AeroVanc in the Treatment of Methicillin-resistant Staphylococcus Aureus Infection in Patients With Cystic Fibrosis

A Phase III, Randomized, Double-blind, Placebo-controlled Study of AeroVanc for the Treatment of Persistent Methicillin-resistant Staphylococcus Aureus Lung Infection in Cystic Fibrosis Patients

This is a multi-center, randomized phase III study to evaluate the clinical effectiveness of AeroVanc in persistent methicillin-resistant Staphylococcus aureus (MRSA) infection in patients with cystic fibrosis (CF).

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis; MRSA
• Intervention / Treatment: Drug: Vancomycin inhalation powder; Drug: Vancomycin inhalation powder; Drug: Placebo inhalation powder

Detailed Description

This is a phase III, 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 patients diagnosed with CF. After the Screening period to confirm study eligibility, participants are randomly assigned in a blinded fashion to receive either AeroVanc 30 mg twice daily (BID), or placebo BID (1:1 active to placebo) by inhalation for 24 weeks or 3 dosing cycles (Period 1). Upon completion of Period 1, participants receive open-label AeroVanc 30 mg BID for an additional 24 weeks or 3 dosing cycles (Period 2), to evaluate long-term safety of AeroVanc. A dosing cycle is defined as 28 days of treatment followed by 28 days of observation.

Participants on a 28-day cyclical on/off anti-Pseudomonal antibiotic regimen enter the Screening period at a time such that the Baseline visit coincide with the end of their anti-Pseudomonas antibiotic cycle. Study drug is thereby administered during the off-cycle, and participants can then resume anti-Pseudomonal therapy during the 28-day observation period. Participants continuing alternating anti-Pseudomonal therapy can continue their treatment during the study drug administration, and observation period.

The primary and secondary analyses are conducted in participants ≤21 years old. Subjects >21 years old are analyzed separately as supportive analyses.

• Study Type: Interventional
• Enrollment (Actual): 188
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • British Columbia Children's Hospital
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • The Hospital for Sick Children
• United States
  • Alabama
    • Mobile, Alabama, United States, 36608
      • Pulmonary Associates of Mobile
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • California
    • Long Beach, California, United States, 90806
      • Miller Childrens Hospital MemorialCare Health System Pediatric Pulmonology
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Los Angeles, California, United States, 90033
      • University of Southern California Keck Medical Center of USC
    • Sacramento, California, United States, 95817
      • UC Davis Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Health Adult Cystic Fibrosis Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida Pediatrics
    • Hollywood, Florida, United States, 33021
      • Memorial Healthcare System
    • Jacksonville, Florida, United States, 32207
      • Nemours Childrens Specialty Care
    • Miami, Florida, United States, 33136
      • University of Miami Bachelor Children's Hospital
    • Orlando, Florida, United States, 32803
      • Central Florida Pulmonary Group
    • Orlando, Florida, United States, 32827
      • Nemours Children's Hospital
    • Orlando, Florida, United States, 32806
      • Arnold Palmer Hospital Pulmonary and Sleep Medical Institute Orlando Health, Inc
    • Pensacola, Florida, United States, 32514
      • Nemours Children's Specialty Care
    • Saint Petersburg, Florida, United States, 33701
      • Johns Hopkins All Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Children's Health Care of Atlanta at Scottish Rite
    • Augusta, Georgia, United States, 30912
      • Augusta Univ Cystic Fibrosis Center
  • Illinois
    • Glenview, Illinois, United States, 60025
      • Chicago CF Care Specialists
    • Morton Grove, Illinois, United States, 60053
      • NorthSurburban Pulmonary Specialists
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children at Indiana University Health
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Department of Pediatrics
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas
    • Wichita, Kansas, United States, 67214
      • Via Christi Health Systems CF Clinic
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville Kosair Charities Pediatric Clinical Research Unit
  • Maine
    • Portland, Maine, United States, 04102
      • Maine Medical Partners Pediatric Specialty Care
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
    • Detroit, Michigan, United States, 48201
      • Wayne State University (HUH)
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy
    • Saint Louis, Missouri, United States, 63110
      • Washington University
    • Saint Louis, Missouri, United States, 63104
      • Cardinal Glennon Children's Hospital /Saint Louis University
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • New Jersey
    • Morristown, New Jersey, United States, 07960
      • Morristown Medical Center
    • New Brunswick, New Jersey, United States, 08901
      • Rutgers-Robert Wood Johnson Medical School
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico Pediatric/Pulmonary
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical College
    • New Hyde Park, New York, United States, 11042
      • Northwell Health, Div of Pulmonary, Critical Care & Sleep Medicine
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Levine Children's Hospital - Atrium Health
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest School of Medicine
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44106
      • University Hospital Cleveland Medical Center
    • Columbus, Ohio, United States, 43205
      • The Research Institute at Nationwide Children's Hospital
    • Dayton, Ohio, United States, 45404
      • Dayton Children's Hospital
    • Toledo, Ohio, United States, 43606
      • Toledo Children's Hospital CF Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Science Center - Pediatric Pulmonary & CF Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Children's Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMCU
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina (MUSC)
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57105
      • Sanford Childrens Specialty Clinic
  • Tennessee
    • Memphis, Tennessee, United States, 38103
      • UTHSC Lebonheur Children's Hospital
  • Texas
    • Austin, Texas, United States, 78723
      • Austin Children's Chest Associates
    • Dallas, Texas, United States, 75235
      • Children's Medical Center Cystic Fibrosis Clinic
    • Fort Worth, Texas, United States, 76104
      • Cook Children Medical Center
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
    • Tyler, Texas, United States, 75708
      • The University of Texas Health Science Center at Tyler
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Health Sciences Center
  • Vermont
    • Colchester, Vermont, United States, 05446
      • University Vermont Medical Center Vermont Lung Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System, Cystic Fibrosis Center
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
    • Spokane, Washington, United States, 99204
      • Providence Medical Research Center
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria

1. Participants ≥6 years of age at time of informed consent form or assent form signing.

2. Confirmed diagnosis of CF, determined by having clinical features consistent with the CF phenotype, plus one of the following:

   1. Positive sweat chloride test (value ≥60 milliequivalent/L),
   2. Genotype with 2 mutations consistent with CF (i.e., a mutation in each of the cystic fibrosis transmembrane conductance regulator genes).
3. Positive sputum culture or a throat swab culture for MRSA at Screening.
4. In addition to the Screening sample, have at least 2 prior sputum or throat swab cultures positive for MRSA, of which at least 1 sample is >6 months prior to Screening. At least 50% of all MRSA cultures (sputum or throat swab culture) collected from the time of the first positive culture (in the previous 1 year) must have tested positive for MRSA. (Note: Screening sample may count towards 50% positive count)
5. FEV1 ≥30% and ≤90% of predicted that is normal for age, gender, race, and height, using the Global Lung Function Initiative equation.
6. At least 1 episode of acute pulmonary infection treated with non-maintenance antibiotics within 12 months prior to the Baseline visit (initiation of treatment with intermittent inhaled anti-Pseudomonal therapy will not qualify as treatment with non-maintenance antibiotics).

7. If female of childbearing potential, an acceptable method of contraception must be used during the study and must be combined with a negative pregnancy test obtained during Screening; sexually active male subjects of reproductive potential who are non-sterile (i.e., male who has not been sterilized by vasectomy for at least 6 months, and were not diagnosed with infertility through demonstration of azoospermia in a semen sample and/or absence of vas deferens through ultrasound) must be willing to use a barrier method of contraception, or their female partner must use an acceptable method of contraception, during the study.

   For purposes of this study, the Sponsor defines "acceptable methods of contraception" as:

   1. Oral birth control pills administered for at least 1 monthly cycle prior to administration of the study drug.
   2. A synthetic progestin implanted rod (eg, Implanon®) for at least 1 monthly cycle prior to the study drug administration but not beyond the 4th successive year following insertion.
   3. Intrauterine devices, inserted by a qualified clinician for at least 1 monthly cycle prior to study drug administration.
   4. Medroxyprogesterone acetate (eg, Depo-Provera®) administered for a minimum of 1 monthly cycle prior to administration of the study drug and continuing through 1 month following study completion.
   5. Hysterectomy or surgical sterilization.
   6. Abstinence.
   7. Double barrier method (diaphragm with spermicidal gel or condoms with contraceptive foam).

   Note: For subjects prescribed Orkambi: Orkambi may substantially decrease hormonal contraceptive exposure, reducing the effectiveness and increasing the incidence of menstruation-associated adverse reactions. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with Orkambi.

8. Able and willing to comply with the protocol, including availability for all scheduled study visits and able to perform all techniques necessary to use the AeroVanc inhaler and measure lung function.
9. Agree not to smoke during any part of the clinical trial (Screening visit through end of study).
10. Participants with a Pseudomonas 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.

Exclusion criteria

1. Use of anti-MRSA treatments prescribed as maintenance therapy (intravenous [IV] or inhaled treatment within 28 days; oral treatment within 14 days) prior to the Baseline visit.
2. Use of non-maintenance antibiotic for pulmonary infection or extrapulmonary MRSA infection (IV or inhaled antibiotic within 28 days; oral antibiotic within 14 days) prior to the Baseline visit.
3. 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. Inability to tolerate inhaled products.
5. First time sputum culture or throat swab culture yielding Burkholderia cepacia, or nontuberculous Mycobacteria in the previous 6 months to Screening.
6. History of lung or other solid organ transplantation or currently on the list to receive lung or other solid organ transplantation.
7. Resistance to vancomycin at Screening (vancomycin resistant Staphylococcus aureus, or vancomycin intermediate resistant Staphylococcus aureus, with minimum inhibitory concentration ≥8 μg/mL).
8. Oral corticosteroids in doses exceeding 10 mg prednisone per day or 20 mg prednisone every other day, or equipotent doses of other corticosteroids.
9. Changes in antimicrobial, bronchodilator, anti-inflammatory or corticosteroid medications within 14 days, or changes in cystic fibrosis transmembrane conductance modulators within 28 days, prior to the Baseline visit.
10. Abnormal laboratory findings or other findings or medical history at Screening that, in the Investigator's opinion, would compromise the safety of the subject or the quality of the study data.
11. Inability to tolerate inhalation of a short acting beta2 agonist
12. Oxygen saturation <90% at Screening.
13. Changes in physiotherapy technique or physiotherapy scheduled within 1 week of the Baseline visit.
14. Administration of any investigational drug or device within 4 weeks prior to the Screening visit and during the study
15. Female with positive pregnancy test result during Screening, pregnant (or intends to become pregnant), lactating or intends to breastfeed during the study.
16. Renal insufficiency, defined as creatinine clearance <50 mL/min using the Cockcroft-Gault equation for adults or Schwartz equation for children at the Screening visit.
17. Abnormal liver function, defined as ≥4x upper limit of normal of serum aspartate aminotransferase or serum alanine aminotransferase, or known cirrhosis at Screening.
18. Diagnosed with clinically significant hearing loss.
19. History of positive result for human immunodeficiency virus, hepatitis B virus or hepatitis C virus.
20. Planned hospitalizations for prophylaxis antibiotic treatment within 28 days prior to Baseline visit or during the double-blind period (Period 1).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Double-blind vancomycin inhalation powder; Vancomycin inhalation powder 30 mg is administered twice daily (BID) during the 24-week double-blind period (Period 1) by inhalation during three dosing cycles, each cycle being 28 days of treatment followed by 28 days of observation.	Drug: Vancomycin inhalation powder; 100 participants are to be treated with double-blind vancomycin inhalation powder (75 subjects ≤21 years old, 25 subjects >21 years old) for 24 weeks during Period 1.; Other Names: AeroVanc; Drug: Vancomycin inhalation powder; In the 24-week Period 2, all participants are to be treated with open-label vancomycin inhalation powder.; Other Names: AeroVanc
Placebo Comparator: Double-blind placebo inhalation powder; Matching placebo is administered BID during the 24-week double-blind period (Period 1) by inhalation during three dosing cycles, each cycle being 28 days of treatment followed by 28 days of observation.	Drug: Placebo inhalation powder; 100 participants are to be treated with double-blind placebo (75 subjects ≤21 years old, 25 subjects >21 years old) for 24 weeks during Period 1.
Experimental: Open-label vancomycin inhalation powder; In the 24-week Period 2, all participants receive AeroVanc 30 mg BID by inhalation during three dosing cycles, each cycle being 28 days of treatment followed by 28 days of observation.	Drug: Vancomycin inhalation powder; 100 participants are to be treated with double-blind vancomycin inhalation powder (75 subjects ≤21 years old, 25 subjects >21 years old) for 24 weeks during Period 1.; Other Names: AeroVanc; Drug: Vancomycin inhalation powder; In the 24-week Period 2, all participants are to be treated with open-label vancomycin inhalation powder.; Other Names: AeroVanc

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted	The mean absolute change from baseline in FEV1 percent predicted was analyzed sequentially at Week 4 (end of Cycle 1), Week 12 (end of Cycle 2) and at Week 20 (end of Cycle 3).	Baseline and Week 4, 12 and 20

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of Pulmonary Exacerbations	The number of pulmonary exacerbations during Period 1 adjusted for the length of follow-up.	Week 20
Time to First Pulmonary Exacerbation	Time to first pulmonary exacerbation requiring use of another antibiotic medication (oral, IV, and/or inhaled). The Outcome Measure Data presented are the median percentiles and 95% confidence intervals from Kaplan-Meier estimates.	Week 20
Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Scores	The CFQ-R was administered every two weeks using a hand-held e-Diary. CFQ-R scores range between 0 and 100, where higher scores indicate a better outcome. The CFQ-R measures functioning in a variety of domains, including Physical Functioning, Vitality, Health Perceptions, Respiratory Symptoms, Treatment Burden, Role Functioning, Emotional Functioning and Social Functioning. The Outcome Measure Data presented are the Respiratory Symptoms Scores.	Baseline and Week 4, 12, and 20
Change From Baseline in Cystic Fibrosis Respiratory Symptom Diary-Chronic Respiratory Symptom Score (CFRSD-CRISS) Scores	The CFRSD-CRISS was administered every two weeks using a hand-held e-Diary. Scores range between 0 and 100, where higher scores indicate a worse outcome.	Baseline and Week 4, 12 and 20
Relative Change in FEV1 Percent Predicted	The mean relative change from Baseline in FEV1 percent predicted	Baseline and Week 4, 12 and 20
Number of Successful Response Cycles	The number of successful response cycles a participant achieves over Period 1. A response in a cycle is defined by at least a 5 % relative improvement in FEV1 percent predicted at the end of each the respective cycle.	Week 20
Area Under the FEV1-time Profile	The mean treatment difference in FEV1 across all post-baseline visits	Week 20

Collaborators and Investigators

• Sponsor: Savara Inc.

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2017
• Primary Completion (Actual): July 28, 2020
• Study Completion (Actual): January 15, 2021

Study Registration Dates

• First Submitted: June 1, 2017
• First Submitted That Met QC Criteria: June 7, 2017
• First Posted (Actual): June 9, 2017

Study Record Updates

• Last Update Posted (Actual): December 16, 2022
• Last Update Submitted That Met QC Criteria: December 14, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Anti-Infective Agents; Anti-Bacterial Agents; Vancomycin
• Other Study ID Numbers: SAV005-04

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No