Safety of Fluconazole Treatment of Premature and Full-term Newborn Infants

Safety of Fluconazole Treatment of Premature and Full-term Newborn Infants - A Study on Interactions by Nonsteroidal Anti Inflammatory Drugs (NSAIDs) With Fluconazole in Respect of Pharmacodynamic Endpoints With Urinary Excretion of Vasoactive Endobiotics

This study will investigate pharmacological interventions between fluconazole and ibuprofen when they are given to premature newborn babys. This in order to find out if the drugs are influencing each other when they are given at the same time. The study is meant to find out if there are reasons to adjust the dose when fluconazole and ibuprofen are given together.

Study Overview

• Status: Completed
• Conditions: Bacterial Infections and Mycoses; Ductus Arteriosis, Patent
• Intervention / Treatment: Drug: Treatment with fluconazole.; Drug: 2. Treatment with both fluconazole and Ibuprofen.; Drug: 3. Treatment with ibuprofen.; Other: 4. No treatment with either fluconazole nor ibuprofen.

Detailed Description

To evaluate the effect of fluconazole and/or ibuprofen on the urinary excretion of two vasoactive arachidonic acid products, thromboxane A2 (TXA2) and prostacycline (PGI2), in newborn infants treated with one or both of these drugs because of fungal infection prophylaxis and/or patent ductus arteriosis (PDA), respectively, as measurement of the possible interactions between these drugs.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 4

Contacts and Locations

Study Locations

• Sweden
  • Stockholm, Sweden, 171 76
    • Neonatal Intensive Care Unit, Karolinska University Hopsital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 months to 9 months (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Newborn infants in need of prophylaxis with fluconazole according to clinical routines and/or clinical indication for treatment of Patent Ductus Arteriosis (PDA), or newborn infants who are not treated with either fluconazole or ibuprofen according to the following study groups:

   1.1 Premature newborn infants with Gestational Age 23+0 to 26+6 weeks who are treated only with fluconazole.

   1.2 Premature newborn infants with Gestational Age 23+0 to 26+6 weeks who are treated with both fluconazole and Ibuprofen.

   1.3 Premature newborn infants with Gestational Age 27+0 to 36+6 who are treated only with ibuprofen.

   1.4 Premature newborn infants with Gestational Age 27+0 to 36+6 and fullterm infants who are not treated either with fluconazole or ibuprofen.

2. Parents that are in command of the Swedish language and capable of understanding the study plan
3. Informed written parental consent

Exclusion Criteria:

1. Infants who need treatment with other drugs that are metabolised by enzyme Cytochrome (CYP2C9) (such as phenytoin, sulphamethoxazole, fluvastatin, sildenafil, losartan, irbesartan, torsemide, tienilic acid), or any other enzyme involved in the metabolism of fluconazole and or NSAIDs, or treatment with drugs that interact with NSAIDs at the cyclooxygenase level, or interact with the vasal effects of the metabolic products of the cyclooxygenase.
2. Infants without possibility to conceive the objectives and implications of the study in the opinion of the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: SUPPORTIVE_CARE
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: 1; Premature newborn infants with Gestational Age 23+0 to 26+6 weeks who are treated only with fluconazole.	Drug: Treatment with fluconazole.
ACTIVE_COMPARATOR: 2; Premature newborn infants with Gestational Age 23+0 to 26+6 weeks who are treated with both fluconazole and Ibuprofen.	Drug: 2. Treatment with both fluconazole and Ibuprofen.
ACTIVE_COMPARATOR: 3; Premature newborn infants with Gestational Age 27+0 to 36+6 who are treated only with ibuprofen.	Drug: 3. Treatment with ibuprofen.
PLACEBO_COMPARATOR: 4; Premature newborn infants with Gestational Age 27+0 to 36+6 and fullterm infants who are not treated either with fluconazole or ibuprofen.	Other: 4. No treatment with either fluconazole nor ibuprofen.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urinary concentrations of prostacycline (PGI2) and thromboxane A2 (TxA2) measured in picogram/milliliter.	To evaluate the effect of fluconazole and/or ibuprofen on the urinary excretion of two vasoactive arachidonic acid products, thromboxane A2 (TXA2) and prostacycline (PGI2), in newborn infants treated with one or both of these drugs for fungal infection prophylaxis and/or patent ductus arteriosis (PDA), respectively.	5 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of thromboxane A2 (TXA2) and prostacycline (PGI2) in relation to genetic variation of the enzymes of the Cytochrome (P4502C) family.	To evaluate if genetic variability in the enzyme Cytochrome (P4502C) influence the urinary excretion of two vasoactive arachidonic acid products: thromboxane A2 (TXA2) and prostacycline (PGI2) in newborn infants treated with fluconazole and/or ibuprofen.	5 days
Number of and type of Adverse Drug Reactions	To evaluate safety of fluconazole and ibuprofen given separately or in combination to newborn infants with clinical indication for treatment with these drugs.	5 days

Collaborators and Investigators

• Sponsor: Anders Rane, MD, PhD, Senior professor
• Collaborators: Karolinska University Hospital
• Investigators: Study Director: Anders Rane, Prof. MD, Karolinska Institutet

Study record dates

Study Major Dates

• Study Start: April 1, 2014
• Primary Completion (ACTUAL): September 1, 2015
• Study Completion (ACTUAL): September 1, 2015

Study Registration Dates

• First Submitted: February 26, 2014
• First Submitted That Met QC Criteria: March 4, 2014
• First Posted (ESTIMATE): March 5, 2014

Study Record Updates

• Last Update Posted (ESTIMATE): September 2, 2015
• Last Update Submitted That Met QC Criteria: September 1, 2015
• Last Verified: September 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Mycoses; Bacterial Infections; Bacterial Infections and Mycoses; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Ibuprofen; Fluconazole
• Other Study ID Numbers: EudraCT number: 2013-003611-21