Inhaled Vancomycin Tolerability, Safety and Pharmacokinetics

Study Overview
=================
Brief Summary
-----------------
The study is carried out to evaluate the safety, tolerability and pharmacokinetics of AeroVanc inhalation powder in healthy volunteers, and in patients with cystic fibrosis.

Detailed Description
-----------------
The study has three main objectives: To evaluate the safety, and tolerability of AeroVanc inhalation powder in healthy volunteers, and in patients with CF. To determine the systemic bioavailability of vancomycin in healthy volunteers following single dose pulmonary administration of 16 mg, 32 mg, and 80 mg doses of AeroVanc in comparison with a 250 mg dose of vancomycin administered intravenously. To estimate the lung sputum concentrations of vancomycin in patients with cystic fibrosis (CF) following single dose pulmonary administration of 32 mg and 80 mg doses of AeroVanc.

Official Title
-----------------
Phase I, Reference-controlled, Dose Escalating Study to Examine the Pharmacokinetics and Safety of AeroVanc Inhalation Powder.

Conditions
-----------------
Healthy, Cystic Fibrosis

Intervention / Treatment
-----------------
* Drug: AeroVanc
* Drug: IV vancomycin hydrochloride


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Healthy Volunteers: Healthy male volunteers between 18 and 50 years of age inclusive. Able to communicate with site personnel and to understand and voluntarily sign the Informed Consent Form. Able and willing to comply with the Protocol, including availability for all scheduled study visits. Body Mass Index (BMI) of 20 to 30 kg/m2 inclusive, and weight between 60-90 kg inclusive. No clinically significant abnormalities at screening determined by medical history, physical examination, blood chemistry, hematology, urinalysis, and 12-lead ECG. Negative urine screen for drugs of abuse and negative alcohol breath test at Screening and prior to dosing. Negative human immunodeficiency virus (HIV) and Hepatitis B and Hepatitis C screening test results. Spirometry (forced expiratory volume in 1 second (FEV1)) value at screening greater than 75% of predicted age-adjusted value. Exclusion Criteria Healthy Volunteers: A history of pulmonary or other disorder likely to influence drug absorption. Evidence or suspicion of clinically significant respiratory, renal, hepatic, central nervous system, cardiovascular or metabolic dysfunction. A history of previous allergies or sensitivity to vancomycin, or other component(s) of the study drug or reference drug. Smokers (ex-smokers who quit smoking must have a one year period of not smoking prior to the study drug administration). Respiratory tract infection within the last two weeks prior to the first study drug administration. Treatment with any prescription medication and/or over-the-counter (OTC) products including vitamins or mineral supplements within 48 hours before Investigational Product administration. Vaccination within one month before the study drug administration. Systolic blood pressure <110 mmHg or >150 mmHg inclusive or diastolic blood pressure <60 mmHg or >90 mmHg inclusive. A history of drug or alcohol abuse. Participation in a clinical study within three months on Investigational Product administration. Donation of blood or plasma within three months of Investigational Product administration. Any other condition which in the view of the Investigator is likely to interfere with the study or put the subject at risk. Inclusion Criteria CF Patients: Able to communicate with site personnel and to understand and voluntarily sign the Informed Consent Form. Able and willing to comply with the protocol, including availability for all scheduled study visits. Have a confirmed diagnosis of cystic fibrosis (by two established methods, e.g. positive sweat chloride value ≥ 60 mEq/L, nasal potential difference test, and/or genotype with two identifiable mutations consistent with CF, accompanied by one or more clinical features consistent with the CF phenotype). Be aged ≥ 18 years old Have FEV1 >40 % of predicted Be able to perform all the techniques necessary to measure lung function No liver enzymes increased by more than twice the upper limit of normal Ability to spontaneously produce bronchial sputum daily Inclusion Criteria CF Patients: Administration of any investigational drug or device within 28 days of Screening and within six half-lives of the investigational drug. Oral corticosteroids in doses exceeding 10 mg per day or 16 mg every other day. History of sputum culture or throat swab culture yielding B. cepacia in the previous two years. History of positive MRSA culture, or sputum culture positive for MRSA at screening. Current daily continuous oxygen supplementation or requirement for more than 2 L/min at night. A history of previous allergies or sensitivity to vancomycin, or other component(s) of the study drug. Changes in antimicrobial, bronchodilator, anti-inflammatory or corticosteroid medications within 7 days prior to Screening. Changes in physiotherapy technique or schedule within 7 days prior to Screening. History of lung transplantation. A chest X-Ray at Screening or within the previous 90 days of Screening, with abnormalities indicating a significant acute finding (e.g., lobar infiltrate and atelectasis, pneumothorax, or pleural effusion). Positive pregnancy test. All women of childbearing potential will be tested. Female of childbearing potential who is lactating or is not practicing acceptable method of birth control (e.g., hormonal or barrier methods, or intrauterine device). Findings at Screening that, in the investigator's opinion, would compromise the safety of the subject or the quality of the study data. History of severe cough/bronchospasm upon inhalation of dry powder inhalation product. Considered terminally ill or eligible for lung transplantation. Have had a significant episode of hemoptysis (>60 mL) in the three months prior to enrolment.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aerovanc 16 mg in healthy volunteers<br> | Drug: AeroVanc<br>* Vancomycin hydrochloride dry powder for inhalation<br>|
| Experimental: AeroVanc 32 mg in healthy volunteers<br> | Drug: AeroVanc<br>* Vancomycin hydrochloride dry powder for inhalation<br>|
| Experimental: AeroVanc 80 mg in healthy volunteers<br> | Drug: AeroVanc<br>* Vancomycin hydrochloride dry powder for inhalation<br>|
| Active Comparator: IV vancomycin in healthy volunteers<br> | Drug: IV vancomycin hydrochloride<br>* Vancomycin hydrochloride solution for intravenous administration<br>|
| Experimental: AeroVanc 32 mg in CF patients<br> | Drug: AeroVanc<br>* Vancomycin hydrochloride dry powder for inhalation<br>|
| Experimental: AeroVanc 80 mg in CF patients<br> | Drug: AeroVanc<br>* Vancomycin hydrochloride dry powder for inhalation<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability - Number of Participants With Treatment Emergent Adverse Events (TEAEs = Adverse Events That Started During or After the First Dose of Study Drug) | Each participant was monitored regularly for Adverse Events (AEs) throughout the study. The Investigator or designee enquired about AEs by asking participants non-leading questions such as: How do you feel? or Have you had any (other) medical problems since your last visit/assessment? Additionally, several safety procedures (physical examinations, vital signs, safety laboratory tests, 12-lead ECGs, and spirometry) were conducted on participants at regular intervals. All AEs reported spontaneously by participants or in response to questioning or observation by the Investigator, including those related to safety procedures, were recorded. For each AE, the Investigator recorded the following assessments: seriousness, severity (Mild, Moderate, or Severe), and relationship to study drug (Not Related, Remote, Possible, Probable, or Highly Probable). AEs were considered drug-related if given a relationship of Possible, Probable, or Highly Probable. | Healthy volunteers = 2 weeks; CF Patients = 1 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Pharmacokinetics - Elimination Half Life (t½) | Blood samples were obtained from the healthy volunteers to evaluate systemic pharmacokinetics of vancomycin after a single dose administration of AeroVanc or a single dose of IV vancomycin. Half-life is the time it takes for the concentration of drug to decline by 50%. | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose | 
| Plasma Pharmacokinetics - Time to Reach the Maximum Plasma Concentration (Tmax) | Blood samples were obtained from the healthy volunteers to evaluate systemic pharmacokinetics of vancomycin after a single dose administration of AeroVanc or a single dose of IV vancomycin. Tmax is the time it takes to reach the maximum plasma concentration of a drug. | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose | 
| Plasma Pharmacokinetics - Maximum Plasma Concentration (Cmax) | Blood samples were obtained from the healthy volunteers to evaluate systemic pharmacokinetics of vancomycin after a single dose administration of AeroVanc or a single dose of IV vancomycin. Cmax is the maximum observed concentration of a drug. | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose | 
| Plasma Pharmacokinetics - Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUCt) | Blood samples were obtained from the healthy volunteers to evaluate systemic pharmacokinetics of vancomycin after a single dose administration of AeroVanc or a single dose of IV vancomycin. AUCt is a way of expressing the total amount of drug exposure over a specified time period. | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose | 
| Plasma Pharmacokinetics - Area Under the Plasma Concentration-time Curve From Time 0 to Infinite Time (AUCinf) | Blood samples were obtained from the healthy volunteers to evaluate systemic pharmacokinetics of vancomycin after a single dose administration of AeroVanc or a single dose of IV vancomycin. AUCinf is a way of estimating the total amount of drug exposure over an infinite time period. | Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose | 
| Lung Pharmacokinetics - Maximum Sputum Concentration (Cmax) | Sputum samples were obtained from the patients with cystic fibrosis to evaluate lung pharmacokinetics of vancomycin after a single dose administration of AeroVanc. Cmax is the maximum observed concentration of a drug. | 1, 8 and 24 hours post-dose | 
| Lung Pharmacokinetics - Minimum Sputum Concentration (Cmin) | Sputum samples were obtained from the patients with cystic fibrosis to evaluate lung pharmacokinetics of vancomycin after a single dose administration of AeroVanc. Cmin is the minimum observed concentration of a drug. | 1, 8 and 24 hours post-dose |