Clinical trial NCT03489629: STaph Aureus Resistance-Treat Early and Repeat (STAR-TER)
Official title: STaph Aureus Resistance-Treat Early and Repeat (STAR-TER)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Cystic Fibrosis
Keywords: Methicillin-resistant Staphylococcus aureus (MRSA)
Early infection
Treatment
Forced Expiratory Volume in 1 Second (FEV1)
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
Collaborators: name: University of Washington
name: Cook Children's Medical Center
name: Indiana University
name: University of Michigan
name: University of Texas Southwestern Medical Center
name: St. Louis Children's Hospital
First posted: 2018-04-05
Enrollment: 42
Sex: ALL
Minimum age (years): 2
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: To evaluate the micro-biologic efficacy and safety of a streamlined treatment for early onset methicillin-resistant staphylococcus aureus (MRSA) in patients with cystic fibrosis.

Detailed description: This is an open-label, multi-center interventional trial in Cystic Fibrosis (CF) patients with new MRSA isolated from the respiratory tract (oropharyngeal (OP) = OP swab, sputum, or bronchoscopy) at a clinical encounter.

Forty-two subjects with new MRSA infection will be enrolled and will receive two weeks of oral trimethoprim-sulfamethoxazole (TMP-SMX) or minocycline depending on age, allergies and antibiotic resistance of prior isolate for 14 days, and nasal mupirocin for 5 days. Subjects old enough to do so will use oral disinfectant gurgle (0.12% chlorhexidine gluconate oral rinse) for 14 days. The primary endpoint will be the proportion of positive MRSA respiratory cultures at Day 28 and this will be compared to our prior STAR-Too results.

Subjects will then have a 14 day wash-out period (i.e., no TMP-SMX or minocycline from Day 14 to Day 28) and all participants will repeat the treatment protocol from Day 29 to Day 42. Repeat cultures will be done at day 56 ± 7 days, most likely combined with their next clinic visit. Results of Day 56 cultures will be an exploratory, secondary outcome.

A subsequent visit will be 3 months later with their routine clinic appointment. Any interim clinic visits will be used to obtain repeat cultures and clinical data.

Assessment of MRSA culture status will be by OP swab for all subjects, with additional sputum in those who expectorate.

Total duration of an individual subject's participation will be six months. Total duration of the study is expected to be 42 months, which includes data analyses and publication.

Due to COVID 19 restrictions, a study amendment was filed in March 2020 for subjects currently active subjects that allowed remote study visit for V3 and V4. Cultures were collected at home and mailed to the Core Study lab, clinical case forms and surveys were completed via video visits. These changes were approved by each study site that this was relevant to i.e. 4 study sites had subjects active at that time.

Eligibility criteria: Inclusion Criteria:

1. Male or female ≥ 2 and ≤ 45 years of age at the Screening Visit.
2. Documentation of a CF diagnosis as evidenced by one or more clinical features consistent with the CF phenotype and one or more of the following criteria:

   1. sweat chloride ≥ 60 milliequivalents/liter by quantitative pilocarpine iontophoresis test (QPIT)
   2. two well-characterized mutations in the cystic fibrosis transmembrane conductive regulator (CFTR) gene
   3. abnormal nasal potential difference(NPD) (change in NPD in response to a low chloride solution and isoproteronol of less than -5 mV)
3. First OR early MRSA colonization defined as:

   1. First MRSA colonization: first documented isolation of MRSA from respiratory tract occurred ≤ 6 months prior to screening
   2. Early MRSA colonization: MRSA was previously isolated from the respiratory tract ≤ 2 times over the past 3.5 years, but this was followed by at least 1 year of documented negative cultures for MRSA
4. MRSA is available to the central laboratory - either the incident MRSA isolate from the clinic visit or the subject is MRSA positive at the screening visit
5. Clinically stable with no significant changes in health status within the 14 days prior to screening
6. 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

Exclusion Criteria:

1. Received antibiotics with activity against MRSA within 28 days prior to screening
2. Use of an investigational agent within 28 days prior to screening
3. For subjects ≥ 6 years of age: FEV1 at screening \< 25% of predicted for age based on the Wang (males \< 18 years, females \< 16 years) or Hankinson (males ≥ 18 years, females ≥ 16 years) standardized equations
4. MRSA from the screening culture or the most recent clinical care visit within 6 months prior to screening resistant to TMP/SMX
5. History of intolerance to topical chlorhexidine or mupirocin
6. History of intolerance to both TMP/SMX and minocycline
7. \< 8 years of age and allergic or intolerant to TMP/SMX
8. ≥ 8 years of age and allergic or intolerant to TMP/SMX and MRSA isolate (from screening or clinical care visit)is resistant to minocycline
9. For females of child bearing potential: pregnant, breastfeeding, or unwilling to use barrier contraception through Day 42 of the study
10. Subjects with history of abnormal renal function will need screening labs showing normal function Abnormal renal function is defined as estimated creatinine clearance \<50 mL/min using the:

    1. Bedside Schwartz Equation for subjects \<18 years of age, and
    2. Levey Glomerular filtration rate (GFR) Equation for subjects ≥ 18 years of age.
11. Subjects with a history of abnormal liver function will need to have screening labs showing normal transaminases. Liver dysfunction is defined as ≥3x upper limit of normal (ULN), of serum aspartate transaminase (AST) or serum alanine transaminase (ALT) or abnormal synthetic function
12. History of solid organ or hematological transplantation
13. Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.

Primary outcomes:
measure: Proportion of STAR-TER subjects with a negative MRSA culture at Day 28 vs. observational arm of historic STAR-Too trial
timeFrame: Day 28
Secondary outcomes:
measure: Proportion of subjects with a protocol-defined pulmonary exacerbation between Baseline and Day 28 treated with antibiotics active against MRSA
timeFrame: Period ranging from start of Baseline and continuing through Day 28
measure: Proportion of subjects with a protocol-defined pulmonary exacerbation between Baseline and Day 28 treated with any oral, inhaled, or IV antibiotics regardless of potential activity against MRSA
timeFrame: Period ranging from start of Baseline and continuing through Day 28
measure: Proportion of subjects treated with oral, inhaled, and IV antibiotics over the six-month study
timeFrame: Period ranging from start of Baseline and continuing through Month 6
measure: Time to protocol-defined pulmonary exacerbation over the six-month study
timeFrame: Period ranging from start of Baseline and continuing through Month 6
measure: Number of protocol-defined pulmonary exacerbations over the six-month study
timeFrame: Period ranging from start of Baseline and continuing through Month 6
measure: MRSA Culture Status
timeFrame: Day 56
measure: Proportion of subjects with >80% compliance for study drug during the first 28 days
timeFrame: Day 28
Other outcomes:
Locations:
city: Denver
country: United States
facility: National Jewish Health
state: Colorado
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Ann Arbor
country: United States
facility: University of Michigan Health System
state: Michigan
city: Saint Louis
country: United States
facility: St. Louis Children's Hospital
state: Missouri
city: Chapel Hill
country: United States
facility: N.C. Memorial Hospital and N.C. Children's Hospital
state: North Carolina
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital, Baylor College of Medicine
state: Texas
city: Seattle
country: United States
facility: University of Washington Medical Center and Seattle Children's
state: Washington
Study officials:
affiliation: University of North Carolina, Chapel Hill
name: Marianne Muhlebach, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Muhlebach MS, Beckett V, Popowitch E, Miller MB, Baines A, Mayer-Hamblett N, Zemanick ET, Hoover WC, VanDalfsen JM, Campbell P, Goss CH; STAR-too study team. Microbiological efficacy of early MRSA treatment in cystic fibrosis in a randomised controlled trial. Thorax. 2017 Apr;72(4):318-326. doi: 10.1136/thoraxjnl-2016-208949. Epub 2016 Nov 15.