Clinical trial NCT03181932: AeroVanc in the Treatment of Methicillin-resistant Staphylococcus Aureus Infection in Patients With Cystic Fibrosis
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: MRSA
Cystic Fibrosis
Lead sponsor: Savara Inc.
Sponsor class: INDUSTRY
First posted: 2017-06-09
Enrollment: 188
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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).

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.

Eligibility criteria: 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).

Primary outcomes:
measure: Absolute Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted
timeFrame: Baseline and Week 4, 12 and 20
Secondary outcomes:
measure: Frequency of Pulmonary Exacerbations
timeFrame: Week 20
measure: Time to First Pulmonary Exacerbation
timeFrame: Week 20
measure: Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Scores
timeFrame: Baseline and Week 4, 12, and 20
measure: Change From Baseline in Cystic Fibrosis Respiratory Symptom Diary-Chronic Respiratory Symptom Score (CFRSD-CRISS) Scores
timeFrame: Baseline and Week 4, 12 and 20
measure: Relative Change in FEV1 Percent Predicted
timeFrame: Baseline and Week 4, 12 and 20
measure: Number of Successful Response Cycles
timeFrame: Week 20
measure: Area Under the FEV1-time Profile
timeFrame: Week 20
Other outcomes:
Locations:
city: Mobile
country: United States
facility: Pulmonary Associates of Mobile
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Long Beach
country: United States
facility: Miller Childrens Hospital MemorialCare Health System Pediatric Pulmonology
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: University of Southern California Keck Medical Center of USC
state: California
city: Sacramento
country: United States
facility: UC Davis Medical Center
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Denver
country: United States
facility: National Jewish Health Adult Cystic Fibrosis Center
state: Colorado
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida Pediatrics
state: Florida
city: Hollywood
country: United States
facility: Memorial Healthcare System
state: Florida
city: Jacksonville
country: United States
facility: Nemours Childrens Specialty Care
state: Florida
city: Miami
country: United States
facility: University of Miami Bachelor Children's Hospital
state: Florida
city: Orlando
country: United States
facility: Central Florida Pulmonary Group
state: Florida
city: Orlando
country: United States
facility: Arnold Palmer Hospital Pulmonary and Sleep Medical Institute Orlando Health, Inc
state: Florida
city: Orlando
country: United States
facility: Nemours Children's Hospital
state: Florida
city: Pensacola
country: United States
facility: Nemours Children's Specialty Care
state: Florida
city: Saint Petersburg
country: United States
facility: Johns Hopkins All Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Children's Health Care of Atlanta at Scottish Rite
state: Georgia
city: Augusta
country: United States
facility: Augusta Univ Cystic Fibrosis Center
state: Georgia
city: Glenview
country: United States
facility: Chicago CF Care Specialists
state: Illinois
city: Morton Grove
country: United States
facility: NorthSurburban Pulmonary Specialists
state: Illinois
city: Indianapolis
country: United States
facility: Riley Hospital for Children at Indiana University Health
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Department of Pediatrics
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas
state: Kansas
city: Wichita
country: United States
facility: Via Christi Health Systems CF Clinic
state: Kansas
city: Louisville
country: United States
facility: University of Louisville Kosair Charities Pediatric Clinical Research Unit
state: Kentucky
city: Portland
country: United States
facility: Maine Medical Partners Pediatric Specialty Care
state: Maine
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Health System
state: Michigan
city: Detroit
country: United States
facility: Wayne State University (HUH)
state: Michigan
city: Kansas City
country: United States
facility: Children's Mercy
state: Missouri
city: Saint Louis
country: United States
facility: Cardinal Glennon Children's Hospital /Saint Louis University
state: Missouri
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Morristown
country: United States
facility: Morristown Medical Center
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers-Robert Wood Johnson Medical School
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Pediatric/Pulmonary
state: New Mexico
city: Albany
country: United States
facility: Albany Medical College
state: New York
city: New Hyde Park
country: United States
facility: Northwell Health, Div of Pulmonary, Critical Care & Sleep Medicine
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Charlotte
country: United States
facility: Levine Children's Hospital - Atrium Health
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest School of Medicine
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: University Hospital Cleveland Medical Center
state: Ohio
city: Columbus
country: United States
facility: The Research Institute at Nationwide Children's Hospital
state: Ohio
city: Dayton
country: United States
facility: Dayton Children's Hospital
state: Ohio
city: Toledo
country: United States
facility: Toledo Children's Hospital CF Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Science Center - Pediatric Pulmonary & CF Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Hershey
country: United States
facility: Penn State Children's Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMCU
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina (MUSC)
state: South Carolina
city: Sioux Falls
country: United States
facility: Sanford Childrens Specialty Clinic
state: South Dakota
city: Memphis
country: United States
facility: UTHSC Lebonheur Children's Hospital
state: Tennessee
city: Austin
country: United States
facility: Austin Children's Chest Associates
state: Texas
city: Dallas
country: United States
facility: Children's Medical Center Cystic Fibrosis Clinic
state: Texas
city: Fort Worth
country: United States
facility: Cook Children Medical Center
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Tyler
country: United States
facility: The University of Texas Health Science Center at Tyler
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Health Sciences Center
state: Utah
city: Colchester
country: United States
facility: University Vermont Medical Center Vermont Lung Center
state: Vermont
city: Charlottesville
country: United States
facility: University of Virginia Health System, Cystic Fibrosis Center
state: Virginia
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Spokane
country: United States
facility: Providence Medical Research Center
state: Washington
city: Morgantown
country: United States
facility: West Virginia University
state: West Virginia
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital
state: British Columbia
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
Study officials:
affiliation: Medical University of South Carolina
name: Patrick Flume, MD
role: PRINCIPAL_INVESTIGATOR
References: