Clinical trial NCT01349192: Early Methicillin-resistant Staphylococcus Aureus (MRSA) Therapy in Cystic Fibrosis (CF)
Official title: Early MRSA Therapy in CF - Culture Based vs. Observant Therapy (Treat or Observe) (Star-TOO - STaph Aureus Resistance - Treat or Observe)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Cystic Fibrosis
Methicillin-resistant Staphylococcus Aureus
Keywords: MRSA
Cystic Fibrosis
Early Infection
Treatment
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
Collaborators: name: CF Therapeutics Development Network Coordinating Center
name: Seattle Children's Hospital
name: Washington University School of Medicine
name: University of Washington
name: University of Colorado, Denver
name: Baylor College of Medicine
name: University of Alabama at Birmingham
name: Cook Children's Medical Center
name: University of Michigan
name: University of Florida
name: University of Texas Southwestern Medical Center
name: Children's Hospital Medical Center, Cincinnati
name: St. Louis Children's Hospital
First posted: 2011-05-06
Enrollment: 47
Sex: ALL
Minimum age (years): 4
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Purpose: There has been a recent, rapid increase in prevalence of Methicillin-resistant Staphylococcus aureus (MRSA) among patients with Cystic Fibrosis (22% across US CF centers in 2009). Some epidemiologic studies suggest possible worse outcomes, a recent analyses showing this with chronic but not intermittent MRSA. Given the chronic difficult to treat lung infections in CF it is unclear how the onset of MRSA should be approached. This randomized, controlled, interventional study seeks to determine if an early eradication protocol is effective for eradication of MRSA and will provide an opportunity to obtain data regarding early clinical impact of new isolation of MRSA.

Participants: Cystic fibrosis patients with new isolation of MRSA from their respiratory culture on a routine clinic visit.

Procedures (methods): Randomized, open-label, multi-center study comparing use of an eradication protocol to an observational group who receives the current standard of care i.e. treatment for MRSA only with pulmonary exacerbations.

Detailed description: The STAR-too study is a randomized, open label, multi-center study in CF patients with new MRSA isolated from the respiratory tract (sputum or oropharyngeal (OP) swab). The purpose of the study is to compare use of a two week eradication treatment protocol to an observational group treated for MRSA only when respiratory symptoms meet the criteria for a protocol defined pulmonary exacerbation during the first 28 days of the study. A total of 90 participants, four years of age or older, with new MRSA infection are planned to be randomized in a 1:1 fashion to either the treatment arm or to the observational control arm. Randomization is stratified by age, P. aeruginosa status at screening and site. Each participant randomized to the treatment arm receives two oral antibiotics for 14 days, topical antibacterial treatment of skin and nares, and a three week environmental decontamination for high risk areas and equipment. Each participant randomized to the observational control arm is followed clinically with usual care except to treat new or worsening pulmonary symptoms with antibiotics between screening and Day 28 only when participant meets criteria for a protocol defined exacerbation. Participants continue in the study for 6 months with study visits at Day 84 and Day 168 corresponding with their normal quarterly visits, this extension of observation provides additional data regarding natural history of MRSA infection and durability of the eradication protocol. The primary outcome is the proportion of participants with MRSA eradicated from respiratory tract cultures at Day 28. The secondary outcomes number of, and time to, pulmonary exacerbations, and use of antibiotics.

Eligibility criteria: Inclusion Criteria:

1. Male or female ≥ 4 and ≤ 45 years of age at the Screening Visit.
2. Documentation of a CF diagnosis as evidenced by one or more clinical features consistent with the CF phenotype and one or more of the following criteria:

   * sweat chloride ≥ 60 mEq/liter by quantitative pilocarpine iontophoresis test (QPIT)
   * two well-characterized mutations in the cystic fibrosis transmembrane conductive regulator (CFTR) gene
   * Abnormal nasal potential difference (change in NPD in response to a low chloride solution and isoproteronol of less than -5 mV)
3. First OR early repeat MRSA colonization defined as:

   * First MRSA colonization: first documented isolation of MRSA from respiratory tract occurred ≤ 6 months prior to screening
   * OR Early repeat MRSA colonization:

   MRSA was previously isolated from the respiratory tract (≤ 2 times), but this was followed by at least 1 year of documented negative cultures for MRSA as noted below:

   -- At least 2 cultures performed at least 3 months apart to document 1 year of culture negativity. Each of these cultures should be documented to have been collected at least 1 week after end of any antibiotic prescription with MRSA activity.

   Patient again recently positive for MRSA from the respiratory tract (within 6 months prior to screening)
4. Clinically stable with no significant changes in health status within the 14 days prior to screening
5. Written informed consent (and assent when applicable) obtained from subject or subject's legal representative and ability for subject to comply with the requirements of the study

A repeat culture from the respiratory tract is obtained at screening but does not have to be positive to be able to enter the study.

Exclusion Criteria:

1. Received antibiotics with activity against MRSA within 28 days prior to screening (see study manual for list of antibiotics)
2. Use of an investigational agent within 28 days prior to screening
3. For subjects ≥ 6 years of age: FEV1 at screening \< 30% of predicted for age based on the Wang (males \< 18 years, females \< 16 years) or Hankinson (males ≥ 18 years, females ≥ 16 years) standardized equations
4. MRSA from the screening culture resistant to rifampin OR resistant to both TMP/SMX and minocycline
5. History of intolerance to oral rifampin, or topical chlorhexidine or mupirocin
6. History of intolerance to both TMP/SMX and minocycline
7. \< 8 years of age and either allergic or intolerant to TMP/SMX or screening MRSA resistant to TMP/SMX
8. ≥ 8 years of age and allergic or intolerant to TMP/SMX and screening MRSA resistant to minocycline
9. ≥ 8 years of age and allergic or intolerant to minocycline and screening MRSA resistant to TMP/SMX
10. For females of child bearing potential: pregnant, breastfeeding, or unwilling to use barrier contraception through Day 15 of the study
11. Abnormal renal function at Screening, defined as estimated creatinine clearance \<50 mL/min using the Cockcroft-Gault equation
12. Abnormal liver function at the time of screening, defined as ≥2x upper limit of normal (ULN), of serum aspartate transaminase (AST) or serum alanine transaminase (ALT)
13. History of solid organ or hematological transplantation
14. Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.

Primary outcomes:
measure: MRSA Culture Status
timeFrame: Day 28
Secondary outcomes:
measure: Antibiotic Use (Proportion of Subjects)
timeFrame: 6 months
measure: Antibiotic Use (Days of Use Per Subject)
timeFrame: 6 months
measure: Pulmonary Exacerbations
timeFrame: 28 days
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: The Children's Hospital-University of Birmingham
state: Alabama
city: Aurora
country: United States
facility: The Children's Hospital
state: Colorado
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Ann Arbor
country: United States
facility: University of Michigan Health System
state: Michigan
city: Minneapolis
country: United States
facility: Children's Hospitals and Clinics of Minnesota Minneapolis
state: Minnesota
city: St. Louis
country: United States
facility: St. Louis Children's Hospital
state: Missouri
city: Chapel Hill
country: United States
facility: N.C Memorial Hospital and N.C Children's Hospital
state: North Carolina
city: Cincinnati
country: United States
facility: CFF Care Center & Pediatric Program Cincinnati Children's Hospital Medical Center
state: Ohio
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Seattle
country: United States
facility: Seattle Children's
state: Washington
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
Study officials:
affiliation: UNC Children's Hospital
name: Marianne S Muhlebach, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Washington
name: Chris Goss, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Muhlebach MS, Beckett V, Popowitch E, Miller MB, Baines A, Mayer-Hamblett N, Zemanick ET, Hoover WC, VanDalfsen JM, Campbell P, Goss CH; STAR-too study team. Microbiological efficacy of early MRSA treatment in cystic fibrosis in a randomised controlled trial. Thorax. 2017 Apr;72(4):318-326. doi: 10.1136/thoraxjnl-2016-208949. Epub 2016 Nov 15.