## Protocol Section
### Identification Module
**NCT ID:** NCT04470479

**Brief Title:** Oral Pilocarpine in the Treatment of the Dry Eye of Patients With Sjogrens Syndrome

**Official Title:** Oral Pilocarpine in the Treatment of the Dry Eye of Patients With Sjogrens Syndrome

#### Organization Study ID Info
**ID:** 0910/03
#### Organization
**Class:** OTHER
**Full Name:** Federal University of São Paulo
### Status Module
#### Completion Date
**Date:** 2006-04-01

**Type:** ACTUAL

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2020-07-14

**Type:** ACTUAL

**Last Update Submit Date:** 2020-07-13

**Overall Status:** COMPLETED

#### Primary Completion Date
**Date:** 2006-04-01

**Type:** ACTUAL

#### Start Date
**Date:** 2005-03-01

**Type:** ACTUAL

**Status Verified Date:** 2020-07

#### Study First Post Date
**Date:** 2020-07-14
**Type:** ACTUAL
**Study First Submit Date:** 2020-07-07
**Study First Submit QC Date:** 2020-07-13
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** Federal University of São Paulo

#### Responsible Party

**Investigator Affiliation:** Federal University of São Paulo

**Investigator Full Name:** Sergio Felberg

**Investigator Title:** Posgraduate Medical Doctor

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** True

**Is US Export:** True

**Oversight Has DMC:** True

### Description Module

**Brief Summary:** The purpose of this study was to access the possible beneficial effects of oral use of pilocarpine in relieving signs and symptoms of patients with Sjogren's syndrome

**Detailed Description:** After being informed about the study, its potential risks and having signed the informed consent form, this placebo-controlled, crossover study involved patients with Sjögren's syndrome to use oral pilocarpine or placebo for ten weeks and after two weeks of medication withdrawal, to invert the treatment for the same period of time. The assessments applied were the Ocular Surface Disease Index, NEI-VFQ-25 questionnaire, non-invasive break-up time, traditional break-up time, evaluation of the cornea and ocular surface with fluorescein and rose bengal dyes, Schirmer test, and tear ferning test. Side effects observed during the treatment period were also assessed.

### Conditions Module

**Conditions:**

- Dry Eye

**Keywords:**

- dry eye

- Sjogren

- pilocarpine hydrochloride

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** CROSSOVER

**Intervention Model Description:** This was a placebo-controlled, crossover study that involved patients with Sjögren's syndrome to use 20mg/day of oral pilocarpine or placebo for ten weeks and after two weeks of medication withdrawal, to invert the treatment for the same period of time. The assessments applied were the Ocular Surface Disease Index, NEI-VFQ-25 questionnaire, non-invasive break-up time, traditional break-up time, evaluation of the cornea and ocular surface with fluorescein and rose bengal dyes, Schirmer test, tear ferning test, osmolarity and the activity of lysozyme. R

##### Masking Info

**Masking:** DOUBLE

**Who Masked:**

- PARTICIPANT

- INVESTIGATOR

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 32

**Type:** ACTUAL

**Phases:**

- PHASE3

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Patients with Sjögren's syndrome were allocated to receive oral pilocarpine 20mg per day, (5mg every 6 hours, for ten weeks.

**Intervention Names:**

- Drug: Pilocarpine Hydrochloride

**Label:** Pilocarpine Hydrochloride

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** Patients with Sjögren's syndrome were allocated to receive placebo administered in the same way (1 tablet every 6 hours), for ten weeks

**Intervention Names:**

- Drug: Placebo

**Label:** placebo

**Type:** PLACEBO_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Pilocarpine Hydrochloride

**Description:** Oral pilocarpine hydrochloride 5mg tablets were administered four times a day for 10 weeks to half the group of selected patients. The other half ingested placebo in the same way. At the end of this period and after two weeks of washing out the medications, the patients had to invert the treatments.

**Name:** Pilocarpine Hydrochloride

**Other Names:**

- Salagen

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- placebo

**Description:** Placebo

**Name:** Placebo

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** The Ocular Surface Disease Index is a valid and reliable instrument for measuring the severity of dry eye disease, and it possesses the necessary psychometric properties to be used as an end point in clinical trials. The answers to the questions generate an index ranging from 0 to 100, where 0 means no complaints related to dry eye and 100 indicates complaints with maximum intensity. (Change = week 10 score - baseline score)

**Measure:** Change from baseline in the Ocular Surface Disease Index questionnaire at week 10

**Time Frame:** Baseline and week 10

**Description:** The Ocular Surface Disease is a valid and reliable instrument for measuring the severity of dry eye disease, and it possesses the necessary psychometric properties to be used as an end point in clinical trials. The answers to the questions generate an index ranging from 0 to 100, where 0 means no complaints related to dry eye and 100 indicates complaints with maximum intensity. (Change = week 22 score - baseline score)

**Measure:** Change from baseline Ocular Surface Disease Index questionnaire at week 22

**Time Frame:** Baseline and week 22

**Description:** The VFQ-25 is a reliable and validated 25-item version of the 51-item National Eye Institute Visual Function Questionnaire (NEI-VFQ). It is especially useful in settings such as clinical trials, where interview length is a critical consideration. The set of responses provided scores between 0 and 100, where 0 means the maximum negative impact of the disease on the quality of life of patients and 100 means no negative impact of the disease on quality of life. (Change = week 10 score - baseline score)

**Measure:** Change from baseline in the NEI-VFQ-25 questionnaire at week 10

**Time Frame:** Baseline and week 10

**Description:** The VFQ-25 is a reliable and validated 25-item version of the 51-item National Eye Institute Visual Function Questionnaire (NEI-VFQ). It is especially useful in settings such as clinical trials, where interview length is a critical consideration. The set of responses provided scores between 0 and 100, where 0 means the maximum negative impact of the disease on the quality of life of patients and 100 means no negative impact of the disease on quality of life. (Change = week 22 score - baseline score)

**Measure:** Change from baseline in the NEI-VFQ-25 questionnaire at week 22

**Time Frame:** Baseline and week 22

**Description:** Tear breakup time is a clinical test used to assess evaporative disease of dry eye. To measure tear breakup time, fluorescein is instilled into the patient's tear film and the patient is asked not to blink while the tear film is viewed under a cobalt blue lighting. The time of appearance of the first tear film break point, recorded in seconds, indicates the tear film breakup time. Times greater than 10 seconds are considered normal. (Change = week 10 measure - baseline measure)

**Measure:** Change from baseline in tear breakup time test at week 10

**Time Frame:** Baseline and week 10

**Description:** Tear breakup time is a clinical test used to assess evaporative disease of dry eye. To measure tear breakup time, fluorescein is instilled into the patient's tear film and the patient is asked not to blink while the tear film is viewed under a cobalt blue lighting. The time of appearance of the first tear film break point, recorded in seconds, indicates the tear film breakup time. Times greater than 10 seconds are considered normal. (Change = week 22 measure - baseline measure)

**Measure:** Change from baseline in tear breakup time test at week 22

**Time Frame:** Baseline and week 22

**Description:** When instilled in the ocular surface, the rose bengal dye will stain dead cells and spaces not covered by the tear film, being a method used to evaluate the damage to the ocular surface caused by the dry eye. For quantification, the van bijesterveld scale was used, which gives a score from 0 to 9 points according to the intensity of the color distributed onto the ocular surface. The van bijesterveld scale is described as follows:

The surface of the eye should be separated into three regions: the nasal bulbar conjunctiva, the cornea and the medial bulbar conjunctiva. Each of these regions may receive a score ranging from 0 to 3 points (0 = not colored, 1 = colored with distant points, 2 = colored with close points and 3 = colored with confluent points). The scores are then added up, generating a global score ranging from 0 to 9 points. Score 0 means no impairment of the ocular surface and score 9 means maximum impairment of the ocular surface).

(Change = week 10 - baseline measure)

**Measure:** Change from baseline in score with rose bengal staining at week 10

**Time Frame:** Baseline and week 10

**Description:** When instilled in the ocular surface, the rose bengal dye will stain dead cells and spaces not covered by the tear film, being a method used to evaluate the damage to the ocular surface caused by the dry eye. For quantification, the van bijesterveld scale was used, which gives a score from 0 to 9 points according to the intensity of the color distributed onto the ocular surface. The van bijesterveld scale is described as follows:

The surface of the eye should be separated into three regions: the nasal bulbar conjunctiva, the cornea and the medial bulbar conjunctiva. Each of these regions may receive a score ranging from 0 to 3 points (0 = not colored, 1 = colored with distant points, 2 = colored with close points and 3 = colored with confluent points). The scores are then added up, generating a global score ranging from 0 to 9 points. Score 0 means no impairment of the ocular surface and score 9 means maximum impairment of the ocular surface).

(Change = week 22 - baseline measure)

**Measure:** Change from baseline in score with rose bengal staining at week 22

**Time Frame:** Baseline and week 22

**Description:** After dripping fluorescein dye on the ocular surface, the cornea of the patients was analyzed with the patient accommodated in the slit lamp and under cobalt blue light. Fluorescein will stain spaces without cells, which represents spaces in distress caused by dry eyes. The score used ranges from 0 to 3 points (0 = not colored, 1 = blush with distant points, 2 = blush with close points and 3 = blush with confluent points). Score 0 means no corneal involvement (absence of keratitis) and score 3 means maximum involvement of the ocular surface) (Change = week 10 - baseline score)

**Measure:** Change from baseline in corneal keratitis score with fluorescein dye at week 10

**Time Frame:** Baseline and week 10

**Description:** After dripping fluorescein dye on the ocular surface, the cornea of the patients was analyzed with the patient accommodated in the slit lamp and under cobalt blue light. Fluorescein will stain spaces without cells, which represents spaces in distress caused by dry eyes. The score used ranges from 0 to 3 points (0 = not colored, 1 = blush with distant points, 2 = blush with close points and 3 = blush with confluent points). Score 0 means no corneal involvement (absence of keratitis) and score 3 means maximum involvement of the ocular surface) (Change = week 22 - baseline score)

**Measure:** Change from baseline in corneal keratitis score with fluorescein dye at week 22

**Time Frame:** Baseline and week 22

**Description:** The Schirmer test measures, in millimeters, the production of the tear film for five minutes. A strip of standardized paper is placed on the lateral third of the lower eyelid of both eyes and after 5 minutes. The tear moistens the paper and the reading of the moistening is done. The test can vary from 0 to 35 millimeters, being considered normal (normal tear flow) values greater than 10 millimeters. Values below 10 millimeters indicate dry eye and the lower the value, the more dry the eye.

(Change = week 10 - baseline measure)

**Measure:** Change from baseline in The Schirmer test at week 10

**Time Frame:** Baseline and week 10

**Description:** The Schirmer test measures, in millimeters, the production of the tear film for five minutes. A strip of standardized paper is placed on the lateral third of the lower eyelid of both eyes and after 5 minutes. The tear moistens the paper and the reading of the moistening is done. The test can vary from 0 to 35 millimeters, being considered normal (normal tear flow) values greater than 10 millimeters. Values below 10 millimeters indicate dry eye and the lower the value, the more dry the eye.

(Change = week 22 - baseline measure)

**Measure:** Change from baseline in The Schirmer test at week 22

**Time Frame:** Baseline and week 22

**Description:** The tear ferning test is a laboratory test but it has the potential to be applied in the clinic setting to investigate the tear film in a simple way. Drying a small sample of tear fluid onto a clean, glass microscope slide produces a characteristic crystallisation pattern, described as a 'tear ferning". The scale proposed by Rolando was used, which classifies the findings into 4 types (type 1, 2, 3 and 4), according to the teardrop crystallization pattern. Patterns 1 and 2 are considered normal and patterns 3 and 4 are considered abnormal and indicate that the tear has an inadequate composition and quality (Change = week 10 - baseline score)

**Measure:** Change from baseline in Tear ferning test (Rolando'score) at week 10

**Time Frame:** Baseline and week 10

**Description:** The tear ferning test is a laboratory test but it has the potential to be applied in the clinic setting to investigate the tear film in a simple way. Drying a small sample of tear fluid onto a clean, glass microscope slide produces a characteristic crystallisation pattern, described as a 'tear ferning". The scale proposed by Rolando was used, which classifies the findings into 4 types (type 1, 2, 3 and 4), according to the teardrop crystallization pattern. Patterns 1 and 2 are considered normal and patterns 3 and 4 are considered abnormal and indicate that the tear has an inadequate composition and quality (Change = week 22 - baseline score)

**Measure:** Change from baseline in Tear ferning test (Rolando'score) at week 22

**Time Frame:** Baseline and week 22

#### Secondary Outcomes

**Description:** A list of the systemic side effects most frequently described with the oral use of pilocarpine was presented to patients, where they could indicate the presence or absence of this effect: the side effects on the list are: sweating, chills, nausea, salivation, abdominal pain, dizziness, facial flushing, rhinitis, weakness, visual blurring, tremor, tachycardia, headache and diarrhea.

**Measure:** The frequency of systemic side effects most frequently reported by patients at week 10

**Time Frame:** week 10

**Description:** A list of the systemic side effects most frequently described with the oral use of pilocarpine was presented to patients, where they could indicate the presence or absence of this effect: the side effects on the list are: sweating, chills, nausea, salivation, abdominal pain, dizziness, facial flushing, rhinitis, weakness, visual blurring, tremor, tachycardia, headache and diarrhea.

**Measure:** The frequency of systemic side effects most frequently reported by patients at week 22

**Time Frame:** week 22

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* Patients with Sjögren's syndrome, both in primary and secondary forms, whose diagnoses were established according to the criteria defined by the - American-European Consensus for the diagnosis of Sjögren's syndrome.
* Patients with the secondary form of the syndrome, collagen disease considered controlled by a rheumatologist, before the start of the trial and stable until the end of the study.
* Systemic therapy instituted up to two months before the beginning of the protocol.
* Literate patients.
* Signature of the informed consent form

Exclusion Criteria:

* Eye or eyelid surface disease not attributed to Sjogren's syndrome.
* Temporary or permanent occlusion of tear points.
* Use of contact lenses.
* Use of systemic medication that is known to influence tear flow.
* Need to modify the systemic treatment of the underlying disease during the trial.
* Pregnancy or breastfeeding.
* Known hypersensitivity reaction to pilocarpine hydrochloride.
* Severe cardio-pulmonary disease.

**Maximum Age:** 65 Years

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Locations

**Location 1:**

**City:** São Paulo

**Country:** Brazil

**Facility:** Irmandade Santa casa de Misericórdia de São Paulo

**Zip:** 01221010

#### Overall Officials

**Official 1:**

**Affiliation:** Federal University of São Paulo

**Name:** Sergio Felberg, MD

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**Access Criteria:** IPD may be requested from the principal investigator upon request by email or letter addressed to registered contacts

**Description:** Detailed description of the methods may be made available after publication

**Info Types:**

- STUDY_PROTOCOL

- ICF

**IPD Sharing:** YES

**Time Frame:** 6 months after publication, for 3 months

### References Module

#### References

**Citation:** Kawakita T, Shimmura S, Tsubota K. Effect of Oral Pilocarpine in Treating Severe Dry Eye in Patients With Sjogren Syndrome. Asia Pac J Ophthalmol (Phila). 2015 Mar-Apr;4(2):101-5. doi: 10.1097/APO.0000000000000040.

**PMID:** 26065354

**Citation:** Cifuentes M, Del Barrio-Diaz P, Vera-Kellet C. Pilocarpine and artificial saliva for the treatment of xerostomia and xerophthalmia in Sjogren syndrome: a double-blind randomized controlled trial. Br J Dermatol. 2018 Nov;179(5):1056-1061. doi: 10.1111/bjd.16442. Epub 2018 May 29.

**PMID:** 29432648

**Citation:** Papas AS, Sherrer YS, Charney M, Golden HE, Medsger TA Jr, Walsh BT, Trivedi M, Goldlust B, Gallagher SC. Successful Treatment of Dry Mouth and Dry Eye Symptoms in Sjogren's Syndrome Patients With Oral Pilocarpine: A Randomized, Placebo-Controlled, Dose-Adjustment Study. J Clin Rheumatol. 2004 Aug;10(4):169-77. doi: 10.1097/01.rhu.0000135553.08057.21.

**PMID:** 17043506

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000007766

- Term: Lacrimal Apparatus Diseases

- ID: D000005128

- Term: Eye Diseases

- ID: D000007637

- Term: Keratoconjunctivitis

- ID: D000003231

- Term: Conjunctivitis

- ID: D000003229

- Term: Conjunctival Diseases

- ID: D000007634

- Term: Keratitis

- ID: D000003316

- Term: Corneal Diseases

- ID: D000001172

- Term: Arthritis, Rheumatoid

- ID: D000001168

- Term: Arthritis

- ID: D000007592

- Term: Joint Diseases

- ID: D000009140

- Term: Musculoskeletal Diseases

- ID: D000012216

- Term: Rheumatic Diseases

- ID: D000014987

- Term: Xerostomia

- ID: D000012466

- Term: Salivary Gland Diseases

- ID: D000009059

- Term: Mouth Diseases

- ID: D000009057

- Term: Stomatognathic Diseases

- ID: D000003240

- Term: Connective Tissue Diseases

- ID: D000001327

- Term: Autoimmune Diseases

- ID: D000007154

- Term: Immune System Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC05

- Name: Musculoskeletal Diseases

- Abbrev: BC07

- Name: Mouth and Tooth Diseases

- Abbrev: BC11

- Name: Eye Diseases

- Abbrev: BC17

- Name: Skin and Connective Tissue Diseases

- Abbrev: BC20

- Name: Immune System Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: BC23

- Name: Symptoms and General Pathology

### Condition Browse Module - Browse Leaves

- ID: M15664

- Name: Sjogren's Syndrome

- Relevance: HIGH

- As Found: Sjogren's Syndrome

- ID: M16355

- Name: Syndrome

- Relevance: LOW

- As Found: Unknown

- ID: M18040

- Name: Dry Eye Syndromes

- Relevance: HIGH

- As Found: Dry Eye

- ID: M10664

- Name: Keratoconjunctivitis Sicca

- Relevance: HIGH

- As Found: Dry Eye

- ID: M10663

- Name: Keratoconjunctivitis

- Relevance: LOW

- As Found: Unknown

- ID: M10786

- Name: Lacrimal Apparatus Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M8271

- Name: Eye Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M6455

- Name: Conjunctivitis

- Relevance: LOW

- As Found: Unknown

- ID: M6453

- Name: Conjunctival Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M10660

- Name: Keratitis

- Relevance: LOW

- As Found: Unknown

- ID: M6539

- Name: Corneal Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M4476

- Name: Arthritis

- Relevance: LOW

- As Found: Unknown

- ID: M4480

- Name: Arthritis, Rheumatoid

- Relevance: LOW

- As Found: Unknown

- ID: M10621

- Name: Joint Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M12097

- Name: Musculoskeletal Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M15045

- Name: Rheumatic Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M6323

- Name: Collagen Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M17724

- Name: Xerostomia

- Relevance: LOW

- As Found: Unknown

- ID: M15285

- Name: Salivary Gland Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M12019

- Name: Mouth Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M12017

- Name: Stomatognathic Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M6464

- Name: Connective Tissue Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M4629

- Name: Autoimmune Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M10200

- Name: Immune System Diseases

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000012859

- Term: Sjogren's Syndrome

- ID: D000015352

- Term: Dry Eye Syndromes

- ID: D000007638

- Term: Keratoconjunctivitis Sicca

### Intervention Browse Module - Ancestors

- ID: D000008916

- Term: Miotics

- ID: D000001337

- Term: Autonomic Agents

- ID: D000018373

- Term: Peripheral Nervous System Agents

- ID: D000045505

- Term: Physiological Effects of Drugs

- ID: D000018721

- Term: Muscarinic Agonists

- ID: D000018679

- Term: Cholinergic Agonists

- ID: D000018678

- Term: Cholinergic Agents

- ID: D000018377

- Term: Neurotransmitter Agents

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

### Intervention Browse Module - Browse Branches

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M13757

- Name: Pilocarpine

- Relevance: HIGH

- As Found: Motivational interview

- ID: M20795

- Name: Muscarinic Agonists

- Relevance: LOW

- As Found: Unknown

- ID: M20758

- Name: Cholinergic Agents

- Relevance: LOW

- As Found: Unknown

- ID: M20504

- Name: Neurotransmitter Agents

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000010862

- Term: Pilocarpine

### Misc Info Module

- Version Holder: 2024-05-24
