<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02219204</url>
  </required_header>
  <id_info>
    <org_study_id>R1142/44/2014</org_study_id>
    <secondary_id>2014/398/A</secondary_id>
    <nct_id>NCT02219204</nct_id>
  </id_info>
  <brief_title>Randomised Research Comparing Acupuncture, Herbal Treatment and Artificial Tear Eye Drops in Dry Eye</brief_title>
  <official_title>Randomised Research Comparing Acupuncture, Herbal Treatment and Artificial Tear Eye Drops in Dry Eye</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Singapore National Eye Centre</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Singapore National Eye Centre</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Dry eye is a major, common medical condition with significant health and economic burden in&#xD;
      Singapore and worldwide. It is a holistic problem affected by living habits, nutrition and&#xD;
      underlying systemic disease, inducing a significant decrease in quality-of-life. The hallmark&#xD;
      of this disease is raised tear osmolarity and inflammation. There is no definitive cure for&#xD;
      this condition, as treatment in the form of lubricants is only symptomatic and treatment with&#xD;
      cyclosporine eyedrops is expensive and may not be well tolerated.&#xD;
&#xD;
      Following the rise in international interest in complementary medicine, randomized-controlled&#xD;
      studies in dry eye using Traditional Chinese Medicine (TCM) have been published, with mixed&#xD;
      results. However, the major limitation of these studies is the lack of objective assessment&#xD;
      for inflammation.&#xD;
&#xD;
      We propose to collaborate with an academically-trained Singapore TCM physician who has&#xD;
      conducted dry eye trials, and synergistically exploit the existing state-of-the-art dry eye&#xD;
      monitoring technologies available at Singapore Eye Research Institute (SERI). This proposal&#xD;
      is cost-effective, building on previous government grants and expertise to provide definitive&#xD;
      scientific evidence on the efficacy and safety of TCM in dry eye. SERI has an international&#xD;
      reputation for interventional studies, and the PI has a good academic relationship with the&#xD;
      above TCM physician. We propose to screen, recruit and treat 150 patients with a herbal&#xD;
      preparation and acupuncture, and evaluate over 4 weeks in a randomized-controlled study.&#xD;
      Tests to be performed will include tear imaging and osmolarity, as well as protein and&#xD;
      cytokine assays.&#xD;
&#xD;
      Singapore is uniquely positioned at the crossroads of the East and the West to take the lead&#xD;
      in this field. Given that there is an increasing patient interest in holistic care in&#xD;
      Singapore and the rise of scientifically trained TCM practitioners, a study like this one is&#xD;
      very timely, and will have tremendous impact to healthcare delivery in Singapore.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Dry eye is a major, common medical condition with significant health burden in Singapore and&#xD;
      worldwide. As much as one third of the adult population in Asian countries are affected by&#xD;
      dry eye. It has been shown that dry eye affects quality of life, including the performing of&#xD;
      daily activities such as reading and driving a car. Moderate severity of dry eye affects some&#xD;
      patients like moderate angina. The direct and indirect cost of treating dry eye is high and&#xD;
      increasing. For example, it costs individuals about US$800 per year to treat dry eye, but the&#xD;
      cost to society for managing such a patient is US$12000 per year. (1-29)&#xD;
&#xD;
      Dry eye is a holistic problem affected by living habits such as working long hours on the&#xD;
      computer and in a dry, air-conditioned environment. It is also associated with poor nutrition&#xD;
      and intake of dietary supplements such as omega-3 and omega-6 fatty acids may help to treat&#xD;
      dry eye. Dry eye is also a systemic immune mediated disease, and aggravated by those with&#xD;
      autoimmune Sjögren's syndrome, rheumatoid arthritis, thyroid disease, systemic lupus&#xD;
      erythematosis, Steven Johnson syndrome and chronic graft versus host disease.&#xD;
&#xD;
      In a recent international workshop, international experts in dry eye agree that the hallmark&#xD;
      of this disease is raised tear osmolarity and ocular surface inflammation. Traditionally, dry&#xD;
      eye is diagnosed by a reduced Schirmer's test and/or reduced tear break up time or the&#xD;
      presence of dry eye symptoms. In addition to these traditional tests, it would be&#xD;
      advantageous to incorporate measurements of osmolarity and inflammation in clinical studies.&#xD;
      There is no definitive cure for this condition, as treatment in the form of lubricants is&#xD;
      only symptomatic and treatment with cyclosporine eye drops is expensive and may not be well&#xD;
      tolerated. Treatment with steroids can be effective but associated with adverse effects such&#xD;
      as sight threatening glaucoma. In summary there is a definite medical need for alternative&#xD;
      therapies in dry eye.&#xD;
&#xD;
      Traditional Chinese Medicine (TCM) is involved in restoring the natural balance of the body,&#xD;
      which results in disease like dry eye when this is disturbed. In TCM philosophy, dry eye may&#xD;
      result from syndromes such as yin deficiency in the liver or kidney. Modalities such as&#xD;
      acupuncture or herbs can be used judiciously to restore the balance in specific patients.&#xD;
&#xD;
      Recently there have been randomized controlled studies in dry eye using acupuncture and&#xD;
      herbs, with mixed results, refer to attachment (Table 1). The major limitation of these&#xD;
      studies is that objective tear film evaluation such as tear osmolarity, and tear cytokines&#xD;
      and proteins, which are indicative of ocular surface inflammation, have not been evaluated.&#xD;
      In addition, some studies suffer from lack of proper controls or randomization.&#xD;
&#xD;
      If the mainstream practitioners of evidence based medicine are convinced that TCM can&#xD;
      fundamentally alter the pathological processes in dry eye, they will be more receptive to&#xD;
      this form of treatment. At the same time, regulatory bodies need to be reassured that TCM is&#xD;
      safe in dry eye, so that more education and promotion of such treatment can benefit more&#xD;
      people.&#xD;
&#xD;
      The PI runs a dry eye clinic twice a week at the Singapore National Eye Centre since 2006. He&#xD;
      is aware that many dry eye patients in Singapore have experienced a host of more conventional&#xD;
      therapies and are eager to attempt alternative forms of therapy. This trend towards TCM and&#xD;
      holistic medicine will continue regardless of the attitudes of 'western' medical&#xD;
      practitioners. This study, when completed, will present an opportunity for bridging the gaps&#xD;
      between the two health care communities who do not normally interact. Since latest scientific&#xD;
      tools in terms of protein science and imaging will be employed in the study, it will&#xD;
      definitely increase the evidence based medicine for TCM in the dry eye field.&#xD;
&#xD;
      The PI has published 67 peer reviewed papers in dry eyes and related ocular surface&#xD;
      processes, including review articles,(30-34) international expert panel report,(35)&#xD;
      epidemiological studies,(36-37) PI initiated and industry sponsored interventional drugs&#xD;
      including randomized controlled drug trials.(38-40) In one pharmacy in Singapore alone, the&#xD;
      cost of dry eye medications amounted to US$1.5 million in one year.(3) He has also found in&#xD;
      an epidemiological study in Singapore people that dry eye impairs visual associated function&#xD;
      related activities of daily living.(41) He established the only dedicated dry eye service in&#xD;
      the region and has produced many papers relating to the assessment of these patients,(42-46)&#xD;
      including one that found dry eye being related to the amount exposure to stressful activities&#xD;
      and conditions.(46) The PI has experience in the biochemical evaluation of patient tears and&#xD;
      materials in dry eye(47-51) and clinical imaging related to dry eye.(52-54) Lastly, he has&#xD;
      also appeared in mass media educational articles including press releases and articles/talks&#xD;
      for layperson and general practitioners.&#xD;
&#xD;
      A survey was conducted among registered TCM practitioners in Singapore and published in a&#xD;
      peer reviewed journal.(55) This showed that a significant proportion of these institutional&#xD;
      practitioners are keen to practice in dry eye. This study was also chosen to be presented as&#xD;
      an oral presentation at the 10th Asean Congress of TCM cum 3rd Asia Advanced Forum on&#xD;
      Acupuncture and Moxibustion. At the same time, the full article has been translated into&#xD;
      Chinese in the congress proceedings page 192-197 to appeal to the audience of TCM physicians.&#xD;
      The PI has also participated in discussion on data analysis in TCM trials. (56-57) In&#xD;
      addition, acupuncture in rabbits had shown to induce changed in tear proteins, although this&#xD;
      has not been evaluated in humans. (58)&#xD;
&#xD;
        1. HYPOTHESIS AND OBJECTIVES&#xD;
&#xD;
           The overall hypothesis is that traditional Chinese medicine modalities of acupuncture&#xD;
           and herbs can improve the symptoms and signs of dry eye, and objectively, these&#xD;
           improvements are associated with reduction of tear osmolarity and reduction of&#xD;
           inflammatory markers such as tear cytokines and proinflammatory proteins. There is also&#xD;
           a long term objective of integrating TCM and mainstream medical care and having a&#xD;
           cost-effective approach to eye disease.&#xD;
&#xD;
           Primary outcome:&#xD;
&#xD;
           • Change in SPEED score (Week4-Week0)&#xD;
&#xD;
           Secondary outcomes:&#xD;
&#xD;
             -  Change in Tear Evaporimetry&#xD;
&#xD;
             -  Change in TCM score (Lung-Kidney Yin deficiency)&#xD;
&#xD;
             -  Change in NIBUT&#xD;
&#xD;
             -  Change in Schirmers I&#xD;
&#xD;
             -  Change in Corneal fluorescein staining (5 zones)&#xD;
&#xD;
             -  Change in Tear osmolarity&#xD;
&#xD;
             -  Change in Tear meniscus height&#xD;
&#xD;
             -  Change in Tear protein/ cytokine levels&#xD;
&#xD;
           1.1 Primary Objectives&#xD;
&#xD;
           We aim to show that dry eye patients treated with acupuncture is efficacious (can&#xD;
           improve symptoms and signs of dry eye) and safe (no ocular and systemic side effects).&#xD;
&#xD;
           1.2 Secondary Objectives&#xD;
&#xD;
           We aim to show that dry eye patients treated with a herbal preparation is efficacious&#xD;
           (can result in reduction of symptoms and signs of dry eye) and safe (no ocular and&#xD;
           systemic side effects).&#xD;
&#xD;
           We also aim to show that objective, definitive hallmarks of dry eye disease, ie. Tear&#xD;
           osmolarity and surrogates of ocular surface inflammation, such as tear cytokines and&#xD;
           proinflammatory proteins, are reduced after treatment by acupuncture and herbal&#xD;
           treatment, compared to control.&#xD;
&#xD;
           1.3 Potential Risks and Benefits: 1.3.1 Potential Risks We will anticipate minimal risk&#xD;
           and discomfort involve in this study.&#xD;
&#xD;
             -  It is possible that eyelid bruising and swelling may occur from acupuncture needles&#xD;
&#xD;
             -  Some slight discomfort from Schirmers I test&#xD;
&#xD;
             -  Nausea, insomnia, headache, loss of appetite, malaise, diarrhoea and abdominal&#xD;
                cramps may occur after herbal consumption&#xD;
&#xD;
           Relatively few complications have been reported from the use of acupuncture. However,&#xD;
           acupuncture can cause potentially serious side effects if not delivered properly by a&#xD;
           qualified practitioner. The most common side effects after acupuncture include soreness,&#xD;
           bruises, fatigue, lightheadedness and involuntary twitching of muscle. Should this event&#xD;
           occur, increased frequency of visits to the eye clinic may be necessary.&#xD;
&#xD;
           1.3.2 Potential Benefits There is no assurance participants will benefit from this&#xD;
           study. However, their participation may contribute to the medical knowledge whether TCM&#xD;
           medicine can fundamentally alter the pathological processes in dry eye. At the same&#xD;
           time, regulatory bodies need to be reassured that TCM is safe in dry eye, so that more&#xD;
           education and promotion of such treatment can benefit more people.&#xD;
&#xD;
        2. STUDY POPULATION 3.1 List The Number and Nature of Subjects to be Enrolled. One hundred&#xD;
           and fifty eligible dry eye subjects will be screened and recruited from SCHMI.&#xD;
&#xD;
      3.2 Criteria for Recruitment and Recruitment Process&#xD;
&#xD;
        1. Subjects meet all the inclusion criteria listed below.&#xD;
&#xD;
        2. Clear of exclusion criteria.&#xD;
&#xD;
      Permission would be sought from the attending TCM physicians before subjects are being&#xD;
      recruited. Eligible subjects will be counselled on the study. If subject is interested,&#xD;
      informed written consent will be obtained from all participants. Thereafter, optometrsits at&#xD;
      SCHMI will schedule a baseline visit to SERI for ocular monitoring.&#xD;
&#xD;
      3.3 Inclusion Criteria&#xD;
&#xD;
      For eligibility each participant presenting at SCHMI must be assessed by the TCM physician&#xD;
      and optometrist, and found to satisfy every one of the following:&#xD;
&#xD;
        1. Age: 40-85 years, visual acuity better than logMAR of 1.0&#xD;
&#xD;
        2. Chief complaint should be dry eye&#xD;
&#xD;
        3. Symptoms:&#xD;
&#xD;
           3.1. SPEED score &gt; 6 3.2. TCM score satisfies lung-kidney yin deficiency profile&#xD;
&#xD;
        4. Signs:&#xD;
&#xD;
      4.1. TBUT (&lt;10s) or Schirmer's test (&lt;10mm/5 mins) 4.2 Any corneal fluorescein staining&#xD;
&#xD;
      3.4 Exclusion Criteria All subjects meeting any of the exclusion criteria at screening visit&#xD;
      will be excluded from participation.&#xD;
&#xD;
        1. Glaucoma or other ophthalmic disease, eg. Extraocular muscle palsies, ectropion,&#xD;
           entropion&#xD;
&#xD;
        2. Ocular allergies, eg. Allergic conjunctivitis, sinusitis, eczema, atopic&#xD;
           keratoconjuntivitis&#xD;
&#xD;
        3. Known of thyroid disorders (diagnosed by physician)&#xD;
&#xD;
        4. Trichiasis&#xD;
&#xD;
        5. Eye surgeries patients including LASIK (within 1 year)&#xD;
&#xD;
        6. Steven-Johnson syndrome&#xD;
&#xD;
        7. Sjogren's syndrome&#xD;
&#xD;
        8. Eye related trauma (within 1 year)&#xD;
&#xD;
        9. Contact lens wear (within 1 year)&#xD;
&#xD;
       10. Punctal occlusion&#xD;
&#xD;
       11. Systemic disease requiring regular medication (except hypertension and lipidemia)&#xD;
&#xD;
       12. Pregnancy or planning to be pregnant&#xD;
&#xD;
       13. Requirement for medications such as anti-microbial, inflammatory, creams (except&#xD;
           moisturizers or cosmetics), or steroidal therapies&#xD;
&#xD;
       14. Unable to do this clinical trial for any reason&#xD;
&#xD;
      4 STUDY DESIGN This is a randomized observer masked parallel group three arm interventional&#xD;
      study.&#xD;
&#xD;
      Treatment arms&#xD;
&#xD;
      There will be 3 trial arms in this study:&#xD;
&#xD;
        -  Control: Systane Ultra Eye drop (n=50)&#xD;
&#xD;
        -  Systane Ultra Eye Drop and Acupuncture treatment (n=50)&#xD;
&#xD;
        -  Systane Ultra Eye Drop and Herbs treatment (n=50)&#xD;
&#xD;
      Study duration: 5 Weeks Recruitment duration: 1 Year&#xD;
&#xD;
      4.1 Randomisation and Blinding&#xD;
&#xD;
      The randomisation procedure used will entail:&#xD;
&#xD;
        1. Presence of two witnesses&#xD;
&#xD;
        2. Drawing of lots&#xD;
&#xD;
        3. Randomization codes for the 3 groups will be noted. For e.g. 001A, 002B, 003C etc.&#xD;
&#xD;
        4. Study information related to randomisation will be filed and kept at SCHMI&#xD;
&#xD;
        5. Only unblinded personnel have access to the randomization code file&#xD;
&#xD;
      Randomisation will be done at SCHMI. Study members at SCHMI will be unblinded as they will be&#xD;
      delivering TCM treatments to the subjects. However, study members at SERI will all be blinded&#xD;
      so as to prevent unintentional biases when assessing and monitoring of ocular surface.&#xD;
&#xD;
      In a situation of a serious event, a decision on whether to open (break) the code for the&#xD;
      specific patient is necessary. Although it is advantageous to retain the blind for all&#xD;
      patients prior to final study analysis, when a serious adverse reaction is judged reportable&#xD;
      on an expedited basis, it is recommended that the blind be broken only for that specific&#xD;
      patient by the designated investigator who is unblind. It is also recommended that, when&#xD;
      possible and appropriate, the blind be maintained for those persons, such as biometrics&#xD;
      personnel, responsible for analysis and interpretation of results at the study's conclusion.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>March 2015</start_date>
  <completion_date type="Actual">December 2015</completion_date>
  <primary_completion_date type="Actual">December 2015</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in SPEED score (Week4-Week0)</measure>
    <time_frame>4 weeks</time_frame>
    <description>Any improvement or discomfort in dry eye symptoms during 4 weeks</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Tear Evaporimetry</measure>
    <time_frame>4 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in TCM score (Lung-Kidney Yin deficiency)</measure>
    <time_frame>4 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Non Invasive Break Up Time</measure>
    <time_frame>4 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Schirmers I</measure>
    <time_frame>4 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Corneal fluorescein staining</measure>
    <time_frame>4 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Tear osmolarity</measure>
    <time_frame>4 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Tear meniscus height</measure>
    <time_frame>4 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Tear protein/ cytokine levels</measure>
    <time_frame>4 weeks</time_frame>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">150</enrollment>
  <condition>Dry Eye</condition>
  <arm_group>
    <arm_group_label>Acupuncture treatment</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>This will be performed twice weekly for 30 days. There will be 8 sessions of acupuncture treatments in total.&#xD;
The needles to be use around the eyes will have the dimensions of 0.25 (diameter) x 13mm (length), while 0.25 x 25mm needles will be used behind the ear (feng chi) and 0.30 X 25mm needles on the upper and lower limbs. These needles will remain in the points for 20 minutes. The depth of penetration will be about 1-2 mm.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Herbal treatment</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>This formulation is called qi ju gan lu yin or Lycium berry, a chrysanthemum beverage. This is a modified version of &quot;qi ju di huang wan&quot; published previously. The senior TCM collaborator, Prof Wei QP has made this modification in order to treat the dry eye patients with &quot;lung-kidney yin deficiency&quot;.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Eye drops</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Acupuncture</intervention_name>
    <arm_group_label>Acupuncture treatment</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Herbal treatment</intervention_name>
    <arm_group_label>Herbal treatment</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age: 40-85 years, visual acuity better than logMAR of 1.0&#xD;
&#xD;
          2. Chief complaint should be dry eye&#xD;
&#xD;
          3. Symptoms:&#xD;
&#xD;
             3.1. SPEED score &gt; 6&#xD;
&#xD;
             3.2. TCM score satisfies lung-kidney yin deficiency profile&#xD;
&#xD;
          4. Signs:&#xD;
&#xD;
        4.1. TBUT (&lt;10s) or Schirmer's test (&lt;10mm/5 mins) 4.2 Any corneal fluorescein staining&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Glaucoma or other ophthalmic disease, eg. Extraocular muscle palsies, ectropion,&#xD;
             entropion&#xD;
&#xD;
          2. Ocular allergies, eg. Allergic conjunctivitis, sinusitis, eczema, atopic&#xD;
             keratoconjuntivitis&#xD;
&#xD;
          3. Known of thyroid disorders (diagnosed by physician)&#xD;
&#xD;
          4. Trichiasis&#xD;
&#xD;
          5. Eye surgeries patients including LASIK (within 1 year)&#xD;
&#xD;
          6. Steven-Johnson syndrome&#xD;
&#xD;
          7. Sjogren's syndrome&#xD;
&#xD;
          8. Eye related trauma (within 1 year)&#xD;
&#xD;
          9. Contact lens wear (within 1 year)&#xD;
&#xD;
         10. Punctal occlusion&#xD;
&#xD;
         11. Systemic disease requiring regular medication (except hypertension and lipidemia)&#xD;
&#xD;
         12. Pregnancy or planning to be pregnant&#xD;
&#xD;
         13. Requirement for medications such as anti-microbial, inflammatory, creams (except&#xD;
             moisturizers or cosmetics), or steroidal therapies&#xD;
&#xD;
         14. Unable to do this clinical trial for any reason&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Louis Tong, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Singapore National Eye Centre</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Singapore National Eye Centre/ Singapore Eye Research Institute</name>
      <address>
        <city>Singapore</city>
        <state>Type a choice below ...</state>
        <zip>168751</zip>
        <country>Singapore</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Singapore</country>
  </location_countries>
  <verification_date>February 2016</verification_date>
  <study_first_submitted>August 14, 2014</study_first_submitted>
  <study_first_submitted_qc>August 15, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 18, 2014</study_first_posted>
  <last_update_submitted>August 3, 2016</last_update_submitted>
  <last_update_submitted_qc>August 3, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 5, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Singapore National Eye Centre</investigator_affiliation>
    <investigator_full_name>Louis Tong</investigator_full_name>
    <investigator_title>Clinician-Scientist, Senior Consultant</investigator_title>
  </responsible_party>
  <keyword>Acupuncture</keyword>
  <keyword>Herbal treatment</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dry Eye Syndromes</mesh_term>
    <mesh_term>Keratoconjunctivitis Sicca</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02219204
org study id: R1142/44/2014
secondary id: 2014/398/A
nct id: NCT02219204
lead sponsor: 
has dmc: No
Dry eye is a major, common medical condition with significant health and economic burden in
      Singapore and worldwide. It is a holistic problem affected by living habits, nutrition and
      underlying systemic disease, inducing a significant decrease in quality-of-life. The hallmark
      of this disease is raised tear osmolarity and inflammation. There is no definitive cure for
      this condition, as treatment in the form of lubricants is only symptomatic and treatment with
      cyclosporine eyedrops is expensive and may not be well tolerated.

      Following the rise in international interest in complementary medicine, randomized-controlled
      studies in dry eye using Traditional Chinese Medicine (TCM) have been published, with mixed
      results. However, the major limitation of these studies is the lack of objective assessment
      for inflammation.

      We propose to collaborate with an academically-trained Singapore TCM physician who has
      conducted dry eye trials, and synergistically exploit the existing state-of-the-art dry eye
      monitoring technologies available at Singapore Eye Research Institute (SERI). This proposal
      is cost-effective, building on previous government grants and expertise to provide definitive
      scientific evidence on the efficacy and safety of TCM in dry eye. SERI has an international
      reputation for interventional studies, and the PI has a good academic relationship with the
      above TCM physician. We propose to screen, recruit and treat 150 patients with a herbal
      preparation and acupuncture, and evaluate over 4 weeks in a randomized-controlled study.
      Tests to be performed will include tear imaging and osmolarity, as well as protein and
      cytokine assays.

      Singapore is uniquely positioned at the crossroads of the East and the West to take the lead
      in this field. Given that there is an increasing patient interest in holistic care in
      Singapore and the rise of scientifically trained TCM practitioners, a study like this one is
      very timely, and will have tremendous impact to healthcare delivery in Singapore.
Dry eye is a major, common medical condition with significant health burden in Singapore and
      worldwide. As much as one third of the adult population in Asian countries are affected by
      dry eye. It has been shown that dry eye affects quality of life, including the performing of
      daily activities such as reading and driving a car. Moderate severity of dry eye affects some
      patients like moderate angina. The direct and indirect cost of treating dry eye is high and
      increasing. For example, it costs individuals about US$800 per year to treat dry eye, but the
      cost to society for managing such a patient is US$12000 per year. (1-29)

      Dry eye is a holistic problem affected by living habits such as working long hours on the
      computer and in a dry, air-conditioned environment. It is also associated with poor nutrition
      and intake of dietary supplements such as omega-3 and omega-6 fatty acids may help to treat
      dry eye. Dry eye is also a systemic immune mediated disease, and aggravated by those with
      autoimmune Sjögren's syndrome, rheumatoid arthritis, thyroid disease, systemic lupus
      erythematosis, Steven Johnson syndrome and chronic graft versus host disease.

      In a recent international workshop, international experts in dry eye agree that the hallmark
      of this disease is raised tear osmolarity and ocular surface inflammation. Traditionally, dry
      eye is diagnosed by a reduced Schirmer's test and/or reduced tear break up time or the
      presence of dry eye symptoms. In addition to these traditional tests, it would be
      advantageous to incorporate measurements of osmolarity and inflammation in clinical studies.
      There is no definitive cure for this condition, as treatment in the form of lubricants is
      only symptomatic and treatment with cyclosporine eye drops is expensive and may not be well
      tolerated. Treatment with steroids can be effective but associated with adverse effects such
      as sight threatening glaucoma. In summary there is a definite medical need for alternative
      therapies in dry eye.

      Traditional Chinese Medicine (TCM) is involved in restoring the natural balance of the body,
      which results in disease like dry eye when this is disturbed. In TCM philosophy, dry eye may
      result from syndromes such as yin deficiency in the liver or kidney. Modalities such as
      acupuncture or herbs can be used judiciously to restore the balance in specific patients.

      Recently there have been randomized controlled studies in dry eye using acupuncture and
      herbs, with mixed results, refer to attachment (Table 1). The major limitation of these
      studies is that objective tear film evaluation such as tear osmolarity, and tear cytokines
      and proteins, which are indicative of ocular surface inflammation, have not been evaluated.
      In addition, some studies suffer from lack of proper controls or randomization.

      If the mainstream practitioners of evidence based medicine are convinced that TCM can
      fundamentally alter the pathological processes in dry eye, they will be more receptive to
      this form of treatment. At the same time, regulatory bodies need to be reassured that TCM is
      safe in dry eye, so that more education and promotion of such treatment can benefit more
      people.

      The PI runs a dry eye clinic twice a week at the Singapore National Eye Centre since 2006. He
      is aware that many dry eye patients in Singapore have experienced a host of more conventional
      therapies and are eager to attempt alternative forms of therapy. This trend towards TCM and
      holistic medicine will continue regardless of the attitudes of 'western' medical
      practitioners. This study, when completed, will present an opportunity for bridging the gaps
      between the two health care communities who do not normally interact. Since latest scientific
      tools in terms of protein science and imaging will be employed in the study, it will
      definitely increase the evidence based medicine for TCM in the dry eye field.

      The PI has published 67 peer reviewed papers in dry eyes and related ocular surface
      processes, including review articles,(30-34) international expert panel report,(35)
      epidemiological studies,(36-37) PI initiated and industry sponsored interventional drugs
      including randomized controlled drug trials.(38-40) In one pharmacy in Singapore alone, the
      cost of dry eye medications amounted to US$1.5 million in one year.(3) He has also found in
      an epidemiological study in Singapore people that dry eye impairs visual associated function
      related activities of daily living.(41) He established the only dedicated dry eye service in
      the region and has produced many papers relating to the assessment of these patients,(42-46)
      including one that found dry eye being related to the amount exposure to stressful activities
      and conditions.(46) The PI has experience in the biochemical evaluation of patient tears and
      materials in dry eye(47-51) and clinical imaging related to dry eye.(52-54) Lastly, he has
      also appeared in mass media educational articles including press releases and articles/talks
      for layperson and general practitioners.

      A survey was conducted among registered TCM practitioners in Singapore and published in a
      peer reviewed journal.(55) This showed that a significant proportion of these institutional
      practitioners are keen to practice in dry eye. This study was also chosen to be presented as
      an oral presentation at the 10th Asean Congress of TCM cum 3rd Asia Advanced Forum on
      Acupuncture and Moxibustion. At the same time, the full article has been translated into
      Chinese in the congress proceedings page 192-197 to appeal to the audience of TCM physicians.
      The PI has also participated in discussion on data analysis in TCM trials. (56-57) In
      addition, acupuncture in rabbits had shown to induce changed in tear proteins, although this
      has not been evaluated in humans. (58)

        1. HYPOTHESIS AND OBJECTIVES

           The overall hypothesis is that traditional Chinese medicine modalities of acupuncture
           and herbs can improve the symptoms and signs of dry eye, and objectively, these
           improvements are associated with reduction of tear osmolarity and reduction of
           inflammatory markers such as tear cytokines and proinflammatory proteins. There is also
           a long term objective of integrating TCM and mainstream medical care and having a
           cost-effective approach to eye disease.

           Primary outcome:

           • Change in SPEED score (Week4-Week0)

           Secondary outcomes:

             -  Change in Tear Evaporimetry

             -  Change in TCM score (Lung-Kidney Yin deficiency)

             -  Change in NIBUT

             -  Change in Schirmers I

             -  Change in Corneal fluorescein staining (5 zones)

             -  Change in Tear osmolarity

             -  Change in Tear meniscus height

             -  Change in Tear protein/ cytokine levels

           1.1 Primary Objectives

           We aim to show that dry eye patients treated with acupuncture is efficacious (can
           improve symptoms and signs of dry eye) and safe (no ocular and systemic side effects).

           1.2 Secondary Objectives

           We aim to show that dry eye patients treated with a herbal preparation is efficacious
           (can result in reduction of symptoms and signs of dry eye) and safe (no ocular and
           systemic side effects).

           We also aim to show that objective, definitive hallmarks of dry eye disease, ie. Tear
           osmolarity and surrogates of ocular surface inflammation, such as tear cytokines and
           proinflammatory proteins, are reduced after treatment by acupuncture and herbal
           treatment, compared to control.

           1.3 Potential Risks and Benefits: 1.3.1 Potential Risks We will anticipate minimal risk
           and discomfort involve in this study.

             -  It is possible that eyelid bruising and swelling may occur from acupuncture needles

             -  Some slight discomfort from Schirmers I test

             -  Nausea, insomnia, headache, loss of appetite, malaise, diarrhoea and abdominal
                cramps may occur after herbal consumption

           Relatively few complications have been reported from the use of acupuncture. However,
           acupuncture can cause potentially serious side effects if not delivered properly by a
           qualified practitioner. The most common side effects after acupuncture include soreness,
           bruises, fatigue, lightheadedness and involuntary twitching of muscle. Should this event
           occur, increased frequency of visits to the eye clinic may be necessary.

           1.3.2 Potential Benefits There is no assurance participants will benefit from this
           study. However, their participation may contribute to the medical knowledge whether TCM
           medicine can fundamentally alter the pathological processes in dry eye. At the same
           time, regulatory bodies need to be reassured that TCM is safe in dry eye, so that more
           education and promotion of such treatment can benefit more people.

        2. STUDY POPULATION 3.1 List The Number and Nature of Subjects to be Enrolled. One hundred
           and fifty eligible dry eye subjects will be screened and recruited from SCHMI.

      3.2 Criteria for Recruitment and Recruitment Process

        1. Subjects meet all the inclusion criteria listed below.

        2. Clear of exclusion criteria.

      Permission would be sought from the attending TCM physicians before subjects are being
      recruited. Eligible subjects will be counselled on the study. If subject is interested,
      informed written consent will be obtained from all participants. Thereafter, optometrsits at
      SCHMI will schedule a baseline visit to SERI for ocular monitoring.

      3.3 Inclusion Criteria

      For eligibility each participant presenting at SCHMI must be assessed by the TCM physician
      and optometrist, and found to satisfy every one of the following:

        1. Age: 40-85 years, visual acuity better than logMAR of 1.0

        2. Chief complaint should be dry eye

        3. Symptoms:

           3.1. SPEED score > 6 3.2. TCM score satisfies lung-kidney yin deficiency profile

        4. Signs:

      4.1. TBUT (<10s) or Schirmer's test (<10mm/5 mins) 4.2 Any corneal fluorescein staining

      3.4 Exclusion Criteria All subjects meeting any of the exclusion criteria at screening visit
      will be excluded from participation.

        1. Glaucoma or other ophthalmic disease, eg. Extraocular muscle palsies, ectropion,
           entropion

        2. Ocular allergies, eg. Allergic conjunctivitis, sinusitis, eczema, atopic
           keratoconjuntivitis

        3. Known of thyroid disorders (diagnosed by physician)

        4. Trichiasis

        5. Eye surgeries patients including LASIK (within 1 year)

        6. Steven-Johnson syndrome

        7. Sjogren's syndrome

        8. Eye related trauma (within 1 year)

        9. Contact lens wear (within 1 year)

       10. Punctal occlusion

       11. Systemic disease requiring regular medication (except hypertension and lipidemia)

       12. Pregnancy or planning to be pregnant

       13. Requirement for medications such as anti-microbial, inflammatory, creams (except
           moisturizers or cosmetics), or steroidal therapies

       14. Unable to do this clinical trial for any reason

      4 STUDY DESIGN This is a randomized observer masked parallel group three arm interventional
      study.

      Treatment arms

      There will be 3 trial arms in this study:

        -  Control: Systane Ultra Eye drop (n=50)

        -  Systane Ultra Eye Drop and Acupuncture treatment (n=50)

        -  Systane Ultra Eye Drop and Herbs treatment (n=50)

      Study duration: 5 Weeks Recruitment duration: 1 Year

      4.1 Randomisation and Blinding

      The randomisation procedure used will entail:

        1. Presence of two witnesses

        2. Drawing of lots

        3. Randomization codes for the 3 groups will be noted. For e.g. 001A, 002B, 003C etc.

        4. Study information related to randomisation will be filed and kept at SCHMI

        5. Only unblinded personnel have access to the randomization code file

      Randomisation will be done at SCHMI. Study members at SCHMI will be unblinded as they will be
      delivering TCM treatments to the subjects. However, study members at SERI will all be blinded
      so as to prevent unintentional biases when assessing and monitoring of ocular surface.

      In a situation of a serious event, a decision on whether to open (break) the code for the
      specific patient is necessary. Although it is advantageous to retain the blind for all
      patients prior to final study analysis, when a serious adverse reaction is judged reportable
      on an expedited basis, it is recommended that the blind be broken only for that specific
      patient by the designated investigator who is unblind. It is also recommended that, when
      possible and appropriate, the blind be maintained for those persons, such as biometrics
      personnel, responsible for analysis and interpretation of results at the study's conclusion.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Investigator)
measure: Change in SPEED score (Week4-Week0)
time frame: 4 weeks
description: Any improvement or discomfort in dry eye symptoms during 4 weeks
measure: Change in Tear Evaporimetry
time frame: 4 weeks
measure: Change in TCM score (Lung-Kidney Yin deficiency)
time frame: 4 weeks
measure: Change in Non Invasive Break Up Time
time frame: 4 weeks
measure: Change in Schirmers I
time frame: 4 weeks
measure: Change in Corneal fluorescein staining
time frame: 4 weeks
measure: Change in Tear osmolarity
time frame: 4 weeks
measure: Change in Tear meniscus height
time frame: 4 weeks
measure: Change in Tear protein/ cytokine levels
time frame: 4 weeks
arm group label: Acupuncture treatment
arm group type: Active Comparator
description: This will be performed twice weekly for 30 days. There will be 8 sessions of acupuncture treatments in total.
The needles to be use around the eyes will have the dimensions of 0.25 (diameter) x 13mm (length), while 0.25 x 25mm needles will be used behind the ear (feng chi) and 0.30 X 25mm needles on the upper and lower limbs. These needles will remain in the points for 20 minutes. The depth of penetration will be about 1-2 mm.
arm group label: Herbal treatment
arm group type: Active Comparator
description: This formulation is called qi ju gan lu yin or Lycium berry, a chrysanthemum beverage. This is a modified version of "qi ju di huang wan" published previously. The senior TCM collaborator, Prof Wei QP has made this modification in order to treat the dry eye patients with "lung-kidney yin deficiency".
arm group label: Eye drops
arm group type: No Intervention
intervention type: Procedure
intervention name: Acupuncture
arm group label: Acupuncture treatment
intervention type: Other
intervention name: Herbal treatment
arm group label: Herbal treatment
criteria: 
gender: All
minimum age: 40 Years
maximum age: 85 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Louis Tong, PhD
role: Principal Investigator
affiliation: Singapore National Eye Centre
facility: 
country: Singapore
responsible party type: Principal Investigator
investigator affiliation: Singapore National Eye Centre
investigator full name: Louis Tong
investigator title: Clinician-Scientist, Senior Consultant
mesh term: Dry Eye Syndromes
mesh term: Keratoconjunctivitis Sicca