Cochrane Database of Systematic Reviews

Oral antihistamines for seasonal allergic conjunctivitis

(Protocol)
Kamegasawa A, Chaoul MM, El Dib R

Kamegasawa A, Chaoul MM, El Dib R.

Oral antihistamines for seasonal allergic conjunctivitis.
Cochrane Database of Systematic Reviews 2014, Issue 6. Art. No.: CD011172.
DOI: 10.1002/14651858.CD011172.

www.cochranelibrary.com

Oral antihistamines for seasonal allergic conjunctivitis (Protocol)

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS
HEADER . . . . . . . . . .
ABSTRACT . . . . . . . . .
BACKGROUND . . . . . . .
OBJECTIVES . . . . . . . .
METHODS . . . . . . . . .
ACKNOWLEDGEMENTS
. . .
REFERENCES . . . . . . . .
APPENDICES . . . . . . . .
CONTRIBUTIONS OF AUTHORS
DECLARATIONS OF INTEREST .
SOURCES OF SUPPORT . . . .

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Oral antihistamines for seasonal allergic conjunctivitis (Protocol)

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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[Intervention Protocol]

Oral antihistamines for seasonal allergic conjunctivitis

Amlia Kamegasawa1 , Mauricio M Chaoul2 , Regina El Dib3
1 Department of Ophthalmology, Otorhinolaryngology and Head and Neck Surgery, Botucatu Medical School, UNESP - Univ Estadual

Paulista, Botucatu, Brazil. 2 Botucatu Medical School, UNESP - Univ Estadual Paulista, Botucatu, Brazil. 3 Department of Anaesthesiology, Botucatu Medical School, UNESP - Univ Estadual Paulista, Botucatu, Brazil
Contact address: Regina El Dib, Department of Anaesthesiology, Botucatu Medical School, UNESP - Univ Estadual Paulista, Distrito
de Rubio Jnior, s/n, Botucatu, So Paulo, 18603-970, Brazil. eldib@fmb.unesp.br. re.lucci@terra.com.br.
Editorial group: Cochrane Eyes and Vision Group.
Publication status and date: New, published in Issue 6, 2014.
Citation: Kamegasawa A, Chaoul MM, El Dib R. Oral antihistamines for seasonal allergic conjunctivitis. Cochrane Database of
Systematic Reviews 2014, Issue 6. Art. No.: CD011172. DOI: 10.1002/14651858.CD011172.
Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT
This is the protocol for a review and there is no abstract. The objectives are as follows:
To evaluate the effectiveness and safety of oral antihistamines (such as loratadine, desloratadine, cetirizine, levocetirizine, fexofenadine,
terfenadine) in patients with SAC.

BACKGROUND

Description of the condition

Ocular allergy affects up to 40% of the general population (Sing
2007; Sing 2010) and has become increasingly prevalent in the
last four decades (Bielory 2000; Davies 1998; Friedlander 1991).
The symptoms include intense itching, photophobia (discomfort
of light) and lacrimation (secretion of tears). Such symptoms affect
daily leisure and work activities of adults and children and, consequently, overall well being and quality of life (Valencio 2007). In
severe cases, increases in lesions of the ocular conjunctiva (membrane of the eye that covers the external surface) may occur and
can cause ptosis (fallen upper eyelid), corneal ulcer (the absence
of epithelium cells, exposing the underlying tissue) and neovascularisation (new blood vessels), with the risk of amblyopia (one eye
does not develop fully) and blindness (Nishiwaki-Dantas 2008;
Ono 2005). Ocular allergy includes a group of diseases that affect
the ocular surface and are associated with a type I hypersensitivity

reaction. The most common clinical form is conjunctivitis (inflammation of the conjunctiva), which is usually associated with
allergic rhinitis (Sing 2007) and is known as rhinoconjunctivitis
(inflammation of the nasal mucous and conjunctiva) (Johanson
2004).
Allergic conjunctivitis is classified as seasonal (SAC), perennial
(PAC), atopic (AKC) and vernal (VKC). SAC is the most common form of eye allergy and is characterised by acute unilateral or
bilateral itching, tearing and conjunctival hyperaemia (increased
blood in the eyes) during the pollination periods of the year. SAC
occurs in previously sensitised individuals when exposed to aeroallergens, such as grass and ragweed pollens (Bielory 2000; Valencio
2007). PAC is a chronic year-round allergy, with some occurrence
of exacerbations, and is probably associated with house dust mites
(Bielory 2000; Bonini 2000; Valencio 2007). AKC is a more severe type of allergic conjunctivitis, occurring most often in the
second to third decade of life. Although it has no seasonality, it
may worsen in the winter. The symptoms include ocular itching,
burning, photophobia and mucous secretion. It may also present

Oral antihistamines for seasonal allergic conjunctivitis (Protocol)

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

as chronic conjunctivitis with scarring, affecting the eyelids and

cornea (the clear front covering of the eye), and can be associated with keratoconus (an abnormal cone-shaped protrusion of
the cornea) and cataracts (a clouding of the natural lens of the eye).
It is estimated that ocular allergy is associated with atopic dermatitis (inflammation of the palpebral skin) in 25% to 50% of cases
(Bonini 2000; Cameron 1989; Coyle 1984; Nishiwaki-Dantas
2008; Sing 2007). VKC is a chronic keratoconjunctivitis (inflammation of the cornea and conjunctiva) that is most common in
young boys (Katelaris 2003). The patients usually report intense
itching and photophobia, with the feeling of a foreign body that
is mainly exacerbated during the spring or summer. VKC patients
present with hyperaemia and conjunctival oedema (swelling from
the excessive accumulation of liquid in the tissue), and moderate
mucous secretion. Furthermore, epithelial erosions (the absence
of some epithelium cells), shield-shaped corneal ulcers, peripheral
neovascularisation and pannus (corneal superficial vascularisation)
may appear in VKC (Bonini 2000; Cameron 1989; Coyle 1984;
Nishiwaki-Dantas 2008; Sing 2007).
Although the signs and symptoms of SAC are relatively mild to
moderate, it is the most common of the allergic eye diseases and
can affect daily activities, productivity at work, and performance
in school, resulting in economic costs on society (Katelaris 2008;
Smith 2005).

Description of the intervention

Several agents have been used in the management of allergic conjunctivitis, including vasoconstrictors (e.g., epinephrine), mast cell
stabilisers (e.g., cromoglycate), double-action agents (e.g., olopatadine), non-hormonal anti-inflammatories (e.g., paracetamol), corticosteroids (e.g., dexamethasone), and oral (e.g., desloratadine)
and topical (e.g., lodoxamide) antihistamines.
Histamine is one of the main mediators of the allergic reaction
and is the result of the contact between allergens and the conjunctival mucosa; its action triggers the initial phase symptoms
of allergy, e.g., itching, and releases multiple pro-inflammatory
cytokines that promote vasoactive effects (Leonardi 2000). Antihistamines act as reverse agonists of the histaminic receptors,
presenting an anti-inflammatory effect (Maichuk 2000), and are
classified as H1 (the most used for ocular allergies), H2 and H3
blockers. As a monotherapy, oral antihistamines are used to control the symptoms of allergic conjunctivitis and rhinoconjunctivitis, however the occurrence of side effects cannot be ruled out
(Leurs 2002). The first generation of antihistamines (e.g., chlorpheniramine, diphenhydramine, doxylamine and pyrilamine) can
present such side effects as drowsiness, sedation, fatigue, headache
and memory disorders, in addition to dry eyes and mouth, blurry
vision and urinary retention (Bielory 2005; el Cuvilo 2006).
Clinical studies have shown that most oral antihistamines, mainly
the second- and third-generation antihistamines (e.g., cetirizine,
levocetirizine, loratadine, and desloratadine) present less side ef-

fects and reduce ocular itching, tearing and redness of seasonal

allergic rhinoconjunctivitis, thus significantly increasing quality
of life. When the symptoms are predominantly ocular, treatment with topical antihistamines, such as olopatadine, ketotifen,
emedastine and epinastine, seems to be more efficient due to
the higher concentration at the site in a short period of time
(Abelson 1993; Bielory 2005; el Cuvilo 2006; Grumetto 2002;
Hansen 2005; Hingorani 1995; Simons 2004; Sprangler 2003;
Timmerman 2000; Torkildsen 2009).

How the intervention might work

The intervention will alleviate the symptoms causing the discomfort of SAC, such as itching (by blocking chemical processes in an
allergic reaction), photophobia and the reduction of visual acuity,
resulting in an improvement of the daily activities and the overall
wellness and quality of life of the patients.

Why it is important to do this review

This systematic review aims to evaluate the effectiveness and safety of oral antihistamines in adults and children with a history
of SAC. Numerous treatment options exist for SAC, including
artificial tears, hormonal and non-hormonal anti-inflammatories,
immunomodulation, conjunctival papilla (lesions of the conjunctiva) surgery and complementary therapy.
A Cochrane systematic review assessing the effectiveness of antihistamines used as adjuncts to topical nasal steroids for intermittent and persistent allergic rhinitis in children reported no effect
due to a lack of evidence (Nasser 2010).

OBJECTIVES
To evaluate the effectiveness and safety of oral antihistamines
(such as loratadine, desloratadine, cetirizine, levocetirizine, fexofenadine, terfenadine) in patients with SAC.

METHODS

Criteria for considering studies for this review

Types of studies
We will consider randomised controlled trials (RCTs). Although
RCTs are not necessarily a good source of evidence to detect uncommon safety events, we will not perform a safety evaluation
through other study designs (e.g., cohort studies).

Oral antihistamines for seasonal allergic conjunctivitis (Protocol)

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Types of participants

Search methods for identification of studies

Adults and children (regardless of gender, age and race) with acute
SAC, diagnosed by clinical history or by an allergen-specific IgE
antibody exam or eosinophil levels, with or without allergic rhinitis
(AR) or asthma, in whom oral antihistamines are being used.

There will be no language, date or publication status restrictions

in the search for trials.
Electronic searches

Types of interventions
We will consider the following comparisons.
Intervention group: oral antihistamine drugs, with or without
the administration of any topical ocular (i.e., artificial tears) or
nasal (i.e., cromoglycate) drugs, or both, prescribed for SAC.
Control group: no intervention, or placebo both topic (tablet,
eyedrop, etc) or oral, or both; oral antihistamine drugs alone with
or without topic placebo; topical ocular (i.e., artificial tears) or
nasal (i.e., cromoglycate) drugs, or both, with or without oral
placebo.
We will also consider comparisons between different oral antihistamine drugs as well as any dosage and duration of therapy.
We will exclude studies on topical steroids, complementary
medicine and surgery.

Types of outcome measures

We will search the Cochrane Central Register of Controlled

Trials (CENTRAL) (which contains the Cochrane Eyes and
Vision Group Trials Register) (latest issue), Ovid MEDLINE,
Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January
1946 to present), EMBASE (January 1980 to present), Latin
American and Caribbean Health Sciences Literature Database
(LILACS) (1982 to present), the metaRegister of Controlled
Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov
(www.clinicaltrials.gov) and the World Health Organization
(WHO) International Clinical Trials Registry Platform (ICTRP)
(www.who.int/ictrp/search/en). We will not use any date or language restrictions in the electronic search for trials.
See: Appendices for details of search strategies for CENTRAL
(Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix 3),
LILACS (Appendix 4), mRCT (Appendix 5), ClinicalTrials.gov
(Appendix 6) and the ICTRP (Appendix 7).
Searching other resources

Primary outcomes

The primary outcome will be patient reported symptoms such as

itching, tearing, red eye, or discomfort as well as overall change of
composite measures of those symptoms. As there will be different
tools evaluating symptoms such as visual analogue scale (VAS) we
will try to transform the data to common measurements where
possible to facilitate meta-analysis. We will assess the outcome
from the date of randomisation to four months (season period).
We will also collect data and meta-analyse the primary outcome
at other commonly reported time points, if possible.

Secondary outcomes

1. Rhinitis-related symptoms such as sneezing, rhinorrhoea

and postnasal drip, pruritus (itching), and nasal congestion
measured by any validated tool such as VAS or non-validated
instrument, or both.
2. Need for rescue medication (other oral antihistamines).
3. Quality of life measures (however defined by study authors).
4. Visual acuity.
5. Adverse events. We will consider any specific adverse effects,
systemic or local, and any clinically diagnosed hypersensitivity or
other adverse reactions related to the control group (e.g., steroid
medication).
We will also collect data about costs as a narrative analysis that can
be used by others to be included in a cost-effectiveness study.

We will check the references of potential studies for additional

published and/or unpublished papers. We will contact experts in
the field for additional citations.

Data collection and analysis

Selection of studies
Two review authors (AK and RED) will independently screen the
abstracts identified by the literature search. We will obtain full
copies of all potentially or definitely related articles. We will resolve
disagreements by consulting with the other review author (MMC).
We will document the excluded studies and reasons for exclusion
in a table entitled Characteristics of excluded studies. We will
include a PRISMA flow chart showing the details of the search
results in the review
Data extraction and management
Two authors (AK and MMC) will independently extract data.
We will resolve any discrepancies by discussion. We will use a
standard data extraction form to extract the following information:
characteristics of the study (design, methods of randomisation);
participants; interventions; outcomes (types of outcome measures,
adverse events) (see Appendix 8 for further information). One

Oral antihistamines for seasonal allergic conjunctivitis (Protocol)

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

author (RED) will enter all data into Review Manager (RevMan
5.2) and a second author (AK) will independently check the data
entered.
Assessment of risk of bias in included studies
For the assessment of study quality, we will use the the risk of
bias tool as described in Chapter 8 of the Cochrane Handbook for
Systematic Reviews of Interventions (Higgins 2011). We will use the
following six separate criteria.
Allocation sequence generation
Low risk of bias: sequence generation was achieved
using computer random number generation or a random number
table. Drawing lots, tossing a coin, shuffling cards, and throwing
dice are adequate if performed by an independent adjudicator.
Uncertain risk of bias: the trial is described as
randomised, but the method of sequence generation was not
specified.
High risk of bias: the sequence generation method is
not, or may not be, random.
Allocation concealment
Low risk of bias: allocation was controlled by a central
and independent randomisation unit, sequentially numbered,
opaque and sealed envelopes or similar, so that intervention
allocations could not have been foreseen in advance of, or
during, enrolment.
Uncertain risk of bias: the trial was described as
randomised, but the method used to conceal the allocation was
not described so that intervention allocations may have been
foreseen in advance of, or during, enrolment.
High risk of bias: if the allocation sequence was
known to the investigators who assigned participants, or if the
study was quasi-randomised.
Blinding (masking) of participants, personnel, and outcome
assessors
Low risk of bias: masking was performed adequately,
or the outcome measurement is not likely to be influenced by
lack of masking.
Uncertain risk of bias: there is insufficient information
to assess whether the type of masking used is likely to induce bias
on the estimate of effect.
High risk of bias: no masking or incomplete masking,
and the outcome or the outcome measurement is likely to be
influenced by lack of blinding.
Incomplete outcome data
Low risk of bias: the underlying reasons for missing
data are unlikely to make treatment effects depart from plausible
values, or proper methods have been employed to handle missing
data.
Uncertain risk of bias: there is insufficient information
to assess whether the missing data mechanism in combination

with the method used to handle missing data are likely to induce
bias on the estimate of effect.
High risk of bias: the crude estimate of effects (eg.,
complete case estimate) will clearly be biased due to the
underlying reasons for missing data, and the methods used to
handle missing data are unsatisfactory.
Selective outcome reporting
Low risk of bias: predefined, or clinically relevant and
reasonably expected outcomes are reported on.
Uncertain risk of bias: not all predefined or clinically
relevant and reasonably expected outcomes are reported on, or
are not reported fully, or it is unclear whether data on these
outcomes were recorded or not.
High risk of bias: one or more clinically relevant and
reasonably expected outcomes were not reported on; data on
these outcomes were likely to have been recorded.
Vested interest bias
Low risk of bias: if the trials funding did not come
from any parties that might have conflicting interests (eg., an
antibacterial agent manufacturer), or if any academic,
professional, financial, or other benefits to the person responsible
for the trial are independent of the direction or statistical
significance of the trial results.
Uncertain risk of bias: if the source of funding was not
clear, or if it is unclear if the person responsible for the trial
stands to benefit according to the direction or statistical
significance of the trial results.
High risk of bias: if the trials source of funding had a
conflict of interest, or if any academic, professional, financial, or
other benefits to the person responsible for the trial are
dependent on the direction or statistical significance of the trial
results.
We will assess all trials for risk of bias. If the risk of bias in a trial is
judged as low in all the listed above domains, the trial will fall in
the low risk of bias group. If the risk of bias in the assessed trials
is judged as uncertain or high in one or more of the specified
domains, then the trial will fall in the high risk of bias group.
In a first step, information relevant for making a judgement on
a criterion will be copied from the original publication into an
assessment table. If additional information is available from study
authors, this will also be entered in the table along with an indication that this is unpublished information. Two review authors
(AK and RED) will independently make a judgment as to whether
the risk of bias for each criterion was considered to be low, uncertain, or high. We will resolve disagreements by discussion.
We will record this information for each included trial in Risk of
bias tables in RevMan (RevMan 2012) and summarise the risk of
bias for each trial in a summary Risk of bias figure and graph.

Oral antihistamines for seasonal allergic conjunctivitis (Protocol)

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Measures of treatment effect

We will process included trial data as described in Chapter 8 of the
Cochrane Handbook for Systematic Reviews of Interventions (Higgins
2011).

(a) Binary outcomes

For dichotomous data (e.g., need for rescue medication, assessment of allergen sensitivity in either the eye or nose, and adverse
events), we will use the risk ratio (RR) as the effect measure with
95% confidence intervals (CIs).

(b) Continuous outcomes

For continuous data (e.g., quality of life, visual acuity and improvement of global symptoms), we will present the results as mean differences (MDs) with 95% CIs. When pooling data across studies,
we will estimate the MD if the outcomes are measured in the same
way between trials. We will use the standardised mean difference
(SMD) to combine trials that measure the same outcome but use
different methods.

(c) Multiplicity issues

We will perform meta-analysis for all outcomes, but only draw a

conclusion based on the primary outcome.

Unit of analysis issues

The unit of analysis will be the patient and eyes according to the
evaluated outcomes.

Dealing with missing data

An intention-to-treat analysis (ITT) is one in which all the participants in a trial are analysed according to the intervention to which
they were allocated, whether they received the intervention or not.
For each trial we will report whether or not the investigators stated
if the analysis was performed according to the ITT principle. If
participants were excluded after allocation, we will report any details provided in full. Therefore, we will perform the analysis on an
ITT basis (Newell 1992) whenever possible. Otherwise, we will
adopt the per protocol analysis.

Assessment of heterogeneity
We will look for clinical heterogeneity by examination of the study
details then test for statistical heterogeneity between trial results
using the Chi2 test and the I2 statistic as described in Chapter 9
of the Cochrane Handbook for Systematic Reviews of Interventions
(Deeks 2011). We will classify heterogeneity using the following
I2 values.

0 to 40%: might not be important;

30% to 60%: may represent moderate heterogeneity;
50% to 90%: may represent substantial heterogeneity; and
75% to 100%: considerable heterogeneity.
Assessment of reporting biases
Apart from assessing the risk of selective outcome reporting considered under Assessment of risk of bias in included studies, we
will assess the likelihood of potential publication bias using funnel
plots, provided that there are at least eight trials. As small studies
in a meta-analysis tend to show larger treatment effects, we will
consider other causes, including: selection biases, poor methodological quality, heterogeneity, artefactual and chance.
Data synthesis
Data analysis will follow the guidelines in Chapter 9 of the
Cochrane Handbook for Systematic Reviews of Interventions (Deeks
2011). We will calculate pooled estimates using the random-effects model for more than two studies. We will attempt to quantify
the proportion of variability within included randomised studies
that is explained by heterogeneity using the I2 statistic (Higgins
2002).
Subgroup analysis and investigation of heterogeneity
In the case of excessive clinical heterogeneity (I2 > 50%), we will
use subgroup analysis to pool the results. Subgroup analyses are secondary analyses in which the participants are divided into groups
according to shared characteristics, and outcome analyses are conducted to determine if any significant treatment effect occurs according to that characteristic. If data permit, we will carry out the
following subgroup analyses.
1. Ages: adults (> or equal to 18 years to 65 years) versus older
adults (> than 65 years) versus children (up to 17 years).
2. Different oral antihistamine drugs (e.g., loratadine versus
cetirizine).
We will perform the Chi2 test for subgroup differences set at a P
value of 0.05.
Sensitivity analysis
We will perform a sensitivity analysis after the original statistical
analysis to examine the effects of different trials. We will include
the following factors in the sensitivity analysis, separating studies
according to:
1. trials with high risk of bias; and
2. trials with rates of withdrawal larger than or equal to 20%.

ACKNOWLEDGEMENTS

Oral antihistamines for seasonal allergic conjunctivitis (Protocol)

Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

The Cochrane Eyes and Vision Group (CEVG) created, and will
execute the electronic search strategies. We acknowledge the support of Anupa Shah and Augusto Azuara-Blanco in the preparation of the protocol and thank Catey Bunce and Senthil Maharajan for their comments on the protocol.
The views expressed in this publication are those of the authors
and not necessarily those of the NIHR, NHS or the Department
of Health.

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Katelaris CH, Bielory L. Evidence-based study design in
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Indicates the major publication for the study

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Copyright 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

APPENDICES

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Conjunctivitis, Allergic] explode all trees
#2 conjunctivitis
#3 pollen near/3 allerg*
#4 hayfever
#5 hay near/2 fever
#6 #1 or #2 or #3 or #4 or #5
#7 ((antihistamin* or anti-histamin*) near/4 oral*)
#8 MeSH descriptor: [Loratadine] explode all trees
#9 loratadine*
#10 desloratadine*
#11 cetirizine*
#12 levocetirizine*
#13 fexofenadine*
#14 terfenadine*
#15 bilastine*
#16 ebastin*
#17 emedastine*
#18 rupatadine*
#19 MeSH descriptor: [Astemizole] explode all trees
#20 astemizole*
#21 MeSH descriptor: [Chlorpheniramine] explode all trees
#22 chlorpheniramine*
#23 MeSH descriptor: [Triprolidine] this term only
#24 triprolidine*
#25 acrivastine*
#26 azelastine*
#27 ketotifen*
#28 MeSH descriptor: [Pseudoephedrine] this term only
#29 pseudoephedrine*
#30 oxatomide*
#31 mizolastine*
#32 acetylaspartic
#33 glutamic
#34 NAAGA
#35 mequitazine*
#36 #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #
26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35
#37 #6 and #36

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Appendix 2. MEDLINE(OvidSP) search strategy

1. randomized controlled trial.pt.
2. (randomized or randomised).ab,ti.
3. placebo.ab,ti.
4. dt.fs.
5. randomly.ab,ti.
6. trial.ab,ti.
7. groups.ab,ti.
8. or/1-7
9. exp animals/
10. exp humans/
11. 9 not (9 and 10)
12. 8 not 11
13. conjunctivitis, allergic/
14. conjunctivitis.tw.
15. (pollen adj3 allerg$).tw.
16. hayfever.tw.
17. (hay adj2 fever).tw.
18. or/13-17
19. ((antihistamin$ or anti-histamin$) adj4 oral$).tw.
20. Loratadine/
21. loratadine$.tw.
22. desloratadine$.tw.
23. Cetirizine/
24. cetirizine$.tw.
25. levocetirizine$.tw.
26. fexofenadine$.tw.
27. Terfenadine/
28. terfenadine$.tw.
29. bilastine$.tw.
30. ebastin$.tw.
31. emedastine$.tw.
32. rupatadine$.tw.
33. Astemizole/
34. astemizole$.tw.
35. Chlorpheniramine/
36. chlorpheniramine$.tw.
37. Triprolidine/
38. triprolidine$.tw.
39. acrivastine$.tw.
40. azelastine$.tw.
41. ketotifen$.tw.
42. Pseudoephedrine/
43. pseudoephedrine$.tw.
44. oxatimide$.tw.
45. mizolastine$.tw.
46. N-acetyl-aspartyl glutamic acid.tw.
47. NAAGA.tw.
48. mequitazine$.tw.
49. or/19-48
50. 18 and 49
51. 12 and 50
Oral antihistamines for seasonal allergic conjunctivitis (Protocol)
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The search filter for trials at the beginning of the MEDLINE strategy is from the published paper by Glanville et al (Glanville 2006).

Appendix 3. EMBASE (OvidSP) search strategy

1. exp randomized controlled trial/
2. exp randomization/
3. exp double blind procedure/
4. exp single blind procedure/
5. random$.tw.
6. or/1-5
7. (animal or animal experiment).sh.
8. human.sh.
9. 7 and 8
10. 7 not 9
11. 6 not 10
12. exp clinical trial/
13. (clin$ adj3 trial$).tw.
14. ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
15. exp placebo/
16. placebo$.tw.
17. random$.tw.
18. exp experimental design/
19. exp crossover procedure/
20. exp control group/
21. exp latin square design/
22. or/12-21
23. 22 not 10
24. 23 not 11
25. exp comparative study/
26. exp evaluation/
27. exp prospective study/
28. (control$ or prospectiv$ or volunteer$).tw.
29. or/25-28
30. 29 not 10
31. 30 not (11 or 23)
32. 11 or 24 or 31
33. exp allergic conjunctivitis/
34. conjunctivitis.tw.
35. (pollen adj3 allerg$).tw.
36. hayfever.tw.
37. (hay adj2 fever).tw.
38. or/33-37
39. ((antihistamin$ or anti-histamin$) adj4 oral$).tw.
40. Loratadine/
41. loratadine$.tw.
42. desloratadine/
43. desloratadine$.tw.
44. Cetirizine/
45. cetirizine$.tw.
46. levocetirizine/
47. levocetirizine$.tw.
48. fexofenadine/
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49. fexofenadine$.tw.
50. Terfenadine/
51. terfenadine$.tw.
52. bilastine/
53. bilastine$.tw.
54. ebastine/
55. ebastin$.tw.
56. emedastine/
57. emedastine$.tw.
58. rupatadine/
59. rupatadine$.tw.
60. Astemizole/
61. astemizole$.tw.
62. Chlorpheniramine/
63. chlorpheniramine$.tw.
64. Triprolidine/
65. triprolidine$.tw.
66. acrivastine$.tw.
67. azelastine/
68. azelastine$.tw.
69. ketotifen/
70. ketotifen$.tw.
71. Pseudoephedrine/
72. pseudoephedrine$.tw.
73. oxatomide/
74. oxatimide$.tw.
75. mizolastine/
76. mizolastine$.tw.
77. n acetylaspartic acid/
78. N-acetyl-aspartyl glutamic acid.tw.
79. NAAGA.tw.
80. mequitazine$.tw.
81. or/39-80
82. 38 and 81
83. 32 and 82

Appendix 4. LILACS search strategy

loratadine OR desloratadine OR cetirizine OR levocetirizine OR fexofenadine OR terfenadine OR bilastine OR ebastine OR emedastine
OR rupatadine OR astemizole OR chlorpheniramine OR triprolidine OR acrivastine OR azelastine OR ketotifen OR pseudoephedrine
OR oxatomide OR mizolastine OR acetylaspartic OR glutamic OR NAAGA OR mequitazine and allergic conjunctivitis

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Appendix 5. metaRegister of Controlled Trials search strategy

(Tablet OR Oral) AND Allergic Conjunctivitis

Appendix 6. Clinicaltrials.gov search strategy

(Tablet OR Oral) AND Allergic Conjunctivitis

Appendix 7. ICTRP search strategy

Allergic Conjunctivitis = Condition AND Tablet OR Oral = Intervention

Appendix 8. Data on study characteristics

Heading in table in Revman

Subheadings for CEVG reviews

Comment

Methods

Study design

Parallel group RCT i.e. people randomised to treatment

Paired eye or intra-individual RCT i.e. eyes randomised to treatment
Cluster RCT i.e. communities randomised to treatment
Cross-over RCT
Other, specify

Eyes

One eye included in study o Specify how eye selected Two eyes
included in study, both eyes received same treatment o Briefly
specify how analysed (best/worst/average/both and adjusted for
within person correlation/both and not adjusted for within person correlation) o Specify if mixture one eye and two eye Two
eyes included in study, eyes received different treatments (pair
matched) o Specify if correct pair-matched analysis done

Participants

Country
Setting
Number of participants
Number of men
Number of women
Average age
Age range
Ethnic group

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(Continued)

Inclusion criteria
Exclusion criteria
Interventions

Intervention
Comparator

Provide sufficient information to enable users of the review to assess the applicability of the intervention to their own setting, and
if possible in a way that allows the intervention to be replicated.
MECIR R65 If a study is included with more than two intervention arms, restrict comments on any irrelevant arms to a brief comment in the table of Characteristics of included studies. MECIR
R70

Outcomes

List

Provide clear and consistent information about outcomes measured

(or reported), how they were measured and the times at which they
were measured. MECIR R66

Notes

Date conducted

Specify dates of recruitment of participants mm/yr to mm/yr

Sources of funding
Declaration of interest

Include details of any declarations of interest among the primary

researchers. MECIR R69

CONTRIBUTIONS OF AUTHORS
Conceiving the review: Cochrane Eyes and Vision Group (CEVG) and Amlia Kamegasawa (AK).
Co-ordinating the review: Regina El Dib (RED).
Writing the protocol: AK and RED.
Responded to comments from peer reviewers and the editorial base: AK, RED and Mauricio M Chaoul (MMC).

DECLARATIONS OF INTEREST
AK, MMC and RED have no known conflict of interests.

SOURCES OF SUPPORT

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Internal sources
No sources of support supplied

External sources
National Institute for Health Resarch (NIHR), UK.
Richard Wormald (Co-ordinating Editor for CEVG) acknowledges financial support for his CEVG research sessions from the
Department of Health through the award made by the NIHR to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute
of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology. The views expressed in this publication are those
of the authors and not necessarily those of the NIHR, NHS or the Department of Health.

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