Persistent Methicillin Resistant Staphylococcus Aureus Eradication Protocol (PMEP)

Cystic Fibrosis Clinical Trial

— PMEP  

Official title:

Persistent MRSA Eradication Protocol (PMEP)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01594827
• Other study ID #: NA_00017536
• Status: Completed
• Phase: Phase 2
• Start date: October 2012
• Est. completion date: December 30, 2017

Study information

• Verified date: February 2019
• Source: Johns Hopkins University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 29
• Est. completion date: December 30, 2017
• Est. primary completion date: December 30, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Cystic Fibrosis
• Staphylococcal Infections

Intervention

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.
• 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.
• Rifampin
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
• Trimethoprim/Sulfamethoxazole (TMP/SMX)
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)
• Doxycycline
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
• Mupirocin Intranasal Creme
Mupirocin 2% intranasal creme: half of single use tube applied into each nostril twice a day for 5 days.
• 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.

Locations

Country	Name	City	State
United States	Johns Hopkins University School of Medicine	Baltimore	Maryland
United States	Rainbow Babies and Children's Hospital	Cleveland	Ohio

Sponsors (3)

Lead Sponsor	Collaborator
Johns Hopkins University	Case Western Reserve University, Cystic Fibrosis Foundation

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Development of Antibiotic Resistance	Number of patients with newly developed MRSA resistance to vancomycin, TMP/SMX, doxycycline, or rifampin.	Day 58 (Visit 5)
Secondary	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

External Links

•   Cystic Fibrosis Foundation website
•   Johns Hopkins Cystic Fibrosis Center website