Traditional Chinese Medicine Ultrasonic Atomization Treatment for Dry Eye Disease

Dry Eye Syndromes Clinical Trial

Official title:

Traditional Chinese Medicine Ultrasonic Atomization Treatment for Dry Eye Disease: A Randomized, Double-masked, Placebo-controlled Trial

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06089317
• Other study ID #: CMDF-21B2005A_R1
• Status: Not yet recruiting
• Phase: N/A
• Start date: March 1, 2024
• Est. completion date: November 30, 2025

Study information

• Verified date: February 2024
• Source: Chinese University of Hong Kong
• Contact: Jennifer Tsoi
• Phone: 3943 5818
• Email: jennifertsoi[@]cuhk.edu.hk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Dry eye disease (DED) is the most prevalent ocular surface disease worldwide. Standard treatments like artificial tears show limited effect. Regarding the ultrasonic atomization, the ultrasonic nebulizer produces consistent steam from the solution with a treatment effect delivered to the ocular surface. We aim to evaluate the effectiveness and safety of traditional Chinese medicine (TCM) ultrasonic atomization as an adjuvant treatment for DED.

This is a randomized double-masked, active- and placebo-controlled trial. 200 subjects will be equally assigned to the herbal compound decoction(CD) group, dendrobium caulis (DC) group, houttuynia cordata (HC) group, placebo atomization(PA) group, and artificial tear (AT) group by stratified permuted block randomization.

Subjects of CD, DC, HC, and PA groups will receive TCM ultrasonic atomization treatment (6 times/week). All patients will receive hypromellose 0.3% w/v lubricant eye drops for a 1-week wash-out and a 4-month follow-up period. Outcomes included non-invasive tear break-up times, corneal and conjunctival fluorescein staining, and other dry eye-related parameter examined by LipiView II Ocular Surface Interferometer, OCULUS® Keratograph 5M, and slit lamp biomicroscope evaluated by masked clinical assessors at baseline, week 1, 2, 3, 4 and month 2, 3, 4. The other subjective questionnaires like the Ocular Surface Disease Index (OSDI) questionnaire are also selected.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 200
• Est. completion date: November 30, 2025
• Est. primary completion date: November 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion criteria:

1. At least one eye of subjects meets DED diagnostic criteria as the Tear Film and Ocular Surface Society (TFOS) Dry Eye Workshop (DEWS II); and

2. Ocular Surface Disease Index (OSDI)=13 and <33; and

3. The age range between years 18-80, no sex limitation; and

4. Symptoms of dry eye for at least 6 months; and

5. Can complete the questionnaires independently and understand Chinese or English.

Exclusion criteria:

1. Had or currently suffering from other concomitant ocular surface diseases, including chronic conjunctivitis, ocular rosacea, cicatricial pemphigoid, graft-versus-host disease, limbal stem cell deficiency, and severe ocular allergy;

2. Received any refractive surgery and corneal surgery before, including corneal transplant; or any eye surgery in the past 6 months;

3. Receiving DED-related medications, including topical steroid eyedrops, topical antibiotics, topical cyclosporin A, and topical diquafosol;

4. Received intense pulsed laser (IPL) or vectored thermal pulsation (VTP) therapy in the past 12 months;

5. Received topical antiglaucomatous treatment in the past 12 months

6. Plans to use contact lenses during treatment and follow-up periods or used contact lenses 2 weeks before the baseline measurement and recruitment;

7. Had or currently suffering from severe cardiopulmonary disease, liver and kidney dysfunction, and severe blood system diseases;

8. Suffering from glucose-6-phosphate dehydrogenase deficiency (G6PD);

9. Had or currently suffering from specific respiratory diseases, e.g. emphysema, bronchitis, asthma, chronic obstructive pulmonary disease, bronchial dilatation;

10. Has adverse reaction history to herbs used in this study before;

11. Whose TCM constitution is manifested as "yang-deficiency" or diagnosed by TCM practitioners that their TCM syndrome is not suitable for the atomization treatment;

12. Pregnancy, preparation for pregnancy, or lactation;

Related Conditions & MeSH terms

• Dry Eye Syndromes
• Eye Diseases
• Keratoconjunctivitis Sicca

Intervention

Combination Product:
• TCM ultrasonic atomization treatment with herbal Compound Decoction (CD)
The subjects will receive TCM ultrasonic atomization treatment with the ultrasonic nebulizer (WH-2000, YueHua, China) 6 days a week, once daily, 10 minutes per session, for 4 weeks. The solution for atomization of the CD group is TCM compound decoction. The prescription of atomization solution in the CD group contains Honeysuckle flower (???) 5g, Chrysanthemum flower (??) 5g, Pale betterflybush flower (???) 5g, Mild mint herb (??) 5g, Barbary wolfberry fruit (???) 10g, and Ophiopogon japonicus (??) 5g. Subjects will be treated with hypromellose 0.3% w/v eye drops four times per day too.
• TCM ultrasonic atomization treatment with Dendrobii Caulis (DC)
The subjects will receive TCM ultrasonic atomization treatment with the ultrasonic nebulizer (WH-2000, YueHua, China) 6 days a week, once daily, 10 minutes per session, for 4 weeks. The solution for atomization of the DC group is Dendrobii Caulis extracts. The prescription of the DC group contains Dendrobium (??) 35g. Subjects will be treated with hypromellose 0.3% w/v eye drops four times per day too.
• TCM ultrasonic atomization treatment with Houttuynia Cordata (HC)
The subjects will receive TCM ultrasonic atomization treatment with the ultrasonic nebulizer (WH-2000, YueHua, China) 6 days a week, once daily, 10 minutes per session, for 4 weeks. The solution for atomization of the HC group is Heartleaf Houttuynia Herb extracts. The prescription of the HC group contains Heartleaf Houttuynia Herb(???) 35g. Subjects will be treated with hypromellose 0.3% w/v eye drops four times per day too.
• Placebo TCM ultrasonic atomization treatment (PA)
The subjects will receive TCM ultrasonic atomization treatment with the ultrasonic nebulizer (WH-2000, YueHua, China) 6 days a week, once daily, 10 minutes per session, for 4 weeks. The solution for atomization of the PA group is low-concentration compound decoction (5%) same with the CD group. Subjects will be treated with hypromellose 0.3% w/v eye drops four times per day too.

Drug:
• Artificial Tears (AT)
The subjects will receive lubricant eye drop (Hypromellose 0.3% w/v Eye Drops) four times per day only.

Locations

Country	Name	City	State
Hong Kong	Hong Kong Eye Hospital	Kowloon
Hong Kong	The Chinese University of Hong Kong Eye Centre (CUHKEC)	Kowloon
Hong Kong	Prince of Wales Hospital	Shatin
Hong Kong	The CUHK Medical Centre (CUHKMC)	Shatin

Sponsors (1)

Lead Sponsor	Collaborator
Chinese University of Hong Kong

Country where clinical trial is conducted

Hong Kong, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Intraocular Pressure (IOP)	The intraocular pressure of the eyes will be assessed by a non-contact tonometer.	4 months
Other	Best Corrected Visual Acuity (BCVA)	Best corrected visual acuity (BCVA) is examined by a standard visual acuity chart.	4 months
Other	Change in Posterior Subcapsular of Lens	The Lens Opacities Classification Systems (LOCS III) will be applied for lens grading.; The posterior subcapsular (P) cataract will be graded referring to five retroillumination images: P1-P5.	4 months
Other	Change in Nuclear Color (NC) of Lens	The Lens Opacities Classification Systems (LOCS III) will be applied for lens grading.; Nuclear color (NC) will be graded referring to referring to six slit-lamp images: NC1-NC6.	4 months
Other	Change in Cortical Cataract (C) of Lens	The Lens Opacities Classification Systems (LOCS III) will be applied for lens grading.; Cortical cataract (C) will be graded referring to five retroillumination images: C1-C5.	4 months
Other	Change in Nuclear Opalescence (NO) of Lens	The Lens Opacities Classification Systems (LOCS III) will be applied for lens grading.; Nuclear opalescence (NO) will be graded referring to six slit-lamp images: NO01-NO06.	4 months
Other	Change in Central Corneal Thickness (CCT) of Corneal Endothelium	Central corneal thickness will be measured with a non-contact specular microscope (Nidek CEM-530, NIDEK Co., Ltd. Japan).	4 months
Other	Change in Corneal Endothelial Cell Density (CD) of Corneal Endothelium	Corneal endothelial cell density will be measured with a non-contact specular microscope (Nidek CEM-530, NIDEK Co., Ltd. Japan).	4 months
Other	Change in Number of Cells Counted (NUM) of Corneal Endothelium	Number of cells counted will be measured with a non-contact specular microscope (Nidek CEM-530, NIDEK Co., Ltd. Japan).	4 months
Other	Constitution in Chinese Medicine Questionnaire (CCMQ)	Constitution in Chinese Medicine Questionnaire (CCMQ) is a self-administered questionnaire with 60 items. It will be applied to classify a person's traditional Chinese medicine constitution out of 9 pre-defined types.	-1 week
Other	Change of a-diversity in Ocular Surface Microbiome	Each eye will be sampled by a sterile, polyester swab on the inferior fornix of the conjunctiva. The swabs will be placed in 2 mL microcentrifuge tubes at 4 °C. Extraction will be performed by laboratory staff, then the sample will be transferred to -80 °C laboratory freezer for long-term storage before further gene expression tests. After genomic DNA extraction from conjunctival swab samples for 16S rRNA sequencing, the resulting amplicons will be filtered, clustered into operational taxonomic units (OTUs) and taxonomically classified using reference databases. The a-diversity will be calculated and reported as ordination plots.	4 months
Other	Change of ß-diversity in Ocular Surface Microbiome	Each eye will be sampled by a sterile, polyester swab on the inferior fornix of the conjunctiva. The swabs will be placed in 2 mL microcentrifuge tubes at 4 °C. Extraction will be performed by laboratory staff, then the sample will be transferred to -80 °C laboratory freezer for long-term storage before further gene expression tests. After genomic DNA extraction from conjunctival swab samples for 16S rRNA sequencing, the resulting amplicons will be filtered, clustered into operational taxonomic units (OTUs) and taxonomically classified using reference databases. The ß-diversity will be calculated and reported as ordination plots.	4 months
Other	Relative Abundance in Ocular Surface Microbiome	Each eye will be sampled by a sterile, polyester swab on the inferior fornix of the conjunctiva. The swabs will be placed in 2 mL microcentrifuge tubes at 4 °C. Extraction will be performed by laboratory staff, then the sample will be transferred to -80 °C laboratory freezer for long-term storage before further gene expression tests. After genomic DNA extraction from conjunctival swab samples for 16S rRNA sequencing, the resulting amplicons will be filtered, clustered into operational taxonomic units (OTUs) and taxonomically classified using reference databases. The relative abundance will be reported.	4 months
Primary	Change in the Ocular Surface Disease Index (OSDI)	The Ocular Surface Disease Index (OSDI) is a 12-item symptom frequency-based questionnaire. It is self-administered to assess DED-related symptoms and severity.; The final OSDI score is calculated by dividing the product of the total sum of the score and 25 by the total number of answered questions, with a range from 0 to 100. The score reflects the severity of DED(normal: 0-12, mild: 13-22, moderate: 23-32, severe: >33).	baseline to 4th week
Primary	Change in Non-invasive Tear Break-up Times (NIBUT)	The non-invasive tear break-up time (NIBUT) will be measured by the OCULUS Keratograph® 5M (Oculus, Wetzlar, Germany). Subjects will be instructed to keep their eyes on as much as possible during the examination. First and average NIBUT will be recorded by the machine accordingly.; Shortening NIBUT(< 10 seconds) suggests instability of the tear film.	baseline to 4th week
Secondary	Change in Ocular Surface Disease Index (OSDI)	The Ocular Surface Disease Index (OSDI) is a 12-item symptom frequency-based questionnaire. It is self-administered to assess DED-related symptoms and severity.; The final OSDI score is calculated by dividing the product of the total sum of the score and 25 by the total number of answered questions, with a range from 0 to 100. The score reflects the severity of DED: normal: 0-12, mild: 13-22, moderate: 23-32, severe: >33).	4 months
Secondary	Change in symptom Assessment iN Dry Eye (SANDE, modified)	Symptom Assessment iN Dry Eye (SANDE) questionnaire is a 2-item frequency- and severity-based visual analog scale. It is self-administered to evaluate the frequency and severity of dry eye symptoms.; The final SANDE score is calculated by obtaining the square root of the product of the frequency of symptoms score and the severity of symptoms score, with a range from 0 (minimal degree of dry eye symptoms) to 100 (maximal degree of dry eye symptoms)	4 months
Secondary	Change in 36-Item Short Form Health Survey (SF-36)	The 36-Item Short Form Health Survey (SF-36) is a 36-item self-administered questionnaire, with 8 domains included: physical functioning (PF), role physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role emotional (RE), and mental health (MH). The physical health sub-scale and Mental health sub-scale will be graded respectively.	4 months
Secondary	Change in the Work Productivity and Activity Impairment Questionnaire: General Health V2.0 (WPAI:GH)	The Work Productivity and Activity Impairment Questionnaire: General Health V2.0 (WPAI: GH) is a 6-item questionnaire that measures impairments in work and activities.	4 months
Secondary	Change in Non-Invasive Tear Break Up Times (NIBUT)	Non-Invasive tear break up time (NIBUT) will be measured by the OCULUS Keratograph® 5M (Oculus, Wetzlar, Germany) in both eyes. Participants were instructed to keep their eyes on as much as possible during the examination. First and average NIKBUTs will be recorded by the machine.; Shortening NIBUT(< 10 seconds) suggests instability of the tear film.	4 months
Secondary	Changes in Tear Meniscus Height (TMH)	The tear meniscus height (TMH) will be measured by the OCULUS Keratograph® 5M (Oculus, Wetzlar, Germany).	4 months
Secondary	Changes in Bulbar Redness	Bulbar conjunctival hyperaemia is automatically evaluated the Keratograph 5M (OCULUS, Wetzlar, Germany) according to the JENVIS grading scale from 0 to 4.	4 months
Secondary	Changes in Lipid Layer Thickness	The lipid layer thickness (LLT) of the tear film will be determined with the LipiView ® II Ocular Surface Interferometer (TearScience, Morrisville, NC). Minimum, Maximum, and Average thickness in nanometers (nm) will be measured.	4 months
Secondary	Changes in Partial Blinking Rate	The partial blinking rate will be reported as the percentage of incomplete blinks. The total and partial blinking times will be automatically recorded by the LipiView ® II Ocular Surface Interferometer (TearScience, Morrisville, NC).	4 months
Secondary	Changes in Meiboscore	The meiboscore grading will be based on the infrared meibography captured by the LipiView ® II Ocular Surface Interferometer (TearScience, Morrisville, NC). Both superior and inferior eyelids will be recorded. The result will be graded by a masked assessor.; The grading scheme is a 3-point scale (grade 0, no meibomian gland atrophy; grade 1, less than 1/3 area of glands lost; grade 2, 1/3-2/3 area of glands lost; grade 3, more than 2/3 area of glands lost)	4 months
Secondary	Change in Tear Film Breakup Time (TBUT)	The tear film breakup time (TBUT) is the time of the initial breakup of the tear film after a full blink. 2% Sodium fluorescein will be instilled in both eyes of the subjects. A masked follow-up assessor will do the examination via the slit lamp with a blue cobalt light. The TBUT will be measured three times with a stopwatch and taken on average.	4 months
Secondary	Change in Corneal and Conjunctival Fluorescein Staining	Fluorescein sodium liquid will be instilled on the ocular surface. After 3 minutes, the corneal and conjunctival punctate epithelial erosions will be observed and graded via the slit lamp biomicroscope with a blue cobalt light.; The Oxford Grading System is selected for grading. The severity will be divided into 6 grades (Grade 0, absent; Grade 1, minimal; Grade 2, mild; Grade 3, moderate; Grade 4, marked; Grade 5, severe)	4 months
Secondary	Change in Expressibility of Meibomian Glands in the Meibomian Glands Yielding Liquid Secretion (MGYLS) (the inferior eyelid)	Expressibility of the inferior eyelid meibomian glands is assessed with the Meibomian Gland Evaluator (TearScience, North Carolina, USA) applied inferior to central aspects of the inferior eyelid margin. The result is graded by a masked assessor.; The meibomian glands yielding liquid secretion (MGYLS) is the total number of glands that yield lipid secretions at the central aspects of the eyelid margin.	4 months
Secondary	Change in Quality of Expressed Meibum	The meibomian gland evaluator will be applied to the central aspects of the inferior eyelid margin. The result will be graded by a masked assessor.; Each gland in each area will be assessed for expressibility and graded according to a 4-point scale: grade 0, no secretion; grade 1, inspissated/ toothpaste-like expression; grade 2, cloudy fluid secretion; and grade 3, clear fluid/normal secretion. The sum scores of 5 glands will be between 0 and 15.	4 months
Secondary	Change in Lid Margin and Eyelash Abnormalities	Lid margin and eyelash abnormalities will be accessed by a slit lamp, including telangiectasia, meibomian gland capping, Demodex lash cylindrical collarettes, staphylococcal lash crusting, and seborrheic lash crusting.; All items will be graded based on a four-point scale: grade 0, absent; grade 1, mild; grade 2, moderate; grade 3, severe.	4 months
Secondary	Change in Tear Film Osmolarity (TFO)	The tear film osmolarity (TFO) is measured by the ScoutPro™ Osmolarity System (TearLab , San Diego, CA) via the disposable test card in both eyes.; The normal osmolarity was considered as lower than 308 mOsm/L in both eyes. A difference more than 8 mOsm/L between two eyes reflects the stability of the tear film.	4 months
Secondary	Changes in Schirmer I test	The Schirmer I test (ST) will be performed by sterile standard filter paper strips without anesthesia. The filter paper strips will be gently put on the temporal side of both lower eyelids for 5 minutes. The wetting length by tears in each strip will be recorded in nanometers (mm) by a masked assessor.; The strips will be collected in sterile centrifuge tubes respectively for further laboratory tests.	4 months
Secondary	Changes in Matrix metallopeptidase 9 (MMP-9)	The MMP-9 enzyme-linked immunosorbent assay (ELISA) development kit (Invitrogen, Carlsbad, CA)) will be applied for measurement of the concentration of MMP-9 in participants' tears.	4 months
Secondary	Adverse events (AEs)	The adverse events (AEs) will be the number of incidents based on a checklist of symptoms, signs, and diseases by patients' reporting, slit-lamp examination, or doctor's diagnosis.	4 months