A Preservative-Free Combination of Sodium Hyaluronate and Trehalose Improves Dry Eye Signs and Symptoms and Increases Patient Satisfaction in Real-Life Settings: The TEARS Study

Abstract

Introduction

Dry eye disease (DED) is a frequently observed condition characterized by ocular discomfort and visual disturbance. It is highly prevalent and impairs patients’ quality of life (QoL). This study assessed the benefit of a preservative-free bioprotectant eye drop formulation containing sodium hyaluronate and trehalose (SH-trehalose) with regards to DED, as well as patient satisfaction, through a large-scale real-life survey.

Methods

In a multi-center, international, prospective observational study, subjects with DED received SH-trehalose for 84 days. Ocular Surface Disease Index (OSDI), Dry Eye Questionnaire-5 items (DEQ-5), and patient satisfaction were assessed at baseline, day 28, and day 84, and clinical evaluations included ocular surface staining, Schirmer test, tear film break-up time (TBUT), and conjunctival hyperemia at baseline and day 84.

Results

A total of 312 patients were evaluated, of whom 82.4% were women. The mean age was 57.9 ± 15.2 years. The mean OSDI score at baseline was 41.7 ± 20.6. After 84 days, the mean OSDI score was 27.3 ± 19.8 (p < 0.001). The percentage of patients with a severe OSDI score decreased from 60.3 to 34.5%. The DEQ-5 score significantly (p < 0.001) improved after 28 and 84 days, as did patient satisfaction. Ocular surface staining, Schirmer test, TBUT, and conjunctival hyperemia scores improved significantly (all p < 0.001) for both eyes with SH-trehalose between baseline and day 84. Tolerance of SH-trehalose was good.

Conclusions

SH-trehalose significantly improved the clinical signs and symptoms of DED after 84 days. Moreover, it significantly increased patient satisfaction and was well tolerated.

Trial Registration

NCT04803240.

Key Summary Points

Dry eye disease (DED) is a frequently observed condition characterized by ocular discomfort and visual disturbance.

This study assessed the benefit of a preservative-free bioprotectant eye drop formulation containing sodium hyaluronate and trehalose (SH-trehalose) with regards to DED, as well as patient satisfaction, through a large-scale real-life survey.

Preservative-free SH-trehalose significantly improved clinical signs and symptoms of DED after 84 days and also significantly increased patient satisfaction and was well tolerated.

Introduction

Dry eye disease (DED) is a frequently observed multifactorial disease of the ocular surface, characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability, hyperosmolarity, inflammation, and neurosensory abnormalities play etiological roles [1]. Insufficient tear production or excessive evaporation can lead to tear hyperosmolarity, which triggers a chain of self-perpetuating events that constitute a vicious circle of DED [2]. In this circle, tear hyperosmolarity may lead to cell morphological changes, leading to inflammatory cascades and cell death, resulting in further tear film instability and tear hyperosmolarity, which continues the circle [2, 3].

The prevalence of DED has been estimated at between 5 and 50%, with a peak of 75% in subjects over 40 years old and a higher prevalence in women [4]. It is frequently associated with discomfort and impaired quality of life (QoL) [5–7].

Due to its multifactorial etiology, DED may be difficult to treat, and choosing the most suitable treatment often remains challenging [8]. The Tear Film & Ocular Surface Society proposed a staged management algorithm presenting a stepwise approach to implementing the various management and therapeutic options, according to DED severity [9]. Artificial tears are considered a mainstay of DED treatment and are recommended as an initial step, in combination with lid hygiene and warm compresses, or progression to more advanced therapies for more severe forms of DED. Sodium hyaluronate (SH) solutions are considered as the gold standard artificial tear treatment [10–13].

The introduction of trehalose, a natural bioprotectant and osmoprotectant, has been shown to help maintain homeostasis and counteract the effects of osmotic stress, desiccation, and inflammation [2, 14–18]. Trehalose supports the restoration of the osmotic balance to the ocular surface, prevents the denaturation of cell membrane lipid bilayers and proteins, and activates autophagy [14–16, 19–21]. Adjuvant treatment with 3% trehalose after LASIK surgery was shown to be superior to standard treatment in improving both objective and subjective parameters of tear quality [22].

A preservative-free eye drop formulation that contains 0.15% sodium hyaluronate and 3% trehalose (SH-trehalose, Thealoz^® Duo, Laboratoires Théa, France) is available in a multidose presentation, which prevents microbial contamination and allows avoiding the use of preservatives such as benzalkonium chloride (BAK), for which toxicity to the ocular surface is well described in the literature [23]. SH-trehalose improves the OSDI score, and other symptoms, especially stinging, itching, and blurred vision, compared to SH alone, and it provides higher patient and investigator efficacy satisfaction, already after 35 days [24]. It also reduces post-cataract signs and symptoms in patients with mild and moderate DED, especially if administered during a pre-surgery period [25–27].

The TEARS (ThEaloz^®Duo sAtisfaction in oculaR Surface) study assessed the effect of SH-trehalose on dry eye signs and symptoms, as well as patient treatment satisfaction, on a large-scale patient population in real-life settings.

Methods

Study Design

This was a multicenter, prospective, observational study conducted in 20 ophthalmological practices in Spain and ten optometrist centers in the United Kingdom under real-life conditions. The study was conducted in accordance with Good Epidemiological Practice guidelines of the International Epidemiological Association and the Declaration of Helsinki and was approved according to local ethics committee approval requirements by the local central ethics committees CEIC Hospital General Universitario José María Morales Meseguer/Spain (central IEC approval No: EST: 75/18) and London/United Kingdom (IRAS ID: 18/19-1033) between January 30, 2018 and February 21, 2019 [28]. All patients provided informed consent prior to inclusion in the study.

Eligible patients of either sex, aged 18 years or older, all had dry eye disease, attended their consultations for various reasons, and required either artificial tears or a change in their current artificial tears for any reason (i.e., due to dissatisfaction or low efficacy). Suitable patients received a prescription for SH-trehalose and were asked to instill one drop in each eye when needed. The prescription decision was made upon the investigator’s decision at inclusion. Permission for the use of the DEQ-5 questionnaire in this study was obtained in a written format.

Endpoints and Assessments

The study planned for three visits at baseline, visit 1 on day 28, and visit 2 on day 84. Visit 1 at day 28 was performed remotely: in Spain, patients were asked to complete a paper version of the questionnaires at home and to return them by post to their ophthalmologist; in the UK, patients were asked to complete an electronic version of the questionnaires, available on the Internet (patients were provided with website details). If the patient did not return the questionnaires, a reminder was issued by the medical staff.

Patient characteristics and ophthalmic history data were collected at baseline. As this was a real-life-setting study, no minimum OSDI scoring nor assessment of clinical signs for DED were required. The Ocular Surface Disease Index (OSDI©) (OSDI, mild: 13-22 points, moderate: 23-32 points, severe: 33-100 points) was assessed at baseline and day 84, and the Dry Eye Questionnaire-5 items (DEQ-5) and global patient satisfaction were assessed at baseline, day 28, and day 84 [29–31]. Global satisfaction was assessed with the following question: “How would you rate your overall satisfaction of the product you have been using?”. Patients could respond with a score ranging from 0 = totally unsatisfied to 10 = completely satisfied. The patients were also asked the following questions at baseline, day 28, and day 84: “Would you recommend this product to your relatives or your friends?” and “Do you prefer your current eye drops, when you compare them to your previous eye drops?”

When it was part of their routine clinical practice, the investigators performed a Schirmer test I (without anesthesia) and assessed the fluorescein tear film break-up time (TBUT) for each eye at baseline and day 84. Corneal and conjunctival (nasal and temporal) staining with fluorescein staining was assessed for each eye with the Oxford 0–15 grading scheme (from 0 = none to 5 = severe) at baseline and day 84 [32]. Conjunctival hyperemia was assessed for each eye with the modified version of the McMonnies and Chapman-Davies scale (from 0 = none to 5 = severe) at baseline and day 84 [33]. The value of the worse eye was considered the eye with the highest (worse) Oxford score at baseline. If the Oxford score was the same in both eyes, then the eye with the lowest Schirmer score was selected. If the Oxford and Schirmer scores were the same in both eyes, then the lowest TBUT score defined the worse eye. If Oxford, Schirmer, and TBUT scores in both eyes were the same at the “worse eye”, then the right eye was considered the worse eye.

The primary criterion was the change from baseline for patient symptoms using the OSDI questionnaire at visit 2 (day 84) [34]. Secondary criteria included the change in percentage of patients with a severe OSDI score (≥ 33 points) at day 84 compared to baseline, the change from baseline for the DEQ-5 questionnaire score, and patient global satisfaction with treatment at baseline, day 28, and day 84. Clinical parameters were collected and analyzed as exploratory data. Adverse events, if any, were collected throughout the study at each visit.

Statistical Analysis

Stratification of the patient population with disease severity with baseline OSDI scores was made (mild: 13–22 points, moderate: 23–32 points, severe: 33–100 points) and an analysis of the change in patient global satisfaction from baseline, at day 28, and day 84, was performed. Categorical data were summarized in terms of frequency tables providing counts and percentages (n, %) or association tables, and were analyzed using Pearson’s chi-squared or McNemar’s test, accordingly. All statistical tests were two-sided, with a significance level of α = 0.05. All confidence intervals provided were 95% two-sided. Analyses were performed using RStudio^TM (RStudio Team, 2020)).

Results

Patient Demographic and Baseline Data

In total, 312 patients participated in this study. Of these, 137 had switched from a previous treatment to SH-trehalose. The mean patient age was 57.9 ± 15.2 years; 82.4% were women, and of these 54.2% were aged at least 55 years. On average, the mean number of times that patients had consulted for their DED was 3.1 ± 3.5 times during the last 3 years prior to participating in this study, and 55.1% had received artificial tears within the last 3 months prior to inclusion. A total of 61.9% of these patients reported previous DED treatments; the mean duration of their use was 2407 ± 8314.2 days (6.6 years). In patients who were previously treated, the mean patient global satisfaction score was 6.4 ± 2.1. The overall OSDI score was 41.7 ± 20.6, with 60.3% of patients obtaining a severe OSDI score (≥ 33 points). In the global study population, the mean Oxford score was 4.0 ± 2.6, the mean Schirmer score 11.7 ± 8.9 and the mean TBUT score 7.0 ± 3.5. Detailed baseline information is given in Table 1.

Table 1.

Main patient characteristics at baseline

	N = 312
Gender (n = 311); (n, %)
Female	257 (82.4%)
Male	54 (17.3%)
Age (n = 311)
Mean ± SD	57.9 ± 15.2
Median	60.0
Min; Max	18.0; 90.0
Women (n,%)
(aged < 55 years of age)	45 (14.4%)
Women (n,%)
(≥ 55 years of age)	169 (54.2%)
Consultations during the 3 years preceding the study (n = 309); (n, %)
Mean ± SD	3.1 ± 2.0
Median	2.0
Min; Max	0.0; 30.0
OSDI
Overall (n = 312)
Mean ± SD	41.7 ± 20.6
Median	41.7
Min; Max	0.0; 100
Mild (n = 30)
Prevalence	15.4%
Mean ± SD	6.8 ± 1.5
Median	7.0
Min; Max	3.0; 10.0
Moderate (n = 28)
Prevalence	15.7%
Mean ± SD	7.2 ± 1.9
Median	7.0
Min; Max	2.0; 10.0
Severe (n = 123)
Prevalence	60.3%
Mean ± SD	6.1 ± 2.2
Median	6.0
Min; Max	0.0; 10.0
Oxford score
Mean ± SD	4.0 ± 2.6
Median	4.0
Min; Max	0.0; 12.0
Schirmer score
Mean ± SD	4.0 ± 2.6
Median	9.0
Min; Max	0.0; 35.0
TBUT (s)
Mean ± SD	7.0 ± 3.5
Median	7.0
Min; Max	0.0; 35.0

6.4% had no OSDI reported and for 2.2% data were missing. OSDI ocular surface disease index, SD standard deviation, TBUT tear film break-up time

Overall Study Population

After 84 days, the mean OSDI score significantly (p < 0.001) decreased from 41.7 ± 20.6 at baseline to 27.3 ± 19.8, corresponding to a mean decrease of 13.95 points.

The percentage of patients with an initial severe OSDI score decreased from 60.3 to 34.5% patients during the study; the OSDI score of 56.3% of patients decreased by 10%, and in 27.8% it decreased by 20% after 84 days. The responder analysis showed that the majority of patients (138, 56.3%) had an improvement of 10% and 68 (27.8%) had an improvement of 20% of their OSDI measurements after 84 days. Figure 1 provides shifts in the percentage of patients with OSDI according to severity at baseline and day 84.

Fig. 1.

OSDI shifts according to severity distribution at baseline and day 84 (global study population). The Ocular Surface Disease Index (OSDI©) (OSDI, mild: 13–22 points, moderate: 23–32 points, severe: 33–100 points) was assessed at baseline and day 84. The percentage of patients with an initially severe OSDI score decreased from 60.3 to 34.5% patients after 84 days

After 28 days, the mean DEQ-5 score with SH-trehalose decreased by 2.3 points and by 3.2 points after 84 days; the decrease was statistically significant (p ≤ 0.001) at both visits, compared to the baseline score. A statistically significant decrease of the DEQ-5 score was observed between baseline and day 28 (p ≤ 0.001), between baseline and day 84 (p < 0.001), and between day 28 and day 84 (p = 0.002). Scores decreased from 10.6 ± 4.6 at baseline to 8.4 ± 4.9 on day 28 and 7.5 ± 5.1 on day 84.

Overall treatment satisfaction scores increased from 6.4 ± 2.1 at baseline to 7.2 ± 1.8 on day 28, and 7.4 ± 1.9 after 84 days of use of SH-trehalose. In total, 76.0% of patients recommended SH-trehalose after 28 days of use, which increased to 78.4% after 84 days. Finally, 70.3% of patients preferred SH-trehalose to their previous eye drops at day 28 and 72.3% preferred them at day 84.

In the worse eye, the mean Oxford score significantly (p < 0.001) decreased from 4.0 ± 2.6 to 2.2 ± 2.0, the mean Schirmer score significantly (p = 0.004) increased from 11.7 ± 8.9 to 12.3 ± 8.1, the mean TBUT significantly (p < 0.001) increased from 7.0 ± 3.5 to 9.0 ± 8.1, and the conjunctival hyperemia score significantly (p < 0.001) decreased by 0.6 points ± 0.9 for both eyes at day 84 compared to baseline. The results of the overall patient population are summarized in Table 2.

Table 2.

Results at day 28 and day 84 in all patients

All patients	n at baseline	Baseline	n at 28 days	28 days	p value	n at 84 days	84 days	p value
OSDI score	305	41.7 ± 20.6				250	27.3 ± 19.8	p < 0.001
Oxford score	307	4.0 ± 2.6				244	2.2 ± 2.0	p < 0.001
Schirmer score	235	11.7 ± 8.9				194	12.3 ± 8.1	p = 0.004
TBUT	273	7.0 ± 3.5				214	9.0 ± 8.1	p < 0.001
DEQ-5	299	10.6 ± 4.6	289	8.4 ± 4.9	p ≤ 0.001	250	7.5 ± 5.1	p < 0.001
Global satisfaction	193	6.4 ± 2.1	284	7.2 ± 1.8	p < 0.001	250	7.4 ± 1.9	p < 0.001

All parameters measured at baseline and day 84: Ocular Surface Disease Index (OSDI^©), Oxford score, Schirmer score, tear film break-up time (TBUT), Dry Eye Questionnaire 5 (DEQ-5) and global patient satisfaction (assessed with the following question: “How would you rate your overall satisfaction of the product you have been using? Please give one number between 0 and 10 (0 = Totally unsatisfied/10 = Completely satisfied)”). DEQ-5 and global patient satisfaction were additionally assessed at day 28. All results compared to baseline showed significant change

Impact of DED on the Patient’s Symptoms and Patient Satisfaction According to the OSDI Score (Mild, Moderate, or Severe)

In patients with mild OSDI, the DEQ-5 score significantly decreased with SH-trehalose from baseline (9.9 ± 3.4) at day 28 (9.0 ± 4.4, p = 0.028) and day 84 (7.5 ± 3.8, p = 0.002) and between both post-baseline visits (p = 0.042). A significant increase in overall treatment satisfaction with SH-trehalose was observed between baseline (6.8 ± 1.5) and day 84 (7.6 ± 2.0, p = 0.025), and between day 28 (7.2 ± 1.9) and day 84 (p = 0.031).

In patients with moderate OSDI, the DEQ-5 score significantly decreased with SH-trehalose from baseline (11.0 ± 4.0) to 9.2 ± 3.7 (p = 0.004) at day 28, and 9.1 ± 3.9 (p = 0.020) at day 84, with no significant increase of patient satisfaction between baseline and day 28 or day 84, or between either post-baseline visit.

A statistically significant (p < 0.001) increase of the DEQ-5 score from baseline (13.8 ± 3.6) was observed in patients with severe OSDI at day 28 (10.8 ± 4.5, p < 0.001) and day 84 (9.7 ± 4.9), and between day 28 and day 84 (p = 0.002). Treatment satisfaction in patients with severe OSDI scores increased between baseline and day 28 (p < 0.001) and between baseline and day 84 (p < 0.001) with mean scores of 6.1 ± 2.2 at baseline, 7.2 ± 1.9 at day 28, and 7.5 ± 1.8 at day 84.

Clinical Outcomes According to Treatment-Naïve and Previously Treated Patients

In treatment-naïve patients (n = 155), the mean Oxford score decreased by 2.0 ± 2.0 (n = 121), the mean Schirmer score and the mean TBUT significantly increased by 0.5 ± 4.8 (n = 90) and 1.6 ± 2.3 (n = 102), respectively, for the worse eye after 84 days of treatment (all p < 0.001, except Schirmer score: p < 0.022).

In previously treated patients (n = 157), the mean Oxford score decreased by 2.0 ± 2.4 (n = 120), and the mean Schirmer score and mean TBUT increased by 0.9 ± 7.6 (n = 96) and 2.0 ± 2.8 (n = 105), respectively, for the worse eye; only the Oxford score and TBUT were statistically significant (Oxford score: p < 0.001, Schirmer score: p = 0.057) after 84 days of treatment.

Outcomes According to Patients Previously Treated with SH-Containing Eye Drops

Among the patients previously treated before the inclusion in the study, 73 received hyaluronic acid. The mean OSDI score significantly decreased (p < 0.001) by 14.9 ± 18.6, the mean DEQ-5 score significantly decreased (p < 0.001) by 3.3 ± 5.3 and the mean patient satisfaction score significantly increased (p = 0.001) by 1.2 ± 2.3 at day 84 compared to baseline. All other parameters (Schirmer test, TBUT, corneal and conjunctival staining, conjunctival hyperemia) showed statistically significant improvements for both eyes after switching to SH-trehalose at day 84, compared to baseline (all p ≤ 0.001, except for the Schirmer score p = 0.031).

Tolerance and Safety

Local tolerance to SH-trehalose was good.

Discussion

Results from this real-life study conducted in 312 patients with DED showed that dry eye signs and symptoms significantly improved with high patient satisfaction after 84 days of SH-trehalose. This treatment duration was recently confirmed by a systematic review [35].

Overall, 84.2% of patients included were women and the age was 57.9 ± 15.2. This is not surprising, as the prevalence of patients with DED increases with age and women are more frequently affected, especially the menopausal and postmenopausal age group [4]. In a survey published in 2013, respondents with DED, 581 (28%) were men and 1518 (72%) were women, which is consistent with our findings [36].

Surprisingly, 60.3% of our patients had severe OSDI (score ≥ 33) at baseline, which was higher than expected. This may be explained by the fact that the majority of the patients were recruited in clinics, thus being more likely to have severe dry eye symptoms. Moreover, 68.6% of the female patients were aged above 55 years, which may further explain the severity of the OSDI score observed at baseline.

Patients consulted a healthcare practitioner for their dry eye 3 times on average during the three years preceding the study. Moreover, when treated before enrolment, patients had used artificial tears for more than 6.5 years. These figures are probably underestimated, as the patients were included during a routine visit. However, these figures confirm the high prevalence of dry eye and the difficulty of efficiently treating it using artificial tears.

Improvements in ocular surface staining, Schirmer test and TBUT demonstrated that SH-trehalose significantly reduces ocular surface damage and improves tear film stability after 84 days. Improvements of dry eye signs and symptoms with a preservative-free combination of SH and trehalose have been previously demonstrated and credited to the bioprotectant and osmoprotectant properties of trehalose, combined with the hygroscopic properties of hyaluronic acid [39]. Other work showed that SH-trehalose significantly reduced DED signs and symptoms and did better than HA alone or carmellose sodium [40–43].

Moreover, the clinical improvements demonstrated in our study may explain the anti-inflammatory role of SH-trehalose, as already shown in an exploratory study during which cytokine levels in tears were reduced, along with a significant goblet cell density recovery after 2 months of treatment with SH-trehalose [42].

Craig et al. investigated the performance of lubricant eye drops for 180 days and they observed a sustainable effect of the OSDI, SANDE, and DEQ-5 score from 90 days onwards, more or less the duration of our study [37]. The authors observed an improvement in ocular surface staining scores from day 120 onwards. In another randomized, active-controlled, investigator-masked, multicenter study evaluating preservative-free SH-trehalose in 52 patients after 84 days, the mean change from baseline of OSDI score was − 30.2 ± 18.7 and the mean change from baseline of Oxford score − 4 ± 2.2 [24]. This was higher than in our study (with a mean OSDI score decrease of − 13.95 and a mean decrease of Oxford score of − 2 ± 2.2, respectively. The Schirmer score increased by 3 mm/5 min, the TBUT by 2.7~s being, again, superior to our study results with respective increases of 0.7 ± 6.4 and 1.8 ± 2.6. These differences can be explained by the real-life settings of our study and poor compliance with DE therapy in real life. A recent cross-sectional study (including 2645 participants showed that the proportion of participants who instilled at the frequency specified in the package insert was 10.2% only. This emphasizes that ophthalmologists need to educate on the importance of regular instillation in order to obtain the appropriate effect of eye drops. In another study, more than half of the patients used eye drops 1–3 times/day for the treatment of DED, and most patients were unable to instill the DED eye drops at the specified frequency (5–6 times/day for artificial tears) [38].

Globally, satisfaction at baseline regarding previous dry eye therapy was considered as good. However, global satisfaction increased with SH-trehalose, which may be explained by the improvement in symptoms. A limitation might be the fact that we used a specifically designed but non-validated satisfaction questionnaire for this study. However, at the time the study was conducted, no specific satisfaction questionnaire was available. When analyzing global satisfaction according to the disease severity, the satisfaction of patients with severe DED significantly increased (p < 0.001), as early as day 28. Surprisingly, this significant improvement was not observed for patients with moderate DED. This may be due to the fact that patients with moderate DED may not experience a notable and immediate improvement of their DED symptoms when using SH-trehalose. Conversely, patients with severe DED may experience immediate relief from DED symptoms, resulting in a significant improvement in satisfaction with no side effects, compared to previously used DED medications [44, 45]. This observation may be considered a bias, as the number of patients with moderate DED (n = 28) was similar to that of patients with mild DED (n = 30), while the number of patients with severe DED was four times higher (n = 123).

Seventy-three patients had previously been treated with SH-containing products. For these patients, all parameters (OSDI, conjunctival hyperemia, Schirmer test, TBUT, Oxford score, global patient satisfaction, and DEQ-5 score) significantly improved (all p ≤ 0.001, except Schirmer test p = 0.031) for both eyes after switching to SH-trehalose at day 84. This further improvement confirms the added value of trehalose in DED care.

The fact that the study was not performed using a randomized comparative design to compare SH-trehalose to other artificial tears or treatments may be considered a limitation. However, as the study was not designed to make direct comparisons but to assess the benefit of SH-trehalose in reducing OSDI, as well as improving quality of life and patient satisfaction under real-life conditions, the presented results are worth considering. Moreover, this study was conducted during the COVID-19 pandemic, which heavily impacted the inclusion of patients. Despite these limitations, and to the best of our knowledge, this is the first time that dry eye symptoms and satisfaction with treatment have been assessed along with clinical signs in real-world settings on a scale of more than 300 patients.

Conclusions

The present study conducted in real-life settings demonstrated that, in a large population, the preservative-free SH-trehalose combination significantly improves DED signs and symptoms after 3 months and is accompanied by high patient satisfaction.

Author Contributions

Antonio J. Mateo-Orobia, Sarah Farrant, Eduardo Del-Prado-Sanz, Alejandro Blasco-Martínez, Miriam Idoipe-Corta, Noelia Lafuente-Ojeda and Luis E. Pablo-Júlvez approved the study protocol and conducted the study, participated in the data analysis, and approved the manuscript content.

Funding

This study was funded by Laboratoires Théa, France. This also includes publication costs, including the journal’s Rapid Service Fee, and the work of the medical writer.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of Interest

Antonio J. Mateo-Orobia, Sarah Farrant, Eduardo Del-Prado-Sanz, Alejandro Blasco-Martínez, Miriam Idoipe-Corta, Noelia Lafuente-Ojeda and Luis E. Pablo-Júlvez declare no financial or personal conflict of interest.

Ethical Approval

The study was conducted in accordance with Good Epidemiological Practice guidelines of the International Epidemiological Association and the Declaration of Helsinki and was approved according to local ethics committee approval requirements by the local central ethics committees CEIC Hospital General Universitario José María Morales Meseguer/Spain (central IEC approval N°: EST: 75/18) and London/United Kingdom (IRAS ID: 18/19–1033) between January 30, 2018 and February 21, 2019. All patients provided informed consent prior to inclusion into the study.