Clinical trial NCT02054156: OPTIMIZing Treatment for Early Pseudomonas Aeruginosa Infection in Cystic Fibrosis
Official title: OPTIMIZing Treatment for Early Pseudomonas Aeruginosa Infection in Cystic Fibrosis: The OPTIMIZE Multicenter, Placebo-Controlled, Double-Blind, Randomized Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cystic Fibrosis
Keywords: Cystic fibrosis (CF)
Azithromycin
Tobramycin solution for inhalation (TIS)
Pseudomonas aeruginosa (Pa)
Early Pseudomonas aeruginosa infection
Pulmonary exacerbation
Standardized anti-pseudomonal therapy
Lead sponsor: Seattle Children's Hospital
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2014-02-04
Enrollment: 221
Sex: ALL
Minimum age (years): 6
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this trial is to compare the effects of treatment with tobramycin solution for inhalation (TIS) with and without azithromycin in people with cystic fibrosis (CF) age 6 months to 18 years who have early isolation of Pseudomonas aeruginosa (Pa) from a respiratory culture. Specimens of blood and sputum or throat swabs will be taken during the study along with pulmonary function testing. Participants will receive initial treatment with TIS followed additional treatment with TIS if quarterly respiratory cultures are positive for Pa in addition to either azithromycin or placebo for 18 months.

Detailed description: Cystic fibrosis (CF) lung disease begins in the first few months of life and follows a course of recurrent lower airway bacterial infection and inflammation and progression of disease over years and decades at a variable pace. With the development of chronic lung infection, obstructive disease progressively worsens, ultimately leading to respiratory failure. Pseudomonas aeruginosa (Pa) is the most important pathogen infecting the CF lower airways, and its acquisition early in life is associated with a pro-inflammatory effect, lower lung function, poor nutritional outcomes, and decreased survival.

Pseudomonas aeruginosa (Pa) infection of the cystic fibrosis (CF) airway typically proceeds from early infection to chronic infection. Although some studies have shown that a minority of individuals with CF spontaneously clear early Pseudomonas aeruginosa (Pa) infection, data from multiple studies suggest that antibiotics are superior to no treatment in clearing Pseudomonas aeruginosa (Pa) from respiratory cultures. Understanding the transition period from early to chronic Pseudomonas aeruginosa (Pa) infection is thus of critical importance in identifying strategies to prevent this progression.

The study will assess the clinical and microbiologic efficacy and safety of azithromycin given three times weekly in combination with standardized tobramycin solution for inhalation (TIS) therapy among children with early Pseudomonas aeruginosa (Pa). TIS therapy is defined as an initial eradication treatment with 1-2 courses of 28 days TIS and subsequent 28 day treatments only at times a quarterly respiratory culture is positive for Pseudomonas aeruginosa (Pa). Eligible participants will be randomized within one month of their Pseudomonas aeruginosa (Pa) positive culture to receive one of the following two treatment strategies for 18 months: (1) oral placebo in addition to standardized TIS therapy, or (2) oral azithromycin in addition to standardized TIS therapy.

At the first study visit, participants will undergo a physical examination and a review of their medical history. Lung function will be measured via spirometry (in children greater than four years of age who are able to perform spirometry), electrocardiogram (ECG) testing will be conducted, and hearing ability will be measured via audiometry. Blood will be drawn for laboratory tests and a specimen will be obtained for a respiratory culture before randomization and study drug dispensing occurs. Subsequent study visits will take place at Day 21, Weeks 13, 26, 39, 52, 65, and 78. At each visit, participants will undergo a physical examination, a spirometry test (as appropriate), a respiratory specimen for Pseudomonas aeruginosa (Pa) culture will be collected and study drug will be dispensed (except at Week 78). Participants will complete self-report or parent-completed respiratory symptom questionnaires and signs and symptoms evaluations will be performed at all visits. Repeat hearing and laboratory tests will be performed at Weeks 39 and 78 and ECG testing will be repeated at Day 21 and Week 78. Participants will be required to maintain a medication diary throughout the study.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 6 months to ≤ 18 years
* Documentation of a CF diagnosis as evidenced by one or more clinical features consistent with the CF phenotype or positive CF Newborn Screening result for immunoreactive trypsinogen (IRT) IRT/DNA or IRT/IRT and one or more of the following criteria:
* sweat chloride ≥ 60 milliequivalent (mEq)/liter by quantitative by pilocarpine iontophoresis test (QPIT)
* two well-characterized mutations in the cystic fibrosis transmembrane conductive regulator (CFTR) gene
* Abnormal nasal potential difference (NPD) (change in NPD in response to a low chloride solution and isoproteronol of less than - 5 mV)
* Documented new positive oropharyngeal, sputum or lower respiratory tract culture for Pa within 30 days of the Baseline Visit (Visit 1), defined as: a) first lifetime documented Pa positive culture; or b) Pa recovered after at least a two-year history of Pa negative respiratory cultures (≥ 1 culture/ year)
* Clinically stable with no evidence of any significant respiratory symptoms at the Baseline Visit that would require administration of intravenous anti- pseudomonal antibiotics, oxygen supplementation, and/or hospitalization as determined by the study physician
* Written informed consent obtained from participant or participant's legal representative (and assent when applicable) and ability for participant to comply with the requirements of the study

Exclusion Criteria:

* Macrolide antibiotic use within 30 days of the Baseline Visit
* Initiation of current course of treatment with TIS \>14 days prior to Baseline Visit
* Weight \<6.0 kg at the Baseline Visit
* History of aminoglycoside hypersensitivity or adverse reaction to inhaled aminoglycoside
* History of azithromycin hypersensitivity or adverse reaction to azithromycin or allergy to macrolide antibiotics
* History of positive respiratory culture for Non-tuberculous mycobacteria (NTM) or Burkholderia cepacia complex within 2 years of the Baseline Visit
* History of unresolved, abnormal renal function (defined as serum creatinine greater than 1.5 times the upper limit of normal for age).
* History of unresolved, abnormal liver function tests (defined as alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) greater than 4 times the upper limit of normal range) or history of portal hypertension
* History of unresolved, abnormal neutropenia (ANC ≤ 1000)
* Abnormal ECG test at the Baseline Visit defined as a QT interval corrected (QTc) (B) of ≥460 msec or history of ventricular arrhythmia
* History of abnormal hearing sensitivity defined as hearing threshold levels \>25 dB HL (decibels Hearing Level) for visual reinforcement audiometry (VRA) at any frequency (500-4000Hz) or \>20 Decibels Hearing Level (dBHL) for play or standard audiometry at any two frequencies (500-8000Hz) in either ear, not associated with middle ear disease (including infection) or a flat (Type B) tympanogram
* New initiation of chronic therapy (greater than 21 days) with drugs known to prolong QT interval (refer to Appendix III) within 30 days prior to the Baseline Visit or coadministration of nelfinavir or oral anticoagulants
* Positive serum or urine pregnancy test at the Baseline Visit (to be performed on all females of child-bearing potential) or for females of child bearing potential: pregnant, breastfeeding, or unwilling to use barrier contraception during participation in the study
* Administration of any investigational drug within 30 days prior to the Baseline Visit
* Presence of a condition or abnormality (e.g., pre-existing heart disease) that in the opinion of the site investigator would compromise the safety of the participant or the quality of the data

Primary outcomes:
measure: Time to a Protocol-defined Pulmonary Exacerbation
timeFrame: Over the 18-month study period
Secondary outcomes:
measure: Time to Pseudomonas Aeruginosa (Pa) Recurrence
timeFrame: Over the 18-month study period
measure: Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Over the 18-month study period
measure: Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Over the 18-month study period
Other outcomes:
Locations:
city: Anchorage
country: United States
facility: CFF Affiliate Program Providence Medical Center
state: Alaska
city: Tucson
country: United States
facility: CFF Care Center Arizona Health Science Center
state: Arizona
city: Little Rock
country: United States
facility: CFF Care Center & Pediatric Program Arkansas Children's Hospital
state: Arkansas
city: Los Angeles
country: United States
facility: Childrens Hospital Los Angeles
state: California
city: Palo Alto
country: United States
facility: CFF Care Center & Pediatric Program Stanford University
state: California
city: Aurora
country: United States
facility: CFF Care Center & Pediatric Program Children's Hospital Colorado
state: Colorado
city: New Haven
country: United States
facility: CFF Care Center & Pediatric Program Yale University
state: Connecticut
city: Jacksonville
country: United States
facility: CFF Care Center & Pediatric Program Nemours Children's Clinic - Jacksonville
state: Florida
city: Saint Petersburg
country: United States
facility: CFF Care Center & Pediatric Program All Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: CFF Care Center & Pediatric Program Emory University
state: Georgia
city: Atlanta
country: United States
facility: CFF Affiliate Program Children's Healthcare of Atlanta
state: Georgia
city: Boise
country: United States
facility: CFF Care Center St. Luke's CF Clinic
state: Idaho
city: Chicago
country: United States
facility: CFF Care Center & Pediatric Program Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: CFF Care Center & Pediatric Program Riley Hospital for Children
state: Indiana
city: Iowa City
country: United States
facility: CFF Care Center & Pediatric Program University of Iowa
state: Iowa
city: Portland
country: United States
facility: CFF Care Center & Pediatric Program Maine Medical Center
state: Maine
city: Boston
country: United States
facility: CFF Care Center & Pediatric Program Children's Hospital Boston
state: Massachusetts
city: Ann Arbor
country: United States
facility: CFF Care Center & Pediatric Program University of Michigan
state: Michigan
city: Detroit
country: United States
facility: CFF Care Center & Pediatric Program Children's Hospital of Michigan
state: Michigan
city: Kansas City
country: United States
facility: CFF Care Center The Children's Mercy Hospital
state: Missouri
city: Saint Louis
country: United States
facility: CFF Care Center & Pediatric Program Cardinal Glennon Children's Hospital/Saint Louis University
state: Missouri
city: Saint Louis
country: United States
facility: CFF Care Center & Pediatric Program St. Louis Children's Hospital
state: Missouri
city: Omaha
country: United States
facility: CFF Care Center & Pediatric Program University of Nebraska Medical Center
state: Nebraska
city: Long Branch
country: United States
facility: CFF Care Center & Pediatric Program Monmouth Medical Center
state: New Jersey
city: New York
country: United States
facility: CFF Care Center & Pediatric Program Columbia University
state: New York
city: Syracuse
country: United States
facility: CFF Care Center & Pediatric Program SUNY Upstate Medical University
state: New York
city: Valhalla
country: United States
facility: CFF Care Center New York Medical College
state: New York
city: Chapel Hill
country: United States
facility: CFF Care Center & Pediatric Program University of North Carolina at Chapel Hill
state: North Carolina
city: Akron
country: United States
facility: CFF Care Center & Pediatric Program Akron Children's Hospital
state: Ohio
city: Cincinnati
country: United States
facility: CFF Care Center & Pediatric Program Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: CFF Care Center & Pediatric Program Rainbow Babies and Children's Hospital
state: Ohio
city: Columbus
country: United States
facility: CFF Care Center & Pediatric Program Nationwide Children's Hospital
state: Ohio
city: Dayton
country: United States
facility: CFF Care Center & Pediatric Program The Children's Medical Center
state: Ohio
city: Portland
country: United States
facility: CFF Care Center & Pediatric Program Oregon Health & Sciences University
state: Oregon
city: Hershey
country: United States
facility: CFF Care Center & Pediatric Program Hershey Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: CFF Care Center & Pediatric Program Children's Hospital of Pittsburgh
state: Pennsylvania
city: Sioux Falls
country: United States
facility: CFF Care Center & Pediatric Program Sanford USD Medical Center
state: South Dakota
city: Memphis
country: United States
facility: CFF Care Center & Pediatric Program University of Tennessee
state: Tennessee
city: Austin
country: United States
facility: CFF Care Center & Pediatric Program Dell Children's Medical Center of Central Texas
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Norfolk
country: United States
facility: CFF Care Center & Pediatric Program Children's Hospital of the King's Daughters
state: Virginia
city: Richmond
country: United States
facility: CFF Care Center Medical College of Virginia
state: Virginia
city: Seattle
country: United States
facility: CFF Care Center & Pediatric Program Seattle Children's Hospital
state: Washington
city: Madison
country: United States
facility: CFF Care Center & Pediatric Program University of Wisconsin
state: Wisconsin
city: Milwaukee
country: United States
facility: CFF Care Center & Pediatric Program Children's Hospital of Wisconsin
state: Wisconsin
Study officials:
affiliation: Seattle Children's Center for Clinical and Translational Research, CF Therapeutics Development Network Clinical Coordinating Center
name: Bonnie Ramsey, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Seattle Children's Core for Biomedical Statistics
name: Nicole Hamblett, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mayer-Hamblett N, Retsch-Bogart G, Kloster M, Accurso F, Rosenfeld M, Albers G, Black P, Brown P, Cairns A, Davis SD, Graff GR, Kerby GS, Orenstein D, Buckingham R, Ramsey BW; OPTIMIZE Study Group. Azithromycin for Early Pseudomonas Infection in Cystic Fibrosis. The OPTIMIZE Randomized Trial. Am J Respir Crit Care Med. 2018 Nov 1;198(9):1177-1187. doi: 10.1164/rccm.201802-0215OC.