Persistent Methicillin Resistant Staphylococcus Aureus Eradication Protocol (PMEP)

NCT01594827 | Completed Phase 2 Results DMC

• 1 other identifier: NA_00017536
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 2

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.

Conditions

Cystic Fibrosis

Keywords

Methicillin-resistant Staphylococcus aureus; Vancomycin

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• Percentage of Patients MRSA Free by Induced Sputum Respiratory Tract Culture

  Day 29

• Change in Forced Expiratory Volume (FEV1)% Predicted From Baseline to Day 58

  Baseline, Day 58

• Time to First CF Exacerbation

  Day 1 to Day 118

• Total Number of Pulmonary Exacerbations

  Days 58 and 118

• Change if FEV1% Predicted From Screening

  Days 29, 58, and 118

Study Arms (2)

Inhaled Vanc and Oral Abx

EXPERIMENTAL

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; Drug: Rifampin; Drug: Trimethoprim/Sulfamethoxazole (TMP/SMX); Drug: Doxycycline; Drug: Mupirocin Intranasal Creme; Drug: 4% chlorhexidine gluconate liquid skin cleanser

Inhaled Placebo and Oral Abx

ACTIVE COMPARATOR

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); Drug: Rifampin; Drug: Trimethoprim/Sulfamethoxazole (TMP/SMX); Drug: Doxycycline; Drug: Mupirocin Intranasal Creme; Drug: 4% chlorhexidine gluconate liquid skin cleanser

Interventions

Inhaled Vancomycin DRUG

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.

Also known as: Vanc

Inhaled Vanc and Oral Abx

Placebo (Sterile Water) DRUG

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.

Also known as: Placebo

Inhaled Placebo and Oral Abx

Rifampin DRUG

Oral Rifampin by mouth for 28 days 1. \>45 kg: 600 mg by mouth daily 2. 35-45 kg : 450 mg by mouth daily 3. 25-34.9 kg: 300 mg by mouth daily

Also known as: Rifadin

Inhaled Placebo and Oral Abx; Inhaled Vanc and Oral Abx

Trimethoprim/Sulfamethoxazole (TMP/SMX) DRUG

Oral trimethoprim/sulfamethoxazole (DS-160/800) 1. \>45 kg: two DS tablets twice a day by mouth (320/1600) 2. 25-45 kg: one DS tablet twice a day by mouth (160/800)

Also known as: Bactrim, Septra

Inhaled Placebo and Oral Abx; Inhaled Vanc and Oral Abx

Doxycycline DRUG

If sulfa intolerant or TMP/SMX Resistant, use instead oral doxycycline 1. \>45 kg: 100 mg by mouth twice a day 2. 35-45 kg : 75 mg by mouth twice a day iii. 25-34.9 kg: 50 mg by mouth twice a day

Also known as: Vibramycin, Adoxa

Inhaled Placebo and Oral Abx; Inhaled Vanc and Oral Abx

Mupirocin Intranasal Creme DRUG

Mupirocin 2% intranasal creme: half of single use tube applied into each nostril twice a day for 5 days.

Also known as: Bactroban

Inhaled Placebo and Oral Abx; Inhaled Vanc and Oral Abx

4% chlorhexidine gluconate liquid skin cleanser DRUG

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.

Also known as: Hibiclens

Inhaled Placebo and Oral Abx; Inhaled Vanc and Oral Abx

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Johns Hopkins University: lead
• Case Western Reserve University: collaborator
• Cystic Fibrosis Foundation: collaborator

Study Sites (2)

Johns Hopkins University School of Medicine

Baltimore, Maryland, 21205, United States

Location

Rainbow Babies and Children's Hospital

Cleveland, Ohio, 44106, United States

Location

Related Publications (4)

• 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.

  PMID: 20551409 BACKGROUND

• 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.

  PMID: 18669817 BACKGROUND

• 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.

  PMID: 24925006 BACKGROUND

• Lo DK, Muhlebach MS, Smyth AR. Interventions for the eradication of meticillin-resistant Staphylococcus aureus (MRSA) in people with cystic fibrosis. Cochrane Database Syst Rev. 2022 Dec 13;12(12):CD009650. doi: 10.1002/14651858.CD009650.pub5.

  PMID: 36511181 DERIVED

Related Links

• Johns Hopkins Cystic Fibrosis Center website

MeSH Terms

Conditions

Cystic Fibrosis

Interventions

Rifampin; Trimethoprim; Sulfamethoxazole; Trimethoprim, Sulfamethoxazole Drug Combination; Doxycycline; Mupirocin; chlorhexidine gluconate

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Pyrimidines; Heterocyclic Compounds, 1-Ring; Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Sulfanilamides; Aniline Compounds; Amines; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Drug Combinations; Pharmaceutical Preparations; Tetracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Epoxy Compounds; Ethers, Cyclic; Ethers; Pyrans; Fatty Acids; Lipids

Limitations and Caveats

Easy termination leading to smaller number of subjects analyzed.

Results Point of Contact

• Title: Dr. Mark Jennings
• Organization: Johns Hopkins Unviversity School of Medicine

mjenni15@jhmi.edu

410-502-7044

Study Officials

• Michael P Boyle, MD

  Johns Hopkins School of Medicine

  PRINCIPAL INVESTIGATOR

• James Chmiel, MD

  Case Western University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 7, 2012
• First Posted: May 9, 2012
• Study Start: October 1, 2012
• Primary Completion: December 30, 2017
• Study Completion: December 30, 2017
• Last Updated: February 26, 2019
• Results First Posted: November 20, 2018

Record last verified: 2019-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)