Inhaled Vancomycin Tolerability, Safety and Pharmacokinetics

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy; Cystic Fibrosis
• Intervention / Treatment: Drug: AeroVanc; Drug: IV vancomycin hydrochloride

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.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Queensland
    • Brisbane, Queensland, Australia, 4101
      • Mater Adult Hospital
  • Western Australia
    • Perth, Western Australia, Australia, 6009
      • Linear Clinical Research Ltd.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria Healthy Volunteers:

1. Healthy male volunteers between 18 and 50 years of age inclusive.
2. Able to communicate with site personnel and to understand and voluntarily sign the Informed Consent Form.
3. Able and willing to comply with the Protocol, including availability for all scheduled study visits.
4. Body Mass Index (BMI) of 20 to 30 kg/m2 inclusive, and weight between 60-90 kg inclusive.
5. 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.
6. Negative human immunodeficiency virus (HIV) and Hepatitis B and Hepatitis C screening test results.
7. Spirometry (forced expiratory volume in 1 second (FEV1)) value at screening greater than 75% of predicted age-adjusted value.

Exclusion Criteria Healthy Volunteers:

1. A history of pulmonary or other disorder likely to influence drug absorption.
2. Evidence or suspicion of clinically significant respiratory, renal, hepatic, central nervous system, cardiovascular or metabolic dysfunction.
3. A history of previous allergies or sensitivity to vancomycin, or other component(s) of the study drug or reference drug.
4. Smokers (ex-smokers who quit smoking must have a one year period of not smoking prior to the study drug administration).
5. Respiratory tract infection within the last two weeks prior to the first study drug administration.
6. Treatment with any prescription medication and/or over-the-counter (OTC) products including vitamins or mineral supplements within 48 hours before Investigational Product administration.
7. Vaccination within one month before the study drug administration.
8. Systolic blood pressure <110 mmHg or >150 mmHg inclusive or diastolic blood pressure <60 mmHg or >90 mmHg inclusive.
9. A history of drug or alcohol abuse.
10. Participation in a clinical study within three months on Investigational Product administration.
11. Donation of blood or plasma within three months of Investigational Product administration.
12. 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:

1. Able to communicate with site personnel and to understand and voluntarily sign the Informed Consent Form.
2. Able and willing to comply with the protocol, including availability for all scheduled study visits.
3. 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).
4. Be aged ≥ 18 years old
5. Have FEV1 >40 % of predicted
6. Be able to perform all the techniques necessary to measure lung function
7. No liver enzymes increased by more than twice the upper limit of normal
8. Ability to spontaneously produce bronchial sputum daily

Inclusion Criteria CF Patients:

1. Administration of any investigational drug or device within 28 days of Screening and within six half-lives of the investigational drug.
2. Oral corticosteroids in doses exceeding 10 mg per day or 16 mg every other day.
3. History of sputum culture or throat swab culture yielding B. cepacia in the previous two years.
4. History of positive MRSA culture, or sputum culture positive for MRSA at screening.
5. Current daily continuous oxygen supplementation or requirement for more than 2 L/min at night.
6. A history of previous allergies or sensitivity to vancomycin, or other component(s) of the study drug.
7. Changes in antimicrobial, bronchodilator, anti-inflammatory or corticosteroid medications within 7 days prior to Screening.
8. Changes in physiotherapy technique or schedule within 7 days prior to Screening.
9. History of lung transplantation.
10. 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).
11. Positive pregnancy test. All women of childbearing potential will be tested.
12. 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).
13. Findings at Screening that, in the investigator's opinion, would compromise the safety of the subject or the quality of the study data.
14. History of severe cough/bronchospasm upon inhalation of dry powder inhalation product.
15. Considered "terminally ill" or eligible for lung transplantation.
16. Have had a significant episode of hemoptysis (>60 mL) in the three months prior to enrolment.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

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

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

Collaborators and Investigators

• Sponsor: Savara Inc.
• Collaborators: INC Research Limited

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (Actual): March 1, 2012
• Study Completion (Actual): March 1, 2012

Study Registration Dates

• First Submitted: February 17, 2012
• First Submitted That Met QC Criteria: February 17, 2012
• First Posted (Estimate): February 23, 2012

Study Record Updates

• Last Update Posted (Estimate): March 31, 2014
• Last Update Submitted That Met QC Criteria: March 3, 2014
• Last Verified: March 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Cystic Fibrosis; Anti-Infective Agents; Anti-Bacterial Agents; Vancomycin
• Other Study ID Numbers: SAV005-01