OPTIMIZing Treatment for Early Pseudomonas Aeruginosa Infection in Cystic Fibrosis

NCT02054156 | Completed Phase 3 Results DMC

• 3 other identifiers: OPTIMIZE-IP-121U01HL114623-01A11U01HL114589-01A1
• Study Type: interventional
• Target: 221
• Locations: 1 country
• Sites: 45

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.

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

Outcome Measures

Primary Outcomes (1)

• Time to a Protocol-defined Pulmonary Exacerbation

  Time to a protocol-defined pulmonary exacerbation requiring oral, inhaled, or intravenous antibiotics, using a prespecified definition available in the study protocol.

  Over the 18-month study period

Secondary Outcomes (3)

• Time to Pseudomonas Aeruginosa (Pa) Recurrence

  Over the 18-month study period

• Adverse Events (AEs) and Serious Adverse Events (SAEs)

  Over the 18-month study period

• Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs)

  Over the 18-month study period

Study Arms (2)

azithromycin and TIS

ACTIVE COMPARATOR

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

Drug: azithromycin; Drug: Tobramycin solution for inhalation

placebo and TIS

PLACEBO COMPARATOR

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

Drug: placebo; Drug: Tobramycin solution for inhalation

Interventions

azithromycin DRUG

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

azithromycin and TIS

placebo DRUG

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

placebo and TIS

Tobramycin solution for inhalation DRUG

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

Also known as: TIS

azithromycin and TIS; placebo and TIS

Eligibility Criteria

• Age: 6 Months - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Bonnie Ramsey: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (45)

CFF Affiliate Program Providence Medical Center

Anchorage, Alaska, 99519-6604, United States

Location

CFF Care Center Arizona Health Science Center

Tucson, Arizona, 85724, United States

Location

CFF Care Center & Pediatric Program Arkansas Children's Hospital

Little Rock, Arkansas, 72202, United States

Location

Childrens Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

CFF Care Center & Pediatric Program Stanford University

Palo Alto, California, 94304, United States

Location

CFF Care Center & Pediatric Program Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

CFF Care Center & Pediatric Program Yale University

New Haven, Connecticut, 06520, United States

Location

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

Jacksonville, Florida, 32207, United States

Location

CFF Care Center & Pediatric Program All Children's Hospital

St. Petersburg, Florida, 33701, United States

Location

CFF Care Center & Pediatric Program Emory University

Atlanta, Georgia, 30324, United States

Location

CFF Affiliate Program Children's Healthcare of Atlanta

Atlanta, Georgia, 30342, United States

Location

CFF Care Center St. Luke's CF Clinic

Boise, Idaho, 83712, United States

Location

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

Chicago, Illinois, 60611-2605, United States

Location

CFF Care Center & Pediatric Program Riley Hospital for Children

Indianapolis, Indiana, 46202-5271, United States

Location

CFF Care Center & Pediatric Program University of Iowa

Iowa City, Iowa, 52242, United States

Location

CFF Care Center & Pediatric Program Maine Medical Center

Portland, Maine, 04102, United States

Location

CFF Care Center & Pediatric Program Children's Hospital Boston

Boston, Massachusetts, 02115, United States

Location

CFF Care Center & Pediatric Program University of Michigan

Ann Arbor, Michigan, 48109-5212, United States

Location

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

Detroit, Michigan, 48201, United States

Location

CFF Care Center The Children's Mercy Hospital

Kansas City, Missouri, 64108, United States

Location

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

St Louis, Missouri, 63104, United States

Location

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

St Louis, Missouri, 63110, United States

Location

CFF Care Center & Pediatric Program University of Nebraska Medical Center

Omaha, Nebraska, 68198, United States

Location

CFF Care Center & Pediatric Program Monmouth Medical Center

Long Branch, New Jersey, 07740, United States

Location

CFF Care Center & Pediatric Program Columbia University

New York, New York, 10032, United States

Location

CFF Care Center & Pediatric Program SUNY Upstate Medical University

Syracuse, New York, 13210, United States

Location

CFF Care Center New York Medical College

Valhalla, New York, 10595, United States

Location

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

Chapel Hill, North Carolina, 27599, United States

Location

CFF Care Center & Pediatric Program Akron Children's Hospital

Akron, Ohio, 44308, United States

Location

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

Cincinnati, Ohio, 45229, United States

Location

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

Cleveland, Ohio, 44106, United States

Location

CFF Care Center & Pediatric Program Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

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

Dayton, Ohio, 45404, United States

Location

CFF Care Center & Pediatric Program Oregon Health & Sciences University

Portland, Oregon, 97239, United States

Location

CFF Care Center & Pediatric Program Hershey Medical Center

Hershey, Pennsylvania, 17033, United States

Location

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

Pittsburgh, Pennsylvania, 15224, United States

Location

CFF Care Center & Pediatric Program Sanford USD Medical Center

Sioux Falls, South Dakota, 57117, United States

Location

CFF Care Center & Pediatric Program University of Tennessee

Memphis, Tennessee, 38103, United States

Location

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

Austin, Texas, 78723, United States

Location

University of Utah

Salt Lake City, Utah, 84132, United States

Location

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

Norfolk, Virginia, 23507, United States

Location

CFF Care Center Medical College of Virginia

Richmond, Virginia, 23298, United States

Location

CFF Care Center & Pediatric Program Seattle Children's Hospital

Seattle, Washington, 98145, United States

Location

CFF Care Center & Pediatric Program University of Wisconsin

Madison, Wisconsin, 53792, United States

Location

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

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (1)

• 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.

  PMID: 29890086 DERIVED

MeSH Terms

Conditions

Cystic Fibrosis; Pseudomonas Infections

Interventions

Azithromycin; Inhalation

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals; Respiratory Mechanics; Respiration; Respiratory Physiological Phenomena; Circulatory and Respiratory Physiological Phenomena

Limitations and Caveats

A DSMB monitored the trial using pre-specified stopping guidelines for efficacy and safety. At the 4th analysis the efficacy bound was crossed. The DSMB determined the study met it's aim and recommended closing the study to enrollment.

Results Point of Contact

• Title: Margaret Kloster
• Organization: Seattle Children's Hospital

margaret.kloster@seattlechildrens.org

2068847862

Study Officials

• Bonnie Ramsey, MD

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

  PRINCIPAL INVESTIGATOR

• Nicole Hamblett, PhD

  Seattle Children's Core for Biomedical Statistics

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Pediatrics

Study Record Dates

• First Submitted: February 1, 2014
• First Posted: February 4, 2014
• Study Start: June 1, 2014
• Primary Completion: August 23, 2018
• Study Completion: August 23, 2018
• Last Updated: October 1, 2019
• Results First Posted: October 1, 2019

Record last verified: 2019-09

Locations

US (45)