Open-Label Phase 1 Study of Aerosolized Amikacin and Fosfomycin in Healthy Volunteers

Study Overview
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Brief Summary
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This study will evaluate systemic and urine pharmacokinetics in spontaneously breathing healthy volunteers following a single dose of amikacin/fosfomycin, using the PARI Investigational eFlow Nebulizer System or the PARI LC Sprint Nebulizer. Three doses (30/12 mg, 60/24 mg, 90/36 mg amikacin/fosfomycin) will be evaluated. Following this evaluation, a single dose and nebulizer will be chosen to further evaluate systemic, bronchoalveolar, and urine pharmacokinetics in spontaneously breathing healthy volunteers.

Detailed Description
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This is a Phase 1 open-label study of three doses of amikacin/fosfomycin. Approximately 30 healthy volunteers will be dosed in five cohorts of six subjects each. The first (sentinel) subject in each of the first three cohorts will be dosed alone. If no significant safety or tolerability events occur, the remaining five subjects in each of the first three cohorts will be dosed. The first cohort (n=6) will be administered the 30/12 mg dose of amikacin/fosfomycin. The second cohort (n=6) will be administered the 60/24 mg dose of amikacin/fosfomycin. The third cohort (n=6) will be administered the 90/36 mg dose of amikacin/fosfomycin. All doses in cohorts 1, 2, and 3 will be delivered with the PARI Investigational eFlow Nebulizer System. The fourth cohort (n=6) will be administered the 90/36 mg dose of amikacin/fosfomycin using the PARI LC Sprint Nebulizer. The fifth cohort (n=6) will test the lowest dose level at which all subjects achieved > 0.3 µg/mL amikacin peak serum concentration. The nebulizer used to deliver doses in cohort 5 will be determined after amikacin concentrations from cohorts 1 through 4 are reviewed.

Official Title
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An Open-Label Phase 1 Study of Aerosolized Amikacin and Fosfomycin Delivered Via the PARI Investigational eFlow Nebulizer System or the PARI LC Sprint Nebulizer in Healthy Volunteers

Conditions
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Healthy

Intervention / Treatment
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* Drug: amikacin/fosfomycin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females aged ≥18 years and ≤ 80 years of age (Cohorts 1, 2, 3, and 4). Males or females aged ≥ 18 years and ≤ 65 years of age (Cohort 5). Females of childbearing potential must be using contraception. Acceptable methods of contraception include male or female condom with spermicide gel or foam, hormonal contraceptive combined with a condom, Intrauterine Device (IUD), tubal ligation, diaphragm with spermicide, or total abstinence with a back-up if the subject becomes active. Able to communicate with site personnel and to understand and voluntarily sign the Informed Consent Form. Exclusion Criteria: History of previous allergy or sensitivity to amikacin or fosfomycin. Use of oral fosfomycin in the 28 days prior to admission to Phase 1 facility. History of reactive airways disease (such as asthma or chronic obstructive pulmonary disease [COPD]), cystic fibrosis, or bronchiectasis. Human Immunodeficiency Virus (HIV) positive. Active Hepatitis B or C. Cigarette/e-Cigarette smoking or use of other nicotine or tobacco containing products within seven days prior to study drug administration. Positive for drugs of abuse or alcohol use at screening or admission to Phase 1 facility. A Breathalyzer test will be used to screen for the presence of alcohol. A urine standard panel will be used to test for the following substances (with serum testing for confirmation, as needed): Opiates Oxycodone Methadone Cocaine Tetrahydrocannabinol (THC) Benzodiazepines Amphetamines / Methamphetamines Barbiturates Methylenedioxy-methamphetamine (MDMA) Phenylcyclohexyl piperidine (PCP) Tricyclic Antidepressants Participation in a clinical study with administration of an investigational drug product within the previous 30 days, or five half-lives of the previously administered investigational product. Donation of blood or significant blood loss within the 8 weeks prior to admission to Phase 1 facility. Donation of plasma within the week prior to admission to Phase 1 facility. Any other condition which in the view of the Investigator is likely to interfere with the study or put the subject at risk. Pregnant or nursing.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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

Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>amikacin/fosfomycin (30/12 mg) delivered via the PARI Investigational eFlow Nebulizer (single dose) | Drug: amikacin/fosfomycin<br>* single aerosolized dose<br>|
| Experimental: Cohort 2<br>amikacin/fosfomycin (60/24 mg) delivered via the PARI Investigational eFlow Nebulizer (single dose) | Drug: amikacin/fosfomycin<br>* single aerosolized dose<br>|
| Experimental: Cohort 3<br>amikacin/fosfomycin (90/36 mg) delivered via the PARI Investigational eFlow Nebulizer (single dose) | Drug: amikacin/fosfomycin<br>* single aerosolized dose<br>|
| Experimental: Cohort 4<br>amikacin/fosfomycin (90/36 mg) delivered via the PARI LC Sprint Nebulizer (single dose) | Drug: amikacin/fosfomycin<br>* single aerosolized dose<br>|
| Experimental: Cohort 5<br>amikacin/fosfomycin (Dose and Nebulizer to be chosen based on results from Cohorts 1 - 4) | Drug: amikacin/fosfomycin<br>* single aerosolized dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak plasma concentration (Cmax) of nebulized amikacin/fosfomycin following delivery of 30/12 mg, 60/24 mg, and 90/36 mg amikacin/fosfomycin via the PARI Investigational eFlow Nebulizer System |  | 10 minutes to 24 hours post-dose | 
| Peak plasma concentration (Cmax) of nebulized amikacin/fosfomycin following delivery of 30/12 mg, 60/24 mg, and 90/36 mg amikacin/fosfomycin via the PARI LC Sprint Nebulizer |  | 10 minutes to 24 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to peak plasma concentration (Tmax) of nebulized amikacin/fosfomycin following delivery of 30/12 mg, 60/24 mg, and 90/36 mg amikacin/fosfomycin via the PARI Investigational eFlow Nebulizer System |  | 10 minutes to 24 hours post-dose | 
| Time to peak plasma concentration (Tmax) of nebulized amikacin/fosfomycin following delivery of 30/12 mg, 60/24 mg, and 90/36 mg amikacin/fosfomycin via the PARI LC Sprint Nebulizer |  | 10 minutes to 24 hours post-dose | 
| Plasma area under the concentration-time curve (AUC) of nebulized amikacin/fosfomycin following delivery of 30/12 mg, 60/24 mg, and 90/36 mg amikacin/fosfomycin via the PARI Investigational eFlow Nebulizer System |  | 10 minutes to 24 hours post-dose | 
| Plasma area under the concentration-time curve (AUC) of nebulized amikacin/fosfomycin following delivery of 30/12 mg, 60/24 mg, and 90/36 mg amikacin/fosfomycin via the PARI LC Sprint Nebulizer |  | 10 minutes to 24 hours post-dose | 
| Peak bronchoalveolar lavage concentration (Cmax) of amikacin/fosfomycin following delivery of nebulized 30/12 mg, 60/24 mg, or 90/36 mg amikacin/fosfomycin via the PARI Investigational eFlow Nebulizer System or the PARI LC Sprint Nebulizer | The dose and nebulizer used for Cohort 5 will be chosen based on plasma Cmax results from Cohorts 1 - 4. | 30 minutes post-dose |