Dexamethasone Irrigation of the Parotid Glands in Primary Sjögren's Syndrome Subjects

A Randomized Within-Subject, Double-Blind, Placebo-Controlled Study of Dexamethasone Irrigation of the Parotid Glands in Primary Sjögren's Syndrome Subjects

Background:

Sjögren's syndrome is an autoimmune disease (where the immune system attacks normal body tissues) that affects the salivary glands. Many people with Sjögren's syndrome are not able to make enough saliva because their salivary glands are inflamed. The dry mouth that results can interfere with daily activities and can lead to dental cavities, mouth sores, and infections. Injections of corticosteroids into the parotid glands can improve saliva production in people with Sjögren's syndrome, but current treatment practices may provide only temporary relief. Researchers are interested in studying the effectiveness of stronger corticosteroid injections (using dexamethasone) to determine how the corticosteroid treatment actually works.

Objectives:

- To evaluate the effectiveness and mechanics of dexamethasone injections to improve saliva production in individuals with primary Sjögren's syndrome.

Eligibility:

- Women between 18 and greater of age who have been diagnosed with primary Sjögren's syndrome, and have had a biopsy of the minor salivary glands in the past 5 years that shows a moderate level of inflammation.

Design:

• Participants will be screened with a full medical history and physical examination, blood and urine tests, and salivary gland biopsies. Participants will also be screened with tests of saliva flow production and evaluation of the salivary ducts and glands, and will complete questionnaires about dry mouth symptoms.
• At the first treatment visit, participants will receive an injection of dexamethasone into one parotid gland and an injection of saline into the other gland. After the injections, participants will provide a blood sample to test the level of dexamethasone in the blood.
• Two weeks after the first treatment, participants will return for an evaluation visit to have saliva flow rate measurements taken, and will complete a questionnaire about dry mouth symptoms.
• Four weeks after the first treatment, participants will have a second treatment for each parotid gland, with the same tests and questionnaires as before.
• Participants will have additional evaluation visits 6 and 8 weeks after the first treatment visit, with a followup telephone call approximately 6 weeks after the last dexamethasone treatment visit.

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.

• INCLUSION CRITERIA:
• Female gender and age 18 and greater.
• Diagnosed with primary SS in Protocol 84-D-0056.
• Stimulated salivary flow of at least 0.01 mL/min from each parotid gland, using the standard operating procedure (SOP) for the National Institute of Dental and Craniofacial Research (NIDCR) Molecular Physiology and Therapeutics Branch (MPTB) Sjögren's Syndrome Clinic
• Minor salivary gland (MSG) biopsy with a focus score of greater than or equal to 1 obtained 0 to 7 years prior to study enrollment. Biopsies from outside of the National Institutes of Health (NIH) must be reviewed by the NIH Pathology Department. An MSG biopsy will be required for the following situations:
• The last biopsy was obtained before the use of rituximab.
• The last biopsy was obtained before the use of immunosuppressants, biologics, or disease-modifying antirheumatic drugs for more than 3 months.
• The last biopsy was obtained before the use of systemic corticosteroids (for more than 2 weeks or for shorter periods at doses of more than 0.5 mg/kg) or local parotid corticosteroids. The use of topical or intra-articular/periarticular corticosteroids will not require a repeat biopsy.
• For women of childbearing potential, use of, or willingness to use, an effective method of birth control during the study. Effective methods include abstinence, history of hysterectomy, tubal ligation, intrauterine device, licensed hormonal methods, condoms, diaphragm, and cervical cap.
• Ability to provide written informed consent prior to entry in the study.

EXCLUSION CRITERIA:

• History of lymphoma.
• History of mycosis, aspergillosis, or other deep fungal infection of the parotid gland.
• History of salivary gland malignancy (primary or metastatic to the salivary gland).
• History of secondary Sjögren's syndrome.
• Parotid infection that does not resolve at least 4 weeks before the start of the Screening Period.
• Any active viral infection that does not resolve by the start of the Screening Period.
• Pregnancy or lactation.
• Use of biologics within 3 months of the start of the Screening Period.
• Any experimental therapy within 3 months before the start of the Screening Period.
• Use of immunosuppressants such as methotrexate, leflunomide, azathioprine, cyclophosphamide, systemic cyclosporine, or systemic corticosteroids within 3 months prior to the start of the Screening Period.
• Use of inhaled corticosteroids within 3 months prior to the start of the Screening Period.
• Use of antimalarials and regular use of NSAIDs unless the dose has been stable (or decreased) for at least 2 months.
• Inability to discontinue the use of saliva stimulants such as pilocarpine and cevimeline for 24 hours before each study visit.
• Parotid intraductal irrigation or instillation with steroids within the past year.
• Use of rituximab within 6 months prior to the start of the Screening Period.
• Allergy to steroids or technetium, or any components of the formulations.
• Current use of warfarin or heparin.
• History of bleeding disorder.
• Both severe atrophy and fibrosis of the MSG noted on the pathology report of the MSG biopsy.
• Inability to comply with protocol procedures and the number of required visits.
• Inability to cannulate one or both parotid glands.
• Parotid fill volume less than 0.5 mL in one or both parotid glands.
• Significant concurrent medical condition or other circumstances that, in the opinion of the principal investigator, could affect the subject's ability to tolerate or complete the study.
• Unable to understand written English for completion of study questionnaires.