Cystic Fibrosis, Methicillin-resistant Staphylococcus Aureus
Conditions
Keywords
MRSA, Cystic Fibrosis, Early Infection, 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.
Interventions
DRUGRifampin
Adult Dose: 300mg twice daily for 14 days. Pediatric Dose: \<40kg : 15mg/kg daily for 14 days divided every 12 hours.
Adult Dose: 320/1600 orally twice daily for 14 days. Pediatric Dose: \<40 kg : 8mg/kg trimethoprim / 40 mg/kg sulfamethoxazole twice a day for 14 days.
DRUGMinocycline
only subjects greater or equal to 8 years of age, who are not able to tolerate TMP/SMX or whose screening MRSA is resistant to TMP/SMX should be prescribed minocycline. Adult dose: 100 mg orally twice daily for 14 days Pediatric dose: \< 50 kg : 2mg/kg orally twice daily for 14 days not to exceed 200mg per day.
DRUGMupirocin
1 gram 2% nasal ointment generously applied to each nostril using a cotton swab twice daily for 14 days.
for subjects able to swish without swallowing. 0.12% chlorhexidine gluconate oral rinse twice daily for 14 days.
DRUG2% Chlorhexidine solution wipes
whole body wash solution wipes once daily for first 5 days.
BEHAVIORALEnvironmental Decontamination
wipe down high touch surfaces and medical equipment with surface disinfecting wipes daily for the first 21 days. wash all linens and towels in hot water once weekly for three weeks.
Sponsors
CF Therapeutics Development Network Coordinating Center
Seattle Children's Hospital
Washington University School of Medicine
University of Washington
University of Colorado, Denver
Baylor College of Medicine
University of Alabama at Birmingham
Cook Children's Medical Center
University of Michigan
University of Florida
University of Texas Southwestern Medical Center
Children's Hospital Medical Center, Cincinnati
St. Louis Children's Hospital
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Masking description
Although this is an open-label study, the PIs and operational study team will remain blinded to the study arm assignments of the aggregate study population and will not view aggregate study results by study arm until after database lock.
Eligibility
Sex/Gender
ALL
Age
4 Years to 45 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MRSA Culture Status | Day 28 | Proportion of subjects with a negative culture for MRSA at Day 28. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
The trial was conducted from April 1, 2011 to September 2014 at 14 CF Foundation accredited care centers in the United States.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Oral antibiotics:
1. Rifampin: Adult Dose: 300mg twice daily for 14 days. Pediatric Dose: \<40kg : 15mg/kg daily for 14 days divided every 12 hours.
2. Trimethoprim/Sulfamethoxazole: Adult Dose: 320/1600 orally twice daily for 14 days.
Pediatric Dose: \<40 kg : 8mg/kg trimethoprim / 40 mg/kg sulfamethoxazole twice a day for 14 days.
Alternative 2) Minocycline: subjects greater or equal to 8 years unable to take TMP/SMX or whose screening MRSA is resistant to TMP/SMX are prescribed minocycline.
Adult dose: 100 mg orally twice daily for 14 days Pediatric dose: \< 50 kg : 2mg/kg orally twice daily for 14 days max 200mg per day.
Topical:
Mupirocin: 1 gram 2% nasal ointment twice daily for 14 days.
Topical: 0.12% chlorhexidine gluconate oral rinse: for 14 days.
Environmental disinfection of high use areas | 24 |
| Observational Subjects are tracked and not treated for their MRSA. If the subject reaches a protocol defined exacerbation within the first 28 days then they will be treated per choice of their primary Pulmonologist. | 21 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Failure to adhere to Protocol | 2 | 0 |
| Overall Study | Lost to Follow-up | 1 | 3 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Treatment | Observational | Total |
|---|---|---|---|
| Age, Continuous | 12.3 years STANDARD_DEVIATION 6.6 | 10.5 years STANDARD_DEVIATION 5.5 | 11.5 years STANDARD_DEVIATION 6.1 |
| Age, Customized Age Category >=12 and <18 years | 6 Participants | 5 Participants | 11 Participants |
| Age, Customized Age Category >18 years | 5 Participants | 1 Participants | 6 Participants |
| Age, Customized Age Category >=4 and <12 years | 13 Participants | 15 Participants | 28 Participants |
| CF Genotype Delta F508 Heterozygous | 14 Participants | 7 Participants | 21 Participants |
| CF Genotype Delta F508 Homozygous | 6 Participants | 12 Participants | 18 Participants |
| CF Genotype Other | 4 Participants | 2 Participants | 6 Participants |
| CF Genotype Unidentified | 0 Participants | 0 Participants | 0 Participants |
| FEV1 Percent of Predicted | 98.5 percent STANDARD_DEVIATION 21.6 | 101.2 percent STANDARD_DEVIATION 11.8 | 99.8 percent STANDARD_DEVIATION 17.6 |
| FEV1 Percent of Predicted Category >100% | 11 Participants | 12 Participants | 23 Participants |
| FEV1 Percent of Predicted Category >=30% to <=50% | 1 Participants | 0 Participants | 1 Participants |
| FEV1 Percent of Predicted Category >50% to <=75% | 1 Participants | 0 Participants | 1 Participants |
| FEV1 Percent of Predicted Category >75% to <=100% | 7 Participants | 5 Participants | 12 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Combined African-American | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Combined Caucasian | 19 Participants | 17 Participants | 36 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Combined Hispanic | 3 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Combined Other | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Female | 10 Participants | 10 Participants | 20 Participants |
| Sex: Female, Male Male | 14 Participants | 11 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 19 / 24 | 13 / 21 |
| serious Total, serious adverse events | 1 / 24 | 1 / 21 |
Outcome results
Primary
MRSA Culture Status
Proportion of subjects with a negative culture for MRSA at Day 28.
Time frame: Day 28
Population: The analysis population is defined as all of the participants who were randomized to a study arm and were assessed for the primary microbiologic efficacy endpoint at both baseline and Day 28.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | MRSA Culture Status | 18 Participants |
| Observation | MRSA Culture Status | 5 Participants |
p-value: 0.000595% CI: [0.25, 0.74]Chi-squared
p-value: 0.000495% CI: [0.23, 0.8]Chi-squared
Secondary
Antibiotic Use (Days of Use Per Subject)
Days of use of oral, inhaled, and IV antibiotics over the 6 month study.
Time frame: 6 months
Population: Intention to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment | Antibiotic Use (Days of Use Per Subject) | 21.9 days | Standard Deviation 23.7 |
| Observation | Antibiotic Use (Days of Use Per Subject) | 31.3 days | Standard Deviation 44 |
p-value: 0.368395% CI: [-30.3, 11.47]t-test, 2 sided
Secondary
Antibiotic Use (Proportion of Subjects)
Proportion of subjects treated with oral, inhaled, and IV antibiotics over the 6 month study.
Time frame: 6 months
Population: Intention to treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Antibiotic Use (Proportion of Subjects) | 17 Participants |
| Observation | Antibiotic Use (Proportion of Subjects) | 13 Participants |
p-value: 0.546395% CI: [-0.18, 0.34]Chi-squared
Secondary
Pulmonary Exacerbations
Proportion of subjects with a protocol-defined pulmonary exacerbation (PE) between baseline and day 28 who are treated with antibiotics active against MRSA.
Time frame: 28 days
Population: Intention to treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Pulmonary Exacerbations | 2 Participants |
| Observation | Pulmonary Exacerbations | 6 Participants |
p-value: 0.120595% CI: [-0.42, 0.03]Chi-squared