The efficacy and safety of topical diquafosol ophthalmic
solution for the treatment of dry eye: A systematic review of
randomized clinical trials
Di Wu1,4, PhD, Wang Qi Chen2, Ryan Li3, Yan Wang4, MD, PhD
1 Tianjin Medical University. 22 Qixiangtai Rd, Heping, Tianjin,
China, 300070
2 University of California, Berkeley, College of Chemistry. 419
Latimer Hall, Berkeley, CA 94720
3 University of Toronto, Faculty of Arts and Science. Sidney
Smith Hall, 100 St. George Street Toronto, Ontario, Canada M5S
3G3
4 Tianjin Eye Hospital & Eye Institute, Tianjin Key Lab of
Ophthalmology and Visual Science, Tianjin Medical University. No 4.
Gansu Rd, Heping District, Tianjin, China, 300020
Corresponding author: Yan Wang, MD, PhD. Tianjin Eye Hospital
& Eye Institute, Tianjin Key Lab of Ophthalmology and Visual
Science, Tianjin Medical University. No 4. Gansu Rd, Heping
District, Tianjin, China, 300020 Tel: 86-22-27305083. Email:
[email protected]
None of the authors has a financial interest related to this
study.
Keywords: diquafosol, dry eye, keratoconjunctivitis sicca,
randomized clinical trials, systematic review
Purpose: To evaluate the efficacy and safety of topical
diquafosol ophthalmic solution treatment for dry eye.
Methods: Randomized clinical trials (RCTs) from MEDLINE, EMBASE
and Cochrane Central Register of Controlled Trials (CENTRAL) were
identified to evaluate the efficacy and safety of topical
administration of diquafosol for dry eye patientsents. Data
evaluation was based on endpoints including Schirmer’s test, tear
film break-up time test (TFBUT), ocular surface staining score,
subjective symptom score and adverse events.
Results: A total of 8 RCTs involving 1516 patients were selected
abiding pre-specified criteria. Significant improvement of
Schirmer’s test values and TFBUT were reported in 40% (2/5) and 80%
(4/5) studies, respectively. Ocular surface staining scores
significantly decreased in 100% (Fluorescein corneal staining: 6/6;
Rose Bengal corneal and conjunctival staining: 4/4) RCTs. Symptoms
significantly improved in 75% (6/8) RCTs in dry eye patients. No
severe adverse events were reported with the concentrations of
diquafosol from 0.5% - 5%. Heterogeneity in study design prevented
meta-analysis from statistical integration and summarization.
Conclusions: Topical diquafosol appears to be a safe therapeutic
option for the treatment of dry eye. The high variability of the
selected RCTs compromised the strength of evidence and limits the
determination of efficacy. However, the topical administration of
diquafosol showed appears to be beneficial in improving the
integrity of the epithelial cell layer of ocular surface and mucin
secretion in dry eye patients. This review indicates a need for
standardized criteria and methods for evaluation to assess the
efficacy of diquafosol in the future clinical trials.
INTRODUCTION
Dry eye or keratoconjunctivitis sicca (KCS) is a multifactorial
disease characterized by increased osmolarity of the tear film and
inflammation of the ocular surface.1 Based on population-based
epidemiologic studies, The International Dry Eye Workshop (2007)
reported the prevalence of dry eye to be a range of approximately
5%-35% at various ages.2-9 Furthermore, tAside from the disturbance
of vision function, the burden of dry eye also may include the
impact on daily activities, social and physical functioning, and
quality of life.10
The pathogenesis of dry eye is a cyclic amplification of the
damage and discomfort associated with the disease. The cascade of
inflammatory events in dry eye caused by tTear hyperosmolarity and
tear film instability have been regarded as the causative and core
mechanism causing ocular surface damage, symptoms of discomfort and
a cascade of inflammatory events in dry eye.1 The activation of
inflammatory signaling pathways (e.g., MAP kinases and NFκB) and
the release of inflammatory cytokines elicits apoptotic death of
surface epithelial cells, including the goblet cells (GCs).11-13
GCs secrete gel-forming mucin that plays an essential role in
maintaining the integrity of the tear film.14,15 The reduction of
GCs leads to a corresponding reduction of mucin, which exacerbates
tear film instability and ocular surface hyperosmolarity,
triggering the progression of dry eye into a vicious cycle.
Therefore, increasing mucin secretion is would be an important
therapeutic target in dry eye syndrome in an effort to break from
this cycle.
Diquafosol, a pharmacological agent under investigation, has
been known as a purinergic P2Y2 receptor agonist that promotes
fluid transfer and mucin secretion by activating P2Y2 receptors
expressed on ocular surface.16,17-20 Previous studies have shown
that the stimulation of water and mucin secretion by diquafosol is
related to the activation of phospholipase C via G proteins caused
by the combination of diquafolsol and P2Y2 receptor, which
consequently increases the concentration of calcium ion within
conjunctival epithelial cells and in GCs.19,21 Animal in vivo
studies, conducted on dogs, rabbits, or age-related dry eye murine
model, demonstrated that the topical administration of diquafosol
appeared to be effective in improving mucin MUC5AC concentration
and aqueous tear secretion.22-24
Even though tThere is evidence demonstrating the improvement of
aqueous tear secretion in animal models22-24, but, no consensus on
the efficacy of diquafosol as a clinical therapy for dry eye has
been established. Diquafosol ophthalmic solution was approved in
Japan in April 2010 as a novel therapeutic option for dry eye, but
it has not yet been accepted by United States Food and Drug
Administration (FDA).25 So far, several randomized clinical trials
(RCTs) have been performed concerning diquafosol and dry eye. To
our knowledge, there has been no reported systematic review or
meta-analysis to provide recommendations to evaluate the treatment
effects of diquafosol for dry eye. This present report aimed to
systematically review the results of RCTs on safety and efficacy of
diquafosol ophthalmic solution in different dry eye types.
MATERIALS AND METHODS
This review was conducted following the Preferred Reporting
Items for Systematic Reviews and Meta-Analyses (PRISMA).26 A
previously written protocol can be found in the Appendix 1. The
details of the protocol abide the recommendations from Cochrane
Handbook for Systematic Reviews of Interventions (Cochrane
Handbook).27
Eligibility Criteria
Types of Studies: RCTs studying the effect of diquafosol
administration as an ophthalmic solution for dry eye disease.
Types of Participants: Male or female participants of any age
≥18 with either subjective or objective diagnosis of dry eye were
considered. Methods of diagnosis can be tear film break-up time
(TFBUT) test, ocular surface staining, symptoms of ocular dryness,
and/or Schirmer’s test.
Types of Intervention: Topical diquafosol administration as an
ophthalmic solution of any vehicles, dose and regiments were
included.
Types of Outcome: Clinical outcomes including symptom score,
ocular surface staining score, TFBUT, Schirmer’s test, and adverse
events.
Literature Search
The Cochrane highly sensitive search strategy was applied to
MEDLINE (1966-2014), EMBASE (1980-2014), and Cochrane Central
Register of Controlled Trials (CENTRAL, the Cochrane Library, Issue
9, 2014) database, with language restriction to English, Chinese,
and French. The initial electronic database search was conducted on
July 21st 2014, using the following terms to search all databases
and registers: diquafosol; diquafosol tetrasodium; diquafosol
sodium; P2Y2 agonist, P2Y2; dry eye; Sjögren syndrome;
keratoconjunctivitis; keratoconjunctivitis sicca. The search
strategy is available in the Appendix 2. Two authors (Wu, D; Chen,
W) conducted the search independently. In addition, all references
of included studies and those of published relevant reviews278, 289
wereare hand searched.
Study Selection
The study selection process was independently completed by two
authors (Wu, D; Chen, W) independently. All titles and abstracts
identified from the search strategy were scanned and reports that
were apparently either notneither about diquafosol, norot
randomized, nor desired they had no associated clinical outcomes
were excluded. After an initial screening, Ffull texts of
potentially eligible studies were obtained and verified inclusion
using a prior constructed eligibility form. Disagreements were
resolved by discussion.
Data Extraction
A data extraction sheet based on “Checklist of items to consider
in data collection or data extraction” from Cochrane Handbook,
pilot-tested it on 3 randomly selected included studies and refined
accordingly.2930 The following data from included studies were
extracted: risk of bias items, study design, characteristics of
participants (total number, age, sex, diagnostic criteria,
country), type of intervention (duration, regimen, concentration),
and type of outcome measures (including outcomes listed in the
eligibility of criteria, missing participants, and length of follow
up). Any unclear or absence of information was confirmed with
original investigators.
Risk of Bias in Individual Studies
Risk of Bias was assessed based on the ‘Risk of bias’ tool
described in Handbook (Version 5.1.0).3031 To determine the
validity of eligible randomized trials, an assessment of the
adequacy of sequence randomization, concealment of allocation,
blinding of participants and personnel, blinding of outcome
assessment, incomplete outcome data, selective outcome reporting
and ‘other issues’ was completed. The bias was defined as high
risk, low risk, or unclear provided by criteria defined in the
Cochrane Handbook for evaluating risk of bias.
Summary Mmeasures
The primary outcome of this systematic review was the evaluation
of the efficacy of topical diquafosol treatment on dry eye by tear
function tests (Schirmer’s test and TFBUT test). Secondary outcomes
of this study included: ocular surface staining score (fluorescein
or Rose Bengal staining), subjective symptom score; and safety
parameters (ocular and systemic adverse events).
Statistical analysis
All selected information was subjected to analysis by RevMan 5
(Review Manager Version 5.2, Copenhagen: The Nordic Cochrane
Centre, The Cochrane Collaboration, 2012). A chi-squared test
evaluated statistical heterogeneity between studies, with
significant heterogeneity (P<0.05) ceasing meta-analysis
RESULT
Due to the presence of between-study heterogeneity induced by
the variation of comparison, follow-up time points, and diquafosol
concentrations for evaluating different outcome measures, it is
inappropriate to report these outcomes in conjunction with
meta-analysis. As an alternative, data yielded from included RCTs
were subjected to descriptive analysis.
Study Selection
Of 375 potentially relevant citations identified from electronic
databases (23 from MEDLINE, 89 from EMBASE, and 19 from CENTRAL),
and hand searches (244 from all references of included studies and
previous relevant reviews), 31 articles were retrieved for
full-text review after adjusting for duplicates and titles and
abstracts screening. A Selectively, a total of 8 RCTs were included
in this systematic review.312-389 DThe details of the selection
process are given in Figure1.
Study Characteristics
Table 1 shows the characteristics of the 8 included studies that
dated from 2001 to 2014. All 8 studies (see Table 1) selected for
the review were RCTs published in English. Seven of which were full
text312-378 and one was conference abstract389. A total of four
trials were performed in Japan,312,334,345,367 three in
America,323,378,389 and one in Korea.356 Two studies were conducted
following two trials each.334, 378 One study included a RCT and a
non-RCT.334 Only the RCT was enrolled in this review. The other
study comprising of with two trials evaluated the safety of
diquafosol and its efficacy separately.378
Methods:
In all, there were five multicenter studies.32,33,35,37,39 Of
the eight studies, four specified the washout period before the
randomization with a mean washout period from previous treatments
of 1.5±0.58 weeks. The mean follow-up time was 1.94±1.94
months.32,33,35,39 (Table 1)
Participants:
The included studies involved 1516 patients with dry eye. Mean
age was 59.87 (range: 36.7 - 65.3) years old, and 73.0% were female
(see Table 2). All studies included provided specified criteria of
dry eye diagnosis. Four studies evaluated diquafosol efficacy in
specific dry eye populations: one study included patients with
short BUT type of dry eye (eyes with Schirmer values ≤ 5 mm were
excluded),334, one study included patients with aqueous-tear
deficient dry eye but not evaporative dry eye,356 one study
included patients with dry eye refractory to sodium hyaluronate
monotherapy,-37 and one study enrolled patients with
mild-to-moderate dry eye.378 (see Table 2). In the remaining 4
studies, type or severity of DED of enrolled patients was not
specified.
Intervention:
Of the 8 included studies, one study recruited 32 patients and
tested topical diquafosol in 1 randomly selected eye, and the other
eye was assigned as control.367 Three studies enrolled 286, 150 and
17 patients respectively, and only one eye from each patient was
selected into study. 312,334,356 However, Nno explicit explanation
relating to the selection of two eyes was documented. Two studies
that recruited 286 and 158 patients remained unclear in the number
of eyes included in trials.345,389 In the remaining 2 studies
(three trials), 527 and 60 enrolled patients were grouped
respectively and randomly to receive either topical diquafosol in
both eyes, or placebo in both eyes.323,378
Different concentrations of diquafosol were evaluated in the 8
studies included in this systematic review with a range from 0.5%
to 5%. Detailed information of regimen can be found in Table 1.
Outcomes:
All studies included in this systematic review evaluated
efficacy of diquafosol ophthalmic solution primarily using Schirmer
I test (without anesthesia, in 5 studies33,34,36-38), Shirmer II
test (with anesthesia, in 1 study38), TFBUT (in 5 studies32,34-37),
ocular surface staining (in 7 studies32-37,39), and symptom score
(in 7 studies32-37,39). Five studies evaluated adverse
events.32,33,35,37,38
Risk of Bias Within Studies
The outcome of ‘Risk of Bias’ assessment is summarized in Figure
2. In terms of selection bias, four of the eight RCTs specified the
methods of random sequence generation.334-367 Two studies provided
the method of allocation concealment.334,367 Regarding performance
biases (blinding of participants and personnel), four of the eight
included studies were double masked,312,323,345,378 and two were
open-label study design,334,356 which were judged as high risk in
both performance bias and detection bias. Among the eight included
RCTs, six were judged as low risk of attrition bias because the
dropouts patients’ number werewas reported clearly and the
percentages werewas believed unlikely to affect the outcome.312-367
Six RCTs included in this systematic review were judged to be free
from reporting bias, as all of the studies’ pre-specified outcomes
were addressed in result.312,334-378 One However, one study didn’t
report the result of TFBUT, which was addressed as an endpoint for
efficacy assessment in methodologies.323 For the only one
conference abstract enrolled in this review, there was no
sufficient information to assess the risk of bias within study.
Outcome of Efficacy
Schirmer I/II Test
Schirmer’s test is a method of assessment indicative of volume
tear fluid secretion. In the result of the included studies, two
out of five studies showed significant improvement.323,356 (Table
3) Hwuang356 reported improvement in both monotherapy and in
combination (diquafosol/ sodium hyaluronate) throughout a three
months period from 1.12 to 3.27mm(/5min). Tauber323 reported of the
subjects with intermediate or high tear volume in diquafosol (1%,
2%) treatment group was significantly higher than placebo group at
six weeks. The other three studied showed no significant
improvement compared with baseline values.334,367,378 No
significant improvement reported from Schirmer II test
assessed.378
TFBUT
TFBUT is indicative of tear film stability. Of the included
studies, five assessed TFBUT.312, 334-367 All five studies reported
improvement. Four out of five studies323-356 reported a significant
improvement compared with baseline or control values (Table 3) with
a range from 0.9-3.9s, and one study showed improvement but is not
statistically significant312.
Ocular surface staining
Ocular surface staining was used to evaluate the integrity of
the superficial cell layers of the ocular surface.3940 Sixeven of
the included studies312,323,345-367,389 evaluated fluorescein
corneal (FC) staining and four312,345-367 evaluated Rose Bengal
(RB) corneal and conjunctival staining. FC staining results all
reported statistically significant amelioration from -0.35 to
-2.12. RB staining results all showed statistically significant
improvement from -0.21 to -3.06.
Subjective ocular symptoms
All 8 studies included in this review evaluated subjective
ocular symptoms, including one evaluated ocular surface disease
index score (OSDI).356 A significant alleviation of at least one
ocular symptom was reported by six studies.312-367 Diquafosol eye
drop treatment showed significant improvement of dry eye sensation
or ocular dryness in four out of five trials evaluating this
symptom312, 334, 367, 378 and foreign body sensation in three out
of six trials323, 367, 378. No However, no mitigation was observed
in eye discharge (evaluated in 4 studies312, 334, 345, 367), ocular
discomfort (evaluated in 3 studies312, 345, 367) and tearing
(evaluated in 2 studies312,334).
Others
One trial assessed tear film stability by performing stability
analysis system (TSAS) measurements with video-keratography.34 No
significant improvement was observed following diquafosol
treatment.
One trial evaluated goblet cell density and squamous metaplasia
degree with performing conjunctival impression cytology, and showed
significant improvement in both assessments after diquafosol
treatment.36
Outcome of Safety
Of the 8 studies included, 5 of which evaluated the safety and
adverse events of topical administration of diquafosol and reported
no serious adverse events.312,323,345,367,378
DISCUSSION
The PRISMA statement, a more updated version of QUOROM
statement, serves as a guideline in the development of a 27-item
checklist and a four-phase flow diagram, which are essential for
transparent reporting of a systematic review.26 The adoption of the
PRISMA statement mitigates problems with incomplete or inadequate
delivery of information such as missing reports and minimizing
bias, thus maximizing the reliability of findings. Thise systematic
review combines evidence and findings across studies to evaluate
efficacy and safety of diquafosol with a more holistic view than
permitted in a single study.
One consideration of this systematic review is the clinical
safety of diquafosol. FromConsidering clinical safety of
diquafosol, the evaluation, no demonstrated noion sof serious
ocular or systemic adverse effect wasis found. Furthermore, the
occurrence of adverse events does not increase with the increase of
the concentration of diquafosol (0.5%-5%). Therefore, as a
secretion stimulating treatment for dry eye, diquafosol, as a
secretion stimulating treatment for dry eye, is clinically
safe.
Another consideration, based on the result of clinical tests
evaluated in the included RCT, is the efficacy of diquafosol.
Ocular surface damage can be evaluated by vital staining, a
hallmark of dry eye disease.401 From the included RCTs, a
significant improvement wereas found in all studies that evaluated
ocular surface staining. This result is congruent with evidence
found in a rat dry eye model.24 In accordance with the pathology of
dry eye and mechanism of diquafosol, the staining scores are
indicative of either the improvement of aqueous tear production or
mucin secretion. Aqueous tear production can be evaluated
clinically using Schirmer’s test. The result from the included RCT
is inconsistent and inconclusive of improvement in aqueous tear
secretion. On the other hand, mucin production, evaluated by TFBUT,
was reported to improve by the majority of the included studies
(4/5). From these trends, one can see a possible correlation
between the function of diquafosol and the improvement of mucine
secretion as well as the mitigation of ocular surface damage, while
however, aqueous tear production does not seem to have a strong
association with diquafosol efficacy.
Even though there are discernable trends in the result, the
evidence is not sufficiently robust to determine the efficacy of
diquafosol primarily due to the high heterogeneous nature of
participants, intervention, comparator, outcome and study design of
the included studies. Firstly, tThe participants of the selected
studies have high variability in patient selection criteria. For
example, among the selected studies, some studies includes while
other excludes patients with Sjögren syndrome. In another case,
while most of the studies require Schirmer’s test value less than
5, one study only includes patients with short TFBUT and Schirmer’s
test value greater than 5.334 Furthermoer, tThe interventions of
the selected study have variation in dosage, combination of therapy
(e.g. sodium hayaluronate + diquafosol), and concentration. The
comparators of the selected studies also have a high variation
including placebo, artificial tears and sodium hayaluronate. The
outcomes of the studies have variation in time point, test, scales,
and reporting formats. The study design has variability as well;
some include double-mask, no blinding and washout/no washout
period.
Aside from heterogeneity, among the RCTs evaluating topical
diquafosol treatment in patients with dry eye, there remain several
other concerns that do not allow us toinhibit us to formulate
conclusions adopting an evidence-based approach to dry eye. First,
the randomized trial did not evaluate a sufficient number of
patients. The only 3 studies with a larger number of participants
(286-527) are sponsored by pharmaceutical companies, of which only
one study includes patients over 300 participants. Furthermore,
among the included study, only two designed a follow up period of
more than 3 months. In the report of the International Dry Eye
Workshop (2007), the Diagnostic Methodology Subcommittee regarded
dry eye as a chronic, symptomatic ocular surface disease.412
Therefore, it is logical to assume that a longer follow-up period
is necessaryneeded. In addition, the follow up period of most study
end as intervention period ends. Only two studies extended the
follow-up one week after the conclusion of the intervention period,
one of which states that “…After discontinuation of study
medication, corneal staining scores in the diquafosol groups, but
not the placebo group, worsened slightly and were no longer
significantly different when compared with placebo”.33 Indicating
further concern with the design of the selected studies. Moreover,
the limited ethnicities of the selected studies (Japan & United
States) may compromise the understanding of the various response to
drug therapy by different race and ethnicity. The several issues
previously discussed prevent us from effectively implementing a
statistical approach.
This systematic review has several limitations on a study and
review level including the quality of the studies varied.
Concerning randomization, limitations include inability to
limitations include unable to assess the quality of the selected
studies due to unclear reports ofting of the randomization method.
Regarding the review process, no unpublished data was selected and
the language of the searched studies was restricted to English,
Chinese, and French.
In summary, the safety of diquafosol is established based on the
included study. Although there is a possible correlation between
diquafosol and mucin secretion and between diquafosol and surface
damage assuagement, the high heterogeneity of the selected study
affects the strength of the findings leading to limitationlimits
thein determination ofing the efficacy of diquafosol on dry eye.
For future trials, this review indicates a need for a neutral
organization to perform a multi-centered, large sample sized, long
term evaluation of the efficacy of diquafosol. Some aspects to
consider for future trials include concentration of diquafosol
[varied] and the duration of efficacy of diquafosol post treatment.
Further suggestions include a standardized comparator in evaluation
of any particular drug for dry eye.
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Figure 1. Flow diagram of systematic process for report
identification.
Figure 2. Risk of bias summary in included studies. Green (+) =
low risk; Red (-) = high risk; Yellow (?) = unclear.
Supplemental Digital Content:
Appendix 1: Protocol of the present systematic review
Appendix 2: Search Strategy
1