Coccidioidomycosis
Conditions
Keywords
coccidioidomycosis, Valley Fever, nikkomycin Z
Brief summary
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
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.
Interventions
DRUGnikkomycin Z
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=4) vs placebo capsule BID (n=1) * 50 mg BID (n=4) vs 250 mg BID (n=4) vs Placebo capsule BID (n=2) * 250 mg BID (n=4) vs 500 mg BID (n=4) vs Placebo capsule BID (n=2) * 500 mg BID (n=4) vs Placebo capsule BID (n=1) At least 4 subjects complete lower dose before randomization includes next higher dose. 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.
DRUGPlacebo
Placebo comparator
Sponsors
FDA Office of Orphan Products Development
University of Arizona
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
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 prior 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Concentration of Nikkomycin Z in the Blood Over Time (AUC) | 0, 0.25, 0.5, 0.75, 1.0, 1.5, 2 , 3, 4, 6, 8 and 12 h hours post-dose on Day 1 and Day 14 |
| Highest Concentration of Nikkomycin Z in the Blood (Cmax) | 0, 0.25, 0.5, 0.75, 1.0, 1.5, 2 , 3, 4, 6, 8 and 12 h hours post-dose on Day 1 and Day 14 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| A - First Dose Level (n=5) nikkomycin Z 50 mg BID x 14 days
nikkomycin Z: 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=4) vs placebo capsule BID (n=1)
* 50 mg BID (n=4) vs 250 mg BID (n=4) vs Placebo capsule BID (n=2)
* 250 mg BID (n=4) vs 500 mg BID (n=4) vs Placebo capsule BID (n=2)
* 500 mg BID (n=4) vs Placebo capsule BID (n=1)
At least 4 subjects complete lower dose before randomization includes next higher dose.
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. | 4 |
| B - Second Dose Level (n=10) nikkomycin Z nikkomycin Z 250 mg BID x 14 days
nikkomycin Z: 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=4) vs placebo capsule BID (n=1)
* 50 mg BID (n=4) vs 250 mg BID (n=4) vs Placebo capsule BID (n=2)
* 250 mg BID (n=4) vs 500 mg BID (n=4) vs Placebo capsule BID (n=2)
* 500 mg BID (n=4) vs Placebo capsule BID (n=1)
At least 4 subjects complete lower dose before randomization includes next higher dose.
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. | 1 |
| C - Third Dose Level (n=10) nikkomycin Z 500 mg BID x 14 days
nikkomycin Z: 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=4) vs placebo capsule BID (n=1)
* 50 mg BID (n=4) vs 250 mg BID (n=4) vs Placebo capsule BID (n=2)
* 250 mg BID (n=4) vs 500 mg BID (n=4) vs Placebo capsule BID (n=2)
* 500 mg BID (n=4) vs Placebo capsule BID (n=1)
At least 4 subjects complete lower dose before randomization includes next higher dose.
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. | 0 |
| D - Fourth Dose Level (n=5) nikkomycin Z 750 BID x 14 days
nikkomycin Z: 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=4) vs placebo capsule BID (n=1)
* 50 mg BID (n=4) vs 250 mg BID (n=4) vs Placebo capsule BID (n=2)
* 250 mg BID (n=4) vs 500 mg BID (n=4) vs Placebo capsule BID (n=2)
* 500 mg BID (n=4) vs Placebo capsule BID (n=1)
At least 4 subjects complete lower dose before randomization includes next higher dose.
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. | 0 |
| Placebo placebo BID x 14 days
Placebo: Placebo comparator | 1 |
| Total | 6 |
Baseline characteristics
| Characteristic | A - First Dose Level (n=5) | B - Second Dose Level (n=10) | C - Third Dose Level (n=10) | D - Fourth Dose Level (n=5) | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 6 Participants |
| Region of Enrollment United States | 4 participants | 1 participants | — | — | 1 participants | 6 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 1 | 0 / 0 | 0 / 0 | 0 / 1 |
| other Total, other adverse events | 3 / 4 | 1 / 1 | 0 / 0 | 0 / 0 | 1 / 1 |
| serious Total, serious adverse events | 0 / 4 | 0 / 1 | 0 / 0 | 0 / 0 | 0 / 1 |
Outcome results
Primary
Concentration of Nikkomycin Z in the Blood Over Time (AUC)
Time frame: 0, 0.25, 0.5, 0.75, 1.0, 1.5, 2 , 3, 4, 6, 8 and 12 h hours post-dose on Day 1 and Day 14
Population: The study was terminated after enrollment of 6 subjects
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| A - First Dose Level (n=5) | Concentration of Nikkomycin Z in the Blood Over Time (AUC) | Day 1 | 3.444 mg*hr/L | Standard Deviation 0.71 |
| A - First Dose Level (n=5) | Concentration of Nikkomycin Z in the Blood Over Time (AUC) | Day 14 | 3.900 mg*hr/L | Standard Deviation 1.583 |
| B - Second Dose Level (n=10) | Concentration of Nikkomycin Z in the Blood Over Time (AUC) | Day 1 | 19.923 mg*hr/L | — |
| B - Second Dose Level (n=10) | Concentration of Nikkomycin Z in the Blood Over Time (AUC) | Day 14 | 24.045 mg*hr/L | — |
Primary
Highest Concentration of Nikkomycin Z in the Blood (Cmax)
Time frame: 0, 0.25, 0.5, 0.75, 1.0, 1.5, 2 , 3, 4, 6, 8 and 12 h hours post-dose on Day 1 and Day 14
Population: The study was terminated after enrollment of 6 subjects
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| A - First Dose Level (n=5) | Highest Concentration of Nikkomycin Z in the Blood (Cmax) | Day 14 | 0.811 mg/L | Standard Deviation 0.248 |
| A - First Dose Level (n=5) | Highest Concentration of Nikkomycin Z in the Blood (Cmax) | Day 1 | 0.710 mg/L | Standard Deviation 0.188 |
| B - Second Dose Level (n=10) | Highest Concentration of Nikkomycin Z in the Blood (Cmax) | Day 1 | 3.748 mg/L | — |
| B - Second Dose Level (n=10) | Highest Concentration of Nikkomycin Z in the Blood (Cmax) | Day 14 | 4.275 mg/L | — |