Endemic Mycoses Treatment With SUBA-itraconazole vs Itraconazole (MSG15)

SUBA-itraconazole Versus Conventional Itraconazole in the Treatment of Endemic Mycoses: a Multi-center, Open-label Comparative Trial

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).

Study Overview

• Status: Completed
• Conditions: Invasive Fungal Infections
• Intervention / Treatment: Drug: SUBA itraconazole; Drug: Conventional itraconazole

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).

• Study Type: Interventional
• Enrollment (Actual): 88
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Panama
  • Panama, Panama
    • Hospital Santo Tomas
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • California
    • Sacramento, California, United States, 95817
      • University of California at Davis
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
    • Chicago, Illinois, United States, 60612
      • Rush University
  • Kansas
    • Overland Park, Kansas, United States, 66211
      • Metro Infectious Disease Associates
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Unniversity of Minnesota
  • Missouri
    • Saint Louis, Missouri, United States, 63130
      • Washington University in St. Louis
  • North Carolina
    • Durham, North Carolina, United States, 27710-1000
      • Duke University Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • University of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SUBA itraconazole; Stage 1: Day 1-3 two 65 mg capsules three times daily with food. Days 4-42 two 65 mg capsules twice daily with food. Stage 2 : Days 43-180 two 65 mg capsules twice daily with food	Drug: SUBA itraconazole; SUBA itraconazole study drug will consist of two 65 mg capsules to be taken three times a day with food for days 1-3 of study. For days 4-180 of study, two 65mg capsules will be taken twice daily with food.
Active Comparator: Conventional itraconazole; Stage 1: Day 1-3 two 100 mg capsules three times daily with food. Days 4-42 two 100 mg capsules twice daily with food. Stage 2 : Days 43-180 two 100 mg capsules twice daily with food	Drug: Conventional itraconazole; Conventional itraconazole comparator drug will consist of two 100 mg capsules to be taken three times a day with food for days 1-3 of study. For days 4-180 of study, two 100 mg capsules will be taken twice daily with food.; Other Names: itraconazole; Sporanox

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of Plasma Itraconazole Levels and Hydroxyitraconazole Levels at Day 14	Percentage of participants to achieve therapeutic itraconazole and hydroxyitraconazole levels by evaluating Inter-patient variability as calculated by co-efficient of variation on plasma specimens collected on Day 14	Day 14
Frequency of Treatment Related Adverse Events Days 1-42	Comparison of the number of treatment related adverse events in each arm occurring Days 1-42.	Day 42

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of Plasma Itraconazole Levels and Hydroxyitraconazole Levels at Day 42	Percentage of patients with therapeutic itraconazole and hydroxyitraconazole levels as measured in plasma trough levels Day 42	Day 42
Resolution of Signs and Symptoms of Invasive Fungal Infection on Day 42	We will measure specific signs and symptoms related to endemic fungal infection, comparing baseline findings to Day 42 findings using physical examination and patient history.	Day 42
The Number of Days of Hospitalization at Day 180	The number of days of Hospitalization occurring between Day 1-180	Day 180

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Collaborators: Washington University School of Medicine; University of California, Davis
• Investigators: Principal Investigator: Andrej SPEC, MD, Washington University School of Medicine; Principal Investigator: Peter G Pappas, MD, University of Alabama at Birmingham; Study Chair: George R Thompson, MD, University of California, Davis

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 17, 2018
• Primary Completion (Actual): May 31, 2021
• Study Completion (Actual): April 29, 2022

Study Registration Dates

• First Submitted: February 1, 2018
• First Submitted That Met QC Criteria: June 18, 2018
• First Posted (Actual): June 28, 2018

Study Record Updates

• Last Update Posted (Actual): July 7, 2023
• Last Update Submitted That Met QC Criteria: June 21, 2023
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Histoplasmosis; Coccidioidomycosis; Blastomycosis
• Additional Relevant MeSH Terms: Infections; Bacterial Infections and Mycoses; Mycoses; Invasive Fungal Infections; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Itraconazole; Hydroxyitraconazole
• Other Study ID Numbers: MSG15; MSG-15 (Other Identifier: Mycoses Study Group); UTN U1111-1228-5154 (Other Identifier: World Health Organization)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No