Persistent Methicillin Resistant Staphylococcus Aureus Eradication Protocol (PMEP)

Study Overview
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Brief Summary
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The prevalence of methicillin resistant Staphylococcus aureus (MRSA) respiratory infection in Cystic Fibrosis (CF) has increased dramatically over the last decade. Evidence suggests that persistent infection with MRSA may result in an increased rate of decline in Forced Expiratory Volume (FEV)1 and shortened survival. Currently there are no conclusive studies demonstrating an effective aggressive treatment protocol for persistent MRSA respiratory infection in CF. Data demonstrating an effective and safe method of clearing persistent MRSA infection are needed. The purpose of this study is to evaluate the safety and efficacy of a 28-day course of vancomycin for inhalation, 250 mg twice a day, (in combination with oral antibiotics) in eliminating MRSA from the respiratory tract of individuals with CF and persistent MRSA infection. Subjects will be assigned in a 1:1 ratio to either vancomycin for inhalation (250 mg twice a day) or taste matched placebo and will be followed for 3 additional months. In addition, both groups will receive oral rifampin, a second oral antibiotic (TMP-SMX or doxycycline, protocol determined), mupirocin intranasal cream and chlorhexidine body washes. Forty patients with persistent respiratory tract MRSA infection will be enrolled in this trial.

Detailed Description
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Primary Objectives The primary objectives of this trial are to: Determine the efficacy of an aggressive treatment protocol in eradicating persistent MRSA infection in individuals with CF. Determine the safety of an aggressive treatment protocol in eradicating persistent MRSA infection in individuals with CF. Secondary Objectives The secondary objectives of this trial are to: Determine the efficacy of an aggressive treatment protocol in improving Forced Expiratory Volume (FEV)1, time to exacerbation, and quality of life in individuals with CF and persistent MRSA infection. Determine if there is benefit to adding nebulized vancomycin to an aggressive oral antibiotic treatment protocol in eradicating persistent MRSA infection in individuals with CF.

Official Title
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Persistent MRSA Eradication Protocol (PMEP)

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Inhaled Vancomycin
* Drug: Placebo (Sterile Water)
* Drug: Rifampin
* Drug: Trimethoprim/Sulfamethoxazole (TMP/SMX)
* Drug: Doxycycline
* Drug: Mupirocin Intranasal Creme
* Drug: 4% chlorhexidine gluconate liquid skin cleanser


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥ 12 years of age. Confirmed diagnosis of CF based on the following criteria: positive sweat chloride > 60 mEq/liter (by pilocarpine iontophoresis) and/or a genotype with two identifiable mutations consistent with CF or abnormal Nasal Potential Difference (NPD), and one or more clinical features consistent with the CF phenotype. 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. Two positive MRSA respiratory cultures in the last two years at least six months apart, plus a positive MRSA respiratory culture at Screening Visit and Run-in (Day -14) Visit. At least 50% of respiratory cultures from the time of the first MRSA culture (in the last two years) have been positive for MRSA. Forced Expiratory Volume (FEV)1 > 40% of predicted normal for age, gender, and height at Screening, for subjects 18 years of age or older.. FEV1> 60% of predicted normal for age, gender, and height at Screening, for subjects 12--17 years of old. Females of childbearing potential must agree to practice one highly effective method of birth control, including abstinence. Note: highly effective methods of birth control are those, alone or in combination, that result in a failure rate less than 1% per year when used consistently and correctly. Female patients who utilize hormonal contraceptives as a birth control method must have used the same method for at least 3 months before study dosing. If the patient is using a hormonal form of contraception, patients will be required to also use barrier contraceptives as rifampin can affect the reliability of hormone therapy. Barrier contraceptives such as male condom or diaphragm are acceptable if used in combination with spermicides Exclusion Criteria: An acute upper or lower respiratory infection, pulmonary exacerbation, or change in routine therapy (including antibiotics) for pulmonary disease within 42 days of the Day 1 Visit (2 weeks prior to Screening visit). Individuals on chronic continuous inhaled antibiotics without interruption who are not willing to substitute vancomycin or placebo for their scheduled inhaled antibiotic during days 0-28 of the study (every other month inhaled antibiotics are acceptable) Use of oral or inhaled anti-MRSA drugs within two weeks of the Screening Visit. History of intolerance to inhaled vancomycin or inhaled albuterol. History of intolerance to rifampin or both TMP/SMX and doxycycline. Resistance to rifampin or both TMP/SMX and doxycycline at Screening. Resistance to vancomycin at Screening. Abnormal renal function, defined as creatinine clearance < 50 mL/min using the Cockcroft-Gault equation for adults or Schwartz equation in children, at Screening. Abnormal liver function, defined as ≥ 3x upper limit of normal (ULN), of serum aspartate transaminase (AST) or serum alanine transaminase (ALT), or known cirrhosis. at the time of Screening. Serum hematology or chemistry results which in the judgment of the investigator would interfere with completion of the study. History of or listed for solid organ or hematological transplantation History of sputum culture with non-tuberculous Mycobacteria in the last 6 months. History of sputum culture with Burkholderia Cepacia in the last year. Planned continuous use of soft contact lenses while taking rifampin and no access to glasses. Current use of oral corticosteroids in doses exceeding the equivalent of 10 mg prednisone a day or 20 mg prednisone every other day Administration of any investigational drug or device within 28 days of Screening or within 6 half-lives of the investigational drug (whichever is longer). Patients on inhaled antibiotics must have been on the same regimen for the 4 months prior to screening Female patients of childbearing potential who are pregnant or lactating, or plan on becoming pregnant Any serious or active medical or psychiatric illness, which in the opinion of the investigator, would interfere with patient treatment, assessment, or adherence to the protocol.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inhaled Vanc and Oral Abx<br>In the experimental arm CF participants are randomized to 28 days of inhaled sterile vancomycin (250 mg twice a day) as well as 28 days of oral/skin antibiotics targeted to aggressively treat MRSA infection: oral rifampin, a second oral antibiotic (TMP/SMX or doxycycline, protocol determined), mupirocin intranasal cream and chlorhexidine body washes. Patients will be followed for 3 months after completion of the treatment protocol. | Drug: Inhaled Vancomycin<br>* On Days 1-28, subjects will receive nebulized Vancomycin. This will be supplied as a 250 mg solution to be nebulized two times a day for 28 days in 5cc sterile water. Patients will use a Pari Sprint nebulizer and Pari Vios compressor as the delivery system.<br>* Other names: Vanc;Drug: Rifampin<br>* Oral Rifampin by mouth for 28 days >45 kg: 600 mg by mouth daily 35-45 kg : 450 mg by mouth daily 25-34.9 kg: 300 mg by mouth daily<br>* Other names: Rifadin;Drug: Trimethoprim/Sulfamethoxazole (TMP/SMX)<br>* Oral trimethoprim/sulfamethoxazole (DS-160/800) >45 kg: two DS tablets twice a day by mouth (320/1600) 25-45 kg: one DS tablet twice a day by mouth (160/800)<br>* Other names: Septra;Drug: Doxycycline<br>* If sulfa intolerant or TMP/SMX Resistant, use instead oral doxycycline >45 kg: 100 mg by mouth twice a day 35-45 kg : 75 mg by mouth twice a day iii. 25-34.9 kg: 50 mg by mouth twice a day<br>* Other names: Adoxa;Drug: Mupirocin Intranasal Creme<br>* Mupirocin 2% intranasal creme: half of single use tube applied into each nostril twice a day for 5 days.<br>* Other names: Bactroban;Drug: 4% chlorhexidine gluconate liquid skin cleanser<br>* Hibiclens 15cc liquid skin cleanser packets (4% chlorhexidine gluconate): use three packets once weekly for four weeks in the shower from the neck to toes, with attention on the axilla, groin, and buttocks.<br>* Other names: Hibiclens;|
| Active Comparator: Inhaled Placebo and Oral Abx<br>In the active comparator arm CF participants are randomized to 28 days of inhaled sterile placebo (saline) and are treated with 28 days of oral/skin antibiotics targeted to aggressively treat MRSA infection: oral rifampin, a second oral antibiotic (TMP/SMX or doxycycline, protocol determined), mupirocin intranasal cream and chlorhexidine body washes. Patients will be followed for 3 months after completion of the treatment protocol. | Drug: Placebo (Sterile Water)<br>* On Days 1-28, subjects will receive 5cc of a nebulized Placebo (Sterile water) twice a day. This is a taste (quinine 0.1mg/mL) matched nebulized placebo (sterile water). Patients will use a Pari Sprint nebulizer and Pari Vios compressor as the delivery system.<br>* Other names: Placebo;Drug: Rifampin<br>* Oral Rifampin by mouth for 28 days >45 kg: 600 mg by mouth daily 35-45 kg : 450 mg by mouth daily 25-34.9 kg: 300 mg by mouth daily<br>* Other names: Rifadin;Drug: Trimethoprim/Sulfamethoxazole (TMP/SMX)<br>* Oral trimethoprim/sulfamethoxazole (DS-160/800) >45 kg: two DS tablets twice a day by mouth (320/1600) 25-45 kg: one DS tablet twice a day by mouth (160/800)<br>* Other names: Septra;Drug: Doxycycline<br>* If sulfa intolerant or TMP/SMX Resistant, use instead oral doxycycline >45 kg: 100 mg by mouth twice a day 35-45 kg : 75 mg by mouth twice a day iii. 25-34.9 kg: 50 mg by mouth twice a day<br>* Other names: Adoxa;Drug: Mupirocin Intranasal Creme<br>* Mupirocin 2% intranasal creme: half of single use tube applied into each nostril twice a day for 5 days.<br>* Other names: Bactroban;Drug: 4% chlorhexidine gluconate liquid skin cleanser<br>* Hibiclens 15cc liquid skin cleanser packets (4% chlorhexidine gluconate): use three packets once weekly for four weeks in the shower from the neck to toes, with attention on the axilla, groin, and buttocks.<br>* Other names: Hibiclens;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients MRSA Free by Induced Sputum Respiratory Tract Culture | The hypothesis for our primary outcome is that the aggressive treatment arm will result in significantly greater eradication of persistent MRSA from the respiratory tract of CF adolescents and adults on day 58 (1 month after completion of therapy) compared to the placebo/standard treatment arm. Our primary outcome will be comparing the proportion of CF patients in the treatment arm who have a negative induced sputum MRSA culture at Day 58 to the proportion of patients in the placebo arm who have a negative induced sputum MRSA culture at Day 58. | Day 58 (Visit 5), approximately 1 month after completion of the MRSA treatment protocol | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients MRSA Free by Induced Sputum Respiratory Tract Culture | Percentage of patients MRSA free by induced sputum respiratory tract culture one day after completion of four-week eradication protocol (Day 29) in intervention arm vs standard treatment arm | Day 29 | 
| Change in Forced Expiratory Volume (FEV1)% Predicted From Baseline to Day 58 | Change in Forced Expiratory Volume (FEV1)% predicted from baseline to day number 58 | Baseline, Day 58 | 
| Time to First CF Exacerbation | Time to First CF Exacerbation using a standardized exacerbation definition from Day 1 to Day 118 | Day 1 to Day 118 | 
| Total Number of Pulmonary Exacerbations | Total Number of Pulmonary Exacerbations using a standardized exacerbation definition at Days 58 and Days 118 in treatment vs. standard care group | Days 58 and 118 | 
| Change if FEV1% Predicted From Screening | Change in FEV1% predicted from Screening at Days 29, 58, and 118 in treatment vs. standard care group | Days 29, 58, and 118 | 
| Change in Patient Reported Quality of Life (CFQ-R)(Respiratory) | Change in Patient Reported Quality of Life (CFQ-R)(respiratory) from baseline to Days 29 and 58. CFQ-R stands for Cystic Fibrosis Quality of Life Measure, Respiratory Domain. Overall range of absolute score 0 to +80. Higher score means better quality of life. Positive change in score means improvement in quality of life. Minimally clinically significant difference: +/- 4.0 units. | Days 29 and 58 | 
| Development of Antibiotic Resistance | Number of patients with newly developed MRSA resistance to vancomycin, TMP/SMX, doxycycline, or rifampin. | Day 58 (Visit 5) | 
| Time to First Anti-MRSA Antibiotics (After Treatment Period) | Time between completion of Study Drug and need for anti-MRSA antibiotics to control or treat symptoms | Completion of Study Drug to Day 118 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Methicillin-resistant Staphylococcus aureus, Vancomycin