Safety and PK of Nikkomycin Z in Healthy Subjects

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. Healthy patients will be eligible to participate and will be allocated to receive nikkomycin Z (various doses) or a placebo.

Detailed Description
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This protocol will serve as a Phase I, randomized, double-blind, placebo controlled, multiple-dose study to evaluate the safety, tolerance and pharmacokinetics of nikkomycin Z. Nikkomycin Z has previously been studied in a single dose protocol in healthy male subjects. This study is designed to run in parallel to protocol VFCE-2007-001 to provide additional data on safety and pharmacokinetics. The study will involve a total of 32 subjects (6 active/2 placebo per group) with a multiple, rising dose strategy.

Official Title
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Phase I, Randomized, Double-blind, Placebo Controlled, Multiple-dose Evaluation of the Safety Tolerance and Pharmacokinetics of Nikkomycin Z in Healthy Subjects

Conditions
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Healthy

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 <= 40 years Male or Female (if female, must have a negative pregnancy test and agrees to use an acceptable contraception method) Able to understand study and give written informed consent Be determined healthy based on a medical and laboratory evaluation Exclusion Criteria: Patients under the age of 18 years or over 40 years Inability to comprehend study and provide written informed consent Inability to comply with the study requirements History of or current evidence of major organ disease including: Renal disease - serum creatinine > 1.5 mg/dL, significant hematuria or proteinuria, known structural abnormality or chronic kidney disease Hepatic disease - active viral hepatitis, history of hepatitis B or hepatitis C, bilirubin > 2.0, ALT or AST above normal upper limit for laboratory, alcoholic liver disease, other chronic liver disease CNS disease or cognitive dysfunction - any past history of epilepsy, CNS infections, stroke, CNS bleed, severe headaches, major psychiatric illness, or current mental status changes Lung disease - history of severe asthma, COPD, pulmonary tuberculosis, or other major lung disease Cardiac disease - history or current evidence of ischemic coronary artery disease, myocardial infarction, heart failure, significant arrhythmia Gastrointestinal disease - presence of inflammatory bowel disease, difficulty swallowing, or any gastrointestinal problem that would limit taking oral medications or that may compromise absorption of oral medications Cancer - History of hematologic malignancy or solid tumor excluding basal cell carcinoma limited to the skin within the past 5 years History of autoimmune or inflammatory disease such as rheumatoid arthritis and lupus Any other history or evidence of disease that in the opinion of the physician would increase the risk for the subject for clinical trial participation Immunocompromised state - solid organ transplant, cancer chemotherapy, BMT with graft versus host disease, immunosuppressive therapy, or HIV infection Recent weight loss of greater than 10% Regular use of prescription medications, over-the-counter medications, or dietary/herbal supplements within 14 days of day 1. Occasional use of acetaminophen or over-the-counter NSAID within the 14 day window may be allowed at the P.I.'s discretion Subjects who received another investigational drug within 30 days of enrollment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>nikkomycin Z 250 mg BID versus placebo BID x 14 days | Drug: nikkomycin Z<br>* Multiple rising doses. Doses packaged on a unit dose basis in 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. 250 mg BID (n=6) vs Placebo capsule BID (n=2), 500 mg BID (n=6) vs Placebo capsule BID (n=2), 750 mg BID (n=6) vs Placebo capsule BID (n=2), 750 mg TID (n=6) 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.<br>|
| Experimental: B<br>nikkomycin Z 500 mg BID versus placebo BID x 14 days | Drug: nikkomycin Z<br>* Multiple rising doses. Doses packaged on a unit dose basis in 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. 250 mg BID (n=6) vs Placebo capsule BID (n=2), 500 mg BID (n=6) vs Placebo capsule BID (n=2), 750 mg BID (n=6) vs Placebo capsule BID (n=2), 750 mg TID (n=6) 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.<br>|
| Experimental: C<br>nikkomycin Z 750 mg BID versus placebo BID x 14 days | Drug: nikkomycin Z<br>* Multiple rising doses. Doses packaged on a unit dose basis in 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. 250 mg BID (n=6) vs Placebo capsule BID (n=2), 500 mg BID (n=6) vs Placebo capsule BID (n=2), 750 mg BID (n=6) vs Placebo capsule BID (n=2), 750 mg TID (n=6) 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.<br>|
| Experimental: D<br>nikkomycin Z 750 mg TID versus placebo TID x 14 days | Drug: nikkomycin Z<br>* Multiple rising doses. Doses packaged on a unit dose basis in 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. 250 mg BID (n=6) vs Placebo capsule BID (n=2), 500 mg BID (n=6) vs Placebo capsule BID (n=2), 750 mg BID (n=6) vs Placebo capsule BID (n=2), 750 mg TID (n=6) 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.<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 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 healthy subjects |  | two weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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nikkomycin Z, pharmacokinetics, toxicity