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Evaluation of Budesonide and How It Interacts With Antifungal Drugs in People With Gastrointestinal Graft-Versus-Host Disease

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ClinicalTrials.gov Identifier: NCT01950507
Recruitment Status : Completed
First Posted : September 25, 2013
Last Update Posted : May 14, 2018
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC)

Brief Summary:

Background:

The gastrointestinal (GI) tract is commonly affected by acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD) in patients who have undergone blood or marrow stem cell transplantation (BMT). Initially, patients are treated with systemic corticosteroids, which produce complete response rates in 35 percent. Although short courses of steroids are preferred to minimize adverse effects, many patients require systemic treatment chronically since GI GVHD can negatively impact quality of life and nutrition status. One option to minimize systemic steroid exposure is by nonabsorbable corticosteroids that act locally on the GI tract.

Budesonide (Entocort EC, AstraZeneca, Wilmington, DE) is an FDA-approved oral topical corticosteroid for the treatment of mild to moderate active Crohn s disease involving the ileum and/or the ascending colon, and for maintenance of clinical remission of mild to moderate Crohn s disease involving the ileum and/or the ascending colon for up to 3 months. It has a high ratio of topical-to-systemic activity with minimally active metabolites, and undergoes extensive first-pass metabolism. Since both intestinal GVHD and Crohn s disease seem to share a similar pathogenic background, budesonide has been used in the BMT setting for GI GVHD, usually in combination with systemic corticosteroids (e.g. methylprednisolone) to improve clinical response and allow for more rapid tapering of systemic corticosteroid doses.

First-pass metabolism is mediated mostly by the cytochrome P450 (CYP450) enzyme system. The liver is the major site of CYP450-mediated metabolism but the enterocytes of the intestinal epithelium are also an important site for drug metabolism. Budesonide undergoes significant metabolism by CYP enzymes with substantial first-pass metabolism. The potential for greater systemic availability of orally administered budesonide exists when it is given concurrently with triazole antifungals, which are commonly prescribed for prophylaxis or treatment of fungal infections after transplantation. Fluconazole and voriconazole are moderate and strong inhibitors of CYP3A4, respectively, and budesonide is a CYP3A4 substrate. Inhibition of CYP3A4 may impair the metabolism of budesonide, resulting in systemic concentrations of budesonide and subsequently, adverse effects such as hyperglycemia. If the presence of fluconazole or voriconazole does impair budesonide s metabolism, then dose adjustments to budesonide may be warranted.

There are no prospective studies evaluating the effects of fluconazole or voriconazole on budesonide s pharmacokinetics in patients who have undergone BMT.

The primary objective of the proposed study is to determine the effects of fluconazole and voriconazole on the trough (Cmin) and peak (Cmax) of budesonide in patients who have undergone BMT and who have GI GVHD.

The primary endpoints are the Cmin and Cmax of budesonide. Secondary endpoints include the Cmin of voriconazole.

Objectives:

The proposed study seeks to determine the effects of fluconazole and voriconazole on the Cminand Cmax of budesonide.

Eligibility:

Adult and pediatric subjects (greater than or equal to 13 years of age and greater than or equal to 49 kg) who are registered to an NCI or NHLBI protocol who have undergone a bone marrow, cord, haplo-cord or peripheral blood stem cell transplantation who have GI GVHD as determined by the medical team and who require treatment with budesonide and are candidates for antifungal therapy are eligible for this study.

Design:

Each subject will serve as his or her own control to minimize the variation in absorption, distribution, metabolism and elimination of oral budesonide that can occur from subject to subject, due to genetic, anatomic or other unidentified differences. For example, genetic polymorphisms of CYP2C19, which is significantly involved in voriconazole s metabolism, could otherwise affect the results of the study (i.e. CYP2C19 poor metabolizers may experience higher voriconazole serum concentrations, which could results in greater CYP3A4 inhibition and higher budesonide exposure). In addition, the longitudinal cohort design of this study will be able to answer the research questions posed with fewer research subjects. Research subjects will be accrued into one of three cohorts depending on the antifungal prophylaxis (or lack thereof) the subject is receiving at study entry and the preference of the medical team for continued antifungal coverage after the initiation of budesonide and systemic corticosteroids. Subjects who are not currently receiving antifungal prophylaxis or who are on fluconazole at baseline are eligible for enrollment in Cohort 1. Subjects in Cohorts 2 and 3 are receiving voriconazole and fluconazole at study entry, respectively. In Cohort 1, if applicable, subjects will stop fluconazole on day -1...


Condition or disease Intervention/treatment Phase
Stem Cell Transplantation Graft vs Host Disease Drug: Budesonide Drug: Fluconazole Drug: Voriconazole Phase 1

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Evaluation of Serum Concentrations of Budesonide in Patients Treated for Gastrointestinal Graft-Versus-Host Disease and the Potential Interaction With Fluconazole or Voriconazole
Study Start Date : September 21, 2013
Actual Primary Completion Date : May 10, 2018
Actual Study Completion Date : May 10, 2018

Resource links provided by the National Library of Medicine





Primary Outcome Measures :
  1. The primary endpoints are the Cmin and Cmax of budesonide [ Time Frame: ongoing ]


Information from the National Library of Medicine

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Ages Eligible for Study:   13 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Adult and pediatric subjects (greater than or equal to 13 years of age and greater than or equal to 49 kg)
  • Be registered to an NIH protocol that includes bone marrow, cord, haplo-cord or peripheral blood stem cell transplantation
  • Have GI GVHD as determined by the medical team that requires treatment with budesonide and systemic corticosteroids (e.g. methylprednisolone or prednisone)
  • Be candidates for antifungal therapy
  • Liver function tests:

    • Alanine aminotransferase (ALT) must be <5 times the upper limit of normal (ULN)
    • Aspartate aminotransferase (AST) must be <5 times ULN

EXCLUSION CRITERIA:

  • Pregnant or breast-feeding
  • Prohibited drugs

    --Note: Treatment with corticosteroids and/or immunosuppressants is permitted

  • Consumption of grapefruit juice or grapefruit in the past seven days prior to study enrollment
  • Inability to take oral medications
  • Allergy(ies) to budesonide, fluconazole, micafungin, voriconazole
  • ECOG performance status greater than or equal to 4 (adults and children 16 years and older) or Lansky perfomance status less than or equal to 30 (children< 16 years old)
  • Psychiatric disorder or mental deficiency that could interfere with the subject s ability to comply with study procedures and requirements
  • Inability to provide informed consent
  • Major anticipated illness or organ failure whereby the subject s anticipated survival within 2 weeks is unlikely (PI discretion)
  • Current documented or suspected invasive fungal infection
  • Intensive care unit (ICU) patient
  • Child-Pugh Class C hepatic impairment
  • AST greater than or equal to 5 times ULN, ALT greater than or equal to 5 times ULN
  • Contraindication to an azole as determined by research team
  • Body weight < 49 kg at the time of study enrollment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01950507


Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Institutes of Health Clinical Center (CC)
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Principal Investigator: Thomas Hughes, Pharm.D. National Institutes of Health Clinical Center (CC)

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT01950507     History of Changes
Other Study ID Numbers: 130197
13-H-0197
First Posted: September 25, 2013    Key Record Dates
Last Update Posted: May 14, 2018
Last Verified: May 10, 2018

Keywords provided by National Institutes of Health Clinical Center (CC):
Fluconazole
Graft Versus Host Disease
Voriconazole
Azoles

Additional relevant MeSH terms:
Graft vs Host Disease
Immune System Diseases
Budesonide
Fluconazole
Voriconazole
Anti-Inflammatory Agents
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists
Cytochrome P-450 CYP2C9 Inhibitors
Cytochrome P-450 CYP2C19 Inhibitors
Cytochrome P-450 CYP3A Inhibitors