BACKGROUND:
Salivary gland dysfunction is one of the major manifestations of Sjögren's (SS). Although inflammation is thought to play an important role in the exocrinopathy, the correlation between glandular dysfunction and inflammation is limited. Systemic anti-inflammatory therapies tested to date, such as tumor necrosis factor antagonists, have not been effective treatments for SS salivary hypofunction, raising doubts about inflammation being the sole cause of salivary gland dysfunction. However, none of these trials tested whether an anti-inflammatory effect was achieved in glandular tissues.
Studies by Izumi et al found that a limited course of low-dose topical corticosteroid applied to the parotid glands resulted in sustained improvement in saliva production. Unfortunately, these studies did not examine the mechanistic effects of corticosteroids on the major salivary glands. A plausible assumption is that corticosteroids improved salivary gland function by reducing inflammation, although other or associated mechanisms, such as an improved transcellular ion transport in epithelial cells cannot be ruled out. This study aims to study the efficacy of low-dose topical corticosteroid (dexamethasone) irrigation of the parotid gland in reducing salivary dysfunction in subjects with SS, and also to evaluate the effects of treatment on inflammation and other possible mechanistic processes.
PRIMARY OBJECTIVE:
\- To determine whether irrigation of the parotid gland with low-dose topical dexamethasone improves parotid salivary gland flow in SS subjects.
SECONDARY OBJECTIVES:
* To perform mechanistic studies to determine the mechanisms of action of low-dose topical corticosteroid irrigation of the parotid gland.
* To assess biomarkers of inflammation and salivary gland dysfunction in SS subjects treated with low-dose topical corticosteroid irrigation of the parotid glands.
* To assess localized safety of dexamethasone irrigation of the parotid gland, as compared with placebo.
STUDY POPULATION:
The study will enroll up to 20 adult females with primary SS in order to randomize and treat 16 subjects. Key enrollment criterion include a focus score of greater than or equal to 3 on minor salivary gland biopsy in the previous 5 years and measurable stimulated bilateral parotid salivary flow (greater than or equal to 0.01 mL/min per gland). Subjects will be recruited from protocol 84-D-0056, conducted at the National Institutes of Health (NIH).
DESIGN:
This will be a single-site, randomized-within-subject, double-blind, placebo-controlled, phase 2 pilot study in which all subjects receive both active drug (dexamethasone) and placebo (normal saline), thereby acting as their own controls.The study design is doubly-repeated measures; within a subject, measures are repeated in both time and treatment (i.e., one side of mouth receives dexamethasone while the other receives placebo.). After baseline assessment of salivary flow and other measurements of salivary function, subjects will be randomly assigned, in a double-blind fashion, to dexamethasone irrigation of one parotid gland and normal saline irrigation of the other parotid gland. They will undergo a total of 2 treatment sessions, 4 weeks apart (Days 0 and 28). Post-treatment assessments of salivary flow, dry mouth symptoms, and adverse events (AEs) will be performed at specified intervals.
OUTCOME MEASURES:
Primary Endpoint:
\- Change in salivary flow from Day 0 to Day 56.
Secondary Endpoints:
* Change in focus score on parotid biopsy from Screening to Day 56.
* Change in salivary flow from Day 0 to study Days 14, 28, 42, and 56.
* Changes in assessments on the Patient Dry Mouth Questionnaire from Day 0 to study Days 14, 28, 42, and 56.
* Changes in assessments on the Sj(SqrRoot)(Delta)gren s Disease Activity Index from Day 0 to study Days 14, 28, 42, and 56.
* Changes in other assessments of salivary function from baseline to study Day 56, including technetium scan of the salivary glands.
* Changes in laboratory measures of inflammation.
* Frequency of AEs related to treatment; AE location (body site, right or left), will be recorded and evaluated, as applicable.
Exploratory endpoints
\- Changes in mechanistic endpoints from baseline to study Days 14, 28, 42, and 56.
