Endemic Mycoses Treatment With SUBA-itraconazole vs Itraconazole

Phase 2

Completed

• Conditions: Invasive Fungal Infections
• Interventions: Drug: SUBA itraconazole; Drug: Conventional itraconazole

• Registration Number: NCT03572049
• Lead Sponsor: University of Alabama at Birmingham

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).

Study Timeline

• Study First Submitted: 2018-02-01
• Study First Submitted QC: 2018-06-18
• Study First Posted: 2018-06-28
• Study Start: 2018-09-17
• Primary Completion: 2021-05-31
• Study Completion: 2022-04-29
• Results First Submitted: 2022-06-02
• Status Verified: 2022-09
• Results First Submitted QC: 2022-09-08
• Results First Posted: 2022-10-06
• Last Update Submitted: 2023-06-21
• Last Update Posted: 2023-07-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 88

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
SUBA itraconazole	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
Conventional itraconazole	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

Primary Outcome Measures

Name	Time	Method
Comparison of Plasma Itraconazole Levels and Hydroxyitraconazole Levels at Day 14	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
Frequency of Treatment Related Adverse Events Days 1-42	Day 42	Comparison of the number of treatment related adverse events in each arm occurring Days 1-42.

Secondary Outcome Measures

Name	Time	Method
Comparison of Plasma Itraconazole Levels and Hydroxyitraconazole Levels at Day 42	Day 42	Percentage of patients with therapeutic itraconazole and hydroxyitraconazole levels as measured in plasma trough levels Day 42
Resolution of Signs and Symptoms of Invasive Fungal Infection on Day 42	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.
The Number of Days of Hospitalization at Day 180	Day 180	The number of days of Hospitalization occurring between Day 1-180

Trial Locations

Locations (12)

Metro Infectious Disease Associates; 🇺🇸 Overland Park, Kansas, United States

Hospital Santo Tomás; 🇵🇦 Panama, Panama

University of Alabama at Birmingham; 🇺🇸 Birmingham, Alabama, United States

Rush University; 🇺🇸 Chicago, Illinois, United States

University of Chicago; 🇺🇸 Chicago, Illinois, United States

University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States

Unniversity of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States

University of Arizona; 🇺🇸 Tucson, Arizona, United States

University of California at Davis; 🇺🇸 Sacramento, California, United States

Washington University in St. Louis; 🇺🇸 Saint Louis, Missouri, United States

University of Wisconsin; 🇺🇸 Madison, Wisconsin, United States

Duke University Medical Center; 🇺🇸 Durham, North Carolina, United States