OPTIMIZing Treatment for Early Pseudomonas Aeruginosa Infection in Cystic Fibrosis (OPTIMIZE)

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Seattle Children's Hospital
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Bonnie Ramsey, Seattle Children's Hospital
ClinicalTrials.gov Identifier:
NCT02054156
First received: February 1, 2014
Last updated: August 4, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
Cystic Fibrosis
Drug: azithromycin
Drug: placebo
Drug: Tobramycin solution for inhalation
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: OPTIMIZing Treatment for Early Pseudomonas Aeruginosa Infection in Cystic Fibrosis: The OPTIMIZE Multicenter, Placebo-Controlled, Double-Blind, Randomized Trial

Resource links provided by NLM:


Further study details as provided by Seattle Children's Hospital:

Primary Outcome Measures:
  • Time to a protocol-defined pulmonary exacerbation [ Time Frame: Over the 18-month study period ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Time to Pseudomonas aeruginosa (Pa) recurrence [ Time Frame: Over the 18-month study period ] [ Designated as safety issue: No ]
  • Safety as measured by the incidence of adverse events and laboratory abnormalities [ Time Frame: Over the 18- month study period ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 274
Study Start Date: June 2014
Estimated Study Completion Date: April 2018
Estimated Primary Completion Date: February 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 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
Drug: azithromycin
3 times weekly, oral suspension, 10 mg/kg/dose up to 500 mg, for 18 months
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
Other Name: TIS
Placebo Comparator: 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
Drug: placebo
3 times weekly, oral suspension, volume-matched to azithromycin, for 18 months
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
Other Name: TIS

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

Ages Eligible for Study:   6 Months to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 including ciprofloxacin and trimethoprim-sulfa (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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02054156

Contacts
Contact: Jean Kirihara 206-884-7593 Jean.kirihara@seattlechildrens.org
Contact: Irene Bondick 206-884-7813 Irene.bondick@seattlechildrens.org

  Show 45 Study Locations
Sponsors and Collaborators
Bonnie Ramsey
Investigators
Principal Investigator: 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
  More Information

No publications provided

Responsible Party: Bonnie Ramsey, Professor of Pediatrics, Seattle Children's Hospital
ClinicalTrials.gov Identifier: NCT02054156     History of Changes
Other Study ID Numbers: OPTIMIZE-IP-12, 1U01HL114623-01A1, 1U01HL114589-01A1
Study First Received: February 1, 2014
Last Updated: August 4, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Seattle Children's Hospital:
Cystic fibrosis (CF)
Azithromycin
Tobramycin solution for inhalation (TIS)
Pseudomonas aeruginosa (Pa)
Early Pseudomonas aeruginosa infection
Pulmonary exacerbation
Standardized anti-pseudomonal therapy

Additional relevant MeSH terms:
Infection
Fibrosis
Cystic Fibrosis
Pseudomonas Infections
Pathologic Processes
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Gram-Negative Bacterial Infections
Bacterial Infections
Pharmaceutical Solutions
Tobramycin
Therapeutic Uses
Pharmacologic Actions
Anti-Bacterial Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on September 18, 2014