Persistent Methicillin Resistant Staphylococcus Aureus Eradication Protocol (PMEP) (PMEP)
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| ClinicalTrials.gov Identifier: NCT01594827 |
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Recruitment Status :
Completed
First Posted : May 9, 2012
Results First Posted : November 20, 2018
Last Update Posted : February 26, 2019
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Sponsor:
Johns Hopkins University
Collaborators:
Case Western Reserve University
Cystic Fibrosis Foundation
Information provided by (Responsible Party):
Johns Hopkins University
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Brief Summary:
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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Cystic Fibrosis | 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 | Phase 2 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 29 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Primary Purpose: | Treatment |
| Official Title: | Persistent MRSA Eradication Protocol (PMEP) |
| Actual Study Start Date : | October 2012 |
| Actual Primary Completion Date : | December 30, 2017 |
| Actual Study Completion Date : | December 30, 2017 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Cystic fibrosis
| Arm | Intervention/treatment |
|---|---|
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Experimental: Inhaled Vanc and Oral Abx
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.
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Drug: Inhaled Vancomycin
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.
Other Name: Vanc Drug: Rifampin Oral Rifampin by mouth for 28 days
Other Name: Rifadin Drug: Trimethoprim/Sulfamethoxazole (TMP/SMX) Oral trimethoprim/sulfamethoxazole (DS-160/800)
Other Names:
Drug: Doxycycline If sulfa intolerant or TMP/SMX Resistant, use instead oral doxycycline
Other Names:
Drug: Mupirocin Intranasal Creme Mupirocin 2% intranasal creme: half of single use tube applied into each nostril twice a day for 5 days.
Other Name: Bactroban Drug: 4% chlorhexidine gluconate liquid skin cleanser 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.
Other Name: Hibiclens |
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Active Comparator: Inhaled Placebo and Oral Abx
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.
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Drug: Placebo (Sterile Water)
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.
Other Name: Placebo Drug: Rifampin Oral Rifampin by mouth for 28 days
Other Name: Rifadin Drug: Trimethoprim/Sulfamethoxazole (TMP/SMX) Oral trimethoprim/sulfamethoxazole (DS-160/800)
Other Names:
Drug: Doxycycline If sulfa intolerant or TMP/SMX Resistant, use instead oral doxycycline
Other Names:
Drug: Mupirocin Intranasal Creme Mupirocin 2% intranasal creme: half of single use tube applied into each nostril twice a day for 5 days.
Other Name: Bactroban Drug: 4% chlorhexidine gluconate liquid skin cleanser 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.
Other Name: Hibiclens |
Primary Outcome Measures :
- Number of Patients MRSA Free by Induced Sputum Respiratory Tract Culture [ Time Frame: Day 58 (Visit 5), approximately 1 month after completion of the MRSA treatment protocol ]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.
Secondary Outcome Measures :
- Percentage of Patients MRSA Free by Induced Sputum Respiratory Tract Culture [ Time Frame: Day 29 ]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
- Change in Forced Expiratory Volume (FEV1)% Predicted From Baseline to Day 58 [ Time Frame: Baseline, Day 58 ]Change in Forced Expiratory Volume (FEV1)% predicted from baseline to day number 58
- Time to First CF Exacerbation [ Time Frame: Day 1 to Day 118 ]Time to First CF Exacerbation using a standardized exacerbation definition from Day 1 to Day 118
- Total Number of Pulmonary Exacerbations [ Time Frame: Days 58 and 118 ]Total Number of Pulmonary Exacerbations using a standardized exacerbation definition at Days 58 and Days 118 in treatment vs. standard care group
- Change if FEV1% Predicted From Screening [ Time Frame: Days 29, 58, and 118 ]Change in FEV1% predicted from Screening at Days 29, 58, and 118 in treatment vs. standard care group
- Change in Patient Reported Quality of Life (CFQ-R)(Respiratory) [ Time Frame: Days 29 and 58 ]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.
- Development of Antibiotic Resistance [ Time Frame: Day 58 (Visit 5) ]Number of patients with newly developed MRSA resistance to vancomycin, TMP/SMX, doxycycline, or rifampin.
- Time to First Anti-MRSA Antibiotics (After Treatment Period) [ Time Frame: Completion of Study Drug to Day 118 ]Time between completion of Study Drug and need for anti-MRSA antibiotics to control or treat symptoms
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| Ages Eligible for Study: | 12 Years and older (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Male or female ≥ 12 years of age.
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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.
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01594827
Locations
| United States, Maryland | |
| Johns Hopkins University School of Medicine | |
| Baltimore, Maryland, United States, 21205 | |
| United States, Ohio | |
| Rainbow Babies and Children's Hospital | |
| Cleveland, Ohio, United States, 44106 | |
Sponsors and Collaborators
Johns Hopkins University
Case Western Reserve University
Cystic Fibrosis Foundation
Investigators
| Principal Investigator: | Michael P Boyle, MD | Johns Hopkins School of Medicine | |
| Principal Investigator: | James Chmiel, MD | Case Western University |
Study Documents (Full-Text)
Documents provided by Johns Hopkins University:
Documents provided by Johns Hopkins University:
Study Protocol and Statistical Analysis Plan [PDF] November 25, 2015
Additional Information:
Publications:
Publications:
| Responsible Party: | Johns Hopkins University |
| ClinicalTrials.gov Identifier: | NCT01594827 |
| Other Study ID Numbers: |
NA_00017536 |
| First Posted: | May 9, 2012 Key Record Dates |
| Results First Posted: | November 20, 2018 |
| Last Update Posted: | February 26, 2019 |
| Last Verified: | February 2019 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
Keywords provided by Johns Hopkins University:
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Methicillin-resistant Staphylococcus aureus Vancomycin |
Additional relevant MeSH terms:
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Cystic Fibrosis Pancreatic Diseases Digestive System Diseases Lung Diseases Respiratory Tract Diseases Genetic Diseases, Inborn Infant, Newborn, Diseases Chlorhexidine Chlorhexidine gluconate Vancomycin Doxycycline Rifampin Trimethoprim Sulfamethoxazole Mupirocin |
Anti-Infective Agents, Local Anti-Infective Agents Disinfectants Dermatologic Agents Anti-Bacterial Agents Antimalarials Antiprotozoal Agents Antiparasitic Agents Antibiotics, Antitubercular Antitubercular Agents Leprostatic Agents Nucleic Acid Synthesis Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Cytochrome P-450 CYP2B6 Inducers |