Table 1.
Randomized controlled trials with trehalose treatment on ocular surface.
| Reference | Clinical Condition (Level of Evidence1) | Trehalose and Other Ingredients, Number of Patients |
Control Treatment, Number of Patients |
Dosing Regimen | Main Findings for Trehalose | Factors of Possible Influence |
|---|---|---|---|---|---|---|
| Dry Eye | ||||||
| Matsuo et al. 2002 [55] | Moderate to severe dry eye (level 2) | 100 mM (3.4%),2 n = 18 200 mM (6.8%), n = 16 |
Saline, n = 18 Saline, n = 16 |
6 times/day for 4 weeks in randomized eyes | Increased TBUT (100 mM only), decreased staining scores. No improvement in dry eye symptom score. No adverse effects. |
Eye drop osmolality 1.3 and 1.8 times higher than control (hyperosmolar) Autoimmune patients. |
| Matsuo et al. 2004 [56] | Moderate to severe dry eye (level 2) | 100 mM (3.4%),2 n = 33 200 mM (6.8%), n = 3 (continuation from Matsuo et al. 2002 trial [55]) |
0.1% HA (Hyalein), weeks 1–4, n = 18 Hydroxyethyl cellulose (Mytear), weeks 5–8, n = 18 |
4 times/day for 4 weeks in both eyes in randomized cross-over design | Increased TBUT, decreased staining scores. No improvement in dry eye symptom score at 4 weeks but improved at 8 weeks. No adverse effects. |
Eye drop osmolality 1.3 and 1.8 times higher than control (hyperosmolar) Mostly Sjögren syndrome patients. |
| Pinto-Bonilla et al. 2015 [57] | Moderate to severe dry eye (level 1) | 3% trehalose + 0.15% HA (Thealoz® Duo), n = 17 | Hydroxypropyl guar + polyethylene glycol + propylene glycol, preservative (Systane®), n = 17 | 5 times/day for 7 days in both eyes in randomized cross-over design | Improved global satisfaction, dry eye symptoms and their impact at work. Improved OSDI and staining scores with no significant difference to control. No adverse effects. |
Open-label (no masking). Short duration. |
| Chiambaretta et al. 2017 [58] | Moderate to severe dry eye (level 1) | 3% trehalose + 0.15% HA (Thealoz® Duo), n = 52 (46 per protocol) | 0.18% HA (Vismed®), n = 53 (45 per protocol) | 3–6 times/day for 84 days in both eyes | Improved Oxford grading score at 35 days (per-protocol dataset). Improved subjective (patient, investigator) evaluation scores. Improved TBUT, Schirmer, van Bijsterveld, and conjunctival hyperaemia score with no significant difference to control. No difference in global tolerability. |
No masking of patients. |
| Doan et al. 2018 [59] | Moderate to severe dry eye (level 1) | 3% trehalose + 0.15% HA (Thealoz® Duo), n = 52 | 0.18% HA (Vismed®), n = 53 | 3–6 times/day for 84 days in both eyes | Improved OSDI at 84 days. | A post hoc analysis of Chiambaretta et al. 2017 [58] No masking of patients. |
| Fondi et al. 2018 [60] | Moderate to severe dry eye (level 1) | 3% trehalose + 0.15% HA + 0.25% carbomer + sorbitol (Thealoz® Duo Gel), n = 45 | 3% trehalose + 0.15% HA (Thealoz® Duo) and 3% trehalose + 0.15% HA + 0.25% carbomer + sorbitol (Thealoz® Duo Gel), n = 45 | Daytime: as frequently as needed Night-time: Thealoz® Duo Gel |
Improved TBUT, staining scores and quality of sleep with no significant difference between groups. No improvement in Schirmer I. Reduced frequency of instillations for Thealoz® Duo Gel. No adverse effects. |
Screening data incompletely reported. No masking of patients. Short duration. |
| Panigrahi et al. 2019 [43] | Moderate or severe dry eye symptoms and mild signs (level 2) | 3% trehalose + 0.1% HA, preservative (TrehalubeTM), n = 9 | 0.5% CMC, preservative (Lubrex®), n = 9 | 2 times/day for 30 days in randomized contralateral eyes | Improved OSDI with no significant difference between groups. Improved TBUT. No improvement in Schirmer 1 or 2. Reduced tear fluid MMP-9, MMP-2, MCP-1, and MMP-9/TIMP-1 ratio. |
No masking of investigators. OSDI measured separately for contralateral eyes. |
| Laihia et al. 2019 [61] | Moderate or severe dry eye (level 1) | 2% trehalose + 0.1% sacha inchi seed oil + 0.2% HA + glycerol, n = 26 | 0.2% HA, n = 26 | 3 times/day for 30 days | Improved ocular protection index (TBUT/interblink interval). Improved TBUT, staining and redness scores, hyperosmolarity and OSDI with no significant difference to control. No adverse device effects. |
Other active agents used with trehalose. |
| Downie et al. 2019 [62] | Mild to severe dry eye (level 1) | 1.5% trehalose3 + flaxseed oil + CMC + glycerol + castor oil + levocarnitine + erythritol (Refresh Optive® MEGA-3), n = 120 | CMC + glycerol + castor oil + L-carnitine + erythritol (Refresh Optive® Advanced), n = 122 | ≥ 2 times/day for 90 days | Improved combined ocular staining score (days 7, 30, 60, and 90), corneal staining (day 90) and conjunctival staining (day 30). Improved burning/stinging (day 60). Improved OSDI, TBUT and staining scores with no significant difference to control. Conjunctival hyperemia (1.7%), instillation site pruritus (1.7%). |
Patients with OSDI score > 65 were excluded. Effects of trehalose and flaxseed oil cannot be distinguished. |
| Ocular Surgery | ||||||
| Mateo Orobia et al. 2017 [63] | LASIK post-treatment (level 1) | 3% trehalose (Thealoz®) and 0.15% HA (Hyabak®), n = 7 | 0.15% HA (Hyabak®), n = 6 | Thealoz® 4 times/day + Hyabak® 5 min later in both eyes Hyabak control: every 2 h for 10 days, 6 times/day for 3 months in both eyes |
Improved SANDE severity and frequency scores. Improved staining scores at 30 and 90 days. No improvement in osmolarity, TBUT, visual acuity, and OSDI. |
Small number of patients with 12/13 males. No masking of patients. |
| Caretti et al. 2019 [64] | Cataract surgery and mild to severe dry eye (level 1) | 3% trehalose + 0.15% HA + 0.25% carbomer + sorbitol (Thealoz® Duo Gel), n = 30 | 0.15% HA (Hyabak®), n = 30 | 2 times/day for 1 month in operated eye | Improved TBUT, OSDI and patients’ global satisfaction score. Improved staining scores and visual acuity with no significant difference to control. No improvement in Schirmer. |
|
| Vagge et al. 2019 [65] | Strabismus surgery (level 2) | Chloramphenicol/betamethasone and 3% trehalose + 0.15% HA + 0.25% carbomer + sorbitol (Thealoz® Duo Gel), n = 31 | Chloramphenicol/betamethasone | 3 times/day for 4 weeks | Improved blurred vision at 1 and 4 weeks, other symptoms at 1 week. Improved conjunctival redness with no significant difference to control. |
Open-label (no masking). Numerical rating of symptoms assessed separately for contralateral eyes. |
| Tear Film Dynamics | ||||||
| Schmidl et al. 2015 [66] | Mild or moderate dry eye (level 1) | 3% trehalose + 0.15% HA (Thealoz® Duo), n = 20 | 0.15% HA (Hyabak®), n = 20 Saline (Hydrabak®), n = 20 |
1 drop in one eye | Increased TFT at 10–240 min. No improvement in TBUT and Schirmer I at 240 min. No adverse effects. |
Custom-built OCT system. One dose only. |
| Wozniak et al. 2017 [67] | Moderate or severe dry eye (level 1) | 3% trehalose + 0.15% HA + 0.25% carbomer + sorbitol (Thealoz® Duo Gel) n = 20 | 0.4% polyethylene glycol + 0.3% propylene glycol + hydroxypropyl guar + sorbitol (Systane® Gel), n = 20 0.2% HA + sorbitol (Hylo®-Gel), n = 20 |
1 drop in both eyes | TFT increase (+66%) lower than with Systane® Gel (+156%) but higher than with Hylo®-Gel (+33%) control at 10-min peak. Increased TFT (less than +20%) at 60 and 120 min. Increased TBUT in all groups at 360 min No increase in Schirmer I at 360 min. |
Same OCT system as in Schmidl et al. 2015 [66] but with higher baseline values. One dose only. |
| Karaca et al. 2019 [68] | Mild or moderate dry eye (level 2) | 3% trehalose + 0.15% HA + 0.25% carbomer + sorbitol (Thealoz® Duo Gel), n = 56 | 0.3% HA (Vismed® Gel), n = 66 | 1 drop in one eye | Lower TMH and TMD for 10–120 min. Lower patient satisfaction at 240 min. No improvement in TBUT, tear osmolarity and Schirmer I at 240 min. |
All patients were with primary Sjögren syndrome. One dose only. |