Endemic Mycoses Treatment With SUBA-itraconazole vs Itraconazole

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).

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.

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.