Clinical trial NCT01746095: Efficacy and Safety Study of AeroVanc for the Treatment of Persistent MRSA Lung Infection in Cystic Fibrosis Patients
Official title: A Phase 2, Randomized, Double Blind, Placebo-controlled Study of AeroVanc for the Treatment of Persistent Methicillin-resistant Staphylococcus Aureus Lung Infection in Cystic Fibrosis Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cystic Fibrosis
Keywords: Cystic Fibrosis
MRSA
Methicillin-resistant Staphylococcus aureus
Lung infection
AeroVanc
Vancomycin
Lead sponsor: Savara Inc.
Sponsor class: INDUSTRY
Collaborators: name: Synteract, Inc.
name: Cystic Fibrosis Foundation
First posted: 2012-12-10
Enrollment: 87
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether AeroVanc treatment is safe and effective in reducing the number of MRSA colony forming units in the lungs of cystic fibrosis patients.

Detailed description: This is a Phase 2a randomized, multicenter, double-blind, placebo-controlled, parallel group study to examine the safety and efficacy of AeroVanc in the treatment of persistent MRSA lung infection in CF patients. Pharmacokinetics will be evaluated in a subgroup by measuring plasma and sputum concentrations of vancomycin.

Prior to treatment, patients will be randomized to receive either AeroVanc twice daily (bid), or placebo bid. Patients will be stratified based on the presence of a Pseudomonas aeruginosa (P. aeruginosa) co-infection that is being treated with a chronic suppression regimen. Patients with P. aeruginosa co-infection can be on any chronic inhaled suppression regimen (or nothing if the patient is considered stable in the opinion of the investigator despite the lack of treatment). Regardless of treatment regimen, if there is an off month, screening should be scheduled so that AeroVanc or placebo administration can be given during this time. Patients with no off month should be screened so that the AeroVanc or placebo administration period coincides with a treatment cycle other than TOBI (e.g., Cayston or colistin). All patients must have at least a 24-hour washout period after stopping their anti-Pseudomonas therapy and prior to the Visit 2 (Baseline) pre-dose microbiology sputum sample. The AeroVanc or placebo treatment duration is 28 days, during which efficacy and safety parameters will be measured, and after which patients will be followed up for 56 days.

There will be two treatment cohorts in this study, each comprised of 40 randomized (1:1 active to placebo) and treated patients (adults ≥18 and children ≥12 years of age). In Cohort 1, patients will be enrolled and randomized to receive the 32 mg dose of AeroVanc bid or placebo bid. Prior to starting enrollment in Cohort 2, a safety evaluation will be carried out by the Data Monitoring Committee (DMC) based on treatment data from the first 20 patients in Cohort 1. Subject to the Sponsor's written communication of the DMC's opinion of acceptable safety, the dose for the active arm in Cohort 2 will be escalated to 64 mg bid. Optionally, the active arm for Cohort 2 may also be kept the same (32 mg bid), or reduced to 16 mg bid, depending on the outcome of the DMC's safety evaluation.

Eligibility criteria: Inclusion Criteria:

1. Adults ≥18 years old (and the legally authorized representatives of children ≥12 but \<18 years old): Able to communicate with site personnel and to understand and voluntarily sign the Informed Consent Form (ICF). Children ≥12 but \<18 years old: Able to communicate with site personnel and to understand and voluntarily sign the Assent Form.
2. Able and willing to comply with the protocol, including availability for all scheduled study visits.
3. Have a confirmed diagnosis of CF, determined by having clinical features consistent with the CF phenotype, plus one of the following: a) Positive sweat chloride test (value ≥60 mEq/L), or b) Genotype with two mutations consistent with CF (ie, a mutation in each of the cystic fibrosis transmembrane conductance regulator \[CFTR\] genes).
4. Be ≥12 years old at time of ICF/Assent Form signing.
5. Have sputum culture positive for MRSA at Screening, with at least 10,000 CFUs/mL of MRSA.
6. In addition to the screening sample, have at least two historical respiratory tract cultures (i.e., sputum and/or throat swab) positive for MRSA prior to Screening and evidence that the MRSA lung infection has persisted for at least 6 months prior to Screening.
7. Have forced expiratory volume in 1 second (FEV1) ≥30% and ≤100% of predicted that is normalized for age, gender, and height at Screening.
8. Evidence, defined as one or both of the following, that the persistent MRSA lung infection is suspected to be causing health consequences.

   * Have had at least one episode of acute pulmonary infection treated with non-maintenance antibiotics within 12 months from Screening. Initiation of treatment with intermittent inhaled anti-Pseudomonas therapy will not qualify as treatment with non-maintenance antibiotics.
   * Requires anti-MRSA treatment as part of a maintenance regimen to prevent pulmonary exacerbations or other respiratory symptoms.
9. Be able to perform all the techniques necessary to use the AeroVanc inhaler and measure lung function.
10. Be able to produce expectorated sputum samples or be able and willing to undergo standardized sputum induction.
11. Agree not to smoke from Screening through the end of the study.
12. Female patients of child-bearing potential are eligible to participate in this study only if they are NOT pregnant or lactating, and if the patient is using a highly effective method of birth control.
13. Patients with P. aeruginosa co-infection must either be stable on a regular suppression regimen of inhaled antibiotics or must be, in the opinion of the investigator, stable despite the lack of such treatment. Patients on a Cayston based therapy must have received at least 2 cycles of Cayston prior to Baseline (can be 2 consecutive months or 2 cycles over 4 months).

Exclusion Criteria:

1. Administration of any investigational drug or device within 28 days prior to ICF/Assent Form signing.
2. Use of iv or inhaled anti-MRSA drugs within 28 days or oral anti-MRSA drugs within 14 days prior to Visit 2 (ie, randomization, Baseline and AeroVanc/placebo treatment initiation).
3. A history of previous allergies or sensitivity to vancomycin, or other component(s) of the study drug or placebo except for a history of red-man syndrome.
4. History of severe cough/bronchospasm upon inhalation of dry powder inhalation product, or nebulized vancomycin.
5. Resistance to vancomycin at Screening (vancomycin resistant Staphylococcus aureus \[VRSA\], or vancomycin intermediate resistant Staphylococcus aureus \[VISA\], with minimum inhibitory concentration \[MIC\] ≥4 mcg/mL).
6. Oral corticosteroids in doses exceeding 10 mg prednisone per day or 20 mg prednisone every other day, or equipotent doses of another corticosteroid.
7. History of sputum culture or throat swab culture yielding B. cepacia or gladioli in the previous two years, or nontuberculosis mycobacteria in the previous six months.
8. An acute upper or lower respiratory infection, or pulmonary exacerbation within 7 days prior to Randomization.
9. Changes in antimicrobial, bronchodilator, anti-inflammatory or corticosteroid medications within 7 days prior to ICF/Assent Form signing.
10. Current daily continuous oxygen supplementation or requirement for more than 2 L/min at night.
11. Changes in physiotherapy technique or schedule within 7 days prior to ICF/Assent Form signing.
12. History of lung or other solid organ transplantation or currently on the list to receive lung or other solid organ transplantation.
13. A chest X-Ray at Screening with abnormalities indicating a significant acute finding (eg, pneumothorax, or pleural effusion).
14. Lactating female or female with a positive pregnancy test result. All women of childbearing potential will be tested.
15. Renal insufficiency, defined as creatinine clearance \<50 mL/min using the Cockcroft-Gault equation for adults or Schwartz equation in children, at Screening.
16. Diagnosed with clinically significant hearing loss.
17. Abnormal liver function, defined as ≥4x upper limit of normal (ULN), of serum aspartate aminotransferase (AST) or serum alanine aminotransferase (ALT), or known cirrhosis at the time of Screening.
18. Serum hematology or chemistry screening results which in the judgment of the Investigator would interfere with completion of the study.
19. Positive for human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV).
20. Other findings or medical history at screening that, in the Investigator's opinion, would compromise the safety of the patient or the quality of the study data.

Primary outcomes:
measure: Change From Baseline in MRSA Sputum Density.
timeFrame: Day 29 of treatment period
Secondary outcomes:
measure: Change From Baseline in MRSA Sputum Density.
timeFrame: Day 8 of treatment period
measure: Change From Baseline in MRSA Sputum Density.
timeFrame: Day 15 of treatment period
measure: Change From Baseline in FEV1
timeFrame: Day 29 of treatment period
measure: Change From Baseline in FVC
timeFrame: Day 29 of treatment period
measure: Change From Baseline in Cystic Fibrosis Respiratory Symptom Diary (CFRSD-CRISS) Scores
timeFrame: Day 29 of treatment period
measure: Time From Start of Dosing to First Administration of Other Antimicrobial Medications (Oral, Intravenous and/or Inhaled) Due to Respiratory Symptoms.
timeFrame: Entire study: Day 1 of treatment period through 8 week post-treatment follow up visit
measure: Time From Start of Dosing to Exacerbation of Signs/Symptoms (Fuchs Criteria).
timeFrame: Entire study: Day 1 of treatment period through 8 week post-treatment follow up visit
measure: Change From Baseline in High Sensitivity CRP
timeFrame: Day 29 of the dosing period
measure: Change From Baseline in Blood Neutrophils
timeFrame: Day 29 of the dosing period
Other outcomes:
Locations:
city: Mobile
country: United States
facility: Pulmonary Associates of Mobile
state: Alabama
city: Little Rock
country: United States
facility: University of Arkansas for Medical Science
state: Arkansas
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles, Division of Pediatric Pulmonology
state: California
city: Denver
country: United States
facility: National Jewish Health
state: Colorado
city: Hollywood
country: United States
facility: Joe DiMaggio Children's Hospital
state: Florida
city: Miami
country: United States
facility: University of Miami - Miller School of Medicine
state: Florida
city: Orlando
country: United States
facility: Central Florida Pulmonary Group
state: Florida
city: Orlando
country: United States
facility: Nemours Children's Clinic and Hospital
state: Florida
city: Tampa
country: United States
facility: New Lung Associates, PA; Lung Transplant, Adult Cystic Fibrosis, and the Center for Advanced Lung Diseases, Tampa General Hospital
state: Florida
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine
state: Illinois
city: Glenview
country: United States
facility: The Cystic Fibrosis Center of Chicago
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky Cystic Fibrosis Clinic
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Boston
country: United States
facility: Massachusetts General Hospital Pediatric Cystic Fibrosis Center
state: Massachusetts
city: Boston
country: United States
facility: Boston Children's Hospital Cystic Fibrosis Center
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University, Harper Hospital, Children's Hospital of Michigan
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New Brunswick
country: United States
facility: Rutgers Robert Wood Johnson Medical School
state: New Jersey
city: New Hyde Park
country: United States
facility: Hofstra North Shore - Long Island Jewish School of Medicine
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Rainbow Babies and Children's Hospital / University Hospitals Case Medical Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Dayton
country: United States
facility: The Children's Medical Center of Dayton
state: Ohio
city: Oklahoma City
country: United States
facility: Santiago Reyes, MD
state: Oklahoma
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Austin
country: United States
facility: Dell Children's Medical Center of Central Texas
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine and Texas Children's Hospital
state: Texas
city: Tyler
country: United States
facility: University of Texas Health Science Center at Tyler
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah, Intermountain Cystic Fibrosis Center
state: Utah
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
Study officials:
affiliation: Case Western Reserve University School of Medicine and Rainbow Babies and Children's Hospital
name: Elliott Dasenbrook, M.D., MHS
role: PRINCIPAL_INVESTIGATOR
References: