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

Phase 2TerminatedNCT01316770

National Institute of Dental and Craniofacial Research (NIDCR)14 enrolled

Overview

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.

Eligibility

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

* 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.

Outcomes

Primary Outcomes

Change in Parotid Salivary Flow From Baseline (Day 0) to Day 56.

Saliva flow rate was determined by weighing the saliva flow collected separately from each parotid (dexamethasone irrigated and placebo irrigated parotid) within a participant and dividing by collection time. Saliva was collected using a Teflon collection cup placed over the parotid duct orifice and held in place by slight negative pressure. Collection time was 1 minute. The primary outcome measure is looking at change from baseline at Study Day 56 and not the flow at any particular time.

Time frame: Baseline (Study Day 0) to Study Day 56

Secondary Outcomes

Change in Parotid Salivary Flow From Baseline (Study Day 0) to Study Day 14.

Saliva flow rate was determined by weighing the saliva flow collected separately from each parotid (dexamethasone irrigated and placebo irrigated parotid) within a participant and dividing by collection time. Saliva was collected using a Teflon collection cup placed over the parotid duct orifice and hel in place by slight negative pressure. Collection time was 1 minute. The outcome measure is looking at change from baseline at Study Day 14 and not the flow at any particular time.

Time frame: Baseline to 14 days post-baseline

Change in Parotid Salivary Flow From Baseline (Day 0) to Day 28.

Saliva flow rate was determined by weighing the saliva flow collected separately from each parotid (dexamethasone irrigated and placebo irrigated parotid) within a participant and dividing by collection time. Saliva was collected using a Teflon collection cup placed over the parotid duct orifice and hel in place by slight negative pressure. Collection time was 1 minute. The outcome measure is looking at change from baseline at Study Day 28 and not the flow at any particular time.

Time frame: Baseline to 28 days post-baseline

Change in Parotid Salivary Flow From Baseline (Day 0) to Day 42.

Saliva flow rate was determined by weighing the saliva flow collected separately from each parotid (dexamethasone irrigated and placebo irrigated parotid) within a participant and dividing by collection time. Saliva was collected using a Teflon collection cup placed over the parotid duct orifice and hel in place by slight negative pressure. Collection time was 1 minute. The outcome measure is looking at change from baseline at Study Day 42 and not the flow at any particular time.

Time frame: Baseline to 42 days post-baseline

Patient Dry Mouth Questionnaire. Question: Do You Have More Difficulty Chewing Your Food Since Starting the Study?

The questionnaire's question is on the whole participant level rather than on the individual parotid level; thus, no treatment group comparisons are possible. Possible responses: Yes or No.

Time frame: Baseline (Study Day 0) through Study Day 56

Patient Dry Mouth Questionnaire. Question: If You Have More Difficulty Chewing Your Food Since Starting the Study, Why?

The questionnaire's question is on the whole participant level rather than on the individual parotid level; thus, no treatment group comparisons are possible. Possible responses: Yes or No.

Time frame: Baseline (Study Day 0) through Study Day 56

Patient Dry Mouth Questionnaire. Question: Have You Experienced Any Changes in Your Sense of Smell Since Starting the Study?

The questionnaire's question is on the whole participant level rather than on the individual parotid level; thus, no treatment group comparisons are possible. Possible responses: Yes or No.

Time frame: Baseline (Study Day 0) through Study Day 56

Patient Dry Mouth Questionnaire: Have You Experienced Any Changes in Your Sense of Taste Since Starting the Study?

The questionnaire's question is on the whole participant level rather than on the individual parotid level; thus, no treatment group comparisons are possible. Possible responses: Yes or No.

Time frame: Baseline (Study Day 0) through Study Day 56

Patient Dry Mouth Questionnaire: If You Have Experienced Any Changes in Your Sense of Taste Since Starting the Study, Specify:

The questionnaire's question is on the whole participant level rather than on the individual parotid level; thus, no treatment group comparisons are possible.

Time frame: Baseline (Study Day 0) through Study Day 56

Patient Dry Mouth Questionnaire: Do You Have Any More Pain or Burning in Your Mouth or Head and Neck Region Since Starting the Study?

The questionnaire's question is on the whole participant level rather than on the individual parotid level; thus, no treatment group comparisons are possible. Possible responses: Yes or No.

Time frame: Baseline (Study Day 0) through Study Day 56

Patient Dry Mouth Questionnaire: If You Have Any More Pain or Burning in Your Mouth or Head and Neck Region Since Starting the Study, Specify:

The questionnaire's question is on the whole participant level rather than on the individual parotid level; thus, no treatment group comparisons are possible.

Time frame: Baseline (Study Day 0) through Study Day 56

Patient Dry Mouth Questionnaire: Do You Use Anything to Keep Your Mouth Moist?

The questionnaire's question is on the whole participant level rather than on the individual parotid level; thus, no treatment group comparisons are possible. Possible responses: Yes or No.

Time frame: Baseline (Study Day 0) through Study Day 56

Patient Dry Mouth Questionnaire: If You Use Something to Keep Your Mouth Moist, Specify:

The questionnaire's question is on the whole participant level rather than on the individual parotid level; thus, no treatment group comparisons are possible.

Time frame: Baseline (Study Day 0) through Study Day 56

Patient Dry Mouth Questionnaire: Does Your Mouth Feel More Dry When You Eat a Meal Since Starting the Study?

The questionnaire's question is on the whole participant level rather than on the individual parotid level; thus, no treatment group comparisons are possible. Possible responses: Yes; No; Not sure.

Time frame: Baseline (Study Day 0) through Study Day 56

Patient Dry Mouth Questionnaire: Does Your Mouth Feel More Dry Other Times of the Day Since Starting the Study?

The questionnaire's question is on the whole participant level rather than on the individual parotid level; thus, no treatment group comparisons are possible. Possible responses: Yes; No; Not sure.

Time frame: Baseline (Study Day 0) through Study Day 56

Patient Dry Mouth Questionnaire: Does the Amount of Saliva in Your Mouth Most of the Time Seem to be:

The questionnaire's question is on the whole participant level rather than on the individual parotid level; thus, no treatment group comparisons are possible. Possible responses: To little; to much; Do not notice it.

Time frame: Baseline (Study Day 0) through Study Day 56

Patient Dry Mouth Questionnaire: Do You Have More Difficulty Swallowing Dry Foods Without Additional Liquids Since Starting the Study?

The questionnaire's question is on the whole participant level rather than on the individual parotid level; thus, no treatment group comparisons are possible. Possible responses: Yes or No.

Time frame: Baseline (Study Day 0) through Study Day 56

Patient Dry Mouth Questionnaire Shift Table. Question: More Difficulty Chewing Food?

Shift table with respect to the change from the Stage II Screening Visit (used as Baseline) for Study Days: 14, 28, 42, and 56

Time frame: Baseline (Study Day 0) through Study Day 56

Patient Dry Mouth Questionnaire Shift Table. Question: Changes in Sense of Smell?

Shift table with respect to the change from the Stage II Screening Visit (used as Baseline) for Study Days: 14, 28, 42, and 56. The shift table data were not sufficiently distributed to permit analysis with McNemar's test on any of the study days.

Time frame: Baseline (Study Day 0) through Study Day 56

Patient Dry Mouth Questionnaire Shift Table. Question: Changes in Sense of Taste?

Time frame: Baseline (Study Day 0) through Study Day 56

Patient Dry Mouth Questionnaire Shift Table. Question: Pain/Burning in Mouth or Head/Neck?

Shift table with respect to the change from the Stage II Screening Visit (used as Baseline) for Study Days: 14, 28, 42, and 56

Time frame: Baseline (Study Day 0) through Study Day 56

Patient Dry Mouth Questionnaire Shift Table. Question: Use Anything to Keep Mouth Moist?

Time frame: Baseline (Study Day 0) through Study Day 56

Patient Dry Mouth Questionnaire Shift Table. Question: Mouth Feel More Dry When You Eat?

Time frame: Baseline (Study Day 0) through Study Day 56

Patient Dry Mouth Questionnaire Shift Table. Question: Mouth Feel More Dry Other Times of Day?

Shift table with respect to the change from the Stage II Screening Visit (used as Baseline) for Study Days: 14, 28, 42, and 56

Time frame: Baseline (Study Day 0) through Study Day 56

Patient Dry Mouth Questionnaire Shift Table. Question: Difficulty Swallowing Dry Foods Without Liquids?

Shift table with respect to the change from the Stage II Screening Visit (used as Baseline) for Study Days: 14, 28, 42, and 56

Time frame: Baseline (Study Day 0) through Study Day 56

Sjögren's Disease Activity Index: Indicate, According to Your Clinical Experience, the Level of Disease Activity in This Patient (Ordinal Numeric Scale)

Ordinal Scale 0:least to 10:greatest level of disease activity

Time frame: Baseline (Study Day 0) through Study Day 56

Sjögren's Disease Activity Index: Indicate, According to Your Clinical Experience, the Level of Disease Activity in This Patient (Nominal Scale)

Nominal scale values: Inactive; Low; Moderate; High

Time frame: Baseline (Study Day 0) through Study Day 56

Sjögren's Disease Activity Index: Do You Consider Your Patient in a Satisfactory State of 'Minimal Disease Activity'?

Response: Yes or No

Time frame: Baseline (Study Day 0) through Study Day 56

Sjögren's Disease Activity Index: Indicate the Level of Disease Activity in This Patient, Taking Into Account the Symptoms of Your Patient's (Dryness, Pain, Physical and Mental Fatigue), Ordinal Scores

Ordinal Scale 0: least to 10: greatest level of disease activity.

Time frame: Baseline (Study Day 0) through Study Day 56

Sjögren's Disease Activity Index: Compared With Baseline, This Participant's Primary Sjögren's Syndrome (pSS) Activity is Now:

Nominal Scale: Much better; Better; The same; Worse; Much worse

Time frame: Baseline (Study Day 0) through Study Day 56

Sjögren's Disease Activity Index: Compared With Baseline, do You Consider Your Patient Presents a Systemic Flare of the Participant's pSS (Primary Sjögren's Syndrome):

Response: Yes; No

Time frame: Baseline (Study Day 0) through Study Day 56

Sjögren's Disease Activity Index Shift Table. Question: Do You Consider Your Patient in a Satisfactory State of "Minimal Disease Activity? The Shift Table Data Was Not Rich Enough to Perform McNemar's Test on the Shift Tables of Any of the Study Days.

Possible Response: Yes or No

Time frame: Baseline (Study Day 0) through Study Day 56

Sjörgen's Disease Activity Index, Shift Table of Disease Activity Based on Patient's Symptoms From Baseline to Study Day 14 , Ordinal Scores

Ordinal Scale 0: least to 10: greatest level of disease activity. Only cells in the shift table with participant counts greater than 0 are listed.

Time frame: Baseline (Study Day 0) through Study Day 14

Sjörgen's Disease Activity Index, Shift Table of Disease Activity Based on Patient's Symptoms From Baseline to Study Day 28 , Ordinal Scores

Ordinal Scale 0: least to 10: greatest level of disease activity. Only cells in the shift table with participant counts greater than 0 are listed.

Time frame: Baseline (Study Day 0) through Study Day 28

Sjörgen's Disease Activity Index, Shift Table of Disease Activity Based on Patient's Symptoms From Baseline to Study Day 42 , Ordinal Scores

Ordinal Scale 0: least to 10: greatest level of disease activity. Only cells in the shift table with participant counts greater than 0 are listed.

Time frame: Baseline (Study Day 0) through Study Day 42

Sjörgen's Disease Activity Index, Shift Table of Disease Activity Based on Patient's Symptoms From Baseline to Study Day 56 , Ordinal Scores

Ordinal Scale 0: least to 10: greatest level of disease activity. Only cells in the shift table with participant counts greater than 0 are listed.

Time frame: Baseline (Study Day 0) through Study Day 56

Sjörgen's Disease Activity Index (SDAI): Indicate, According to Your Clinical Experience, the Level of Disease Activity in This Patient (Nominal Scale) the Shift From Baseline to the Given Study Day, Nominal Scale

Possible response on nominal scale: Inactive; Low; Moderate; High SDAI.

Time frame: Baseline (Study Day 0) to Study Day 56

Sjörgen's Disease Activity Index (SDAI): Indicate, According to Your Clinical Experience, the Level of Disease Activity in This Patient the Shift From Baseline to Study Day 14, Ordinal Scale

Ordinal Scale 0: least to 10: greatest level of disease activity. Only cells in the shift table with participant counts greater than 0 are listed.

Time frame: Baseline (Study Day 0) to Study Day 14

Sjörgen's Disease Activity Index (SDAI): Indicate, According to Your Clinical Experience, the Level of Disease Activity in This Patient the Shift From Baseline to Study Day 28, Ordinal Scale

Ordinal Scale 0: least to 10: greatest level of disease activity. Only cells in the shift table with participant counts greater than 0 are listed.

Time frame: Baseline (Study Day 0) to Study Day 28

Sjörgen's Disease Activity Index (SDAI): Indicate, According to Your Clinical Experience, the Level of Disease Activity in This Patient the Shift From Baseline to Study Day 42, Ordinal Scale

Ordinal Scale 0: least to 10: greatest level of disease activity. Only cells in the shift table with participant counts greater than 0 are listed.

Time frame: Baseline (Study Day 0) to Study Day 42

Sjörgen's Disease Activity Index (SDAI): Indicate, According to Your Clinical Experience, the Level of Disease Activity in This Patient the Shift From Baseline to Study Day 56, Ordinal Scale

Ordinal Scale 0: least to 10: greatest level of disease activity. Only cells in the shift table with participant counts greater than 0 are listed.

Time frame: Baseline (Study Day 0) to Study Day 56

Summary Statistics of MRI Scans

Medical evaluations of MRI Scans. Possible evaluations include: i) Normal; ii) Abnormal, not clinically significant; iii) Abnormal, clinically significant.

Time frame: Stage II Screening (within 6 wks before Baseline (Study Day 0)) through Study Day 56

Shift Table of the Change in Parotid MRI at Study Day 56 From Stage II Screening Visit

Change in the evaluations of the parotid MRI scans at Study Day 56 from Stage II Screening Visit. Possible MRI evaluations at both Baseline and Study Day 56 include: i)Normal; ii) Abnormal, not clinically significant (Abnormal ncs); and iii) Abnormal, clinically significant (Abnormal cs).

Time frame: Stage II Screening (within 6 wks before Baseline (Study Day 0)) through Study Day 56

Summary Statistics of Technetium Scans

Medical evaluations of Technetium Scans. Possible evaluations include: i) Normal; and ii) Abnormal.

Time frame: Stage II Screening (within 6 wks before Baseline (Study Day 0)) through Study Day 56

Shift Table of the Change in Parotid Technetium Scan at Study Day 56 From Stage II Screening Visit

Change in the evaluations of the parotid technetium scans at Study Day 56 from Stage II Screening Visit. Possible technetium scan evaluations at both Baseline and Study Day 56 include: Normal; Abnormal.

Time frame: Stage II Screening (within 6 wks before Baseline (Study Day 0)) through Study Day 56

Summary Statistics of Focus Score

Focus score is the number of mononuclear cell infiltrates containing at least 50 inflammatory cells in a 4 mm² glandular section. Focus scores ≥1 are key criteria used in the diagnosis of inflammation in the oral component of Sjögren's Syndrome. Higher numbers are associated with more inflammation. (Range 0-12).

Time frame: Stage II screening (within 6 wks before baseline) through 56 days post-baseline

Shift Table of Focus Scores From Stage II Screening to Study Day 56

Focus score is the number of mononuclear cell infiltrates containing at least 50 inflammatory cells in a 4 mm² glandular section. Table data are the shift in focus score from Stage II Screening to Study Day 56. Only shift table cells with more than 0 participants were included in the Outcome Measure Data Table below.

Time frame: Stage II Screening (within 6 wks before baseline) through 56 days post-baseline

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes