Safety and PK of Nikkomycin Z for Coccidioides Pneumonia Treatment

Study Overview
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Brief Summary
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The purpose of this study is to determine if nikkomycin Z is safe when administered at different dose levels for 14 days. The study will also determine blood levels and urinary excretion of nikkomycin Z in relation to dose administered. Patients with mild forms of Valley Fever pneumonia will be eligible to participate and will be allocated to receive treatment with nikkomycin Z (various doses) or a placebo. A secondary goal of this study is to evaluate the effectiveness and dose response of nikkomycin Z in an exploratory analysis.

Detailed Description
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Every year there are 50,000 new U.S. cases of coccidioidomycosis (Valley Fever). The majority of these illnesses occur as a result of endemic exposure in Arizona and California. The benefits of antifungal therapy for uncomplicated disease are not currently established. Current therapies for serious and complicated forms of coccidioidomycosis are only partially effective and in themselves are unable to eradicate the fungus from sites of infection, commonly resulting in breakthrough infection and/or relapse. Nikkomycin Z is effective in the mouse model and results in improved microbiological response over fluconazole. The goals of this study include: 1) Evaluating the safety and tolerance of nikkomycin Z following administration of multiple doses (50 mg Q 12 h to 750 mg Q 8 h) for two week and 2) Evaluating the pharmacokinetics of nikkomycin Z after single and multiple doses in relationship to dose. The study will include patients with uncomplicated Coccidioides pneumonia (mild illness) which will allow exploratory analysis of efficacy and dose response based on biomarkers.

Official Title
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Phase I/II Evaluation of the Safety, Pharmacokinetics, and Preliminary Effectiveness of Nikkomycin Z in the Treatment of Patients With Uncomplicated Coccidioides Pneumonia

Conditions
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Coccidioidomycosis

Intervention / Treatment
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* Drug: nikkomycin Z


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 18 years and <= 50 years Male or Female (if female, must have a negative pregnancy test and agree to use an acceptable contraception method) Able to understand study and give written informed consent Have a respiratory illness with at least one of the following: Cough, chest pain dyspnea or tachypnea, sputum production, or fever/chills/night sweats Have a new or suspected new pulmonary infiltrate on Chest X-ray Have a positive coccidioidal serology by EIA or immunodiffusion Exclusion Criteria: Patients under the age of 18 years or over 50 years Patients with a history of confirmed coccidioidal infection Laboratory diagnosis of another etiology for the inclusion-defining illness Inability to comprehend study and provide informed consent History of or current evidence of major organ disease Concomitant use of prednisone and other corticosteroids not permitted Concomitant immunosuppressive therapy is not permitted Concomitant antibacterial therapy is not permitted

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>nikkomycin Z 50 mg BID versus placebo BID x 14 days | Drug: nikkomycin Z<br>* Stage I: Multiple rising doses. Doses packaged on a unit dose basis in 50 and 250 mg capsules. Subjects take 1-3 capsules per dosing block for 14 days unless ADE or study withdrawal. Dose escalation unless a dose-limiting adverse effect is noted. Subjects assigned to BID dosing will receive 28 doses and subjects assigned to TID dosing will receive 42 doses. 50 mg BID (n=8) vs placebo capsule BID (n=2) 250 mg BID (n=8) vs Placebo capsule BID (n=2) 500 mg BID (n=8) vs Placebo capsule BID (n=2) 750 mg TID (n=8) vs Placebo capsule TID (n=2) At least 4 subjects complete lower dose before randomization includes next higher dose, thus there are 4 arms for active intervention and corresponding placebos. Stage II will be a single dose level selected based on pharmacodynamics and safety from Stage I for 20 additional subjects using 4:1 randomization.<br>|
| Experimental: B<br>nikkomycin Z 250 mg BID versus placebo BID x 14 days | Drug: nikkomycin Z<br>* Stage I: Multiple rising doses. Doses packaged on a unit dose basis in 50 and 250 mg capsules. Subjects take 1-3 capsules per dosing block for 14 days unless ADE or study withdrawal. Dose escalation unless a dose-limiting adverse effect is noted. Subjects assigned to BID dosing will receive 28 doses and subjects assigned to TID dosing will receive 42 doses. 50 mg BID (n=8) vs placebo capsule BID (n=2) 250 mg BID (n=8) vs Placebo capsule BID (n=2) 500 mg BID (n=8) vs Placebo capsule BID (n=2) 750 mg TID (n=8) vs Placebo capsule TID (n=2) At least 4 subjects complete lower dose before randomization includes next higher dose, thus there are 4 arms for active intervention and corresponding placebos. Stage II will be a single dose level selected based on pharmacodynamics and safety from Stage I for 20 additional subjects using 4:1 randomization.<br>|
| Experimental: C<br>nikkomycin Z 500 mg BID versus placebo BID x 14 days | Drug: nikkomycin Z<br>* Stage I: Multiple rising doses. Doses packaged on a unit dose basis in 50 and 250 mg capsules. Subjects take 1-3 capsules per dosing block for 14 days unless ADE or study withdrawal. Dose escalation unless a dose-limiting adverse effect is noted. Subjects assigned to BID dosing will receive 28 doses and subjects assigned to TID dosing will receive 42 doses. 50 mg BID (n=8) vs placebo capsule BID (n=2) 250 mg BID (n=8) vs Placebo capsule BID (n=2) 500 mg BID (n=8) vs Placebo capsule BID (n=2) 750 mg TID (n=8) vs Placebo capsule TID (n=2) At least 4 subjects complete lower dose before randomization includes next higher dose, thus there are 4 arms for active intervention and corresponding placebos. Stage II will be a single dose level selected based on pharmacodynamics and safety from Stage I for 20 additional subjects using 4:1 randomization.<br>|
| Experimental: D<br>nikkomycin Z 750 mg TID versus placebo TID x 14 days | Drug: nikkomycin Z<br>* Stage I: Multiple rising doses. Doses packaged on a unit dose basis in 50 and 250 mg capsules. Subjects take 1-3 capsules per dosing block for 14 days unless ADE or study withdrawal. Dose escalation unless a dose-limiting adverse effect is noted. Subjects assigned to BID dosing will receive 28 doses and subjects assigned to TID dosing will receive 42 doses. 50 mg BID (n=8) vs placebo capsule BID (n=2) 250 mg BID (n=8) vs Placebo capsule BID (n=2) 500 mg BID (n=8) vs Placebo capsule BID (n=2) 750 mg TID (n=8) vs Placebo capsule TID (n=2) At least 4 subjects complete lower dose before randomization includes next higher dose, thus there are 4 arms for active intervention and corresponding placebos. Stage II will be a single dose level selected based on pharmacodynamics and safety from Stage I for 20 additional subjects using 4:1 randomization.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine safety and tolerance of nikkomycin Z in relatively healthy subjects following administration of multiple doses. |  | four weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the multiple dose pharmacokinetics of nikkomycin Z in patients with uncomplicated coccidioidal pneumonia |  | 2 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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coccidioidomycosis, Valley Fever, nikkomycin Z