OPTIMIZing Treatment for Early Pseudomonas Aeruginosa Infection in Cystic Fibrosis

NCT ID: NCT02054156

Last Updated: 2019-10-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 221 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-06-30
• Study Completion Date: 2018-08-23

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.

Conditions

Cystic Fibrosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

azithromycin and TIS

azithromycin and tobramycin solution for inhalation (TIS) Azithromycin 3 times weekly, oral suspension, 10 mg/kg/dose up to 500 mg, for 18 months Tobramycin solution for inhalation (TIS), 300 mg, twice daily for 28 days when respiratory cultures are found positive for Pa at study visits for 18 months

Group Type: ACTIVE_COMPARATOR

azithromycin

Intervention Type: DRUG

3 times weekly, oral suspension, 10 mg/kg/dose up to 500 mg, for 18 months

Tobramycin solution for inhalation

Intervention Type: DRUG

300 mg, twice daily for 28 days when respiratory cultures are found positive for Pa at study visits for 18 months

placebo and TIS

placebo and tobramycin solution for inhalation (TIS) Placebo 3 times weekly, oral suspension, volume-matched to azithromycin, for 18 months Tobramycin solution for inhalation (TIS), 300 mg, twice daily for 28 days when respiratory cultures are found positive for Pa at study visits for 18 months

Group Type: PLACEBO_COMPARATOR

placebo

Intervention Type: DRUG

3 times weekly, oral suspension, volume-matched to azithromycin, for 18 months

Tobramycin solution for inhalation

Intervention Type: DRUG

300 mg, twice daily for 28 days when respiratory cultures are found positive for Pa at study visits for 18 months

Interventions

azithromycin

3 times weekly, oral suspension, 10 mg/kg/dose up to 500 mg, for 18 months

Intervention Type: DRUG

placebo

3 times weekly, oral suspension, volume-matched to azithromycin, for 18 months

Intervention Type: DRUG

Tobramycin solution for inhalation

300 mg, twice daily for 28 days when respiratory cultures are found positive for Pa at study visits for 18 months

Intervention Type: DRUG

Other Intervention Names

TIS

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

• Minimum Eligible Age: 6 Months
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Bonnie Ramsey

OTHER

Sponsor Role: lead

Responsible Party

Bonnie Ramsey

Professor of Pediatrics

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Bonnie Ramsey, MD

Role: PRINCIPAL_INVESTIGATOR

Seattle Children's Center for Clinical and Translational Research, CF Therapeutics Development Network Clinical Coordinating Center

Nicole Hamblett, PhD

Role: PRINCIPAL_INVESTIGATOR

Seattle Children's Core for Biomedical Statistics

Locations

CFF Affiliate Program Providence Medical Center

Anchorage, Alaska, United States

CFF Care Center Arizona Health Science Center

Tucson, Arizona, United States

CFF Care Center & Pediatric Program Arkansas Children's Hospital

Little Rock, Arkansas, United States

Childrens Hospital Los Angeles

Los Angeles, California, United States

CFF Care Center & Pediatric Program Stanford University

Palo Alto, California, United States

CFF Care Center & Pediatric Program Children's Hospital Colorado

Aurora, Colorado, United States

CFF Care Center & Pediatric Program Yale University

New Haven, Connecticut, United States

CFF Care Center & Pediatric Program Nemours Children's Clinic - Jacksonville

Jacksonville, Florida, United States

CFF Care Center & Pediatric Program All Children's Hospital

St. Petersburg, Florida, United States

CFF Care Center & Pediatric Program Emory University

Atlanta, Georgia, United States

CFF Affiliate Program Children's Healthcare of Atlanta

Atlanta, Georgia, United States

CFF Care Center St. Luke's CF Clinic

Boise, Idaho, United States

CFF Care Center & Pediatric Program Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, United States

CFF Care Center & Pediatric Program Riley Hospital for Children

Indianapolis, Indiana, United States

CFF Care Center & Pediatric Program University of Iowa

Iowa City, Iowa, United States

CFF Care Center & Pediatric Program Maine Medical Center

Portland, Maine, United States

CFF Care Center & Pediatric Program Children's Hospital Boston

Boston, Massachusetts, United States

CFF Care Center & Pediatric Program University of Michigan

Ann Arbor, Michigan, United States

CFF Care Center & Pediatric Program Children's Hospital of Michigan

Detroit, Michigan, United States

CFF Care Center The Children's Mercy Hospital

Kansas City, Missouri, United States

CFF Care Center & Pediatric Program Cardinal Glennon Children's Hospital/Saint Louis University

St Louis, Missouri, United States

CFF Care Center & Pediatric Program St. Louis Children's Hospital

St Louis, Missouri, United States

CFF Care Center & Pediatric Program University of Nebraska Medical Center

Omaha, Nebraska, United States

CFF Care Center & Pediatric Program Monmouth Medical Center

Long Branch, New Jersey, United States

CFF Care Center & Pediatric Program Columbia University

New York, New York, United States

CFF Care Center & Pediatric Program SUNY Upstate Medical University

Syracuse, New York, United States

CFF Care Center New York Medical College

Valhalla, New York, United States

CFF Care Center & Pediatric Program University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States

CFF Care Center & Pediatric Program Akron Children's Hospital

Akron, Ohio, United States

CFF Care Center & Pediatric Program Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

CFF Care Center & Pediatric Program Rainbow Babies and Children's Hospital

Cleveland, Ohio, United States

CFF Care Center & Pediatric Program Nationwide Children's Hospital

Columbus, Ohio, United States

CFF Care Center & Pediatric Program The Children's Medical Center

Dayton, Ohio, United States

CFF Care Center & Pediatric Program Oregon Health & Sciences University

Portland, Oregon, United States

CFF Care Center & Pediatric Program Hershey Medical Center

Hershey, Pennsylvania, United States

CFF Care Center & Pediatric Program Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States

CFF Care Center & Pediatric Program Sanford USD Medical Center

Sioux Falls, South Dakota, United States

CFF Care Center & Pediatric Program University of Tennessee

Memphis, Tennessee, United States

CFF Care Center & Pediatric Program Dell Children's Medical Center of Central Texas

Austin, Texas, United States

University of Utah

Salt Lake City, Utah, United States

CFF Care Center & Pediatric Program Children's Hospital of the King's Daughters

Norfolk, Virginia, United States

CFF Care Center Medical College of Virginia

Richmond, Virginia, United States

CFF Care Center & Pediatric Program Seattle Children's Hospital

Seattle, Washington, United States

CFF Care Center & Pediatric Program University of Wisconsin

Madison, Wisconsin, United States

CFF Care Center & Pediatric Program Children's Hospital of Wisconsin

Milwaukee, Wisconsin, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 29890086 (View on PubMed)

Provided Documents

Document Type: Statistical Analysis Plan

View Document

Document Type: Study Protocol

View Document

Other Identifiers

1U01HL114623-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

1U01HL114589-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

OPTIMIZE-IP-12

Identifier Type: -

Identifier Source: org_study_id