Clinical trial NCT01323101: Doxycycline Effects on Inflammation in Cystic Fibrosis
Official title: Effect of Doxycycline on Sputum Biomarkers of Inflammation and Lung Epithelial Repair in Patients With Cystic Fibrosis.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Cystic Fibrosis
Lead sponsor: University of Southern California
Sponsor class: OTHER
First posted: 2011-03-25
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Doxycycline is known to exhibit immune modulatory activities beyond its antibacterial effects. In particular, doxycycline is a potent inhibitor of matrix metalloproteinase 9, which is a protease derived largely from neutrophils. Recent studies demonstrate a significant correlation between pulmonary disease severity and sputum concentrations of MMP-9 in patients with CF. In addition, sputum MMP-9 levels are associated with airway remodeling in CF.

The goal of this study is to determine the therapeutic potential of doxycycline in modulating host airway inflammation in patients with CF. Specifically, the study will characterize the PK /PD of doxycycline, evaluate the safety of short term therapy, and explore the concentration effect relationship between doxycycline exposure and sputum biomarker levels.

Detailed description: This study will consist of a prospective, open-label, randomized, controlled trial conducted in 24 patients with cystic fibrosis. Twenty subjects will be stratified in a 1:2 ratio based on baseline FEV1 into mild (\> 70%) or moderate (40-70%) pulmonary disease in order to control for disease severity within each dose level. The subjects will be randomized in blocks of four to receive no drug, 40mg, 100mg, or 200mg daily for 28 days.

Sputum samples will be obtained in all groups by induction with hypertonic saline at baseline, 8, 24, and 48 hours following the first dose and then weekly for 4 weeks. Sputum will also be collected at two follow up visits after the treatment period at weeks 5 and 6.

In the doxycycline group, serial blood samples (5 mL) for determination of doxycycline concentrations will be obtained before and at 0, 0.5, 1, 2, 4, 12, 24, and 48 hours following the 1-hr infusion of a single IV dose. Once daily dosing of doxycycline will resume immediately following the 48-hour blood sample and will continue until day 28. Additional levels will be obtained pre-dose, and 1, 2, and 3 hours after doses administered on days 14 and 28. A sample of blood will be obtained at baseline, and at days 28 for inflammatory marker analyses.

Eligibility criteria: Inclusion Criteria:

* Age greater than 18 years
* Clinically stable (FEV1 within 10% of baseline)
* FEV1 \> 40% predicted

Exclusion Criteria:

* Use of clinically significant concomitant drug therapy such as long-term use of nonsteroidal anti-inflammatory drugs or corticosteroids
* Known hypersensitivity to doxycycline
* Pregnancy or attempting to conceive, breast feeding, initiation of or change in hormonal method of contraception within 4 weeks of baseline or during the study
* Use of systemic antibiotics (except oral azithromycin) within 4 weeks of baseline
* Use of doxycycline within 60 days of baseline
* Known history of gastrointestinal bleeding or gastrointestinal ulceration.

Primary outcomes:
measure: To determine the effect of doxycycline on inflammatory biomarkers
timeFrame: Within 42 days
Secondary outcomes:
measure: To characterize the pharmacokinetics, pharmacodynamics and safety of doxycycline in patients with cystic fibrosis
timeFrame: Within 42 days
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California
state: California
Study officials:
affiliation: University of Southern California
name: Paul M Beringer, Pharm.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Beringer PM, Owens H, Nguyen A, Benitez D, Rao A, D'Argenio DZ. Pharmacokinetics of doxycycline in adults with cystic fibrosis. Antimicrob Agents Chemother. 2012 Jan;56(1):70-4. doi: 10.1128/AAC.05710-11. Epub 2011 Oct 24.