Early Methicillin-resistant Staphylococcus Aureus (MRSA) Therapy in Cystic Fibrosis (CF)

Phase 2

Terminated

• Conditions: Cystic Fibrosis; Methicillin-resistant Staphylococcus Aureus
• Interventions: Drug: Rifampin; Drug: Trimethoprim/Sulfamethoxazole; Drug: Minocycline; Drug: Mupirocin; Drug: chlorhexidine gluconate oral rinse; Drug: 2% Chlorhexidine solution wipes; Behavioral: Environmental Decontamination

• Registration Number: NCT01349192
• Lead Sponsor: University of North Carolina, Chapel Hill

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.

Study Timeline

• Study Start: 2011-04
• Study First Submitted: 2011-05-04
• Study First Submitted QC: 2011-05-05
• Study First Posted: 2011-05-06
• Primary Completion: 2015-01
• Study Completion: 2015-05
• Results First Submitted: 2016-11-02
• Status Verified: 2017-04
• Results First Submitted QC: 2017-04-05
• Last Update Submitted: 2017-04-05
• Results First Posted: 2017-05-15
• Last Update Posted: 2017-05-15

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 47

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment	Rifampin	Subjects are treated with two oral antibiotics, topical antibiotics, and are instructed to use environmental decontamination techniques.
Treatment	Trimethoprim/Sulfamethoxazole	Subjects are treated with two oral antibiotics, topical antibiotics, and are instructed to use environmental decontamination techniques.
Treatment	Minocycline	Subjects are treated with two oral antibiotics, topical antibiotics, and are instructed to use environmental decontamination techniques.
Treatment	Mupirocin	Subjects are treated with two oral antibiotics, topical antibiotics, and are instructed to use environmental decontamination techniques.
Treatment	chlorhexidine gluconate oral rinse	Subjects are treated with two oral antibiotics, topical antibiotics, and are instructed to use environmental decontamination techniques.
Treatment	Environmental Decontamination	Subjects are treated with two oral antibiotics, topical antibiotics, and are instructed to use environmental decontamination techniques.
Treatment	2% Chlorhexidine solution wipes	Subjects are treated with two oral antibiotics, topical antibiotics, and are instructed to use environmental decontamination techniques.

Primary Outcome Measures

Name	Time	Method
MRSA Culture Status	Day 28	Proportion of subjects with a negative culture for MRSA at Day 28.

Secondary Outcome Measures

Name	Time	Method
Antibiotic Use (Proportion of Subjects)	6 months	Proportion of subjects treated with oral, inhaled, and IV antibiotics over the 6 month study.
Antibiotic Use (Days of Use Per Subject)	6 months	Days of use of oral, inhaled, and IV antibiotics over the 6 month study.
Pulmonary Exacerbations	28 days	Proportion of subjects with a protocol-defined pulmonary exacerbation (PE) between baseline and day 28 who are treated with antibiotics active against MRSA.

Trial Locations

Locations (13)

St. Louis Children's Hospital; 🇺🇸 St. Louis, Missouri, United States

University of Texas Southwestern Medical Center; 🇺🇸 Dallas, Texas, United States

The Children's Hospital; 🇺🇸 Aurora, Colorado, United States

Cook Children's Medical Center; 🇺🇸 Fort Worth, Texas, United States

Children's Hospitals and Clinics of Minnesota Minneapolis; 🇺🇸 Minneapolis, Minnesota, United States

The Children's Hospital-University of Birmingham; 🇺🇸 Birmingham, Alabama, United States

University of Florida; 🇺🇸 Gainesville, Florida, United States

University of Michigan Health System; 🇺🇸 Ann Arbor, Michigan, United States

N.C Memorial Hospital and N.C Children's Hospital; 🇺🇸 Chapel Hill, North Carolina, United States

CFF Care Center & Pediatric Program Cincinnati Children's Hospital Medical Center; 🇺🇸 Cincinnati, Ohio, United States

University of Washington Medical Center; 🇺🇸 Seattle, Washington, United States

Seattle Children's; 🇺🇸 Seattle, Washington, United States

Baylor College of Medicine; 🇺🇸 Houston, Texas, United States