Clinical trial NCT03572049: Endemic Mycoses Treatment With SUBA-itraconazole vs Itraconazole
Official title: SUBA-itraconazole Versus Conventional Itraconazole in the Treatment of Endemic Mycoses: a Multi-center, Open-label Comparative Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Invasive Fungal Infections
Keywords: Histoplasmosis
Coccidioidomycosis
Blastomycosis
Lead sponsor: University of Alabama at Birmingham
Sponsor class: OTHER
Collaborators: name: University of California, Davis
name: Washington University School of Medicine
First posted: 2018-06-28
Enrollment: 88
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a prospective, multi-center, randomized, open-label parallel arm study involving patients with proven or probable invasive endemic fungal infection to ascertain the pharmacokinetics, safety, efficacy, tolerability and health economics of oral SUBA-itraconazole compared to conventional itraconazole. Patients will receive randomized open-label study drug (SUBA-itraconazole or conventional itraconazole) over a 42 day period and then continue therapy until Day 180. Patients will be stratified based on clinically reported infection with the human immunodeficiency virus (HIV).

Detailed description: This is a prospective, multi-center, randomized, open-label parallel arm study involving patients with proven or probable invasive endemic fungal infection to ascertain the pharmacokinetics, safety, efficacy, and tolerability of oral SUBA-itraconazole or itraconazole. Patients will receive randomized open-label study drug (either SUBA- itraconazole 130 mg twice daily or itraconazole 200 mg twice daily) over a 42-day period and then continue on their assigned open-label therapy until day 180.

The study sample size will be 80 evaluable patients - target enrollment (three arms: approximately 40 histoplasmosis, 20 coccidioidomycosis, 20 other endemic fungal infections).

Eligibility criteria: Inclusion Criteria:

1. Male and female patients age \> 18 years who have given written informed consent to participate
2. Patients with a proven or probable endemic mycosis (Histoplasma, Coccidioides, Paracoccidioides, Blastomyces, Sporothrix, Talaromyces marneffei (formerly Penicillium marneffei) according to current EORTC/MSG (Mycoses Study Group) criteria, including patients who:

   * Are immunosuppressed, including as a result of HIV/AIDS
   * Have had a heart, lung or bone marrow transplant
   * Have had chemotherapy for cancer
   * Are otherwise normal hosts

Exclusion Criteria:

1. Significant liver dysfunction as evidenced by at least 5 times greater than upper limits of normal baseline ALT (alanine aminotransferase) , AST (aspartate aminotransferase), alkaline phosphatase, or total bilirubin.
2. Use of an alternative antifungal therapy (IV or oral) for more than 14 days for this infection, with the exception of Coccidioidomycosis. Subjects with Coccidioidomycosis who previously received fluconazole therapy for more than 14 days may be included, if in the opinion of the investigator, they are having an inadequate response or, are intolerant of fluconazole (e.g. due to adverse events). Such subjects must washout from fluconazole for 7 days (\~5 half-lives of fluconazole) before starting investigational therapy.
3. Evidence of CNS (central nervous system) infection.
4. Unable to take PO medications.
5. Female patients who are lactating or pregnant.

   Women should be:
   1. Postmenopausal for 1 year,
   2. Post-hysterectomy or bilateral oophorectomy,
   3. If of child bearing potential have a negative β-HCG (human chorionic gonadotropin) at screening and using highly effective method of birth control throughout course of study or remain abstinent for duration of study.
6. Documented intolerance, allergy or hypersensitivity to an azole.
7. Inability to comply with study treatment, study visits, and study procedures.
8. Known history of congestive cardiac failure on medical treatment, fungal endocarditis, or other causes of ventricular dysfunction that may outweigh the benefit of itraconazole.
9. Patients with active TB (tuberculosis)
10. Concurrent use of astemizole, rifampin/rifampicin, rifabutin, ergot alkaloids, long acting barbiturates, carbamazepine, pimozide, quinidine, neostigmine, terfenadine, ketoconazole, valproic acid, or St. John's wort in the 5 days prior to first administration of study drug.
11. Any known or suspected condition of the patient that may jeopardize adherence to the protocol requirements or impede the accurate measurement of efficacy.
12. Treatment with any investigational agent in the 30 days prior to study entry.
13. Patients unlikely to survive 30 days (including severe fungal disease defined by systolic blood pressure (SBP) \< 90; hypoxia \< 60).
14. Patients with body weight \< 40 kg.

Primary outcomes:
measure: Comparison of Plasma Itraconazole Levels and Hydroxyitraconazole Levels at Day 14
timeFrame: Day 14
measure: Frequency of Treatment Related Adverse Events Days 1-42
timeFrame: Day 42
Secondary outcomes:
measure: Comparison of Plasma Itraconazole Levels and Hydroxyitraconazole Levels at Day 42
timeFrame: Day 42
measure: Resolution of Signs and Symptoms of Invasive Fungal Infection on Day 42
timeFrame: Day 42
measure: The Number of Days of Hospitalization at Day 180
timeFrame: Day 180
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Sacramento
country: United States
facility: University of California at Davis
state: California
city: Chicago
country: United States
facility: Rush University
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Overland Park
country: United States
facility: Metro Infectious Disease Associates
state: Kansas
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Minneapolis
country: United States
facility: Unniversity of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University in St. Louis
state: Missouri
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Panama
country: Panama
facility: Hospital Santo Tomás
Study officials:
affiliation: University of Alabama at Birmingham
name: Peter G Pappas, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Davis
name: George R Thompson, MD
role: STUDY_CHAIR
affiliation: Washington University School of Medicine
name: Andrej Spec, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Thompson GR 3rd, Lewis P, Mudge S, Patterson TF, Burnett BP. Open-Label Crossover Oral Bioequivalence Pharmacokinetics Comparison for a 3-Day Loading Dose Regimen and 15-Day Steady-State Administration of SUBA-Itraconazole and Conventional Itraconazole Capsules in Healthy Adults. Antimicrob Agents Chemother. 2020 Jul 22;64(8):e00400-20. doi: 10.1128/AAC.00400-20. Print 2020 Jul 22.