sent to a central laboratory for pharmacokinetic 
testing.  The CSF will also be sent to a central laboratory for pharmacokinetic testing. 
Procedures for collection, processing, storage, and shipment of pharmacokinetic samples 
from blood (plasma) and CSF are included in the Administrative Binder.
2.8
STATISTICAL ANALYSIS PLAN SUMMARY
Key elements of the statistical analysis plan are summarized below; the comprehensive 
plan is provided in Section 3.5 of the protocol details. 
2.8.1
Efficacy Analyses 
The primary and secondary endpoints, primary analysis population, and statistical 
methods that will be employed for the efficacy analyses are presented in Table 2-2. 
 
 
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The primary hypothesis will be evaluated by comparing the caspofungin treatment group 
to the amphotericin B deoxycholate treatment group with respect to the proportion of 
patients with fungal-free survival at the 2-week posttherapy follow-up visit.  
All efficacy evaluations will use a full analysis set (FAS) patient population, which 
includes those patients who receive at least one dose of study therapy and have a 
documented (culture-confirmed) diagnosis of invasive candidiasis (see Section 2.2, 
Inclusion Criteria).  All patients, irrespective of body weight at study entry, will be 
grouped together for the primary evaluation.  Subgroup evaluation based on the 3 body 
weight categories at study entry (<1000 grams, 1000-1500 grams, >1500 grams) will also 
be displayed.  Of note, a per-protocol population will also be evaluated for the primary 
and secondary efficacy endpoints (see Section 3.5.5.1, Efficacy Analysis Populations). 
The treatment comparisons for the primary and secondary efficacy analyses will be made 
using the difference in response rates between the 2 treatment groups and its 95% 
confidence interval. The confidence interval for the difference in response rates will be 
calculated using a methodology proposed by Miettinen and Nurminen [17].
 
 
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Table 2-2
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approacha
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary
Proportion of patients with 
fungal-free survival through the 
2-week posttherapy period
P
Miettinen and 
Nurminen method
FAS
A patient with 
missing data 
will be 
considered a 
failure.
Proportion of patients with 
fungal-free survival through the 
2-week posttherapy period
S
Miettinen and
Nurminen method
PP
Observed data
Secondary
Proportion of patients reporting 
fungal-free survival at the end 
of study therapy
P
Miettinen and 
Nurminen method
FAS
A patient with 
missing data 
will be 
considered a 
failure.
Proportion of patients reporting 
fungal-free survival at the end 
of study therapy
S
Miettinen and 
Nurminen method
PP
Observed data
a P=Primary approach; S=Secondary approach.
2.8.2
Safety Analyses
All safety tabulations will use an all-patients-as-treated (APaT) population, which 
includes all patients who receive at least one dose of study therapy.  There are no safety 
parameters that rise to the level of formal statistical testing in this study (i.e., no Tier 1 
events).
 
 
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2.8.3
Power and Sample Size
This study will enroll approximately 60 patients in the caspofungin treatment group and 
30 patients in the amphotericin B deoxycholate treatment group, to achieve 80% power 
(2-sided, α=0.05) to demonstrate the primary efficacy hypothesis that caspofungin is 
superior to amphotericin B deoxycholate with regard to the proportion of patients with 
fungal-free survival at the 2-week posttherapy follow-up visit.  The minimum criterion 
for success is that the lower bound of the 95% CI for the difference between the 2 
treatment groups (caspofungin minus amphotericin B deoxycholate) in the primary 
efficacy endpoint is >0.
The sample size is based on an underlying response rate of 50% for the amphotericin B 
deoxycholate treatment group from the recently published comparative study in 32 
neonates and infants with invasive candidiasis where a favorable response was observed 
in 86.7% of caspofungin-treated patients and 41.7% of amphotericin B deoxycholate-
treated patients [9].  The study is designed to have 80% power to demonstrate the 
superiority of caspofungin over amphotericin B deoxycholate at an overall two-sided, 5% 
alpha-level, if the underlying treatment difference in fungal-free survival at the 2-week 
posttherapy visit is ~30 percentage points (or larger). 
 
 
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3. PROTOCOL DETAILS
3.1
RATIONALE
Caspofungin is a parenteral echinocandin antifungal agent that has received approval in 
the United States, the European Union (EU), and over 80 other countries for the treatment 
of adult patients (≥18 years of age) for one or more of the following: (1) invasive 
aspergillosis in patients who are refractory to or intolerant of other therapies (i.e., 
amphotericin B deoxycholate, lipid formulations of amphotericin B, and/or itraconazole); 
(2) esophageal candidiasis; (3) candidemia and other Candida infections, including intra-
abdominal abscesses, peritonitis, and pleural space infection; and (4) empirical therapy of 
suspected invasive fungal infections in febrile, neutropenic patients [1, 2].  Furthermore, 
caspofungin has been approved for use in pediatric patients (≥3 months of age) in over 60 
countries worldwide for the same indications as in adults.
As of 11-Jan-2012, a total of 2036 adult and pediatric subjects/patients have received at 
least one dose of caspofungin in the global registration studies. In these studies, 
caspofungin was administered for up to 196 days at daily doses ranging between 5 mg 
and 210 mg. Integrated safety data has been summarized across 1951 of these 2036 
subjects.  Of the 1951 subjects, 42% experienced at least one drug-related adverse 
experience during caspofungin therapy or within the 14-day posttherapy follow-up 
period. The most common drug-related adverse experiences were pyrexia (9.3%), 
increased ALT (6.5%), increased AST (6.0%), increased alkaline phosphatase (5.2%), 
chills (5.2%), and headache (4.6%). Across all studies, caspofungin has a favorable safety 
profile, with few serious, drug-related adverse experiences and few discontinuations due 
to drug-related adverse experiences. The incidence of drug-drug-interactions with 
caspofungin has also been relatively infrequent.  Additional details regarding the 
pharmacokinetics, safety, and efficacy of caspofungin in adult patients are further 
described in the Investigator’s Brochure (IB).
3.1.1
Rationale for This Study
Fungal Infections in Pediatric Patients, including Neonates and Infants
The epidemiological rise in invasive fungal infections (IFI) in pediatric patients rivals the 
increases seen in the adult population.  As in adults, IFI are commonly seen in pediatric 
patients with childhood malignancies or those pediatric patients undergoing 
hematopoietic stem cell transplantation or pediatric surgery [14].  Candida remains the 
most common cause of IFI in children. In 2000 alone, candidemia was diagnosed in an 
estimated 1,118 hospital admissions of all pediatric patients (≤20 years of age) in the 
United States.  This yielded a frequency of 43 cases per 100,000 pediatric admissions 
(95% CI, 35-52 cases per 100,000 pediatric admissions).  In comparison, candidemia was 
seen in 30 cases per 100,000 adult admissions (95% CI, 26-34 cases per 100,000 adult 
admissions). The estimated annual incidence of candidemia among all pediatric and adult 
admissions is 0.043% and 0.03%, respectively [15].
 
 
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In the neonatal and infant population, candidemia and other forms of invasive candidiasis 
are a major medical concern.  Candida species represent the second most common 
pathogen among nosocomial blood stream infections and the most common fungal 
infection in infants less than 1 year of age [5].  Furthermore, in the United States in 2003, 
the overall incidence of invasive candidiasis among neonates was 15 cases per 10,000 
neonatal admissions (95% CI, 13-16 case per 10,000 neonatal admissions) [3].  However, 
incidence has been shown to vary widely between clinical centers [4, 6-7].  C. albicans is 
the most frequently isolated species, and C. parapsilosis is the most frequently isolated 
non-C. albicans species [4, 7, 18-22].
Invasive candidiasis is an opportunistic infection resulting from either the immaturity of 
the immune system, a depleted immune response in a critically ill neonate, an increased 
colonization rate, or invasive intensive-care procedures. 
The risks associated with 
infection include a young gestational age and a very low birth weight [4, 14].  In a study 
published from Israel, the incidence of acquired fungal sepsis in neonates ranged from 
0.4 to 2 cases per 1000 live-births; fungal sepsis was seen in 1.1% of all neonatal 
intensive care unit (NICU) admissions.  The incidence of invasive candidiasis in this 
population is inversely related to the weight of the infant, with cumulative incidence rates 
of 0.26%, 3.1%, and 5.5% in infants with birth weights ≥2500g, very low birth weights 
(VLBW, <1500g), or extremely low birth weights (ELBW, <1000g), respectively [16]. 
Notably, the current antifungal regimens administered in the neonatal population are 
associated with significant toxicity, multiple drug-drug interactions, or limitations in 
spectrum of activity.  
To date, four clinical studies (Protocols 033, 042, 043, 044) have been conducted to 
evaluate caspofungin in pediatric patients 3 months to 17 years of age.  Two 
pharmacokinetic studies (Protocols 033 and 042) have demonstrated that caspofungin, 
administered at a 50 mg/m2 once-daily maintenance dose in pediatric patients (3 months 
to 17 years of age), resulted in plasma pharmacokinetic parameters commensurate with 
those achieved in adults receiving the 50-mg once-daily maintenance dosing regimen.  
The results of the other 2 studies confirm that the efficacy and safety of caspofungin at 
the 50-mg/m2 daily maintenance dose is comparable to that seen in caspofungin-treated 
adults.  Additional details regarding the pharmacokinetics, safety, and efficacy of 
caspofungin in pediatric patients (3 months to 17 years of age) are further detailed in the 
IB.
Based on these studies, caspofungin has been approved for use in pediatric patients 
≥3 months of age in over 60 countries worldwide for the same indications as in adults. 
Importantly, the indications and age range for use vary by country [1, 2].  
Caspofungin Use in Neonates and Infants Less than 3 Months of Age 
The pharmacokinetics and safety of caspofungin in the neonatal patient population were 
evaluated in a prospective pharmacokinetic trial (Protocol 058).  Protocol 058 was an 
open-label, noncomparative study to investigate the safety, tolerability, and 
pharmacokinetics of caspofungin in neonates and infants <3 months of age.  In this study, 
the pharmacokinetics in 18 neonates and infants receiving single or multiple once-daily 
doses of 25-mg/m2 were generally similar to that in adults receiving a 50-mg once-daily 
 
 
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maintenance dose.  Caspofungin was well tolerated in the 18 patients included in this 
study; in fact, no drug-related adverse experiences were noted in any of the 18 
caspofungin recipients [8].  Efficacy in the neonatal population can also be anticipated 
based on the efficacy of caspofungin against invasive candidiasis in pediatric patients 
3 months to 17 years of age enrolled in the documented infection study (Protocol 043).  
The data from Protocol 043 demonstrated an 80% success rate in children and 
adolescents with invasive candidiasis (including a 73% response rate in children <6 years 
of age) [23].  
The efficacy of caspofungin in the treatment of invasive candidiasis and other Candida 
infections in neonates and infants was recently demonstrated in a randomized, double-
blind, prospective clinical trial in 32 neonates comparing caspofungin to amphotericin B 
deoxycholate (see Table 3-1) [9]. In this study conducted at a single site in Saudi Arabia, 
newborn infants received either caspofungin (2 mg/kg/day, n=15) or amphotericin B 
deoxycholate (1 mg/kg/day, n=17).  A favorable response at the end of intravenous 
therapy, the primary timepoint for efficacy, was observed at a greater rate in patients who 
received caspofungin (86.7%) than those who received amphotericin B deoxycholate 
(41.7%) (p=0.04).  Importantly, caspofungin was effective in all sites of Candida 
infection, including all 3 cases with Candida meningitis and 4 of 5 patients with Candida 
endocarditis.  The proportion of patients who experienced at least 1 drug-related 
laboratory adverse event was significantly lower in neonates who received caspofungin 
compared to those who received amphotericin B deoxycholate (p<0.05).  
 
 
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Table 3-1
Randomized, Comparative Trial of Caspofungin vs. Amphotericin B Deoxycholate in Neonates
Lead Author
Study Design
Treatment
N
Daily Dose
Agea
(Mean ± SD, 
Days)
Candida Species 
(n)
Site of Infection 
(n)
Response Rateb
% (n/N)
Safety Endpoints
% (n/N)
Mohamed WA 
and Ismail M[9]
Single-center, 
prospective, 
randomized, 
controlled trial
Caspofungin
15
2 mg/kg
21.1 ± 3.1
C. albicans (11)
C. parapsilosis (3)
C. tropicalis (1)
Meningitis (3)
Ventriculitis (1)
Endocarditis (5)
Endophthalmitis (2)
Urinary candidiasis (3)
Osteomyelitis (1)
86.7% 
(13/15) 
Clinical AE:  
26.7% (4/15)
Laboratory AE:  
33.3% (5/13) 
Discontinuation 
due to AE:
0% (0/15)
Amphotericin B 
deoxycholate
17
1 mg/kg
22.3 ± 2.4
C. albicans (13)
C. parapsilosis (2)
C. tropicalis (2)
Meningitis (4)
Ventriculitis (1)
Endocarditis (4)
Endophthalmitis (3)
Urinary candidiasis (4)
Osteomyelitis (1)
41.7%
(5/12c)
Clinical AE:  
64.7% (11/17)
Laboratory AE:  
76.4% (13/17) 
Discontinuation 
due to AE:  29.4% 
(5/17)
a Age at onset of Candida infection
b Favorable response at the end of intravenous therapy, the primary time point for determination of efficacy in the study
c Five patients in the amphotericin B deoxycholate group withdrew due to drug-related adverse events and were not included in the calculation of the response rate.
N = Overall sample size for each treatment group
n = Number of patients in each subcategory within a specific treatment group.
 
 
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Published data from several case series in neonates with invasive candidiasis (two from 
Costa Rica, one from Italy, and one from Detroit, Michigan, United States) provide 
additional evidence of efficacy in this age group (see Table 3-2) [10-13].  In these 
studies, caspofungin therapy was begun only after initial therapy with conventional 
antifungals (amphotericin B deoxycholate, fluconazole, and/or flucytosine) had failed; in 
other words, the Candida infection was resistant to, or the patient was intolerant of, the 
initial therapy.  In 29 of 75 cases, caspofungin treatment was added to a conventional 
antifungal regimen, while caspofungin monotherapy was given in the remaining 46 cases.  
Collectively, 53 of 75 neonates received either a caspofungin dose of 2 mg/kg or 
25 mg/m2, and the favorable response rate across these series was in excess of 80%.  
Importantly, caspofungin was effective in all sites of Candida infection, including all 
6 patients with Candida meningitis in these 4 case series. 
Caspofungin was well 
tolerated, with few drug-related adverse events reported.  The drug-related adverse events 
were consistent with those reported in older children and adults.  
 
 
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Table 3-2
Case Series Documenting Caspofungin Use in Neonates 
Publication
Country
Number 
of 
Patients
Findings
Mondello I 
et al.
[10]
Italy
16

All infants or neonates (15 very low birth weight and 1 full 
term)

Caspofungin added to conventional therapy:  25 mg/m2 (11), 
50 mg/m2 (4), and 1 dose unspecified

Favorable response estimated to be >81% (13/16) 

No adverse event (AE) attributed to caspofungin; reported 
AEs (n) included:
Transient mild hypokalemia (4)
Thrombocytopenia (1)
Deaths (4):  severe intraventricular hemorrhage (1), ICI 
(3, all dosed at 25 mg/m2)
Natarajan G 
et al.
[11]
United 
States
13

All infants or neonates (12 preterm and 1 term)

All caspofungin use at 1 mg/kg daily (5 patients had 1.5 
mg/kg loading dose)

All as combination salvage therapy with lipid amphotericin 
B, amphotericin B deoxycholate, fluconazole, or 5-FC

Success in 11 (85%) of 13 patients 

No serious drug-related AEs

Reported AEs (n) included:
Thrombophlebitis on initial dose; further doses tolerated 
with increased dilution & infusion duration (1)
Transaminase elevation (4)
Hypokalemia (2)
Isolated direct hyperbilirubinemia (1)
2 deaths not related to caspofungin
Odio CM et 
al.
[12]
Costa 
Rica
10

All infants or neonates 

Caspofungin mostly at 2 mg/kg daily 

All caspofungin as salvage monotherapy following initial 
amphotericin B deoxycholate use

Success in 10 (100%) of 10 patients

No demonstrable toxicity
Odio CM et 
al.
[13]
Costa 
Rica
36

All infants or neonates 

Caspofungin at 2 mg/kg daily or 3 mg/kg for meningitis (3 
patients)

All caspofungin as salvage monotherapy following initial 
amphotericin B deoxycholate use

100% favorable response (36/36 pts with sterilized 
blood/cerebrospinal fluid [CSF])
All 3 patients with Candida meningitis had sterile 
follow-up CSF cultures
1 patient relapsed and was successfully treated with a 
second course of caspofungin

No demonstrable toxicity
 
 
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With the approval of the use of caspofungin in many countries in children and 
adolescents between the ages of 3 months to 17 years, and with the availability of 
preclinical data in juvenile rodent model and pharmacokinetic data in infants and 
neonates (Protocol 058), this study will prospectively evaluate the safety and efficacy of 
caspofungin in the treatment of invasive candidiasis in the youngest pediatric group, the 
neonatal and infant population less than 3 months of age.
Amphotericin B Use in Neonates and Infants Less than 3 Months of Age
The IDSA clinical practice guideline for the management of candidiasis [29] 
recommends amphotericin B deoxycholate as the first-line treatment for invasive 
candidiasis in neonates/young infants at a dose of 1 mg/kg/day.  Publications describing 
prospective, randomized, comparator-controlled trials of amphotericin B deoxycholate in 
neonatal candidiasis are predominantly limited to three studies, each enrolling less than 
60 patients in total and less than 35 in the amphotericin B deoxycholate treatment groups, 
as shown in Table 3-3. Measurements of treatment success, which varied among these 
studies, ranged from 41.7% to 67.6% for the amphotericin B deoxycholate group. 
Although limited in population sizes, two of these studies showed that patients treated 
with amphotericin B deoxycholate had more findings of hepatotoxicity, namely elevated 
alkaline phosphatase and total serum bilirubin, than comparators [9, 24].  As noted 
comparator-controlled trial of caspofungin versus amphotericin B deoxycholate, greater 
rates of drug-related laboratory abnormalities were also observed in patients who 
received amphotericin B deoxycholate than those who received caspofungin (see
Table 3-1) [9].  Nephrotoxicity is generally the most concerning side effect for neonates 
[27]; however, it has been reported that nephrotoxicity associated with amphotericin B 
deoxycholate use in infants and children is generally less severe than in adults, likely due 
to the more rapid clearance in children [25].  In addition, evidence suggests that 
amphotericin B deoxycholate is generally well tolerated in premature infants [26, 27].  
For this reason, liposomal preparations are not generally used in this patient population.
 
 
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Table 3-3
Clinical Trials of Amphotericin B Deoxycholate in the Neonatal Population
Publication
Study Description
(Year Conducted)
Dose of 
Amphotericin 
B 
Deoxycholate 
Findings
Mohamed 
WA and 
Ismail M 
[9]
Caspofungin vs. 
amphotericin B 
deoxycholate
(October 2008 to 
September 2010)
1 mg/kg/day

See Table 3-1

Nephrotoxicity was seen in 11.8% 
(2/17 patients) in the amphotericin 
B deoxycholate group and 0% in 
caspofungin group
Dreissen 
M, et al.
[24]
Fluconazole vs. 
amphotericin B 
deoxycholate 
(June 1992 to June 1993)
1 mg/kg/day

Neonates <3 months of age were 
eligible for enrollment

In total, 24 neonates were enrolled, 
with 11 patients receiving 
amphotericin B deoxycholate

Survival rate of 55% (6/11) in 
amphotericin B deoxycholate group 
and 67% (8/12) patients in the 
fluconazole group

Amphotericin B deoxycholate 
group demonstrated more signs of 
hepatotoxicity, specifically 
elevated alkaline phosphatase and 
total and direct serum bilirubin.
Linder N, 
et al [26]
Amphotericin B 
deoxycholate vs. two 
different amphotericin B 
lipid formulations 
(January 1996 to 
December 2000)
1 mg/kg/day

Mean gestational age of patients 
was 29.3 (± 4.2) weeks

In total, 56 neonates were enrolled, 
with 34 patients receiving 
amphotericin B deoxycholate

Sterilization of blood was observed 
in 67.6% of patients treated with 
amphotericin B deoxycholate 
monotherapy, and 100% of patients 
with addition of a second 
antifungal agent

No immediate local or systemic 
adverse events were reported

No renal function deterioration was 
reported
3.1.2
Rationale for Dose and Regimen 
The recommended dose for caspofungin for this study is 2 mg/kg daily.  This dose is 
based on the published data referenced above as well as the simulated results from the 
prior pharmacokinetic and safety study for caspofungin in neonates and infants 
<3 months of age (Protocol 058).
 
 
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In Protocol 058, neonates and infants with documented or highly suspected Candida
infections received a single or multiple doses of caspofungin at 25 mg/m2 once daily. The 
duration of caspofungin treatment in patients receiving multiple doses was a minimum of 
4 days and a maximum of 28 days. Blood for plasma pharmacokinetic (PK) sampling was 
collected predose (at screening), at 1 hour and 24 hours post-caspofungin infusion on Day 
1, and at 1 hour and 24 hours post-caspofungin infusion on Day 4 (corresponding to 
presumed steady-state peak and trough concentrations, respectively).  Caspofungin was 
generally safe and well tolerated in this study population.  On Day 1, the geometric mean 
ratios (90% CIs) for the neonates and infants relative to adults receiving the standard 
adult dose were 1.07 (0.89, 1.30) and 1.36 (1.04, 1.78), at 1 and 24 hours post-dose, 
respectively.  On Day 4, the geometric mean ratios (90% CIs) for the neonates and 
infants relative to adults receiving the standard adult dose were 1.18 (0.95, 1.46) and 1.21 
(0.90, 1.63), at 1 and 24 hours post-dose, respectively.  Overall, these pharmacokinetic 
results suggest that the pharmacokinetics in neonates and infants <3 months of age 
receiving single or multiple, once-daily caspofungin doses of  25 mg/m2 are fairly similar 
to those of adults receiving caspofungin at 50 mg once daily and the peak concentrations 
observed in neonates/infants did not exceed the range of clinical experience in adults. 
Based on these results, it was also determined that a loading dose is likely not required in 
this pediatric age group.  
Measurements of height are not routinely performed in the neonatal/infant population; 
therefore, a dosing regimen based on body surface area is not preferred in this patient 
population.  As a result, simulations for weight-based dosing were performed for the 
12 patients who received multiple doses of caspofungin in Protocol 058.  After 
calculating the actual dose received (in milligrams) based on each patient’s BSA and 
adjusting by each patient’s weight, the 25 mg/m2 dose equated to a mean daily dose of 
~2.1 mg/kg and median of ~2.0 mg/kg.  Actual Day 4 C1hr and C24hr data were adjusted 
based on the dose the patient would have received had a 2 mg/kg dose been administered.  
Depending on the relative weight to BSA ratio of a given patient, estimated caspofungin 
concentrations were increased or decreased using a weight-based dosing scheme 
compared to BSA-based.  However, the mean C1hr and C24hr values were nearly 
unchanged, and a decrease in variability was noted.  Therefore, based on this analysis, a 
weight-based dose of 2 mg/kg of caspofungin is deemed roughly equivalent to 25 mg/m2.  
The proposed 2 mg/kg daily dose for caspofungin to be evaluated in this study is also 
consistent with the caspofungin dose evaluated in a prospective, randomized, double-
blind study of the efficacy, safety, and tolerability of caspofungin compared to 
amphotericin B deoxycholate in 32 neonates [9].  As shown in Table 3-1, a favorable 
response at the end of intravenous therapy, the primary timepoint for efficacy in this 
study, was observed at a greater rate in patients who received caspofungin (86.7%) than 
those who received amphotericin B deoxycholate (41.7%) (p=0.04).  Furthermore, as 
outlined in Table 3-2, a proposed 2 mg/kg daily dose for caspofungin in this study is 
supported by efficacy and safety observations from 4 case series in neonates from Costa 
Rica, Italy, and the US [10-13] where 53 of 75 neonates received either a reported 
2 mg/kg dose or 25 mg/m2 dose and the favorable response rate across these series was in 
excess of 80%.  No loading dose was used in these various studies, thereby further 
confirming its limited value in this patient population.
 
 
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Finally, a preclinical study in the juvenile rodent model also provides useful information 
for the use of caspofungin in disseminated (including CNS) candidiasis [28], which is a 
complication commonly seen in the neonatal population.  This study confirmed that 
either a 1 or 2 mg/kg once-daily dosing regimen of caspofungin would be associated with 
efficacy in the treatment of candidiasis in both CNS and other tissues.  
In summary, a 25 mg/m2 or 2 mg/kg daily dose of caspofungin appears to demonstrate 
desirable pharmacokinetics in neonates and infants <3 months of age; the peak
concentrations were not elevated beyond the clinical range of peak concentrations that 
have been observed to be well-tolerated in adults, and the trough concentrations in this 
age group were not reduced from those observed in adults at the 50 mg daily dose.  In 
addition, the 2 mg/kg dose (without a loading dose) has been demonstrated to be safe and 
effective in a prospective, randomized, controlled clinical trial and other smaller efficacy 
studies.  Therefore, a daily dose of 2 mg/kg (without a loading dose) has been selected for 
evaluation in this clinical trial.   Importantly, the recommended daily maintenance dose 
for caspofungin in infants/toddlers over the age of 3 months is 50 mg/m2.  However, for 
the purposes of this study, the daily maintenance dose of 2 mg/kg is to be used 
throughout the treatment duration, even for patients who reach 3 months of age while on 
study therapy.
The daily dose for amphotericin B deoxycholate (1 mg/kg per body weight) was chosen 
based on the recommended standard dose in the IDSA guidelines for use in the neonatal 
population with invasive candidiasis [14, 24, 29].  Additionally, in the three studies listed 
in Table 3-3, patients in the amphotericin B deoxycholate treatment groups received a 
1-mg/kg daily dose.  Furthermore, although there is a relationship between total dose 
administered and tissue concentrations for amphotericin B deoxycholate, there is no 
conclusive clinical evidence that doses higher than 1 mg/kg/day are necessary for 
successful therapy in the pediatric population [25].
3.1.3
Rationale for Study Design
The current trial has been designed as a randomized, multicenter, comparator-controlled 
study to collect prospective data for caspofungin (relative to the current standard, 
amphotericin B deoxycholate) in the treatment of neonatal candidiasis.  A double-blind 
approach has been instituted to ensure an unbiased evaluation of the efficacy, safety, and 
tolerability data for caspofungin (relative to amphotericin B deoxycholate) in this 
relatively frail population.  A 2:1 randomization scheme of caspofungin to amphotericin 
B deoxycholate has been implemented to maximize the available efficacy and safety data 
for caspofungin in this indication, which is further supported by the comparative efficacy 
and safety study of caspofungin versus amphotericin B deoxycholate (see Table 3-1) [9]. 
There are currently no standard approved criteria for the evaluation of efficacy in infants 
and neonates with invasive candidiasis.  The primary efficacy endpoint chosen for this 
study (i.e., fungal-free survival at 2 weeks following the completion of study therapy) is 
deemed an appropriate parameter as it incorporates 2 objective parameters: survival at 
least 2 weeks after study therapy and the requirement of Candida eradication from 
follow-up cultures following the onset of study therapy.  
 
 
 
 
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The power and sample size are based on an underlying response rate of 50% for the 
amphotericin B deoxycholate treatment group from the recently published comparative 
study in 32 neonates and infants with invasive candidiasis where a favorable response 
was observed in 86.7% of caspofungin-treated patients and 41.7% of amphotericin B 
deoxycholate-treated patients [9].  The study is designed to have 80% power to 
demonstrate the superiority of caspofungin over amphotericin B deoxycholate at an 
overall two-sided, 5% alpha-level, if the underlying treatment difference in fungal-free 
survival at the 2-week posttherapy visit is ~30 percentage points (or larger).  The 
SPONSOR believes the chosen sample size should allow for a reasonable evaluation of 
the efficacy of caspofungin against amphotericin B deoxycholate (both as an active 
comparator in this study and from historical data from the literature).
3.2
STUDY PROCEDURES
3.2.1
Concomitant Medication(s)/Treatment(s)
Drugs specifically excluded in the exclusion criteria must not be administered. 
Medications not permitted at any time during course of study therapy include rifampin 
and any systemic antifungal agent (oral or IV) other than the study therapy.    
Should there be a clinical indication for any additional medication during the course of 
the study, the name of the drug, dosage (if required), and date(s) of administration must 
be recorded on the appropriate electronic case report form (eCRF).
3.2.2
Diet/Activity/Other
There are no dietary restrictions for this study.
3.2.3
Procedures
Study procedures should be conducted as summarized in the Study Flow Chart in 
Section 1.7.  The following subsections provide additional details for each of the study 
procedures.
3.2.3.1
Informed Consent
3.2.3.1.1
General Informed Consent
General Informed Consent
The investigator or designated study personnel must obtain written informed consent 
from the parent (or guardian) of each potential patient prior to the initiation of any study-
related procedures.  Consent must be documented with dated signatures on the consent 
form from both the parent (or guardian) of the patient and the study personnel conducting 
the consent discussion.  A copy of the signed informed consent will be given to the 
patient's parent (or guardian).
 
 
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3.2.3.2
Assignment of Baseline Number
After informed consent has been obtained, the patient will be assigned a unique baseline 
number.  The baseline number identifies the patient for all study-related procedures that 
occur prior to randomization to a treatment group (at which time an allocation number 
will be assigned).  Baseline numbers will be 9-digit numbers containing the 4-digit, 
SPONSOR-assigned investigator site number followed by a sequential 5-digit patient 
number (e.g., site number = 0017; sequential patient number = 00001; Baseline Number 
= 001700001).
Each baseline number will be assigned only once and baseline numbers should not be 
reassigned for any reason.  A single patient will not be assigned more than one baseline 
number.  If a patient needs to be rescreened for any reason, the same baseline number 
should be used.
3.2.3.3
Screening Procedures
Once consent has been obtained and a baseline number has been assigned, the patient will 
undergo preliminary prestudy evaluations which will include the following procedures 
(also refer to the Screening Visit on the Study Flow Chart, Section 1.7):

Complete documentation of medical history:  This should include a description of all 
relevant underlying medical history and risk factors for Candida infection.  Specific 
risks for Candida infection in this patient population are outlined in Appendix 6.2.  
All relevant underlying medical history and risk factors will be recorded on the 
appropriate eCRF. In addition, both the chronological and gestational age of the 
patient should be recorded on the appropriate eCRF. 

Chest X-ray:  A chest X-ray does not need to be repeated if a prior chest X-ray was 
performed within 10 days prior to the initiation of study therapy.   The results should 
be recorded on the appropriate eCRF.  

Complete evaluation of the diagnosis of invasive candidiasis: A detailed description 
of all symptoms and signs of the Candida infection at screening should be performed.    
These symptoms and signs of infection should be recorded on the appropriate eCRF.  
In addition, documentation of all tests confirming the diagnosis of invasive 
candidiasis (i.e., radiographs, histopathology, cultures, and any detailed descriptions 
of sterile invasive procedures) should also be collected.  Importantly, as noted below, 
cultures and histopathology positive for Candida infection must have been obtained 
from sites of infection within 96 hours prior to study entry. 

Vital signs (including weight): Measurements of the patient's weight and vital signs 
(pulse, respiratory rate, blood pressure, and temperature) are required.  The vital sign 
findings should be recorded on the appropriate eCRF.  

Physical examination:  A physical examination, including a detailed description of the 
nature and extent of the invasive Candida infection, is required for study entry.  Any 
abnormal findings should be recorded on the appropriate eCRF.  

Blood cultures: The blood cultures which confirm the evidence of invasive Candida 
infection during the screening phase must have been obtained within 96 hours prior to 
 
 
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study entry.  These results should be recorded on the appropriate eCRF.   Isolates 
from blood cultures obtained at the time of diagnosis and at study entry, if available, 
must be saved and sent to the fungal isolate central laboratory for identification and 
antifungal susceptibility testing.  
Importantly, two sets of blood cultures must be obtained at screening in all patients.  
All blood culture results should be recorded on the appropriate eCRF.   NOTE:  
Although 2 sets of blood cultures are collected from all patients, patients with 
candidemia must only have 1 positive Candida culture for study entry.   
For those patients enrolled with candidemia, specific management of arterial and 
venous catheters is also indicated:
(a) Where feasible, all peripheral intravenous or arterial catheters in place at the time 
a positive blood culture for Candida is identified should be removed.  If removal 
or replacement of a catheter is not feasible, the investigator should consult with 
the SPONSOR Clinical Monitor (or designee) as to whether the patient should be 
allowed to enroll in the study.  
(b) Where feasible, all central venous catheters in place at the time a positive blood 
culture for Candida is identified should be removed.  If removal or replacement of 
a central venous catheter is not feasible, the investigator should consult with the 
SPONSOR Clinical Monitor (or designee) as to whether the patient should be 
allowed to enroll in the study.  

Non-blood culture samples: For non-fungemic infections, cultures (or biopsies) from 
non-blood site(s) which confirm the presence of invasive Candida infection must be 
collected within 96 hours prior to study entry.  All results should be recorded on the 
appropriate eCRF.    The isolates from cultures obtained at the time of diagnosis and 
at study entry, if available, must be saved and sent to the fungal isolate central 
laboratory for identification and antifungal susceptibility testing.

Other radiographic studies:  Where appropriate, radiographic studies from the site(s) 
of Candida infection (i.e., echocardiogram, chest/abdominal ultrasound, CT, MRI) 
should also be obtained within 96 hours of study entry.  All results should be recorded 
on the appropriate eCRF.   
In general, in patients with invasive Candida abscesses, consideration should be 
given to have the abscess drained and/or removed via percutaneous puncture or open 
surgery prior to study entry OR within the first 72 hours following study entry.  
Special considerations for other specific non-blood sites are included below:
(a) Candida endocarditis: A transthoracic (or transesophageal) echocardiograph 
should be performed within 96 hours prior to study entry.
(b) Candida meningoencephalitis: All patients should have a positive culture for 
Candida from a cerebrospinal fluid (CSF) sample collected via a lumbar/cisternal 
puncture within 96 hours prior to study entry.  Additional CSF for glucose, 
protein, and cell count (i.e., RBC, WBC, cell differential) assessments should also 
 
 
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be collected at the time CSF culture was obtained (within 96 hours prior to study 
entry).
(c) Candida septic arthritis or osteomyelitis:  Patients with bone infections should 
have a positive culture for Candida from either the intraarticular joint (i.e., 
synovial) fluid or from a bony tissue sample collected via a sterile procedure 
within 96 hours prior to study entry.  In patients with septic arthritis or 
osteomyelitis abutting an intraarticular joint, synovial fluid for glucose, protein, 
cell count (i.e., RBC, WBC, cell differential), and cast/crystal assessment should 
also be collected at the time a joint fluid culture was obtained (within 96 hours 
prior to study entry).  For patients with osteomyelitis, consideration should also be 
given to performing an appropriate radiograph (including X-ray, CT, or MRI) of 
the involved bone within the 96 hours prior to study entry.

Blood for laboratory safety tests: Selected hematology and blood chemistry tests from 
blood will be performed at screening.  The selected laboratory tests for safety 
evaluation are outlined in Appendix 6.1. The results, which will be tested locally, 
should be recorded on the appropriate eCRF.

CSF for pharmacokinetic evaluation:  If a patient undergoes any procedure in the 
prestudy (screening) period that involves collecting CSF, approximately 350 μL of 
CSF should be retained to serve as a baseline sample for measurement of caspofungin 
concentration.   The CSF will be sent to a central laboratory for pharmacokinetic 
testing.  The exact time of CSF sampling should be recorded on the appropriate 
eCRF.
3.2.3.4
Randomization and Stratification
After written consent has been obtained, all screening procedures have been completed, 
and all inclusion/exclusion criteria have been met, the patient will be assigned an 
allocation number.  Once an allocation number is assigned, it cannot be re-assigned to 
another patient.   
In an effort to strive for adequate representation of patients from different weight groups 
(reflective of patient gestational age) in both treatment arms, randomization will be 
stratified into 3 weight categories (based on weight at study entry): <1000 grams, 1000 to 
1500 grams, and >1500 grams. Patients will be stratified into each of the weight 
categories in a manner consistent with the 2:1 randomization of caspofungin to 
amphotericin B deoxycholate.
A single patient/subject cannot be assigned more than 1 allocation number.
3.2.3.5
Treatment Evaluation/Follow-Up
3.2.3.5.1
Procedures Performed During the Treatment Phase 
While on study therapy, the patient will undergo the following procedures (also refer to 
the Study Therapy Visit on the Study Flow Chart, Section 1.7):
 
 
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
Assessment of symptoms and signs of the invasive Candida infection:  An assessment 
of symptoms and signs of the Candida infection should be performed daily while on 
study therapy and on the last day of study therapy.  These findings should be recorded 
on the source documents and the appropriate eCRF.  

Vital signs (including weight): Certain vital signs (pulse, respiratory rate, blood 
pressure, and temperature) should be performed at least once daily while on study 
therapy and on the last day of study therapy.  It is preferred that the method for 
obtaining temperatures (e.g., oral or tympanic) is consistent throughout the course of 
study therapy. The most abnormal vital sign findings within the previous 24 hours 
should be recorded on the appropriate eCRF.  Weight should also be collected at least 
once weekly while on study therapy as a standard procedure when evaluating vital 
signs and to ensure the appropriate dose of study therapy is being maintained.  
Weight should also be collected on the day of pharmacokinetic assessment (Day 4 or 
Day 7).  The weekly weight result should also be recorded on the appropriate eCRF.  

Physical examination:  A physical examination, including a detailed description of the 
nature and extent of the invasive Candida infection, should be performed on Day 4 
and Day 7 of study therapy, twice weekly thereafter (while on study therapy), and on 
the last day of study therapy.  Any abnormal findings should be recorded on the 
appropriate eCRF.  

Follow-up blood cultures: For patients with candidemia, follow-up blood cultures 
should be collected periodically while on study therapy until cultures are negative for 
Candida (on at least 2 separate occasions). All results should be recorded on the 
appropriate eCRF. The general IDSA guidelines for treatment management of 
candidemia are included in Appendix 6.3.

Follow-up cultures from non-blood samples:  Patients with non-blood sites of 
invasive candidiasis should have follow-up cultures collected from the non-blood site 
of Candida infection, as clinically indicated by the patient’s signs and symptoms of 
infection and radiographic abnormalities. All results should be recorded on the 
appropriate eCRF. Specifically, patients with known meningoencephalitis should 
have follow-up CSF cultures performed on a periodic basis while on study therapy 
until negative follow-up CSF cultures are documented.   The general IDSA guidelines 
for treatment management of non-fungemic sites of infection are included in 
Appendix 6.3.

Follow-up radiographs:  Follow-up radiographs should be performed from the site(s) 
of infection (e.g., echocardiogram, chest/abdominal ultrasound, CT, or MRI) as 
clinically indicated, based on the site of infection. If a radiographic study that helped 
confirm the diagnosis of invasive candidiasis is deemed necessary to assess the 
outcome the outcome of study therapy, the follow-up radiographic study must be 
obtained within 72 hours (3 days) prior to the completion of study therapy. All results 
should be recorded on the appropriate eCRF. The general IDSA guidelines for 
treatment management of the various sites of invasive Candida infection are included 
in Appendix 6.3.
 
 
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
Study therapy administration:  During the study therapy period, the study drug (either 
caspofungin or amphotericin B deoxycholate) will be prepared by the unblinded 
pharmacist as outlined in Section 2.4.2 (Treatment Plan).  All study therapy 
(caspofungin or amphotericin B deoxycholate) will be administered intravenously as 
a single once-daily dose.  Each infusion should be administered over approximately 2 
hours.  The IV line should be flushed thoroughly after each study therapy infusion.  
Infusion of study therapy may be given through either a pediatric syringe pump or 
ambulatory pump if this will help ensure that the patient receives the complete dose.  
As these 2 products differ in color, opaque masking of the infusion materials (e.g., 
infusion syringe and tubing) will be used to ensure adequate blinding of the treatment 
group.  The unblinded pharmacist will be responsible to cover the infusion materials 
with opaque masking.  Importantly, the unblinded pharmacist will not be involved in 
any of the postinfusion evaluations for the patient.  All study personnel involved with 
the postinfusion evaluations of safety and efficacy outcomes, including the study 
coordinator(s), investigator, or subinvestigator(s), must have no access to the 
treatment group assignment or the preparation of the study infusion.  Additional 
details on study therapy preparation are included in the Pharmacy Binder.  
Of note, total parenteral nutrition (TPN) can be administered to patients enrolled in 
this study.  However, it is preferred that TPN is not infused through the same 
intravenous line as the study therapy.  For those patients with catheters containing 
multiple lumens, study therapy should be administered via a separate lumen than the 
lumen used for TPN infusion.  For patients with single lumen catheters as the only 
intravenous access site, TPN should be held during the 2-hour infusion of study 
therapy. In this case, the IV line should be flushed thoroughly prior to and following 
study therapy infusion.  

Blood for laboratory safety tests: Selected hematology and blood chemistry tests from 
blood will be performed on Day 4 (± 1 day) and Day 7 of study therapy, twice weekly 
thereafter (while on study therapy), and on the last day of study therapy.  The selected 
laboratory tests for safety evaluation are outlined in Appendix 6.1.  The results, which 
will be tested locally, should be recorded on the appropriate eCRF.

Blood (plasma) for pharmacokinetic evaluation: Three blood samples (each 350 μL) 
should be collected from all patients.  Each patient will be randomly assigned to one 
of 8 sampling schedules; all 3 samples are to be taken on the same study day.  Half of 
the patients will have samples taken on Study Day 4 and the other half will have 
samples taken on Study Day 7.  If it is not possible to take samples on the assigned 
Study Day, it is recommended that samples be taken on the following Study Day.  
Blood samples will be collected from all patients at the time of peak concentration 
(immediately after the end of study therapy infusion) and time of trough 
concentration (approximately 24 hours after the start of study therapy infusion but 
prior to the next day’s dose).  In addition, a sample will be collected at an 
intermediate time between peak and trough times as shown in Table 3-4, in Section 
3.3.2.  Plasma will be separated from blood and sent to a central laboratory for 
pharmacokinetic testing. The exact time and date of blood sampling should be 
recorded on the appropriate eCRF.
 
 
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Weight should be measured within 12 hours prior to the infusion of study therapy on 
the assigned day of pharmacokinetic blood sampling, and the study therapy dose 
given on the pharmacokinetic sample day should be adjusted to reflect the most 
recently measured weight.

CSF for pharmacokinetic evaluation:  If a patient undergoes any procedure that 
involves collecting CSF while on study therapy, approximately 350 μL of CSF should 
be retained for pharmacokinetic assessments.   The CSF will also be sent to a central 
laboratory for pharmacokinetic testing.  The exact time and date of CSF sampling 
should be recorded on the appropriate eCRF.

Monitoring for adverse experiences:  Patient will be monitored daily for adverse 
experiences while on study therapy. Any findings consistent with an adverse 
experience should be recorded on the appropriate eCRF. Please refer to Section 3.4 
(Safety Measurements) for further details.  

Efficacy evaluation: Resolution or progression of disease should be documented by 
assessment of symptoms and signs, follow-up culture results, and follow-up 
radiographic studies, as appropriate.  An efficacy evaluation for fungal-free survival 
will be performed on the last day of study therapy.  This evaluation will be recorded 
on the appropriate eCRF.  Please refer to Section 3.3 (Efficacy Measurements) for 
further details.
3.2.3.5.2
Procedures Performed During the Posttherapy Follow-up Visits
At the 2- and 8-week posttherapy follow-up visits, the patient will undergo the following 
procedures (also refer to the Follow-up Assessment Visit on the Study Flow Chart, 
Section 1.7):

Assessment of symptoms and signs for invasive Candida infection: Potential 
symptoms and signs of the patient's Candida infection will be assessed at the 2-week 
and 8-week posttherapy follow-up visits.  Any findings should be recorded on the 
source documents and the appropriate eCRF.  

Vital signs: Assessments of specific vital signs (pulse, respiratory rate, blood 
pressure, and temperature) should be performed at the 2-week and 8-week 
posttherapy follow-up visits.  These findings should be recorded on the appropriate 
eCRF.  

Physical examination:  A physical examination, including a detailed description of the 
nature and extent of the Candida infection, should be performed at the 2-week and 8-
week posttherapy follow-up visits.  Any abnormal findings should be recorded on the 
appropriate eCRF.  

Follow-up blood or non-blood samples:  Patients should have follow-up blood (or 
pertinent non-blood) cultures collected, as clinically indicated, by the patient’s signs 
and symptoms of infection and radiographic abnormalities through the 8-week 
posttherapy follow-up visit.  All results should be recorded on the appropriate eCRF.  

Follow-up radiographs:  Follow-up radiographs should be performed from the site(s) 
of infection (e.g., echocardiogram, chest/abdominal ultrasound, CT, or MRI) as 
 
 
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clinically indicated based on the site of infection, through the 8-week posttherapy 
follow-up visit.   All results should be recorded on the appropriate eCRF.  

Blood for laboratory safety tests: Selected hematology and blood chemistry tests from 
blood will be performed at the 2-week posttherapy follow-up visit.  The selected 
laboratory tests for safety evaluation are outlined in Appendix 6.1. The results, which 
will be tested locally, should be recorded on the appropriate eCRF.

Monitoring for adverse experiences:  After the completion of study therapy, patient 
will be monitored for adverse experiences through the 2-week posttherapy follow-up 
visit.  Any findings consistent with an adverse experience should be recorded on the 
appropriate eCRF.  Please refer to Section 3.4 (Safety Measurements) for further 
details.

Efficacy evaluation: Resolution or progression of disease should be documented by 
assessment of symptoms and signs, follow-up culture results, and follow-up 
radiographic studies, as appropriate.  An efficacy evaluation for fungal-free survival 
will be performed at the 2-week posttherapy follow-up visit.   An efficacy evaluation 
for the development of complicated candidiasis will be performed through the 8-week 
posttherapy follow-up visit.   These evaluations will be recorded on the appropriate 
eCRFs. Please refer to Section 3.3 (Efficacy Measurements) for further details.
3.2.3.6
Blinding/Unblinding
This is a double-blind study in which the patients, the investigator (and site staff, with the 
exception of the unblinded pharmacists who will not be involved in patient assessment), 
and members of the SPONSOR staff (or designee) directly involved with the conduct of 
the study will remain blinded to the treatment administered to all patients.
In the event that an individual patient becomes unblinded to treatment group (either 
accidental unblinding or emergency unblinding for a serious adverse experience), the 
investigator must do the following:

Immediately notify the SPONSOR Clinical Monitor or Clinical Scientist (CS), or 
respective designees;

Promptly document the circumstances in the patient's chart;

Document the unblinding on the Patient Unblinding Log located in the 
Administrative Binder.
Every effort should be made to contact the Clinical Monitor or CS (or their respective 
designees) prior to performing an emergency unblinding of any patient.
3.2.3.7
Discontinuation/Withdrawal from Study
Subjects/patients may withdraw at any time or be dropped from the study at the discretion 
of the investigator should any untoward effects occur. In addition, a subject/patient may 
be withdrawn by the investigator or the SPONSOR if he/she violates the study plan or for 
administrative and/or other safety reasons. The investigator or study coordinator must 
notify the SPONSOR immediately when a subject/patient has been discontinued/ 
withdrawn due to an adverse experience (telephone or FAX). When a subject/patient 
 
 
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discontinues/withdraws prior to study completion, all applicable activities scheduled for 
the final study visit should be performed at the time of discontinuation. Any adverse 
experiences which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 3.4 SAFETY 
MEASUREMENTS - DETAILS.
3.2.3.7.1
Discontinuation/Withdrawal Criteria
Discontinuation from study therapy should be done for the following reason(s):

The patient's parent (or guardian) refuses further treatment or follow-up and 
withdraws consent.

Continuation is not in the best interest of the patient, in the judgment of the 
investigator.

Failure to demonstrate or sustain clinical improvement after a course of study 
therapy.  In general, patients who do not have some clinical evidence of improvement 
by Day 7 of therapy should be discontinued.

Significant progression of invasive candidiasis after at least 72 hours of study 
therapy.

The need to increase the dose of the antifungal study therapy or to give another 
systemic antifungal drug in addition to the antifungal study therapy. 

Development of signs or symptoms of a rapidly progressive underlying disease that 
would preclude evaluation of therapy, or that would render continuation in the study 
inadvisable, in the judgment of the investigator.

Development of concomitant fungal infection with an organism that is not susceptible 
to the antifungal study therapy.

Instances in which pretherapy or follow-up microbiologic studies indicate that the 
etiologic pathogen(s) of the index infection is/are not susceptible to amphotericin B 
deoxycholate and/or caspofungin.

Development of a serious adverse experience related to study therapy or the 
occurrence of an adverse clinical experience or clinically significant laboratory 
change or abnormality that, in the judgment of the investigator, warrants withdrawal 
of the patient from the antifungal study therapy.

An elevated AST or ALT lab value that is greater than or equal to 3 X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2 X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2 X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.  NOTE: Patients will be 
discontinued from study therapy but followed for safety until the abnormal value(s) 
has/have normalized, stabilized, or returned to baseline.

Development of nephrotoxicity, which in the opinion of the investigator, warrants 
discontinuation of study therapy.  
 
 
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
Requirement for treatment with an investigational drug.
If a patient discontinues from study therapy for any reason, evaluations (e.g., cultures, 
radiographic studies) should be performed as clinically indicated at that time. An efficacy 
assessment of response to study therapy should be documented at the time of study 
therapy discontinuation.  Unless the patient is also withdrawing from the study, the 
patient should be followed for safety and for the efficacy endpoint through the end of the 
follow-up period.
Withdrawal from study should be considered for the following reason(s):

The patient's parent (or guardian) refuses further treatment or follow-up and 
withdraws consent.
If a patient discontinues/withdraws from the study for any reason, an efficacy assessment of 
response to study should be documented at the time of study discontinuation/withdrawal.
3.3
EFFICACY/PHARMACOKINETIC MEASUREMENTS
3.3.1
Clinical and Laboratory Measurements for Efficacy
A detailed description and evaluation of the Candida infection will be performed at 
screening, daily while on study therapy, on the last day of study therapy, and at the 2-
week and 8-week posttherapy follow-up visits.  Resolution or progression of the Candida
infection should be documented by assessment of signs and symptoms, radiographic 
studies (when clinically indicated), and follow-up blood cultures or, as appropriate, other 
follow-up cultures (including urine or CSF).
Based on all available data, an efficacy assessment will be made at the end of study 
therapy and at the 2-week posttherapy follow-up visit.  The efficacy endpoint will be 
based on fungal-free survival (i.e., the proportion of patients who survived at the 
timepoint of interest 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 
at the time of evaluation. If a culture is not obtained on the day of assessment, then 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 microbiologic eradication 
would be considered achieved. Although fungal-free survival will be assessed at 2 
different time points (end of study therapy and the 2-week posttherapy follow-up visit), 
the primary efficacy time point will be at the 2-week posttherapy follow-up visit.   
NOTE:  Fungal-free survival assumes no additional antifungal therapy is required for the 
treatment of the underlying Candida infection once study therapy has ended; however, 
once study therapy has ended, prophylaxis with an antifungal agent (e.g., fluconazole) 
may be administered, if this is deemed appropriate by the investigator.
 
 
 
 
 
 
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. 
The efficacy with caspofungin in neonates and infants enrolled in this study will be 
compared descriptively to the efficacy in caspofungin-treated patients enrolled with 
invasive candidiasis in the prior Phase II pediatric documented infection study (Protocol 
043, children and adolescents [3 months to 17 years]) and prior Phase III adult studies 
(Protocols 014 and 801).
3.3.2
Measurements for Pharmacokinetics
Three blood samples (each 350 μL) should be collected from all patients.  Each patient 
will be randomly assigned to one of 8 sampling schedules; all 3 samples are to be taken 
on the same study day.  Half of the patients will have samples taken on Study Day 4 and 
the other half will have samples taken on Study Day 7.  If it is not possible to take 
samples on the assigned Study Day, it is recommended that samples be taken on the 
following Study Day.  
Blood samples will be collected from all patients at the time of peak concentration 
(immediately after the end of study therapy infusion) and time of trough concentration 
(approximately 24 hours after the start of study therapy infusion but prior to the next 
day’s dose).  In addition, a sample will be collected at an intermediate time between peak 
and trough times as shown in Table 3-4.  Plasma will be separated from blood and sent to 
a central laboratory for pharmacokinetic testing. The exact time and date of blood 
sampling should be recorded on the appropriate eCRF.
Table 3-4
Pharmacokinetic Sample Schedule
Sample 
Schedule
Number 
of 
Patients
Study 
Days
Peak
(Sample 1)
Interim
(Sample 2)
Trough 
(Sample 3)
1
12
Day 4
Within 5 
minutes after 
the end of 
the 1-hr 
infusion
Between 2 and 4 hr postdose
Within 15 
minutes 
prior to 
Day 5 dose
2
11
Between 6 and 8 hr postdose
3
11
Between 10 and 12 hr postdose
4
11
Between 14 and 16 hr postdose
5
12
Day 7
Within 5 
minutes after 
the end of 
the 1-hr 
infusion
Between 2 and 4 hr postdose
Within 15 
minutes 
prior to
Day 8 dose
6
11
Between 6 and 8 hr postdose
7
11
Between 10 and 12 hr postdose
8
11
Between 14 and 16 hr postdose
Volume of blood drawn for 
each PK sample:
350 μL
350 μL
350 μL
 
 
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Weight should be measured within 12 hours prior to the infusion of study therapy on the 
assigned day of pharmacokinetic blood sampling, and the study therapy dose given on the 
pharmacokinetic sample day should be adjusted to reflect the most recently measured 
weight.
If a patient undergoes any procedure that involves collecting CSF while on study therapy, 
approximately 350 μL of CSF should be retained for pharmacokinetic assessments.  If 
available, a baseline (or prestudy) CSF sample should also be retained.
Plasma will be separated from blood and sent to a central laboratory for pharmacokinetic 
testing.  The CSF will also be sent to a central laboratory for pharmacokinetic testing.  
Procedures for collection, processing, storage, and shipment of pharmacokinetic samples 
from blood (plasma) and CSF are included in the Administrative Binder.
3.3.3
Microbiological Measurements
In addition to local microbiological testing, identification and susceptibility testing will 
be performed at a central laboratory contracted by Merck on the following isolates:  (a) 
Candida isolates collected at study entry, (b) at any time subsequent fungal isolates are 
obtained, and (c) at any time that there is clinical or laboratory evidence of persistence or 
progression of the infectious process.  The investigator should ensure that the Candida
isolate(s) obtained from the invasive site of infection at these time points are saved and 
sent to the fungal isolate central laboratory.  
Procedures for collection, processing, storage, and shipment of microbiological samples 
from blood (plasma) and other non-blood sites of Candida infection are included in the 
Administrative Binder.
3.3.4
Data Monitoring Committee 
The Data Monitoring Committee (DMC) is a group with pertinent expertise that reviews 
on a regular basis accumulating safety data during the study to assess the effects of the 
study drug.  With the exception of a non-voting SPONSOR (or designee) statistician, the 
members of the committee are independent of the SPONSOR and clinical investigators 
participating in the trial, and will not have any other involvement in the study, nor will 
they have any relation to the study participants.  The statistician role may alternatively be 
filled by an individual external to the SPONSOR (or its designee).  
To guarantee the unbiased performance of its task, the DMC will initially receive blinded 
study data from the designated statistician.   If required to address a safety concern, 
unblinded safety data may be requested by and provided to the DMC. 
Prior to scheduled meetings, the DMC will be provided with the following reports, which 
are cumulative and generated from a current data file:

Patient enrollment status, including counts of patients enrolled by study site 

Blinded counts tables of  all adverse events (AEs), drug-related AEs, serious AEs, 
drug-related serious AEs, and AEs leading to discontinuation

Blinded counts tables of clinically significant laboratory AEs
 
 
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The need for additional reports will be assessed once the DMC members have been 
appointed and the study is initiated.  Unblinded data may be provided to the DMC by the 
SPONSOR (or its designee) upon request.
Based upon review of the accumulating safety data, the DMC will recommend if the 
study should continue, be modified, or terminated for safety reasons.  The DMC may also 
recommend steps needed to ensure the safety of study participants and integrity of the 
trial or trial data.  Guidelines for making such recommendations will be developed by the 
SPONSOR (or its designee) and DMC in advance of the evaluation of study data by the 
DMC.  Following each meeting, the DMC Chairperson will be responsible for reporting 
post-meeting decisions and/or recommendations (e.g., discontinuation of study due to a 
major safety concern) to a steering committee comprised of Merck Senior Management 
members (Merck Senior Management Committee, or MSMC).  It will be the 
responsibility of the MSMC to carefully consider and appropriately implement the 
recommendations of the DMC and to ensure the investigators and the respective 
Institutional Review Boards (IRBs)/Independent Ethical Committees (IECs) are properly 
notified.  The MSMC will inform the protocol team of any modifications to the protocol.  
The investigator, study site staff, and blinded SPONSOR personnel will remain strictly 
blinded to specific patient treatment group assignments until the study has ended.
Further details regarding the DMC and its functions will be described in the DMC 
Charter.
3.4
SAFETY MEASUREMENTS
3.4.1
Clinical and Laboratory Measurements for Safety
All patients who receive one or more doses of study therapy will be evaluated for the 
presence of adverse experiences while on study therapy and through the 2-week 
posttherapy follow-up visit.  To assist with these safety assessments, a physical 
examination will be performed at prestudy, twice weekly throughout the study therapy 
period (including Day 4 and Day 7), on the last day of study therapy, and at the 2- and 
8-week posttherapy follow-up visits. In addition, selected laboratory safety tests will be 
performed at screening, on Day 4 (or Day 3 or Day 5) and Day 7 of study therapy, twice 
weekly thereafter while on study therapy, on the last day of study therapy, and at the 
2-week posttherapy follow-up visit (see Appendix 6.1).  
To address the secondary safety objective, the following safety endpoints will be 
evaluated: (1) the development of adverse experience(s) during the study therapy period 
or during the 2-week posttherapy follow-up period; (2) the development of drug-related 
adverse experience(s) during the study therapy period or during the 2-week posttherapy 
follow-up period; (3) the development of serious adverse experience(s) during study 
therapy period or during the 2-week posttherapy follow-up period; (4) the development of 
drug-related, serious adverse experience(s) during study therapy period or during the 
2-week posttherapy follow-up period; (5) the development of adverse experiences that 
necessitate discontinuation of study therapy; and (6) the development of drug-related 
adverse experiences that necessitate discontinuation of study therapy.
 
 
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3.4.2
Management of Adverse Events
Patients will be monitored for any evident adverse experiences at all study visits (through 
the 2-week posttherapy follow-up visit), and the information will be recorded on the 
appropriate eCRF.  Decisions to temporarily withhold study therapy because of an 
adverse experience will be reviewed on a case-by-case basis by the investigator.  
Guidelines for managing certain adverse experiences are presented below.  The 
investigator will use discretion in the application of these guidelines.
For those circumstances not described below that require a hold on administration of 
study therapy, it may be possible to reinitiate study therapy upon resolution of the 
laboratory abnormality or clinical adverse experience. Individual cases should be 
discussed with the investigator and SPONSOR Clinical Monitor (or designee).
Liver Enzyme Abnormalities
Safety assessments of injury or damage to the liver will be performed by monitoring of 
liver function tests during and at the end of study therapy.  Laboratory tests should be 
repeated if AST or ALT increase to ≥2 times the baseline value.  If on repeated measures, 
the laboratory test elevated at study entry continues to rise (and reaches 6 times the upper 
limit of normal), study therapy should be discontinued as described in Section 3.2.3.7.1. 
However, if the enzyme elevations are clearly due to another etiology, the case may be 
discussed with the SPONSOR Clinical Monitor (or designee) prior to discontinuing the 
patient from study therapy.  If liver enzymes return to normal, rechallenge with the study 
therapy may be allowed.  The decision will be made by the investigator in consultation 
with the SPONSOR Clinical Monitor (or designee).
Any elevated AST or ALT lab value that is greater than or equal to 3 X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2 X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2 X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing will be evaluated.  The trial site guidance for 
assessment and follow up of these criteria can be found in the Administrative Binder.
Other Adverse Experiences
While receiving study therapy, patients who develop any adverse experience that is felt to 
possibly be related to the study drug, and for which interruption of therapy is clinically 
indicated, should have their study therapy stopped.
3.4.3
Recording Adverse Experiences
An adverse experience is defined as 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 adverse experience.
 
 
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Changes resulting from normal growth and development which do not vary significantly 
in frequency or severity from expected levels are not to be considered adverse 
experiences. Examples of this may include, but are not limited to, teething, typical crying 
in infants and children, and onset of menses or menopause occurring at a physiologically 
appropriate time.
Adverse experiences may occur in the course of the use of a Merck product in clinical 
studies or within the follow-up period specified by the protocol, or prescribed in clinical 
practice, from overdose (whether accidental or intentional), from abuse, and from 
withdrawal.
Adverse experiences may also occur in screened subjects/patients during any 
preallocation baseline period as a result of a protocol-specified intervention including 
washout or discontinuation of usual therapy, diet, placebo treatment, or a procedure.
Such events will be recorded at each examination on the Adverse Experience Case 
Report Forms/Worksheets.
3.4.4
Definition of an Overdose for This Protocol
Any overdose, whether or not associated with an adverse experience, must be reported 
within 24 hours to the SPONSOR (or its designee).
For this protocol, an overdose is defined as any daily dose that exceeds 2 times the 
prescribed dose in a 12-hour period.
3.4.4.1
Reporting of Overdose to SPONSOR
If an adverse experience(s) is associated with (“results from”) the overdose of test drug or 
vaccine, the adverse experience(s) is reported as a serious adverse experience, even if no 
other criteria for serious are met.
If a dose of test drug or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology 
“accidental or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse experience must be reported within 
24 hours to one of the individuals listed on the sponsor contact information page found in 
the Administrative Binder.
3.4.5
Immediate Reporting of Adverse Experiences to the SPONSOR
3.4.5.1
Serious Adverse Experiences
Any serious adverse experience, including death due to any cause, which occurs to any 
subject/patient entered into this study or within 14 days following cessation of treatment 
or within the established off therapy follow-up period for safety described in the protocol, 
 
 
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whether or not related to the investigational product, must be reported within 24 hours to 
one of the individual(s) listed on the contact information page.
Additionally, any serious adverse experience considered by an investigator who is a 
qualified physician to be possibly, probably, or definitely related to the investigational 
product that is brought to the attention of the investigator at any time outside of the time 
period specified in the previous paragraph also must be reported immediately to one of 
the individuals listed on the sponsor contact information page found in the administrative 
binder.
All subjects/patients with serious adverse experiences must be followed up for outcome.
3.4.5.2
Selected Nonserious Adverse Experiences
Events of clinical interest for this trial include:
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*NOTE: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Administrative Binder.
3.4.6
Evaluating Adverse Experiences
Refer to Table 3-5 for instructions in evaluating adverse experiences.
 
 
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Table 3-5
An investigator who is a qualified physician, will evaluate all adverse experiences as to:
Maximum
Mild
awareness of sign or symptom, but easily tolerated  (for pediatric studies, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric studies, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric studies, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse experience is any adverse experience occurring at any dose that:
†Results in death; or
†Is life threatening; or places the subject/patient, in the view of the investigator, at immediate risk of death from the experience as it occurred [Note: This does not include an adverse 
experience that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the hospitalization is a 
precautionary measure for continued observation).   (Note:  Hospitalization [including hospitalization for an elective procedure] for a preexisting condition which has not worsened does 
not constitute a serious adverse experience.); or
†Is a congenital anomaly/birth defect (in offspring of subject/patient taking the product regardless of time to diagnosis); or
Is a cancer; or
Is an overdose (Whether accidental or intentional.)  Any overdose whether or not associated with an adverse experience must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse experience when, based upon 
appropriate medical judgment, the event may jeopardize the subject/patient and may require medical or surgical intervention to prevent one of the outcomes listed previously (designated 
above by a †).
Duration
Record the start and stop dates of the adverse experience.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse experience cause the test drug to be discontinued?
Relationship to 
test drug 
Did the test drug cause the adverse experience?   The determination of the likelihood that the test drug caused the adverse experience will be provided by an investigator who is a qualified 
physician.  The investigator’s signed/dated initials on the source document or worksheet, that supports the causality noted on the AE form, ensures that a medically qualified assessment 
of causality was done.  This initialed document must be retained for the required regulatory time frame.  The criteria below are intended as reference guidelines to assist the investigator in 
assessing the likelihood of a relationship between the test drug and the adverse experience based upon the available information.  
The following components are to be used to assess the relationship between the test drug and the AE; the greater the correlation with the components and their respective elements 
(in number and/or intensity), the more likely the test drug caused the adverse experience (AE):
Exposure
Is there evidence that the subject/patient was actually exposed to the test drug such as:  reliable history, acceptable compliance assessment (pill count, diary, etc.), 
expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the test drug? 
Is the time of onset of the AE compatible with a drug-induced effect?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
 
 
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE:  (continued)
to test drug
(continued)
Dechallenge
Was the dose of test drug discontinued or reduced?
      If yes, did the AE resolve or improve?
           If yes, this is a positive dechallenge.    If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of the test drug; 
or (3) the study is a single-dose drug study.)
Rechallenge
Was the subject/patient reexposed to the test drug in this study?
      If yes, did the AE recur or worsen?
          If yes, this is a positive rechallenge.    If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or permanent disability, or (2) the study is a single-dose drug study.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY THE 
TEST DRUG, OR IF REEXPOSURE TO THE TEST DRUG POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT/PATIENT, THEN 
THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL MONITOR AND THE INSTITUTIONAL REVIEW 
BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency with 
Study Drug 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the test drug or drug class pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including consideration of the 
above elements.
Record one of the following:
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a drug relationship).
Yes, there is a reasonable possibility 
of drug relationship.
There is evidence of exposure to the test drug.  The temporal sequence of the AE onset relative to the administration of the test drug is reasonable.  The AE is more 
likely explained by the test drug than by another cause.
Depending on data collection method employed, drug relationship may be further graded as follows:
Definitely related 
There is evidence of exposure to the test drug.  The temporal sequence of the AE onset relative to administration of the test drug is reasonable.   The AE is more 
likely explained by the test drug than by another cause.  Dechallenge is positive.  Rechallenge (if feasible) is positive.  The AE shows a pattern consistent with 
previous knowledge of the test drug or test drug class.
Probably related 
There is evidence of exposure to the test drug.  The temporal sequence of the AE onset relative to administration of the test drug is reasonable.  The AE is more 
likely explained by the test drug than by another cause.  Dechallenge (if performed) is positive.
Possibly related 
There is evidence of exposure to the test drug.  The temporal sequence of the AE onset relative to administration of the test drug is reasonable.  The AE could have 
been due to another equally likely cause.  Dechallenge (if performed) is positive.
No, there is not a reasonable 
possibility of drug relationship
Subject did not receive the test drug OR temporal sequence of the AE onset relative to administration of the test drug is not reasonable OR there is another obvious 
cause of the AE.  (Also entered for a subject with overdose without an associated AE.)
Depending on data collection method employed, drug relationship may be further graded as follows:
Probably not 
related 
There is evidence of exposure to the test drug.  There is another more likely cause of the AE.  Dechallenge (if performed) is negative or ambiguous.  Rechallenge (if 
performed) is negative or ambiguous.
Definitely not 
related 
The subject/patient did not receive the test drug.   OR    Temporal sequence of the AE onset relative to administration of the test drug is not reasonable.   OR   There 
is another obvious cause of the AE.
 
 
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3.4.7
SPONSOR Responsibility for Reporting Adverse Experiences
All adverse experiences will be reported to regulatory agencies, IRB/IECs, and 
investigators in accordance with all applicable global laws and regulations.
3.5
STATISTICAL ANALYSIS PLAN (SAP)
3.5.1
Responsibility for Analysis
This section details the statistical analysis strategy and procedures for this study.  If, after 
the study has begun, but prior to any unblinding, changes are made to the primary 
objective, or the statistical methods related to this objective, then the protocol will be 
amended (consistent with ICH Guideline E-9).  Changes to secondary or 
 
 and/or statistical analyses made after the protocol has been finalized, along 
with an explanation as to when and why they occurred, will be listed in the Clinical Study 
Report (CSR) for the study.  
 
3.5.2
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of 
the Clinical Biostatistics department of the SPONSOR (or its designee).
Because this is a double-blind with in-house blind study, the investigator, study 
participant, and SPONSOR personnel (or their designees) will remain blinded to the IV 
antifungal study therapy regimen.  In order to maintain this blind, preparation and 
administration of the IV study therapy must be performed by someone other than the 
person(s) who will evaluate the patient for efficacy response and presence of adverse 
experiences.  As these 2 products differ in color, opaque masking will be used over the 
infusion materials (e.g., infusion syringe and tubing) to ensure adequate blinding of the 
treatment group.
Unblinding of the data will not take place until medical/scientific review has been 
performed, protocol violators have been identified, and the data have been declared final 
and complete.
3.5.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 2.1 (Objectives and 
Hypotheses).
3.5.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for between-treatment differences are 
listed below.
3.5.4.1
Efficacy/Pharmacokinetic Endpoints
3.5.4.1.1
Pharmacokinetic Endpoints
Pharmacokinetic (PK) profile (Cmax [peak], C24 hr [trough]) of the administered dose of 
caspofungin will be determined for neonates and infants less than three months of age on 
 
 
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or around Days 4 and 7 of study therapy.  Pharmacokinetic profiling will be the 
responsibility of the Drug Metabolism department of the SPONSOR (or its designee).
3.5.4.1.2
Efficacy Endpoints
An initial description of efficacy measurements is provided in Section 3.3.1.
The primary efficacy endpoint of interest will be fungal-free survival at two weeks 
posttherapy. Fungal-free survival is defined as those patients who survived at the time 
point of interest 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 
at the time of evaluation.  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.  Fungal-free survival also assumes no 
additional antifungal therapy is required for the treatment of the underlying Candida 
infection once study therapy has ended; however, once study therapy has ended, 
prophylaxis with an antifungal agent (e.g., fluconazole) may be administered, if this is 
deemed appropriate by the investigator.
The secondary efficacy endpoint will be fungal-free survival at the end of study therapy.
3.5.4.2
Safety Endpoints
There are no safety parameters that rise to the level of formal statistical testing for this 
study (i.e., no Tier 1 events).
To address the secondary safety objective, the following safety endpoints will be 
evaluated: (1) the development of adverse experience(s) during the study therapy period 
or during the 2-week posttherapy follow-up period; (2) the development of drug-related 
adverse experience(s) during the study therapy period or during the 2-week posttherapy 
follow-up period; (3) the development of serious adverse experience(s) during study 
therapy period or during the 2-week posttherapy follow-up period; (4) the development of 
drug-related, serious adverse experience(s) during study therapy period or during the 
2-week posttherapy follow-up period; (5) the development of adverse experiences that 
 
 
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necessitate discontinuation of study therapy; and (6) the development of drug-related 
adverse experiences that necessitate discontinuation of study therapy.
3.5.5
Analysis Populations
3.5.5.1
Efficacy Analysis Populations
All efficacy evaluations will use the Full Analysis Set (FAS) patient population, which 
includes those patients who receive at least 1 full dose of study therapy and have a 
documented (culture-confirmed) diagnosis of invasive candidiasis. All patients, 
irrespective of body weight at study entry, will be grouped together for the primary 
evaluation.  Subgroup evaluation based on the 3 body weight categories at study entry 
(<1000 grams, 1000-1500 grams, >1500 grams) will also be displayed.    
A supportive analysis using the Per-Protocol population will be performed for the 
primary and secondary efficacy endpoints.  The Per-Protocol population excludes 
patients due to important deviations from the protocol that may substantially affect the 
results of the primary and secondary efficacy endpoints. Inclusion within the per-protocol 
population mandates meeting all of the following:  

The patient must have a documented (culture-confirmed) diagnosis of invasive 
candidiasis.

The patient must not receive >1 day of concomitant systemic antifungal therapy while 
on study therapy, if the total duration of study therapy is 3 weeks or less.  For 
durations of study therapy exceeding 3 weeks, the patient must not receive 
concomitant systemic antifungal therapy while on study therapy, that amounts to 
more than 5% of the total duration of study therapy.

The patient must have a 2-week posttherapy efficacy evaluation, including an 
appropriate microbiological assessment completed either at this visit or confirmed 
prior to that visit.

The patient must receive at least 5 full days of study therapy.
The patient must not commit any protocol violations that interfere with the assessment of 
efficacy. 
The final determination on protocol violations, and thereby the composition of the Per-
Protocol population, will be made prior to the final unblinding of the database and will be 
documented in a separate memo. A patient who violates the protocol at randomization 
(e.g., certain inclusion or exclusion criteria, such as the use of prohibited prior treatment) 
will be excluded from the Per Protocol population.  For patients who violate the protocol 
during the study (e.g., taking prohibited concomitant medication), data obtained 
subsequent to the violation will be excluded from analysis.
Patients who receive incorrect study medication for their entire treatment period will be 
counted in the treatment group for the treatment actually received.  Otherwise, patients 
will be included in the treatment group to which they are randomized for the analysis of
 
 
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efficacy data using both the FAS and Per-Protocol populations.  In the event 3 or more 
patients receive the incorrect study medication for their entire treatment period, a 
sensitivity analysis will be performed with such patients included in the treatment group 
to which they were initially randomized for the analysis of efficacy data using both the 
FAS and Per-Protocol populations.  Details on the approach to handling missing data are 
provided in Section 3.5.6 (Statistical Methods).
3.5.5.2
Safety Analysis Population
The All Patients as Treated (APaT) population will be used for the analysis of safety data 
in this study.  The APaT population consists of all randomized patients who received at 
least one dose of study treatment. Patients will be included in the treatment group 
corresponding to the study treatment they actually received for the analysis of safety data 
using the APaT population.  For most patients, this will be the treatment group to which 
they are randomized.  Patients who take incorrect study treatment for the entire treatment 
period will be included in the treatment group corresponding to the study treatment 
actually received. 
At least one laboratory or vital sign measurement obtained subsequent to at least one dose 
of study treatment is required for inclusion in the analysis of each specific parameter.  To 
assess change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in 
Section 3.5.6 (Statistical Methods).
3.5.6
Statistical Methods
Statistical testing and inference for safety analyses are described in 3.5.6.2. Efficacy 
results that will be considered to be statistically significant after consideration of the 
strategy for controlling the Type I error are described in Section 3.5.6.1 (Multiplicity). 
Nominal p-values may be (will be) computed for other efficacy analyses as a measure of 
strength of association between the endpoint and the treatment effect rather than formal 
tests of hypotheses.  Unless otherwise stated, all statistical tests will be conducted at the 
α=0.05 (2-sided) level.
3.5.6.1
Statistical Methods for Efficacy Analyses
The primary efficacy analysis will compare the caspofungin treatment group to the 
amphotericin B deoxycholate treatment group with respect to the proportion of patients 
with fungal-free survival at the 2-week posttherapy period.  The minimum criterion for 
success is that the lower bound of 95% CI for the difference between the 2 treatment 
groups (caspofungin minus amphotericin B deoxycholate) in the primary efficacy 
endpoint is >0.
 
 
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The treatment comparisons for the primary and secondary efficacy analyses will be made 
using the difference in response rates between the 2 treatment groups and its 95% 
confidence interval. The confidence interval for the difference in response rates will be 
calculated using a methodology proposed by Miettinen and Nurminen [17]. 
Patients who have missing data for a given endpoint at the timepoint of interest will be 
counted as a failure for that endpoint at that timepoint.
 
 
 
 
Also, the caspofungin efficacy results from this study will be compared descriptively to 
the efficacy results for patients with invasive candidiasis in a prior Phase II pediatric 
documented infection study (Protocol 043, children and adolescents aged 3 months to 
17 years) and prior Phase III adult studies (Protocols 014 and 801).
Table 3-6 summarizes the key efficacy analyses.
 
 
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Table 3-6
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary
Proportion of patients with 
fungal-free survival through the 
2-week posttherapy period
P
Miettinen and 
Nurminen method
FAS
A patient with 
missing data 
will be 
considered a 
failure.
Proportion of patients with 
fungal-free survival through the 
2-week posttherapy period
S
Miettinen and 
Nurminen method
PP
Observed data
Secondary
Proportion of patients reporting 
fungal-free survival at the end 
of study therapy
P
Miettinen and 
Nurminen method
FAS
A patient with 
missing data 
will be 
considered a 
failure.
Proportion of patients reporting 
fungal-free survival at the end 
of study therapy
S
Miettinen and 
Nurminen method
PP
Observed data
P=Primary approach; S=Secondary approach.
3.5.6.2
Statistical Methods for Safety Analyses
Safety and tolerability are assessed by clinical review of all safety parameters, including 
adverse experiences and laboratory values.
The analysis of safety results will follow a tiered approach (Table 3-7).  The tiers differ 
with respect to the analyses that will be performed.  Safety parameters or adverse 
experiences of special interest that are identified a priori constitute "Tier 1" safety 
endpoints that will be subject to inferential testing for statistical significance with p-
values and 95% CI provided for between-group comparisons.  Other safety parameters 
 
 
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will be considered Tier 2 or Tier 3.  Tier 2 parameters will be assessed via point estimates 
with 95% CI provided for between-group comparisons; only point estimates by treatment 
group are provided for Tier 3 safety parameters.
Adverse experiences (specific terms as well as system organ class terms) that are not pre-
specified as Tier-1 endpoints will be classified as belonging to "Tier 2" or "Tier 3", based 
on the number of events observed.  Membership in Tier 2 requires that at least 4 patients 
in any treatment group exhibit the event; all other adverse experiences will belong to Tier 
3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences.  Because many 95% confidence 
intervals may be provided without adjustment for multiplicity, the confidence intervals 
should be regarded as a helpful descriptive measure to be used in review, not a formal 
method for assessing the statistical significance of the between-group differences in 
adverse experiences and predefined limits of change.
Continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters that are not pre-specified as Tier-1 endpoints will be considered Tier 3 safety 
parameters.  Summary statistics for baseline, on-treatment, and change from baseline 
values will be provided by treatment group in table format.
P-values (Tier 1 only) and 95% confidence intervals (Tier 1 and Tier 2) will be provided 
for between-treatment differences in the percentage of patients with events; these 
analyses will be performed using the Miettinen and Nurminen method (1985), an 
unconditional, asymptotic method.  For this protocol, there are no Tier 1 events.
 
 
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Table 3-7
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpointa
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
None
--
--
--
Tier 2
Any AE
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Discontinuation due to AE
X
X
Discontinuation due to a Drug-Related AE
X
X
Specific AEs, SOCs, or PDLCsb (incidence ≥4  
in one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCsb (incidence <4 
in all of the treatment groups)
X
Change from Baseline Results (Labs, ECGs, 
Vital Signs)
X
a
Adverse Experience references refer to both Clinical and Laboratory AEs.
b
Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier-2 
endpoints.
Note: SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X  = results will be provided.
3.5.6.3
Summaries of Baseline Characteristics and Demographics
The comparability of the treatment groups with respect to baseline characteristics will 
focus on clinical (rather than statistical) equivalence of the treatment groups.  No 
statistical hypothesis tests will be performed on these characteristics.  Mean, median, 
standard deviation, and range will be tabulated for characteristics which are continuous.  
Characteristics which are categorical, such as gender and race, will be summarized by 
count and percent.
3.5.7
Multiplicity
No multiplicity adjustments are planned for any of the evaluations in this study.  
3.5.8
Sample Size and Power Calculations
3.5.8.1
Sample Size and Power for Efficacy
This study will randomize approximately 90 patients at a 2:1 ratio into either the 
caspofungin treatment group (N = 60) or the amphotericin B deoxycholate treatment 
group (N = 30) and has 80% power to demonstrate the superiority of caspofungin over 
amphotericin B deoxycholate at an overall two-sided, 5% alpha-level, if the underlying 
treatment difference in fungal-free survival at 2 weeks posttherapy is approximately 
30 percentage points (or larger).  Randomization of approximately 90 patients should 
 
 
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yield approximately 84 FAS evaluable patients, assuming an approximate 5% drop-out 
rate.  The power and sample size are based on an underlying response rate of 50% for the 
amphotericin B deoxycholate treatment group, based on a review of the available data in 
the literature, including the recent comparative efficacy and safety study of caspofungin 
versus amphotericin B deoxycholate in which a favorable response was observed in 
41.7% of amphotericin B deoxycholate-treated patients (see Table 3-1) [9].  On balance, 
the literature suggests most currently available antifungal agents are associated with 
successful outcomes in 40-80% of the patients [9, 24, 26, 30-36]; however, the efficacy 
with amphotericin B deoxycholate from the recent analysis was on the lower end (~40%) 
[9]. The caspofungin data from retrospective analyses and the recent comparative study 
demonstrated a relatively high success rate (80-100%) [9-13]. The minimum criterion for 
success is that the lower bound of 95% CI for the difference between the 2 treatment 
groups (caspofungin minus amphotericin B deoxycholate) in the primary efficacy 
endpoint is >0. Given the assumed response rate in the amphotericin B deoxycholate 
treatment group, this may occur when the observed difference between treatment groups 
is approximately 30 percentage points (or larger). 
Assuming the same 2:1 randomization ratio and superiority hypothesis with 80% power, 
Table 3-8 displays sample size requirements for a few favorable response rate 
combinations, along with the difference and 95% CI for the difference.
Table 3-8
Superiority Sample Size Projections 
Based on 80% Power and 2:1 (Caspofungin:Amphotericin B Deoxycholate)
Allocation Ratio
Percent Favorable 
Caspofungin Response 
(A)
Percent Favorable 
Amphotericin B 
Deoxycholate 
Response (B)
Sample Size Projection
Total  (A:B)
Difference and
2-Sided 95% Confidence 
Interval for the 
Differencea (A – B)
70
40
93   (62:31)
30  (7.9, 48.1)
65
40
137  (92:45)
25  (7.5, 41.4)
60
40
218  (146:72)
20  (5.9, 33.2)
80
50
84   (56:28)
30  (9.3, 50.3)
75
50
127  (85:42)
25  (7.7, 42.2)
70
50
206  (137:69)
20  (5.3, 33.1)
90
60
66   (44:22)
30  (11.0, 53.6)
85
60
105  (70:35)
25  (8.3, 43.8)
80
60
177  (118:59)
20  (5.6, 33.9)
a Calculated using the Miettinen and Nurminen method.
3.5.8.2
Sample Size and Power for Safety
In a previous pediatric study (Protocol 043) in which 38 patients (aged 6 months to 
17 years, mean 8 years) with invasive candidiasis were treated with caspofungin, the 
 
 
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proportion of patients with one or more drug-related adverse experiences was 23.7%.  
With this figure as a guide and the assumption that experience in neonates/infants is 
similar to that of the pediatric patients, a drug-related adverse experience rate of 23.7 ± 
10.8% (95% CI calculated using the binomial distribution) is projected for 60 patients in 
the caspofungin treatment group. 
While the above is the projected drug-related adverse experiences rate based on a 
previous study rate, it does not address possible study outcomes based on an observed 
number of adverse experiences within each treatment group.  Given anticipated sample 
sizes of 60 patients on caspofungin and 30 patients on amphotericin B deoxycholate, 
Table 3-9 summarizes the difference (caspofungin – amphotericin B deoxycholate) and 
95% CI for the difference for possible drug-related adverse experience outcome 
combinations.
 
 
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Table 3-9
Difference (Caspofungin – Amphotericin B Deoxycholate) and 95% Confidence Interval for the Differences a
for Possible Drug-Related Adverse Experience Outcome Combinations
Caspofungin 
Therapy
(N = 60)
Amphotericin B Deoxycholate Therapy (N = 30)
N Events (%)
3 (10.0)
6 (20.0)
9 (30.0)
12 (40.0)
15 (50.0)
18 (60.0)
3  (5.0)
-5.0 (-21.2, 
5.9)
-15.0 (-32.9, -
1.8)
-25.0 (-43.5, -
9.7)
-35.0 (-53.4, -18.0)
-45.0 (-62.6, -
26.8)
-55.0 (-71.2, -36.1)
6 (10.0)
0.0 (-16.7, 
12.4)
-10.0 (-28.4, 4.6)
-20.0 (-39.1, -
3.5)
-30.0 (-49.0, -11.9)
-40.0 (-58.2, -
20.8)
-50.0 (-67.0, -30.2)
9 (15.0)
5.0 (-12.1, 
18.4)
-5.0 (-23.9, 10.5)
-15.0 (-34.6, 
2.4)
-25.0 (-44.5, -6.2)
-35.0 (-53.8, -
15.1)
-45.0 (-62.6, -24.5)
12 (20.0)
10.0 (-7.6, 
24.1)
0.0 (-19.4, 16.2)
-10.0 (-30.1, 
8.0)
-20.0 (-40.0, -0.6)
-30.0 (-49.4, -9.6)
-40.0 (-58.2, -19.0)
15 (25.0)
15.0 (-3.0, 
29.6)
5.0 (-14.8, 21.7)
-5.0 (-25.5, 
13.4)
-15.0 (-35.5, 4.8)
-25.0 (-44.9, -4.2)
-35.0 (-53.7, -13.7)
18 (30.0)
20.0 (1.7, 34.9)
10.0 (-10.2, 
27.0)
0.0 (-20.9, 18.7)
-10.0 (-30.8, 10.1)
-20.0 (-40.3, 1.1)
-30.0 (-49.2, -8.4)
21 (35.0)
25.0 (6.4, 40.0)
15.0 (-5.5, 32.1)
5.0 (-16.2, 23.9)
-5.0 (-26.2, 15.3)
-15.0 (-35.6, 6.3)
-25 (-44.6, -3.2)
a Calculated using the Miettinen and Nurminen method.
 
 
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3.5.8.3
Subgroup Analysis
No formal subgroup evaluations will be performed and 95% CIs will not be displayed.  
Only counts and percents will be displayed.  For the main efficacy endpoint, the results 
will be displayed by gender and race.  Subgroup evaluation by weight stratification 
categories (<1000g, 1000-1500g, >1500g) and use of prestudy systemic (oral or IV) 
antifungal prophylaxis, will also be displayed.   Other subgroup evaluations, based on site 
of Candida infection, underlying demographics, or region, may also be performed.
3.5.9
Interim Analyses
While no formal interim analysis is planned for this study, an external DMC will 
periodically evaluate the blinded safety data (see Section 3.3.4).
3.5.10 Compliance (Medication Adherence)
Study medication will be administered in a supervised clinical setting and missed or 
incorrect dosing will be uncommon.  Patients who miss a dose or receive an incorrect 
dose will be described in the CSR as to why the dose was missed or incorrect.
3.5.11 Extent of Exposure
The extent of exposure (dose and duration) to caspofungin will be summarized by the 
number of patients exposed to caspofungin for defined periods of time. Dose is defined as 
the daily dose, expressed as mg/kg.  The main table will display the number of days on 
caspofungin irrespective of dose.  There will also be a dose by duration table displaying 
the actual mgs/day of caspofungin received by the patients. 
3.6
LABELING, PACKAGING, STORAGE, DISPENSING, AND RETURN OF 
CLINICAL SUPPLIES
3.6.1
Product Descriptions
Investigational materials will be provided by the SPONSOR as summarized in Table 3-
10.
Table 3-10
Product Descriptions
Product Name & Potency
Dosage Form
Caspofungin acetate 
50 mg/vial
(CANCIDAS™, MK-0991)
Intravenous
Amphotericin B deoxycholate
50 mg/vial
Intravenous
3.6.2
Primary Packaging 
Supplies will be affixed with a clinical label in accordance with regulatory requirements.  
The clinical supplies will be open-labeled and each vial will contain a component 
 
 
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identification (CID) number for management of the supplies through an Interactive Voice 
Response System (IVRS) (see Section 3.6.6).
Patients will receive the IV study therapy following preparation by an unblinded 
pharmacist, for a minimum of 14 days and maximum of 90 days.  A patient's parent (or 
guardian) will remain blinded to the IV study therapy that the patient receives.  
Importantly, the unblinded pharmacist will be uninvolved in any of the postinfusion 
evaluations for the patient.  All study personnel involved with the postinfusion 
evaluations of safety and efficacy outcomes, including the study coordinator(s), 
investigator, or subinvestigator(s), must have no access to the treatment group assignment 
or the preparation of the study infusion.
3.6.3
Clinical Supplies Disclosure
The IVRS should be used in order to unblind subjects/patients and to unmask drug 
identity. The SPONSOR (or its designee) will not provide disclosure envelope with the 
clinical supplies. Drug identification information is to be unmasked ONLY if necessary 
for the welfare of the subject/patient. Every effort should be made not to unblind the 
subject/patient unless necessary. Prior to unblinding, the investigator will attempt to 
contact the SPONSOR's Clinical Research Associate (CRA) or designee.  Any 
unblinding that occurs at the site must be documented.
3.6.4
Storage and Handling Requirements
The storage conditions will be indicated on the label.
Vials of study drug (caspofungin and amphotericin B deoxycholate) will be shipped to 
the sites to be stored at 2°C to 8°C (35.6°F to 46.4°F). Upon receipt at the investigational 
site, the vials should be removed from the outer secondary shipping box and placed 
immediately into the refrigerator. The temperature monitoring device must be deactivated 
upon receipt of the shipment. Directions for inactivation are specified in the Instructions 
to Site, which are enclosed with each shipment.  The temperature monitoring device will 
indicate whether the shipment has remained within the specified temperatures. Return the 
temperature monitoring device according to instructions accompanying the shipment.  
Notify the SPONSOR CRA (or designee) immediately if the temperature monitoring 
device is in alarm.  Store and hold product until instructed otherwise. 
The clinical supplies storage area at the site must be monitored by the site staff for 
temperature consistency with the acceptable storage temperature range specified in this 
protocol or in the product label attached to the protocol.  Documentation of temperature 
monitoring should be maintained. Supplies should be stored in the original nested box 
with the lid closed to minimize exposure to light.  If the refrigerator in which the study 
supplies are stored deviates from the 2°C to 8°C (35.6°F to 46.4°F) range, study 
supplies should be suspended and the SPONSOR's CRA (or designee) be contacted 
immediately. The study supplies must NOT be frozen.  
It is strongly recommended that a non-frost free laboratory grade refrigerator is used to 
store the study drug supplies. This type of refrigerator is less likely to have wide 
 
 
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temperature fluctuations, so it will be more likely to stay within the 2°C to 8°C (35.6°F to 
46.4°F) temperature range. A daily refrigerator temperature log must be maintained at the 
site. The refrigerator must be equipped with an appropriately calibrated min/max 
thermometer and/or circular chart temperature recorder. The temperature log will be 
reviewed by the SPONSOR (or designee) throughout the study. An appropriate back-up 
system (i.e. alarm, generator) and study site personnel telephone numbers should be in 
place in the event of a refrigerator failure.
3.6.5
Standard Policies / Return of Clinical Supplies
As the clinical supplies (vials) will be provided as unblinded supplies, investigational 
clinical supplies must be received by a designated person (e.g., unblinded pharmacist) at 
the study site, handled and stored safely and properly, and kept in a secured location. 
Clinical supplies are to be dispensed only in accordance with the protocol. The unblinded 
pharmacist is responsible for keeping accurate records of the clinical supplies received 
from the SPONSOR (or its designee), the amount dispensed to and returned by the 
subjects/patients, and the amount remaining at the conclusion of the study.  The 
SPONSOR's CRA (or designee) should be contacted with any questions concerning 
investigational products where special or protective handling is indicated. At the end of 
the study, all clinical supplies including partial and empty containers must be returned as 
indicated on the Contact Information page(s).
U.S. sites should follow instructions for the Clinical Supplies Return Form and contact 
your SPONSOR representative (or designee) for review of shipment and form before 
shipping.
For sites outside of the United States, the local country SPONSOR personnel (or its 
designees) will provide appropriate documentation that needs to be completed for drug 
accountability.
3.6.6
Distributing to Sites and Dispensing to Subjects/Patients
Designated study personnel (e.g., unblinded pharmacist) will have access to IVRS to 
allocate patients, to assign drug to subjects/patients, and to manage the distribution of 
clinical supplies. Each person accessing the IVRS system must be assigned an individual 
unique PIN.  They must use only their assigned PIN to access the system and they must 
not share their assigned PIN with anyone.
3.7
DATA MANAGEMENT
The investigator or qualified designee is responsible for recording and verifying the 
accuracy of subject data.  By signing this protocol, the investigator acknowledges that 
his/her electronic signature is the legally binding equivalent of a written signature.  By 
entering his/her electronic signature, the investigator confirms that all recorded data have 
been verified as accurate.
Information regarding Data Management procedures for this protocol will be provided by 
the SPONSOR.
 
 
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3.8
BIOLOGICAL SPECIMENS
Information regarding biological specimens for this protocol will be provided by the 
SPONSOR (or its designee).
 
 
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4. ADMINISTRATIVE AND REGULATORY DETAILS
4.1
CONFIDENTIALITY
4.1.1
Confidentiality of Data
For Studies Conducted Under the U.S. IND
Particular attention is drawn to the regulations promulgated by the Food and Drug 
Administration under the Freedom of Information Act providing, in part, that information 
furnished to clinical investigators and Institutional Review Boards will be kept 
confidential by the Food and Drug Administration only if maintained in confidence by 
the clinical investigator and Institutional Review Board.
For All Studies
By signing this protocol, the investigator affirms to the SPONSOR that information 
furnished to the investigator by the SPONSOR will be maintained in confidence and such 
information will be divulged to the Institutional Review Board, Ethics Review 
Committee, or similar or expert committee; affiliated institution; and employees only 
under an appropriate understanding of confidentiality with such board or committee, 
affiliated institution and employees. Data generated by this study will be considered 
confidential by the investigator, except to the extent that it is included in a publication as 
provided in the Publications section of this protocol.
4.1.2
Confidentiality of Subject/Patient Records
For All Studies
By signing this protocol, the investigator agrees that the SPONSOR (or SPONSOR 
representative), Institutional Review Board/Independent Ethics Committee (IRB/IEC), or 
Regulatory Agency representatives may consult and/or copy study documents in order to 
verify worksheet/case report form data. By signing the consent form, the subject/patient 
agrees to this process. If study documents will be photocopied during the process of 
verifying worksheet/case report form information, the subject/patient will be identified by 
unique code only; full names/initials will be masked prior to transmission to the 
SPONSOR.
For Studies Conducted Under the U.S. IND
By signing this protocol, the investigator agrees to treat all patient data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, 
rules and regulations, including all applicable provisions of the Health Insurance 
Portability and Accountability Act and its implementing regulations, as amended from 
time to time (“HIPAA”).
4.1.3
Confidentiality of Investigator Information
For All Studies
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and study site 
 
 
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personnel, may be used and disclosed for study management purposes, as part of a 
regulatory submissions, and as required by law. This information may include:

name, address, telephone number, and email address;

hospital or clinic address and telephone number;

curriculum vitae or other summary of qualifications and credentials; and

other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
SPONSOR, and subsidiaries, affiliates and agents of the SPONSOR, in your country and 
other countries, including countries that do not have laws protecting such information. 
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory agencies or to other 
investigators. By signing this protocol, the investigator expressly consents to these uses 
and disclosures.
For Multicenter Studies
In order to facilitate contact between investigators, the SPONSOR may share an 
investigator’s name and contact information with other participating investigators upon 
request.
4.2
COMPLIANCE WITH LAW, AUDIT, AND DEBARMENT
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of 
Good Clinical Practice; and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is attached.
The investigator also agrees to allow monitoring, audits, Institutional Review Board/ 
Independent Ethics Committee review, and regulatory agency inspection of trial-related 
documents and procedures and provide for direct access to all study-related source data 
and documents.
The investigator agrees not to seek reimbursement from subjects/patients, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the SPONSOR.
The Investigator shall prepare and maintain complete and accurate study documentation 
in compliance with Good Clinical Practice standards and applicable federal, state, and 
local laws, rules and regulations; and, for each subject/patient participating in the study, 
provide all data, and upon completion or termination of the clinical study submit any 
 
 
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other reports to the SPONSOR as required by this protocol or as otherwise required 
pursuant to any agreement with the SPONSOR.
Study documentation will be promptly and fully disclosed to the SPONSOR by the 
investigator upon request and also shall be made available at the investigator’s site upon 
request for inspection, copying, review, and audit at reasonable times by representatives 
of the SPONSOR or any regulatory agencies. The investigator agrees to promptly take 
any reasonable steps that are requested by the SPONSOR as a result of an audit to cure 
deficiencies in the study documentation and worksheets/case report forms.
International Conference of Harmonization Good Clinical Practice guidelines 
(Section 4.3.3) recommend that the investigator inform the subject’s primary physician 
about the subject’s participation in the trial if the subject has a primary physician and if 
the subject agrees to the primary physician being informed.
According to European legislation, a SPONSOR must designate a principal or 
coordinating investigator (CI) to review the report (summarizing the study results) and 
confirm that to the best of his/her knowledge the report accurately describes conduct and 
results of the study. The SPONSOR may consider one or more factors in the selection of 
the individual to serve as the CI (e.g., thorough understanding of clinical trial methods, 
appropriate enrollment of subject/patient cohort, timely achievement of study milestones, 
availability of the CI during the anticipated review process).
The investigator will promptly inform the SPONSOR of any regulatory agency 
inspection conducted for this study.
Persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on this SPONSOR’s studies. 
The investigator will immediately disclose in writing to the SPONSOR if any person who 
is involved in conducting the study is debarred, or if any proceeding for debarment is 
pending or, to the best of the investigator’s knowledge, threatened.
In the event the SPONSOR prematurely terminates a particular trial site, the SPONSOR 
will promptly notify that site’s IRB/IEC.
4.3
COMPLIANCE WITH FINANCIAL DISCLOSURE REQUIREMENTS
By signing this protocol, the investigator agrees to provide to the SPONSOR accurate 
financial information to allow the SPONSOR to submit complete and accurate 
certification and disclosure statements as required by U.S. Food and Drug Administration 
regulations (21 CFR Part 54). The investigator further agrees to provide this information 
on a Financial Disclosure/Certification Form that is provided by Merck Sharp & Dohme 
Corp., a subsidiary of Merck & Co., Inc. This requirement also extends to 
subinvestigators. The investigator also consents to the transmission of this information to 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., in the United States for 
these purposes. This may involve the transmission of information to countries that do not 
have laws protecting personal data.
 
 
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4.4
QUALITY CONTROL AND QUALITY ASSURANCE
By signing this protocol, the SPONSOR agrees to be responsible for implementing and 
maintaining quality control and quality assurance systems with written SOPs to ensure 
that trials are conducted and data are generated, documented, and reported in compliance 
with the protocol, accepted standards of Good Clinical Practice, and all applicable 
federal, state, and local laws, rules and regulations relating to the conduct of the clinical 
study.
4.5
COMPLIANCE WITH INFORMATION PROGRAM ON CLINICAL 
TRIALS FOR SERIOUS OR LIFE THREATENING CONDITIONS
Under the terms of The Food and Drug Administration Modernization Act (FDAMA), 
the SPONSOR of the study is solely responsible for determining whether the study is 
subject to the requirements for submission to the Clinical Trials Data Bank, 
http://clinicaltrials.gov/.  Merck, as SPONSOR of this study, will review this protocol and 
submit the information necessary to fulfill this requirement.  Merck entries are not limited 
to FDAMA mandated trials.  Merck’s voluntary listings, beyond those mandated by 
FDAMA, will be in the same format as for treatments for serious or life-threatening 
illnesses.  Information posted will allow patients to identify potentially appropriate trials 
for their disease conditions and pursue participation by calling a central contact number 
for further information on appropriate study locations and site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligation 
under FDAMA is that of the SPONSOR and agrees not to submit any information about 
this study to the Clinical Trials Data Bank.
4.6
PUBLICATIONS
This study is intended for publication, even if terminated prematurely. Publication may 
include any or all of the following: posting of a synopsis online, abstract and/or 
presentation at a scientific conference, or publication of a full manuscript.  The 
SPONSOR will work with the authors to submit a manuscript describing study results 
within 12 months after the last data become available, which may take up to several 
months after the last patient visit in some cases such as vaccine trials.  However, 
manuscript submission timelines may be extended on OTC studies.   For studies intended 
for pediatric-related regulatory filings, the investigator agrees to delay publication of the 
study results until the SPONSOR notifies the investigator that all relevant regulatory 
requirements on the study drug have been  fulfilled with regard to pediatric-related 
regulatory filings.   Merck will post a synopsis of study results for approved products on 
www.clinicalstudyresults.org and www.clinicaltrials.gov by 12 months after the last 
patient's last visit or within 7 days of product approval in any major markets (United 
States, Europe or Japan), whichever is later.  These timelines may be extended for 
products that are not yet marketed, if additional time is needed for analysis, to protect 
intellectual property, or to comply with confidentiality agreements with other parties.  
Authors of the primary results manuscript will be provided the complete results from the 
Clinical Study Report, subject to the confidentiality agreement. 
 
 
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For multicenter studies, subsequent to the multicenter publication (or after public 
disclosure of the results online at www.clinicalstudyresults.org if a multicenter 
manuscript is not planned), an investigator and his/her colleagues may publish their data 
independently.  In most cases, publication of individual site data does not add value to 
complete multicenter results, due to statistical concerns.  In rare cases, publication of 
single site data prior to the main paper may be of value.  Limitations of single site 
observations in a multicenter trial should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and 
design, or acquisition of data, or analysis and interpretation of data; 2) drafting the article 
or revising it critically for important intellectual content; and 3) final approval of the 
version to be published. Authors should meet conditions 1, 2, and 3.  Significant 
contributions to study execution may also be taken into account to determine authorship, 
provided that contributions have also been made to all three of the preceding authorship 
criteria. Although publication planning may begin before conducting the study, final 
decisions on authorship and the order of authors’ names will be made based on 
participation and actual contributions to the study and writing, as discussed above. The 
first author is responsible to defend the integrity of the data, method(s) of data analysis, 
and the scientific content of the manuscript.  
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. SPONSOR review can be expedited to meet 
publication timelines.
 
 
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5. LIST OF REFERENCES
1.
CANCIDAS™ 
(Caspofungin 
Acetate),
European 
Summary 
of 
Product 
Characteristics, 2009.  
2.
CANCIDAS™ (Caspofungin Acetate), United States Product Circular, 2010.
3.
Zaoutis TE, Heydon K, Localio R, Walsh TJ, Feudtner C. Outcomes attributable to 
neonatal candidiasis. Clin Infect Dis.  2007; 44:1187-93.
4.
Benjamin DK, Stoll BJ, Gantz MG, Walsh MC, Sánchez PJ, Das A, et al. Neonatal 
candidiasis: epidemiology, risk factors, and clinical judgment. Pediatrics.  2010; 
126(4):e865-73.
5.
Wisplinghoff H, Seifert H, Tallent SM, Bischoff T, Wenzel RP, Edmond MB. 
Nosocomial bloodstream infections in pediatric patients in United States hospitals: 
epidemiology, clinical features and susceptibilities. Pediatr Infect Dis J.  2003; 
22(8):686-91.
6.
Benjamin DK, Jr., Stoll BJ, Fanaroff AA, McDonald SA, Oh W, Higgins RD, et al. 
Neonatal candidiasis among extremely low birth weight infants: Risk factors, 
mortality rates, and neurodevelopmental outcomes at 18 to 22 months. Pediatrics.  
2006; 117(1):84-92.
7.
Fridkin SK, Kaufman D, Edwards JR, Shetty S, Horan T, the National Nosocomial 
Infections Surveillance System Hospitals. Changing incidence of Candida
bloodstream infections among NICU patients in the United States: 1995-2004. 
Pediatrics. 2006; 117(5):1680-7.
8.
Saez-Llorens X, Macias M, Maiya P, et al. Pharmacokinetics and safety of 
caspofungin in neonates and infants less than 3 months of age. Antimicrobial Agents 
and Chemotherapy, 2009; 53:869-75.
9.
Wahab Mohamed WA, Ismail M. A randomized, double-blind, prospective study of 
caspofungin vs. amphotericin B for the treatment of invasive Candidiasis in newborn 
infants. J Trop Pediatr. 2011; 10.1093/tropej/fmr025:[published online 25-Feb-
2011]
10. Mondello I, Rossi A, Serrao G, Foti F, Timpani G, Manzoni P, et al. Preterm 
neonates in NICU treated with caspofungin: our experience [Abstract]. Early Hum 
Dev.  2009;85:S98.
11. Natarajan G, Lulic-Botica, M, Rongkavilit C, Pappas A, Bedard M.  Experience 
with caspofungin in the treatment of persistent fungemia in neonates.  Journal of 
Perinatology, 2005; 25:770-777.
 
 
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12. Odio CM, Araya R, Pinto LE, et al.  Caspofungin therapy of neonates with invasive 
candidiasis.  Pediatric. Infectious Diseases  Journal, 2004; 23:1093-7. 
13. Odio CM, Castro CE, Vasques S, Lazo J, Herrera ML.  Caspofungin Therapy for 
neonates with invasive candidiasis cared for at intensive care units. Presented at the 
47h Annual ICAAC Meeting, Chicago, Illinois USA, September 2007.
14. Steinbach W, Walsh TJ.  Mycoses in pediatric patients.  Infectious Disease Clinics 
of North America.  2006; 20:663-78.
15. Zaoutis TE, Argon J, Chu J, et al.  The epidemiology and attributable outcomes of 
candidemia in adults and children hospitalized in the United States: A propensity 
analysis.  Clinical Infectious Diseases.  2005; 41:1232-9.  
16. Makhoul IR, Kassis I, Smolkin T, et al.  Review of 49 neonates with acquired fungal 
sepsis: further characterization.  Pediatrics.  2001; 107:61-6. 
17. Miettinen O, Nurminen M.  Comparative analysis of two rates.  Stat Med. 1985; 
4:213-26.
18. Dotis J, Roilides E. Candidemia in the pediatric intensive care unit: what’s different 
from candidemia in adults?  Curr Fungal Infect Rep.  2011; 5:49-55.
19. Zaoutis T.  Candidemia in children.  Curr Med Res Opin.  2010; 26(7):1761-8.
20. Pfaller MA, Castanheira M, Messer SA, Moet GJ, Jones FN.  Variation in Candida
spp. distribution and antifungal resistance rates among bloodstream infection 
isolates by patient age: report from SENTRY Antimicrobial Surveillance Program 
(2008-2009).  Diagn Microbiol Infect Dis.  2010; 68(3):278-83.
21. Zaoutis TE, Foraker E, McGowan KL, Mortensen J, Campos J, Walsh TJ, et al.  
Antifungal susceptibility of Candida spp. isolated from pediatric patients: a survey 
of 4 children’s hospitals.  Diagn Microbiol Infect Dis.  2005; 52:295-8.
22. Blyth CC, Chen SCA, Slavin MA, Serena C, Nguyen Q, Marriott D, et al.  Not just 
little adults: candidemia epidemiology, molecular characterization, and antifungal 
susceptibility in neonatal and pediatric patients.  Pediatrics. 2009; 123(5):1360-8.
23. Zaoutis T, Jafri H ,Huang LM, Locatelli F, Barzilai A, Ebell W, Steinbach W, 
Bradley J, Lieberman J,Hsiao CC, Seibel N, Laws HJ, Gamba M, Petrecz M, Taylor 
A, Strohmaier K, Chow J, Kartsonis N, Ngai A,  A prospective, multicenter study of 
caspofungin for the treatment of documented Candida or Aspergillus infections in 
pediatric patients.  Pediatrics 2009;123:877-884.
24. Driessen M, Ellis JB, Cooper PA, et al.   Fluconazole versus amphotericin B for the 
treatment of neonatal fungal septicemia: a prospective, randomized trial. Pediatr 
Infect Dis J. 1996; 15:1107-12.
 
 
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25. Zaoutis T, Benjamin D, Steinbach W.  Antifungal treatment in pediatric patients.  
Drug Resistance Updates.  2005;8:235-245.
26. Linder N, Klinger G, Shalit I, et al.  Treatment of candidemia in premature infants: 
comparison of 3 amphotericin B preparations.  J Antimicrob Chemother.  2003; 
4:663-7.
27. Tiffany K, Smith P, Benjamin D.  Neonatal candidiasis: prophylaxis and treatment.  
Expert Opin Pharmacother.  2005; 6(10):1647-55.
28. Flattery A, Hickey E, Gill C, et al.  Efficacy of caspofungin in a juvenile mouse 
model of central nervous system candidiasis. Poster M-1836.  Presented in poster 
format at the 47h Annual ICAAC Meeting, Chicago, Illinois USA, September 2007.
29. Pappas PG, Kauffman CA, Andes D, Benjamin DK, Jr., Calandra TF, Edwards JE, 
Jr., et al.  Clinical practice guidelines for the management of candidiasis:  2009 
update by the Infectious Diseases Society of America.  Clin Infect Dis.  
2009;48:503-35.
30. Scarcella A, Pasquariello MB, Giugliano B, et al.  Liposomal amphotericin B 
treatment for neonatal fungal infections.  Pediatr Infect Dis J. 1998; 17:146-8.
31. Lopez Sastre JB, Coto Cotallo GD, Fernandez Colomer B.  Neonatal invasive 
candidiasis: a prospective multicenter study of 118 cases.   Am J Perinatology 2003; 
20:153-63.
32. Adler-Shohet F, Waskin H, Lieberman JM.  Amphotericin B lipid complex for 
neonatal invasive candidiasis.  Arch Dis Child Fetal Neonat.  2001; 84:F131-3.
33. Juster-Reicher A, Flidel-Rimon O, Amitay M, et al.  High-dose liposomal 
amphotericin B in the therapy of systemic candidiasis in neonates.  Eur J Clin 
Microbiol.  2003; 22:603-7.
34. Huttova M, Hartmanova I, Kralinsky K, et al.  Candida fungemia in neonates treated 
with fluconazole: report of 40 cases, including 8 with meningitis.  Pediatr Infect Dis 
J. 1998; 17:1012-15.
35. Wainer S, Cooper PA, Gouws H, et al.  Prospective study of fluconazole therapy in 
systemic neonatal fungal infection.  Pediatr Infect Dis J. 1997; 167:763-7.
36. Smith PB, Steinbach WJ, Benjamin DK.  Invasive Candida infections in the 
neonate.  Drug Res Updates.  2005; 8:147-62. 
 
 
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6. APPENDICES
6.1
LABORATORY SAFETY STUDIES
Tests to be done at screening (baseline prestudy), on Day 4 (+/- 1 day) and Day 7 of 
study therapy, twice weekly thereafter on study therapy, on the last day of study therapy, 
and at the 2 weeks following the completion of study therapy.  
Hematology Laboratory Test
White blood cell count (Total WBC)
White blood cell differential
Blood platelet count
Whole blood hematocrit
Blood hemoglobin test
Blood Chemistry Test
Serum alanine aminotransferase test
Serum aspartate aminotransferase test
Serum blood urea nitrogen test (or serum blood urea test)
Serum creatinine test
Serum potassium test
Direct serum bilirubin test 
Total serum bilirubin test
 
 
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6.2
RISK FACTORS OF INVASIVE CANDIDIASIS IN NEONATES AND 
INFANTS LESS THAN 3 MONTHS OF AGE
Risk factors
Comments
Classic risk (also described in adults)
Use of multiple or broad spectrum antibiotics 
and/or prolonged use of antibiotics
The length of antibiotic treatment is as 
important as the spectrum of antibiotics used.
Central venous catheters or prolonged 
intravascular catheterization
Parenteral hyperalimentation or intravenous 
fat emulsion
Colonization with Candida and/or previous 
episode of mucocutaneous candidiasis
Risk factors unique to this age group
Prematurity/ very low birth weight
~90% of affected neonates are very low birth 
weight (<1500 gm)
Endotracheal tube or existing tracheostomy
Many neonates have some type of respiratory 
insufficiency
Congenital malformations, including GI 
malformations and congenital heart disease
Most frequently seen in infants >2,500 gm at 
birth with prolonged NICU hospitalization
Gastrointestinal tract diseases
Necrotizing enterocolitis and anatomical 
abnormalities requiring surgery
 
 
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6.3
GENERAL GUIDELINES FOR THE MANAGEMENT OF INVASIVE CANDIDA INFECTIONS
The following guidelines, adapted from the Infectious Diseases Society of America (IDSA) Treatment Guidelines for the treatment of invasive 
candidiasis [29], should generally be implemented in the management of the patients enrolled in this study.  However, as there are no dedicated 
guidelines for neonatal candidiasis, some of these guidelines may require some modification in the neonatal/infant population on a case-by-case 
basis.
Candida Infection
Guidelines for Management
Candidemia

Please indicate in the source documents if the initial & follow-up blood cultures were obtained through an indwelling IV catheter or by percutaneous 
venipuncture (via peripheral draw).  Please also indicate if all IV catheters in place at time of positive culture were removed or changed.

Although blood cultures are often not considered final until Day 7, blood cultures should be drawn periodically until negative on 2 separate 
occasions. Additional blood cultures should be drawn if clinically indicated (e.g., persistent fever, persistent leukocytosis, clinical change such as 
hypotension, tachycardia).

If cultures become negative during study therapy, the microbiology response should be eradication even if a culture was not obtained on the last day 
of study therapy.

For a patient to be considered as having microbiological eradication, follow-up blood cultures while on study therapy must become negative for 
Candida sp.  Assessment of microbiological eradication should be based on the last available blood culture performed while on study therapy. 
Peritonitis

Patients who develop peritonitis while on peritoneal dialysis: 
Removal of peritoneal dialysate catheter should be considered at study entry or within the first 72 hours following the onset of study therapy.
Clinical findings (signs and symptoms) of infection should be followed daily while on study therapy.
Follow-up peritoneal fluid cultures (and fluid assessment of cell count, protein, glucose) should be collected prior to the completion of study therapy 
to assure eradication.

Surgical patients (or any other patients) who develop peritonitis:  
Patients with an intraabdominal source of the peritonitis or with an unclear etiology should have a radiographic study (abdominal ultrasound, CT, or 
MRI) documented within 96 hours prior to study entry.  
Surgical repair or drainage of perforation, leak, or other abdominal abnormality should be considered prior to study entry or within the first 72 hours 
following study entry.
Clinical findings (signs and symptoms) of infection should be followed daily while on study therapy.
Follow-up radiographs (ultrasound, CT, or MRI) should be repeated prior to end of study therapy (within 72 hours) to verify the resolution.  
Follow-up peritoneal fluid cultures (including fluid assessment of cell count, protein, and/or glucose) should be collected prior to the completion of 
study therapy, as clinically indicated.  
 
 
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Candida Infection
Guidelines for Management
Abscess involving
intraabdominal 
cavity or organ

Surgical drainage or aspiration drainage of abscess collection should be considered at study entry or within the first 72 hours following the onset of 
study therapy.

Patients who develop an intraabdominal abscess as a result of prior surgery or other intra-abdominal pathology (e.g., GI cancer) should also have a 
radiographic study (e.g., abdominal ultrasound, CT, or MRI) performed within the 96 hours prior to study entry to document the extent of the 
infection. 

Clinical findings (signs and symptoms) of infection should be followed daily while on study therapy.

Follow-up radiographs (e.g., ultrasound, CT, or MRI) should be repeated prior to the end of study therapy (within 72 hours) to verify the abscess 
process has resolved.

Follow-up cultures from the invasive site of infection should be collected prior to the completion of study therapy, as clinically indicated.
Abscess involving 
other cavity or organ

Surgical drainage or aspiration drainage of abscess collection should be considered at study entry or within the first 72 hours following the onset of 
study therapy.

Patients who develop an abscess as a result of prior surgery or other organ pathology (e.g., cancer) should also have a radiographic study (e.g., 
ultrasound, CT, or MRI) performed within the 96 hours prior to study entry to document the extent of the infection.  

Clinical findings (signs and symptoms) of infection should be followed daily while on study therapy.

Follow-up radiographs (e.g., ultrasound, CT, or MRI) should be repeated prior to the end of study therapy (within 72 hours) to verify the abscess 
process has resolved.

Follow-up cultures from the invasive site of infection should be collected prior to the completion of study therapy, as clinically indicated.
Pleural space 
infection (empyema)

A radiographic study (e.g., chest x-ray or CT) should be performed within 96 hours prior to study entry in those patients who develop pleuritis to 
document the extent of infection. In patients who develop empyema following a recent surgery, efforts must be made to assure there is no active 
connection (i.e., fistula, etc.) with either the GI tract or the exterior.

Ongoing chest tube drainage of the pleural space is usually required in these patients.

Clinical findings (signs and symptoms) of infection should be followed daily while on study therapy.

Follow-up radiography (chest x-ray or CT) should be repeated prior to the end of study therapy (within 72 hours) to verify the infectious process has 
resolved.

Follow-up pleural fluid cultures (including fluid assessment of cell count, protein, and/or glucose) should be collected prior to the completion of 
study therapy, as clinically indicated.
 
 
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Candida Infection
Guidelines for Management
Pneumonia
A radiographic study (chest x-ray or, preferably, chest CT) should be performed within 96 hours prior to study entry in those patients who develop 
pneumonia to document the extent of infection. 
Clinical findings (signs and symptoms) of infection should be followed daily while on study therapy.
Follow-up radiography (chest x-ray or, preferably, chest CT) should be repeated prior to the end of study therapy (within 72 hours) to verify the 
infectious process has resolved.
Follow-up lung tissue biopsy (for histopathology or culture) should be collected prior to the completion of study therapy, as clinically indicated.
Endophthalmitis

Clinical findings (signs and symptoms) of infection should be followed daily while on study therapy.

Two sets of blood cultures should be collected periodically until cultures are negative for Candida sp. on 2 separate occasions.

A follow-up dilated eye examination should be performed by an ophthalmologist within 72 hours following the completion of study therapy.  
Chronic 
disseminated 
candidiasis 
(hepatosplenic)

All patients must have an appropriate abdominal radiograph (e.g., ultrasound, CT, or MRI) performed within the 96 hours prior to study entry to 
document the extent of the lesions.

Clinical findings (signs and symptoms) of infection should be followed daily while on study therapy.

Follow-up radiography (e.g., ultrasound, CT, or MRI) should be repeated prior to the end of study therapy (within 72 hours) to verify the infectious 
process has resolved or all lesions have fully calcified.
 
 
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Several general points apply to all infections:

If a culture is not obtained on last day of study therapy, then the last culture after 
study entry should be used to assist in the assessment of microbiological eradication.  
If the last culture is negative for Candida sp., then microbiological eradication is 
deemed appropriate.

If no follow-up cultures from a non-blood site of infection were obtained during the 
study therapy course to document eradication, then in order to consider the 
microbiologic evaluation as "presumptive" eradication, there must be resolution of 
clinical signs and symptoms and resolution of radiographic evidence of infection.
Please assure all symptoms and signs of infection (collected daily), all relevant 
radiographs or other diagnostic procedures (e.g., echocardiogram, CT, MRI), and all 
relevant cultures are recorded on the appropriate eCRFs.  Similarly, please ensure all 
surgical procedures performed to alleviate the infection are recorded on the appropriate 
eCRFs.
 
 
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7. ATTACHMENTS
Merck Code of Conduct for Clinical Trials
 
 
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Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these 
trials in compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding 
concern in the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with 
local and/or national regulations and in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of 
the party (parties) employed for their execution (e.g., contract research organizations, collaborative research 
efforts). This Code is not intended to apply to trials which are observational in nature, or which are retrospective. 
Further, this Code does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific 
purpose of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of 
facilities and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial 
initiation, sites are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus 
source documentation according to standard operating procedures.  Per Merck policies and procedures, if 
fraud, misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When 
necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review committees 
notified and data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase 
or pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication 
of results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical 
issues of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able 
to defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, 
except that changes required urgently to protect subject safety and well-being may be enacted in anticipation of 
IRB/ERC approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  
Potential subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a 
minimum, trial designs will take into account the local standard of care.  Subjects are never denied access to 
appropriate medical care based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed 
consent for participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their 
access to, or receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by 
law, only the investigator, sponsor (or representative) and/or regulatory authorities will have access to 
confidential medical records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized 
by an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives 
to enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may 
be made to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent 
on chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or 
sponsoring institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC 
may wish to alter the wording of the disclosure statement to be consistent with financial practices at that 
institution.  As noted above, publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will 
be consistent with local guidelines and practices including, in the U.S., those established by the American 
Medical Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in 
signing the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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8. SIGNATURES
8.1
SPONSOR’S REPRESENTATIVE
TYPED NAME
SIGNATURE
DATE
8.2
INVESTIGATOR
I agree to conduct this clinical study in accordance with the design outlined in this 
protocol and to abide by all provisions of this protocol (including other manuals and 
documents referenced from this protocol); deviations from the protocol are acceptable 
only with a mutually agreed upon protocol amendment. I agree to conduct the study in 
accordance with generally accepted standards of Good Clinical Practice. I also agree to 
report all information or data in accordance with the protocol and, in particular, I agree to 
report any serious adverse experiences as defined in the SAFETY MEASUREMENTS 
section of this protocol. I also agree to handle all clinical supplies provided by the 
SPONSOR and collect and handle all clinical specimens in accordance with the protocol. 
I understand that information that identifies me will be used and disclosed as described in 
the protocol, and that such information may be transferred to countries that do not have 
laws protecting such information. Since the information in this protocol and the 
referenced Investigator’s brochure is confidential, I understand that its disclosure to any 
third parties, other than those involved in approval, supervision, or conduct of the study is 
prohibited. I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure, or access by third parties.
TYPED NAME
SIGNATURE
DATE
 
 
03L5Z6
 
 
04Z4C7