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The laughter exercise group viewed an instructional video and participants were requested to vocalise the phrases \u201cHee hee hee, hah hah hah, cheese cheese cheese, cheek cheek cheek, hah hah hah hah hah hah\u201d 30 times per five minute session. Investigators assessing study outcomes were masked to group assignment but participants were unmasked for practical reasons.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main outcome measures<\/jats:title>\n                    <jats:p>The primary outcome was the mean change in the ocular surface disease index (0-100, higher scores indicating worse ocular surface discomfort) from baseline to eight weeks in the per protocol population. The non-inferiority margin was 6 points of this index score. Main secondary outcomes included the proportion of patients with a decrease from baseline in ocular surface disease index score of at least 10 points and changes in dry eye disease signs, for example, non-invasive tear break up time at eight weeks.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>299 participants (mean age 28.9 years; 74% female) were randomly assigned to receive laughter exercise (n=149) or 0.1% sodium hyaluronic acid (n=150). 283 (95%) completed the trial. The mean change in ocular surface disease index score at eight weeks was \u221210.5 points (95% confidence interval (CI) \u221213.1 to \u22127.82) in the laughter exercise group and \u22128.83 (\u221211.7 to \u22126.02) in the control group. The upper boundary of the CI for difference in change between groups was lower than the non-inferiority margin (mean difference \u22121.45 points (95% CI \u22125.08 to 2.19); P=0.43), supporting non-inferiority. Among secondary outcomes, the laughter exercise was better in improving non-invasive tear break up time (mean difference 2.30 seconds (95% CI 1.30 to 3.30), P&lt;0.001); other secondary outcomes showed no significant difference. No adverse events were noted in either study group.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The laughter exercise was non-inferior to 0.1% sodium hyaluronic acid in relieving subjective symptoms in patients with dry eye disease with limited corneal staining over eight weeks intervention.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>\n                      ClinicalTrials.gov\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"NCT04421300\" ext-link-type=\"clintrialgov\">NCT04421300<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  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