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Trial registered on ANZCTR


Registration number
ACTRN12616000686404
Ethics application status
Approved
Date submitted
3/05/2016
Date registered
25/05/2016
Date last updated
25/05/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Early versus delayed initiation of amphotericin B deoxycholate in the empiric treatment of persistent neutropenic fever
Scientific title
Early versus delayed initiation of amphotericin B deoxycholate in the empiric treatment of persistent neutropenic fever
Secondary ID [1] 289126 0
None.
Universal Trial Number (UTN)
U1111-1182-5576
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Persistent neutropenic fever 298605 0
Condition category
Condition code
Infection 298675 298675 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Initiation of amphotericin B deoxycholate on day 4 (early initiation or treatment A) .
Fourth day of fever (38.3 degrees Celsius or more), i.e., persistent fever (i.e., despite being treated with broad-spectrum antibiotics).
Administration method: First, these patients will receive 1 L of normal saline (NaCl 0.9%) intravenously for 1 hour. Then, they will receive 1 L of 5% dextrose in water (D5W) plus 1 mg/kg daily of amphotericin B deoxycholate plus one vial (10 mL) of Multiple Vitamins for Infusion (Dextrevit Registered Trademark) given by slow infusion (12 hours). The 12-hour infusion is a combination of the D5W, amphotericin B deoxycholate and Multiple Vitamins, which are all given once daily. Amphotericin B deoxycholate will continue for at least 48 hours after the patient is afebrile and his absolute neutrophil count is 500 cells/mm3 or more. The latter decision will be made by the research team. A team member will also monitor adherence on a daily basis.
Intervention code [1] 294632 0
Treatment: Drugs
Comparator / control treatment
Initiation of amphotericin B deoxycholate on day 6 (delayed initiation or treatment B). These patients will receive placebo the fourth and fifth day.
Placebo administration will be as follows: First, these patients will receive 1 L of normal saline (NaCl 0.9%) intravenously for 1 hour. Then, they will receive 1 L of 5% dextrose in water (D5W) plus one vial (10 mL) of Multiple Vitamins for Infusion (Dextrevit Registered Trademark) given by slow infusion (12 hours).
Control group
Placebo

Outcomes
Primary outcome [1] 298168 0
Difference in time for fever resolution.
This outcome will be assessed using a mercury thermometer.
Timepoint [1] 298168 0
Inhospital fever resolution (i.e., the follow-up to determine the primary outcome will be for the whole length of hospitalization since patients can not be discharged while having a fever).
Secondary outcome [1] 323347 0
Difference in length of stay.
This outcome will be assessed by reviewing medical records.
Timepoint [1] 323347 0
The follow-up to determine this secondary outcome will be for the whole length of hospitalization since patients can not be discharged while having a fever.
Secondary outcome [2] 323348 0
Difference in inhospital mortality.
This outcome will be assessed by reviewing medical records.
Timepoint [2] 323348 0
The follow-up to determine this secondary outcome will be for the whole length of hospitalization since patients can not be discharged while having a fever.
Secondary outcome [3] 323349 0
Difference in mortality due to invasive mycoses.
This outcome will be assessed by reviewing medical records.
Considering this outcome, the diagnostic information included in the medical records will be CT reports, biopsy material, galactomannan assays, and the like.
Timepoint [3] 323349 0
This outcome will be daily assessed during hospitalization and then at 28 days post discharge.
Secondary outcome [4] 323350 0
Difference in nephrotoxicity.
This outcome will be assessed by serum creatinine, and it is defined as a relative increase in serum creatinine 2-fold or more over baseline and/or an absolute increase of 0.5 mg/dL or more above baseline.
Timepoint [4] 323350 0
This outcome will be daily assessed during hospitalization and then at 28 days post discharge.
Secondary outcome [5] 323351 0
Difference in hepatotoxicity.
This outcome will be assessed by liver function tests, and it is defined as an increase of at least three times the transaminases' baseline level.
Timepoint [5] 323351 0
This outcome will be daily assessed during hospitalization and then at 28 days post discharge.
Secondary outcome [6] 323352 0
Difference in hypokalemia.
This outcome will be assessed by serum potassium, and it is defined as a serum potassium level of less than 3.5 mEq/L.
Timepoint [6] 323352 0
This outcome will be daily assessed during hospitalization and then at 28 days post discharge.
Secondary outcome [7] 323353 0
Difference in hypomagnesemia.
This outcome will be assessed by serum magnesium, and it is defined as a serum magnesium level of less than 1.5 mEq/L.
Timepoint [7] 323353 0
This outcome will be daily assessed during hospitalization and then at 28 days post discharge.

Eligibility
Key inclusion criteria
1. Neutropenic fever,
2. High-risk patient,
3. Persistent fever,
4. No source of infection at the time of randomization.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Hemodynamic instability before randomization,
2. Chronic kidney disease stage 4 and 5.
3. Use of amphotericin B deoxycholate in the last four weeks,
4. Respiratory failure (PaO 2 / FiO 2 <301) prior to randomization,
5. History of severe adverse reaction to amphotericin B deoxycholate,
6. Pregnancy,
7. History of invasive fungal disease,
8. Chronic liver disease.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Sealed opaque envelopes.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computerised sequence generation.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Based on a previous report (Malhotra et al, 2014), sample size was calculated using comparisons of means. Calculation was performed using alpha = 0.05, beta = 0.20, and two tails. A total sample size of 24 (12 in each group) would be required to demonstrate a statistically significant difference between groups. Assuming a dropout rate of 20%, the total sample size was increased to 30, as follows: N = n / (1-z%), where N is the adjusted final sample size, n the calculated sample size, and z% the dropout expected rate.
Data distribution will be assessed with the use of Kolmogorov–Smirnov test. Continuous variables will be compared using Student's t-test or Mann-Whitney U test. The continuous variables will be presented as mean +/- SD or median (25, 75), The Chi-square test or Fisher's exact test will be used to compare categorical variables. The categorical variables will be presented as frequency and percentage. Statistical analyses will be conducted using SPSS v.20 (SPSS Inc. Software, Chicago, Illinois, USA), and a p-value below 0.05 (p<0.05) will be considered significant.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/06/2016
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment outside Australia
Country [1] 7848 0
Mexico
State/province [1] 7848 0
Nuevo Leon

Funding & Sponsors
Funding source category [1] 293495 0
Hospital
Name [1] 293495 0
Hospital Universitario "Dr. Jose Eleuterio Gonzalez"
Country [1] 293495 0
Mexico
Primary sponsor type
Individual
Name
Adrian Camacho-Ortiz
Address
Coordinacion de Epidemiologia y Servicio de Infectologia, Hospital Universitario "Dr. Jose Eleuterio Gonzalez", Madero y Gonzalitos s/n, Col. Mitras Centro, C.P. 64460, Monterrey, Nuevo Leon, Mexico.
Country
Mexico
Secondary sponsor category [1] 292322 0
Individual
Name [1] 292322 0
Guillermo Delgado-Garcia
Address [1] 292322 0
Departamento de Medicina Interna, Hospital Universitario “Dr. Jose Eleuterio Gonzalez”. Madero y Gonzalitos s/n, Col. Mitras Centro, C.P. 64460, Monterrey, Nuevo Leon, Mexico.
Country [1] 292322 0
Mexico

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294938 0
Faculty of Medicine and University Hospital ethics committee
Ethics committee address [1] 294938 0
Subdireccion de Investigacion, Facultad de Medicina, Universidad Autonoma de Nuevo Leon. Madero y Gonzalitos s/n, Col. Mitras Centro, C.P. 64460, Monterrey, Nuevo Leon, Mexico.
Ethics committee country [1] 294938 0
Mexico
Date submitted for ethics approval [1] 294938 0
Approval date [1] 294938 0
19/04/2016
Ethics approval number [1] 294938 0
MI16-00002

Summary
Brief summary
A large proportion of health care facilities in developing countries does not have the diagnostic armamentarium necessary to undertake a complete preemptive therapy for high-risk patients with persistent neutropenic fever. Likewise, the use of liposomal amphotericin B is limited by its cost. Therefore, we designed this study to determine the optimal time for starting empirical antifungal therapy with amphotericin B deoxycholate in high-risk patients with persistent neutropenic fever, which could provide a timely resolution of symptoms and potentially a reduction in mortality. This is a single-center, randomized, double-masked, placebo-controlled, parallel-group study. Eligible patients will be randomized on the fourth day of fever to treatment A (early therapy) or B (delayed therapy). In treatment A, amphotericin B deoxycholate will be initiated on the fourth day of fever. In treatment B, placebo will be initiated on the fourth day of fever and, on the sixth day, the latter will be switched to amphotericin B deoxycholate. The primary outcome will be the time to fever resolution after the start of amphotericin B deoxycholate.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 65558 0
Prof Adrian Camacho-Ortiz
Address 65558 0
Coordinacion de Epidemiologia y Servicio de Infectologia, Hospital Universitario "Dr. Jose Eleuterio Gonzalez". Madero y Gonzalitos s/n, Col. Mitras Centro, C.P. 64460, Monterrey, Nuevo Leon, Mexico.
Country 65558 0
Mexico
Phone 65558 0
+518183891138
Fax 65558 0
Email 65558 0
[email protected]
Contact person for public queries
Name 65559 0
Guillermo Delgado-Garcia
Address 65559 0
Departamento de Medicina Interna, Hospital Universitario “Dr. Jose Eleuterio Gonzalez”, Universidad Autonoma de Nuevo Leon. Madero y Gonzalitos s/n, Col. Mitras Centro, C.P. 64460, Monterrey, Nuevo Leon, Mexico.
Country 65559 0
Mexico
Phone 65559 0
+518111705754
Fax 65559 0
Email 65559 0
[email protected]
Contact person for scientific queries
Name 65560 0
Guillermo Delgado-Garcia
Address 65560 0
Departamento de Medicina Interna, Hospital Universitario “Dr. Jose Eleuterio Gonzalez”, Universidad Autonoma de Nuevo Leon. Madero y Gonzalitos s/n, Col. Mitras Centro, C.P. 64460, Monterrey, Nuevo Leon, Mexico.
Country 65560 0
Mexico
Phone 65560 0
+518111705754
Fax 65560 0
Email 65560 0
[email protected]

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