Clinical trial NCT01537666: Inhaled Vancomycin Tolerability, Safety and Pharmacokinetics
Official title: Phase I, Reference-controlled, Dose Escalating Study to Examine the Pharmacokinetics and Safety of AeroVanc Inhalation Powder.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Cystic Fibrosis
Lead sponsor: Savara Inc.
Sponsor class: INDUSTRY
Collaborators: name: INC Research Limited
First posted: 2012-02-23
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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)
timeFrame: Healthy volunteers = 2 weeks; CF Patients = 1 week
Secondary outcomes:
measure: Plasma Pharmacokinetics - Elimination Half Life (t½)
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose
measure: Plasma Pharmacokinetics - Time to Reach the Maximum Plasma Concentration (Tmax)
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose
measure: Plasma Pharmacokinetics - Maximum Plasma Concentration (Cmax)
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose
measure: Plasma Pharmacokinetics - Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUCt)
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose
measure: Plasma Pharmacokinetics - Area Under the Plasma Concentration-time Curve From Time 0 to Infinite Time (AUCinf)
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose
measure: Lung Pharmacokinetics - Maximum Sputum Concentration (Cmax)
timeFrame: 1, 8 and 24 hours post-dose
measure: Lung Pharmacokinetics - Minimum Sputum Concentration (Cmin)
timeFrame: 1, 8 and 24 hours post-dose
Other outcomes:
Locations:
city: Brisbane
country: Australia
facility: Mater Adult Hospital
state: Queensland
city: Perth
country: Australia
facility: Linear Clinical Research Ltd.
state: Western Australia
Study officials:
References: