Invasive Fungal Infections
Conditions
Keywords
Histoplasmosis, Coccidioidomycosis, Blastomycosis
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).
Interventions
DRUGSUBA 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.
DRUGConventional 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.
Sponsors
University of California, Davis
Washington University School of Medicine
University of Alabama at Birmingham
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
Panama, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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
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. | 42 |
| 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
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. | 46 |
| Total | 88 |
Baseline characteristics
| Characteristic | Conventional Itraconazole | Total | SUBA Itraconazole |
|---|---|---|---|
| Age, Continuous | 48 years | 50 years | 53 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 6 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 40 Participants | 81 Participants | 41 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 17 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants | 8 Participants | 1 Participants |
| Race (NIH/OMB) White | 32 Participants | 59 Participants | 27 Participants |
| Sex: Female, Male Female | 20 Participants | 36 Participants | 16 Participants |
| Sex: Female, Male Male | 26 Participants | 52 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 42 | 0 / 46 |
| other Total, other adverse events | 16 / 42 | 22 / 46 |
| serious Total, serious adverse events | 4 / 42 | 12 / 46 |
Outcome results
Primary
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
Time frame: Day 14
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SUBA Itraconazole | Comparison of Plasma Itraconazole Levels and Hydroxyitraconazole Levels at Day 14 | 60.5 percentage of participants |
| Conventional Itraconazole | Comparison of Plasma Itraconazole Levels and Hydroxyitraconazole Levels at Day 14 | 71.0 percentage of participants |
Primary
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.
Time frame: Day 42
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SUBA Itraconazole | Frequency of Treatment Related Adverse Events Days 1-42 | 15 adverse events |
| Conventional Itraconazole | Frequency of Treatment Related Adverse Events Days 1-42 | 27 adverse events |
Secondary
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
Time frame: Day 42
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SUBA Itraconazole | Comparison of Plasma Itraconazole Levels and Hydroxyitraconazole Levels at Day 42 | 69.3 percentage of participants |
| Conventional Itraconazole | Comparison of Plasma Itraconazole Levels and Hydroxyitraconazole Levels at Day 42 | 58.0 percentage of participants |
Secondary
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.
Time frame: Day 42
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SUBA Itraconazole | Resolution of Signs and Symptoms of Invasive Fungal Infection on Day 42 | 29 Participants |
| Conventional Itraconazole | Resolution of Signs and Symptoms of Invasive Fungal Infection on Day 42 | 30 Participants |
Secondary
The Number of Days of Hospitalization at Day 180
The number of days of Hospitalization occurring between Day 1-180
Time frame: Day 180
| Arm | Measure | Value (MEAN) |
|---|---|---|
| SUBA Itraconazole | The Number of Days of Hospitalization at Day 180 | 5 Days |
| Conventional Itraconazole | The Number of Days of Hospitalization at Day 180 | 7 Days |