OPTIMIZing Treatment for Early Pseudomonas Aeruginosa Infection in Cystic Fibrosis

Cystic Fibrosis Clinical Trial

— OPTIMIZE  

Official title:

OPTIMIZing Treatment for Early Pseudomonas Aeruginosa Infection in Cystic Fibrosis: The OPTIMIZE Multicenter, Placebo-Controlled, Double-Blind, Randomized Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02054156
• Other study ID #: OPTIMIZE-IP-12
• Secondary ID: 1U01HL114623-01A
• Status: Completed
• Phase: Phase 3
• Start date: June 2014
• Est. completion date: August 23, 2018

Study information

• Verified date: September 2019
• Source: Seattle Children's Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 221
• Est. completion date: August 23, 2018
• Est. primary completion date: August 23, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis
• Infection
• Pseudomonas Infections

Intervention

Drug:
• azithromycin
3 times weekly, oral suspension, 10 mg/kg/dose up to 500 mg, for 18 months
• placebo
3 times weekly, oral suspension, volume-matched to azithromycin, for 18 months
• 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

Locations

Country	Name	City	State
United States	CFF Care Center & Pediatric Program Akron Children's Hospital	Akron	Ohio
United States	CFF Affiliate Program Providence Medical Center	Anchorage	Alaska
United States	CFF Care Center & Pediatric Program University of Michigan	Ann Arbor	Michigan
United States	CFF Affiliate Program Children's Healthcare of Atlanta	Atlanta	Georgia
United States	CFF Care Center & Pediatric Program Emory University	Atlanta	Georgia
United States	CFF Care Center & Pediatric Program Children's Hospital Colorado	Aurora	Colorado
United States	CFF Care Center & Pediatric Program Dell Children's Medical Center of Central Texas	Austin	Texas
United States	CFF Care Center St. Luke's CF Clinic	Boise	Idaho
United States	CFF Care Center & Pediatric Program Children's Hospital Boston	Boston	Massachusetts
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 Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
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 Children's Hospital of Michigan	Detroit	Michigan
United States	CFF Care Center & Pediatric Program Hershey Medical Center	Hershey	Pennsylvania
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 Nemours Children's Clinic - Jacksonville	Jacksonville	Florida
United States	CFF Care Center The Children's Mercy Hospital	Kansas City	Missouri
United States	CFF Care Center & Pediatric Program Arkansas Children's Hospital	Little Rock	Arkansas
United States	CFF Care Center & Pediatric Program Monmouth Medical Center	Long Branch	New Jersey
United States	Childrens Hospital Los Angeles	Los Angeles	California
United States	CFF Care Center & Pediatric Program University of Wisconsin	Madison	Wisconsin
United States	CFF Care Center & Pediatric Program University of Tennessee	Memphis	Tennessee
United States	CFF Care Center & Pediatric Program Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	CFF Care Center & Pediatric Program Yale University	New Haven	Connecticut
United States	CFF Care Center & Pediatric Program Columbia University	New York	New York
United States	CFF Care Center & Pediatric Program Children's Hospital of the King's Daughters	Norfolk	Virginia
United States	CFF Care Center & Pediatric Program University of Nebraska Medical Center	Omaha	Nebraska
United States	CFF Care Center & Pediatric Program Stanford University	Palo Alto	California
United States	CFF Care Center & Pediatric Program Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	CFF Care Center & Pediatric Program Maine Medical Center	Portland	Maine
United States	CFF Care Center & Pediatric Program Oregon Health & Sciences University	Portland	Oregon
United States	CFF Care Center Medical College of Virginia	Richmond	Virginia
United States	CFF Care Center & Pediatric Program Cardinal Glennon Children's Hospital/Saint Louis University	Saint Louis	Missouri
United States	CFF Care Center & Pediatric Program St. Louis Children's Hospital	Saint Louis	Missouri
United States	CFF Care Center & Pediatric Program All Children's Hospital	Saint Petersburg	Florida
United States	University of Utah	Salt Lake City	Utah
United States	CFF Care Center & Pediatric Program Seattle Children's Hospital	Seattle	Washington
United States	CFF Care Center & Pediatric Program Sanford USD Medical Center	Sioux Falls	South Dakota
United States	CFF Care Center & Pediatric Program SUNY Upstate Medical University	Syracuse	New York
United States	CFF Care Center Arizona Health Science Center	Tucson	Arizona
United States	CFF Care Center New York Medical College	Valhalla	New York

Sponsors (2)

Lead Sponsor	Collaborator
Bonnie Ramsey	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Time to Pseudomonas Aeruginosa (Pa) Recurrence	Time to Pseudomonas aeruginosa (Pa) recurrence after the first quarter of treatment	Over the 18-month study period
Secondary	Adverse Events (AEs) and Serious Adverse Events (SAEs)	The number and percentage of participants with at least one event over the 18-month study period.	Over the 18-month study period
Secondary	Rate of Adverse Events (AEs) and Serious Adverse Events (SAEs)	Rate is defined as the number of events per participant follow-up month.	Over the 18-month study period