Clinical trial NCT01594827: Persistent Methicillin Resistant Staphylococcus Aureus Eradication Protocol (PMEP)
Official title: Persistent MRSA Eradication Protocol (PMEP)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cystic Fibrosis
Keywords: Methicillin-resistant Staphylococcus aureus
Vancomycin
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: Case Western Reserve University
name: Cystic Fibrosis Foundation
First posted: 2012-05-09
Enrollment: 29
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: Primary Objectives

The primary objectives of this trial are to:

1. Determine the efficacy of an aggressive treatment protocol in eradicating persistent MRSA infection in individuals with CF.
2. 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:

1. 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.
2. 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.

Eligibility criteria: Inclusion Criteria:

1. Male or female ≥ 12 years of age.
2. 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.
3. 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.
4. 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.
5. At least 50% of respiratory cultures from the time of the first MRSA culture (in the last two years) have been positive for MRSA.
6. Forced Expiratory Volume (FEV)1 \> 40% of predicted normal for age, gender, and height at Screening, for subjects 18 years of age or older..
7. FEV1\> 60% of predicted normal for age, gender, and height at Screening, for subjects 12--17 years of old.
8. 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:

1. 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).
2. 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)
3. Use of oral or inhaled anti-MRSA drugs within two weeks of the Screening Visit.
4. History of intolerance to inhaled vancomycin or inhaled albuterol.
5. History of intolerance to rifampin or both TMP/SMX and doxycycline.
6. Resistance to rifampin or both TMP/SMX and doxycycline at Screening.
7. Resistance to vancomycin at Screening.
8. Abnormal renal function, defined as creatinine clearance \< 50 mL/min using the Cockcroft-Gault equation for adults or Schwartz equation in children, at Screening.
9. 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.
10. Serum hematology or chemistry results which in the judgment of the investigator would interfere with completion of the study.
11. History of or listed for solid organ or hematological transplantation
12. History of sputum culture with non-tuberculous Mycobacteria in the last 6 months.
13. History of sputum culture with Burkholderia Cepacia in the last year.
14. Planned continuous use of soft contact lenses while taking rifampin and no access to glasses.
15. Current use of oral corticosteroids in doses exceeding the equivalent of 10 mg prednisone a day or 20 mg prednisone every other day
16. Administration of any investigational drug or device within 28 days of Screening or within 6 half-lives of the investigational drug (whichever is longer).
17. Patients on inhaled antibiotics must have been on the same regimen for the 4 months prior to screening
18. Female patients of childbearing potential who are pregnant or lactating, or plan on becoming pregnant
19. 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.

Primary outcomes:
measure: Number of Patients MRSA Free by Induced Sputum Respiratory Tract Culture
timeFrame: Day 58 (Visit 5), approximately 1 month after completion of the MRSA treatment protocol
Secondary outcomes:
measure: Percentage of Patients MRSA Free by Induced Sputum Respiratory Tract Culture
timeFrame: Day 29
measure: Change in Forced Expiratory Volume (FEV1)% Predicted From Baseline to Day 58
timeFrame: Baseline, Day 58
measure: Time to First CF Exacerbation
timeFrame: Day 1 to Day 118
measure: Total Number of Pulmonary Exacerbations
timeFrame: Days 58 and 118
measure: Change if FEV1% Predicted From Screening
timeFrame: Days 29, 58, and 118
measure: Change in Patient Reported Quality of Life (CFQ-R)(Respiratory)
timeFrame: Days 29 and 58
measure: Development of Antibiotic Resistance
timeFrame: Day 58 (Visit 5)
measure: Time to First Anti-MRSA Antibiotics (After Treatment Period)
timeFrame: Completion of Study Drug to Day 118
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins University School of Medicine
state: Maryland
city: Cleveland
country: United States
facility: Rainbow Babies and Children's Hospital
state: Ohio
Study officials:
affiliation: Johns Hopkins School of Medicine
name: Michael P Boyle, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Case Western University
name: James Chmiel, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Dasenbrook EC, Checkley W, Merlo CA, Konstan MW, Lechtzin N, Boyle MP. Association between respiratory tract methicillin-resistant Staphylococcus aureus and survival in cystic fibrosis. JAMA. 2010 Jun 16;303(23):2386-92. doi: 10.1001/jama.2010.791.
citation: Dasenbrook EC, Merlo CA, Diener-West M, Lechtzin N, Boyle MP. Persistent methicillin-resistant Staphylococcus aureus and rate of FEV1 decline in cystic fibrosis. Am J Respir Crit Care Med. 2008 Oct 15;178(8):814-21. doi: 10.1164/rccm.200802-327OC. Epub 2008 Jul 31.
citation: Jennings MT, Boyle MP, Weaver D, Callahan KA, Dasenbrook EC. Eradication strategy for persistent methicillin-resistant Staphylococcus aureus infection in individuals with cystic fibrosis--the PMEP trial: study protocol for a randomized controlled trial. Trials. 2014 Jun 12;15:223. doi: 10.1186/1745-6215-15-223.