POS vs FLU for First Line Treatment of Coccidioidomycosis (Study P04558Am1)(COMPLETED)

Study Overview
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Brief Summary
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To evaluate the safety of posaconazole (POS) in the treatment of coccidioidomycosis. Period A consisted of 2 blinded arms, posaconazole and fluconazole. Recruitment was stopped, and participants in Period A may have been eligible to roll over to an open-label, non-comparitive Period B. During Period B, participants received posaconazole for a treatment duration not to exceed 12 months.

Official Title
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A Multicenter, Randomized, Controlled, Double-Blind, Double-Dummy, Two-Arm Study of Posaconazole vs Fluconazole in the Treatment of Coccidioidomycosis

Conditions
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Coccidioidomycosis

Intervention / Treatment
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* Drug: Posaconazole
* Drug: Fluconazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Thirteen years of age or older, 34 kg (75 lb) or more, either sex, and any race; Coccidioides immitis (C. immitis) or Coccidioides posadasii (C. posadasii) identified by culture or microscopic examination from skeletal disease, chronic active pulmonary disease, or soft tissue disease; Coccidioidomycosis score of >=6; Clinical laboratory safety tests within normal limits or clinically acceptable to the sponsor; Free of any clinically significant disease that would interfere with study evaluations; Willing to give written informed consent and able to adhere to study medication dose, mandatory procedures (including human immunodeficiency virus (HIV) testing), and visit schedules; Able to swallow food or a nutritional supplement; Use of a medically accepted method of contraception; Negative serum pregnancy test at Screening and negative urine pregnancy test at Randomization; Women of childbearing potential not currently sexually active must agree to use a medically accepted method of contraception should they become sexually active while participating in the study. Exclusion Criteria: Key Exclusion Criteria Excluded Medications at Enrollment Medications that are known to interact with POS or FLU and that may lead to serious or life threatening side effects within 7 days prior to initiating study drug; Medications known to lower the serum concentration/efficacy of azole antifungals within 7 days prior to study drug start; Prior investigational drug use or biologic product administration within 30 days before study drug start; Prior antifungal treatment for the current episode of infection with a total cumulative dose of >=8 g of any azole, >=4 mg/kg of amphotericin B deoxycholate, or >=20 mg/kg of lipid amphotericin B; Antiretrovirals that are substrates of CYP3A4 administered to HIV-positive subjects, as it is not currently known how POS or FLU may affect such drugs or the potential to cause adverse reactions. Excluded Concomitant Conditions Immediately life-threatening coccidioidomycosis; Confirmed or suspected meningeal coccidioidomycosis; Pulmonary coccidioidomycosis in HIV-negative subjects for less than 3 months; Any condition requiring use of prohibited drugs; Cluster of Differentiation 4 (CD4) count of <200 cells/mm3 or any auto-immune deficiency syndrome (AIDS)-defining illness in HIV-positive subjects in the prior 30 days. Excluded Baseline Laboratory Studies Moderate or severe liver dysfunction (aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 times upper limit of normal (ULN)) or a total bilirubin level or direct bilirubin > 3 times ULN plus ALT or AST >2 times ULN (Hy's Rule); Moderate or severe renal dysfunction (creatinine clearance (CrCl) <20 mL/min) or dialysis required or expected to be required within the study period; Electrocardiogram (ECG) with a prolonged QTc interval by manual reading: QTc >450 msec for males and QTc >470 msec for females. General Exclusion Criteria Prior enrollment in this study or other POS studies; Failed treatment with FLU or POS at any time in the past; History of hypersensitivity or idiosyncratic reactions to azole drug therapy; Women who are pregnant, intend to become pregnant, or are breast-feeding; Situation or condition that may interfere with optimal participation in the study; Part of the staff personnel directly involved with this study; Family member of the investigational study staff.

Ages Eligible for Study
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Minimum Age: 13 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Posaconazole<br>Eligible subjects will be stratified at Baseline by disease site (skeletal, lung, or soft tissue) and by immune status (immunocompromised or non-immunocompromised) and will then be randomly assigned to receive Posaconazole 400 mg orally (PO) (oral suspension 40 mg/mL) administered twice daily with meals or oral nutritional supplements for 12 months. | Drug: Posaconazole<br>* Posaconazole 400 mg orally (PO) (oral suspension 40 mg/mL) administered twice daily with meals or oral nutritional supplements for 12 months<br>|
| Active Comparator: Fluconazole<br>Eligible subjects will be stratified at Baseline by disease site (skeletal, lung, or soft tissue) and by immune status (immunocompromised or non-immunocompromised) and will then be randomly assigned to receive Fluconazole 400 mg PO (given as two 200-mg oral encapsulated tablets) administered once daily for 12 months. Fluconazole treatment or placebo only occurred during Period A. | Drug: Fluconazole<br>* Fluconazole 400 mg PO (given as two 200-mg oral encapsulated tablets) administered once daily for 12 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-related Treatment-emergent Adverse Events (TRAEs) That Occurred With Posaconazole (POS) or Fluconazole (FLU) in Period A | Treatment-emergent adverse events are defined as new events that occur following subject entry into the study or events that worsen following study entry state. Treatment-related adverse events are defined as new events that occur following subject entry into the study or events that worsen following study entry state and are judged by the investigator to be possibly, probably or definitely related to study medication. | 12 months | 
| Number of Participants With Treatment-related Treatment-emergent Adverse Events (TRAEs) That Occurred With Posaconazole (POS) in Period B | Treatment-emergent adverse events are defined as new events that occur following subject entry into the study or events that worsen following study entry state. Treatment-related adverse events are defined as new events that occur following subject entry into the study or events that worsen following study entry state and are judged by the investigator to be possibly, probably or definitely related to study medication. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs)That Occurred With POS or FLU in Period A | Treatment-emergent adverse events are defined as new events that occur following subject entry into the study or events that worsen following study entry state. | 12 months | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) That Occurred With POS in Period B | Treatment-emergent adverse events are defined as new events that occur following subject entry into the study or events that worsen following study entry state. | 12 months | 
| Number of Participants With Laboratory Test Abnormalities (at Least a 1 Grade Shift From Baseline) That Occurred With POS or FLU in Period A | Severity grading was based on Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. This is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE; Grade 2 Moderate AE; Grade 3 Severe AE; Grade 4 Life-threatening or disabling AE; Grade 5 Death related to AE. | 12 months | 
| Number of Participants With Laboratory Abnormalities (at Least a 1 Grade Shift From Baseline) That Occurred With POS in Period B | Severity grading was based on Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. This is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE; Grade 2 Moderate AE; Grade 3 Severe AE; Grade 4 Life-threatening or disabling AE; Grade 5 Death related to AE. | 12 months | 
| Number of Participant Discontinuations Due to Adverse Events and/or Laboratory Evaluations of Safety in Period A |  | 12 months | 
| Number of Participant Discontinuations Due to Adverse Events and/or Laboratory Evaluations of Safety in Period B |  | 12 months |