Clinical trial NCT02547116: Epidemiology and Treatment of Small-colony Variant Staphylococcus Aureus in Cystic Fibrosis
Official title: Epidemiology and Treatment of Small-colony Variant Staphylococcus Aureus in Cystic Fibrosis
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE4
Conditions: Cystic Fibrosis
MRSA
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
First posted: 2015-09-11
Enrollment: 0
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Methicillin-susceptible (MSSA) and Methicillin-resistant (MRSA) Staphylococcus aureus (SA) are two of the most important infectious pathogens in CF, with 69% of CF patients having lung infection with MSSA or MRSA in the last year. Wolter and co-workers recently demonstrated that a specific morphologic subtype of MSSA and MRSA, small-colony variant Staph aureus (SCV-SA), is associated with greater decline in lung function and worse clinical outcomes. SCV-SA is already recognized for its ability to contribute to persistent infection, likely due to SCV-SA's ability for intracellular growth, as well as its increased antibiotic resistance compared to normal-colony SA. To investigate the epidemiology and clinical significance of SCV-SA in CF, and explore the hypothesis that SCV-SA may require unique antibiotic treatment strategies to optimize clinical response, the investigators will perform the following:

1. Characterize the epidemiology of SCV-SA infection in both an adult and pediatric CF population and investigate the clinical significance of SCV-SA infection in CF by comparing clinical characteristics and outcomes of CF patients with SCV-SA compared to those with to normal-colony MSSA/MRSA.
2. Characterize the unique microbiologic characteristics of SCV-SA infection in CF by evaluating antibiotic susceptibility profiles and molecular characteristics of SCV-SA in a two large CF patient populations.
3. Perform a 16-patient pilot study of a novel treatment for SCV-SA infection in CF, utilizing low dose rifampin in combination with standard anti-SA antibiotics.

These investigations will delineate the role of SCV-SA as a pathogen in CF and provide guidance to optimize treatment strategies of MSSA/MRSA CF lung infection.


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 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 SCV-SA respiratory cultures in the last two years at least six months apart, plus a positive SCV-SA respiratory culture at Screening Visit and Run-in (Day -14) Visit.
5. FEV1 \>30% of predicted normal for age, gender, and height at Screening.
6. Weight \> 35 kg
7. 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 14 days of the screening visit.
2. Use of oral or inhaled anti-MRSA drugs within two weeks of the Screening Visit.
3. History of intolerance to rifampin or TMP/SMX, minocycline, and doxycycline.
4. Resistance to rifampin or TMP/SMX, minocycline and doxycycline at screening.
5. Abnormal renal function, defined as creatinine clearance \<50 mL/min using the Cockcroft-Gault equation for adults or Schwartz equation in children, at Screening.
6. 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.
7. Serum hematology or chemistry results which in the judgment of the investigator would interfere with completion of the study.
8. History of or listed for solid organ or hematological transplantation
9. History of sputum culture with non-tuberculous Mycobacteria in the last 6 months.
10. History of sputum culture with Burkholderia Cepacia in the last year.
11. Planned continuous use of soft contact lenses while taking rifampin and no access to glasses.
12. Taking voriconazole and unable to discontinue its use while enrolled in the study.
13. Administration of any investigational drug or device within 28 days of screening or within 6 half-lives of the investigational drug (whichever is longer)
14. Female patients of childbearing potential who are pregnant or lactating, or plan on becoming pregnant
15. 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.
16. Patients taking certain drugs will be excluded from the study:

    a. Drugs, which are contraindicated when rifampin is used (in addition to voriconazole): i. Antiretrovirals: fosamprenavir, atazanavir, lopinavir, saquinavir, nelfinavir, tipranavir, darunavir, rilpivirine,telaprevir, boceprevir, elvitegravir, maraviroc ii. Drugs used to increase systemic exposure of antiretrovirals: Cobicistat iii. Anthelmintic/Antimalarial agents: praziquantel, artemether iv. Antianginal agent: ranolazine v. Psychiatric medications: lurasidone b. Other drugs, not contraindicated, but listed as having major drug to drug interactions i. Antiretrovirals: ritonavir, indinavir, efavirenz, nevirapine, etavirine

Primary outcomes:
measure: change in small colony variant Staph. aureus colony forming units on induced sputum respiratory culture
timeFrame: Culture specimens obtained at: Baseline, within 2 weeks of end of standard antibiotic course (control), 1 week prior to intervention, and within 2 weeks of end of intervention
Secondary outcomes:
measure: change in lung function, as measured by forced expiratory volume in one second (FEV1)
timeFrame: FEV1 measured at: Baseline, within 2 weeks of end of standard antibiotic course (control), 1 week prior to intervention, and within 2 weeks of end of intervention
measure: patient reported symptoms/quality of life, as captured in the Cystic Fibrosis Questionnaire-Revised (CFQ-R)
timeFrame: CFQ-R administered at: Baseline, within 2 weeks of end of standard antibiotic course (control), 1 week prior to intervention, and within 2 weeks of end of intervention
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins University School of Medicine
state: Maryland
Study officials:
affiliation: Johns Hopkins University
name: Mark T Jennings, MD, MHS
role: PRINCIPAL_INVESTIGATOR
References: