Shoja.qxd

MOHAMMAD

SHOJA*

MOHAMMAD

BEHSHARATY*

SUMMARY: The purpose of this study is to compare the efficacy of Ketotifen fumarate 0.025% (Zaditen)

with Cromolyn sodium 4% eye drops in prevention of itching, tearing and redness in vernal keratoconjunctivitis

(VKC).

This double masked randomized single center clinical trial conducted between April and August 2004 in

Yazd. One hundred eligible patients with clinical diagnosis of moderate VKC were randomly assigned to Zaditen

(Group A, n=50) and Cromolyn sodium (Group B, n=50) eye drops for a 4 week period. Itching, lacrimation,

redness and photophobia were scored on a 4-point severity scale.

At the follow up visits, the responder rate based on subjects assessment of global efficacy was significantly

greater in Ketotifen group (71.5%) than in Cromolyn group (53%). A clear response to treatment occurred in

94.4% of Zaditen patients and 81.2% of sodium Cromoglycate patients. The investigator's assessment of respon-

der rates also showed that Ketotifen was superior to Cromolyn sodium (p=0.001). Ketotifen produced a signif-

icantly better outcome than Cromolyn (p<0.05) for relief of signs and symptoms of VKC. Ketotifen fumarate

treatment significantly reduced the total signs and symptoms score for each patient compared to day 0.

Ketotifen had a faster onset of action and provided better symptom relief than Cromolyn: the rapid onset of

action and symptom control, make Zaditen a valuable treatment for VKC.

Key words : VKC, Allergic conjunctivitis, Zaditen.

Ophthalmology

INTRODUCTION

Vernal keratoconjunctivitis (VKC) is a bilateral ocular

allergic disease tending to occur in children during spring

and summer months (1). The disease occurs in warm

temperate zone and is more common in the Middle East,

Mediterranean area (2), and Iran.

VKC can certainly pose a threat to vision due to

corneal involvement (3).

The immunopathogenesis appears to involve both

types I and IV hypersensitivity (4, 5). The treatment of

VKC is quite prolonged and demands good compliance.

Presently moderate to severe cases were treated

with mast-cell stabilizers such as Cromolyn sodium and

topical corticosteroids (6).

However, the risks of prolonged use of corticos-

teroids are cataract and glaucoma, and should be

reserved for treatment of severe eye symptoms. In VKC

mast cell degranulation and release of histamine stimulate

* From Department of Ophthalmology, Shahid Sadughi School of

Medicine, Yazd, Iran.

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35Medical Journal of Islamic World Academy of Sciences 16:1, 35-40, 2006

Medical Journal of Islamic World Academy of Sciences 16:1, 35-40, 200636

COMPARISON OF ZADITEN WITH CROMOLYN SHOJA, BEHSHARATY

day 7 and 15. Responder rates were also assessed at the termi-

nation visit held at day 30.

Ocular status assessment

Different symptoms (itching, tearing, burning, redness) and

signs (watery, discharge increase, swelling, presence of follicles)

of VKC were evaluated at their enrollment (day zero) and at dif-

ferent times after starting treatment (7, 15 and 30 days). Symp-

toms and signs were classified in four stages: 0- Absent, 1- Mild,

2- Moderate and 3- Severe. The total symptoms and signs score

(TSSS) for each subject were obtained by adding the values of

each symptoms and signs divided by the total number of them.

Each patient was instructed to grade his or her symptoms of itch-

ing, photophia, watering, and mucoidal discharge on a scale from

0 to 3. The patients scored their symptoms for both eyes. Clinical

signs (conjunctival erythema, conjunctival chemosis, papillae,

limbal hypertrophy, presence of follicles) were also collected from

the right eye of each patient at the beginning, follow-up and at the

end of the study. Each patient was examined and clinically

scored by an ophthalmologist who did not know either clinical

status in the pre or post treatment period or the groups of patients

(A or B). Subjects were asked to assess the overall effect of treat-

ment using a five point grading scale (Table 1).

Tolerability and safety

Assessment of tolerability was based on adverse data

obtained by the subject volunteering the information and by the

physician. At the end of the treatment investigator provided a

global assessment of safety and tolerability using the same 5-

point scale as efficacy (Table 1).

Statistical analysis

The Kaplan-Meier technique was used to describe the onset

time distributions of the two treatments, with the planned observa-

tion time intervals. The onset time distributions were compared

between the two treatment groups using a long-rank test and a

general linear means model. The long-rank test was used to

check the primary efficacy variable. This test is most sensitive to

postpone the responder rate, signs and symptoms were analyzed

using logistic regression for binary and ordinary data respectively.

nerve endings and leading to dilation of the blood vessels

causing itching and redness (7). Mast cell stabilizing by

Cromolyn has an important role for treatment. More

recently interest has focused on the possibility of topical

application of histamine H1-antagonists.

Ketotifen a benzocycloheptathiophene derivate has

been used in the treatment of asthma (8). It blocks hista-

mine H1 receptors, stabilizes mast cells and prevents

eosinophil accumulation and degranulation (9, 10).

Ketotifen fumarate 0.025% ophthalmic solution

(Zaditen) has been developed recently for alleviating the

ocular signs and symptoms of VKC (11). Recent clinical

trials demonstrated that Zaditen 0.025% eye drop was

efficacious and safe, providing a rapid onset and long

duration of action (12-14).

The purpose of this study was to compare the effi-

cacy and safety of ketotifen fumarate 0.025% ophthalmic

solution (Zaditen) with Cromolyn sodium 4% in the treat-

ment of moderate VKC.

MATERIALS AND METHODS

Subjects

This study was performed between April and August 2004

in Yazd province. One hundred subjects (68 males and 32

females ) enrolled in this research.

Subjects eligible for inclusion were required to be between

age of 8 and 25 years and suffering from moderate VKC, and all

had papillae on the upper tarsal conjunctiva, conjunctival ery-

thema, limbal hypertrophy and typical mucoid discharge. Sub-

jects with history of dry eye, other form of allergic conjunctivitis,

allergy to antihistamines, the ocular surgery within 2 months

before study and who had systemic or ocular corticosteroids or

mast cell slabitisers within 4 weeks of randomization were

excluded. Patients’ written informed consent was required. The

trial was conducted in accordance with the declaration of Helsinki

prior to enrolment as study design.

Study design

This was single center double - masked randomized com-

parative clinical trial, and the patients were randomly divided into

two equal groups (A and B).

Group A patients (n=50) received topical Zaditen 0.025%

twice a day and placebo one time a day. Topical Cromolyn

sodium 4% was prescribed to Group B (n=50) three times a day.

Each group contained 34 males and 16 females.

Treatment was given to each group for 4 weeks, the pack-

aging of all trial medications was identical in appearance. The

study involved three visits, a screening visit and two treatment

visits. Primary analysis was at the follow up visit held between

Table 1: Subject and investigator assessment of global efficacy

relative to baseline.

Score

Change

from baseline

Description

0 Excellent Complete relief of ocular symptoms

1 Good Distinct relief of ocular symptoms

2 Fair Some relief from ocular symptoms

3 Poor No relief from ocular symptoms

4 Deterioration Worsening of ocular symptoms

Medical Journal of Islamic World Academy of Sciences 16:1, 35-40, 2006

COMPARISON OF ZADITEN WITH CROMOLYN SHOJA, BEHSHARATY

RESULTS

One hundred subjects were screened (68 males, 32

females). The homogeneity of treatment groups was

checked with regard to age, sex and baseline sum score.

No significant difference was noted. Study participants

were between the ages of 8 and 25 years (mean 16.3)

and had a duration of disease ranging from 1 to 15 years

(median duration 8.3 years).

Primary efficacy variable

The primary efficacy variables were a physicians

clinical judgement scale and patients overall judgement

scale of improvement from baseline.

The median time to onset of action was 15 minutes

for Zaditen versus 45 minutes for Cromolyn. Onset of

action was defined at first time interval in which at least a

20% decrease in composite ocular symptom score

occurred. At each post-dose time point, more subjects

receiving Zaditen had 20% or more reduction in symp-

toms than those receiving Cromolyn. Analyses of the time

to onset distribution (Figure 1) showed Zaditen to be sta-

tistically superior to Cromolyn (p=0.028).

Both primary efficacy variables showed significantly

greater overall improvement of VKC from baseline with

Zaditen than Cromolyn.

Responder rate

Responders were patients whose sum score of three

main eye symptoms decreased by at least 3 points from a

baseline score. After 7 days of treatment 59% of Zaditen

treated patients and 53% of Cromolyn treated patients

showed improvements of their symptoms and signs. With

continued treatment through day 14 symptoms control

was achieved in 81% of Group A and 63% of Group B and

this difference was significant (p<0.001).

At the final visit the responder rate as judged by the

subject was significantly greater with Zaditen compared to

Cromolyn (p=0.01).

Moreover administration of Zaditen eye drop for thirty

days significantly (p<0.0001) reduced the TSSS for each

patient between days 0 and 30.

A clear response to treatment (an improvement of

sum scores of ≥ 3 points compared to base line) occurred

in 94.4% of Zaditen treated patients and 81.2% of Cro-

molyn patients. Based on subject daily records the supe-

riority of Zaditen in relieving signs and symptoms

including redness and tearing was observed from the

beginning of the treatment and was most marked during

Figure 1: Onset of action by treatment groups.

Ketotifen (n=50) Cromolyn (n=50)

45 60 90

Time after drug administration (min)

100

Table 2: Mean ocular sign and symptoms at day 5-8 visit.

Mean Score P value

Signs and symptoms Zaditen (n=50) Cromolyn (n=50) Zaditen V Cromolyn

Redness 0.68 0.90 0.03

Itching 1.25 1.44 0.27

Tearing 0.53 0.88 0.01

Lid swelling 0.40 0.43 0.85

Discharge 0.12 0.24 0.82

Composite score 2.98 3.89 0.02

Subjects with

20% symptom reduction (%)

Medical Journal of Islamic World Academy of Sciences 16:1, 35-40, 200638

COMPARISON OF ZADITEN WITH CROMOLYN SHOJA, BEHSHARATY

the first day. Zaditen was superior to Cromolyn in prevent-

ing itching (p<0.001) and redness (p<0.005) at most

assessments. Mean scores for eyelid swelling and mucous

discharge were generally low for Zaditen Group (Table 2).

At the termination visit the analysis showed signifi-

cantly better relief of signs and symptoms with Zaditen

than Cromolyn (p=0.0), with mean composite sign and

symptom score of 2.98 and 3.89, respectively (Table 2).

Analysis of the mean composite ocular symptoms scores

versus time showed Zaditen to have a faster onset of

action in the relief of ocular symptoms (2 hours post-dose)

than Cromolyn sodium (Figure 2). At the end of treatment

global assessment of efficacy by the investigator was con-

sidered at least 91.4% for Zaditen and 78% for Cromolyn

sodium.

Safety

Both treatments were generally well tolerated and

majority of adverse events were of mild transient irritation

and burning. However, the droupout rate due to adverse

events was lower in the Zaditen Group (n=2.4%) com-

pared to Cromolyn (n = 4.8%).

Investigator global assessment of tolerability gave an

opinion of at least satisfactory in 95.6% of Zaditen -and

86.3% of Cromolyn sodium, treated patients.

DISCUSSION

VKC is a common, prevalent and clinically significant

IgE mediated hypersensivity response. VKC is an

immunopathological disease in which the number of mast

cells in substantia propria increase (15-16). Activation of

mast cells by IgE bound receptor crosslinking by allergen

promotes the release of several mediators such as hista-

mine, prostaglandins and cytokinase, all of which con-

tribute to the symptoms of VKC (17,18). The mast cell is

considered to play a pivotal role in producing symptoms

and signs of VKC (19). Current therapy of VKC focuses on

modulation of the immune system and pharmacologic

inhibition of the chemical mediators involved in the

immune response. Mast cell stabilizers and antihista-

mines are two of the most commonly used groups of ther-

apeutic agents. They stabilize the mast cell membranes

by preventing calcium influx across the mast cell mem-

branes, thereby preventing mast cell degranulation and

mediator release. The new antihistamines have been

demonstrated to be capable of affecting several phen-

emonea of the allergic inflammation including mediator

release (20,21).

Among these drugs, new multiple - action agents like

Ketotifen fumarate (Zaditen) is histamine H1- receptor

antagonist, as well as mast cell stabilizer.

In addition,

in vitro

and animal studies (22) have

shown that Zaditen inhibits the activation and chemotaxis

of eosinophils into the conjunctiva, (23) which is an impor-

tant step in the late phase of the immune response.

Cromolyn sodium as a mast cell stabilizer is effective

and safe in the treatment of VKC, but topical steroids are

often required which increase the chance of bacterial ker-

atitis, cataract and glaucoma, so we decided to perform a

randomized double blind study in order to investigate and

compare the effect of the topical Ketotifen with Cromolyn

sodium in modarate VKC.

Figure 2: Change in mean composite ocular symptom scores over time.

123456789End

Time (h)

Ketotifen Cromolyn

Ocular symptoms

(mean sum of scores)

Medical Journal of Islamic World Academy of Sciences 16:1, 35-40, 2006

COMPARISON OF ZADITEN WITH CROMOLYN SHOJA, BEHSHARATY

In the present study main VKC symptoms decreased

significantly by day 3 with sustained improvement on days

7 and 14.

The results of this study showed that Zaditen 0.025%

applied topically twice a day was superior to Cromolyn

QID (p=0.001). Zaditen produced a significantly better

outcome than Cromolyn (p < 0.05) for relief of signs and

symptoms of VKC. Leonardi’s study (24) showed investi-

gators assessment of responder rates for Zaditen was

superior to Cromolyn that is similar to our study. A recent

study by Andrea (25) reported a clear response of 91.2%

for Zaditen and 83.5% for Cromolyn treatment groups that

was similar to our study.

In the current study as Friedrich Horak’s (12) report

Zaditen was found to have a faster onset of action than

Cromolyn. In term of efficacy, Zaditen was numerically

superior to Cromolyn for the majority of the individual

symptoms score (26).

We can conclude that at 15 minute and 4-hour

Zaditen was superior to Cromolyn in preventing itching and

redness which was the same as Greiner’s results (27).

In this study the responder after 7 days of treatment

was 59% for Zaditen and 53% for Cromolyn treated

patients, however, in Kidd's report (28) these were 56.5%

and 49.3% respectively. In this study at the follow up visit

the responder rate based on subject’s assessment global

efficacy was significantly greater in Zaditen group (71.5%)

than in Cromolyn group (51%). That was not comparible

with Kidd's study with responder rate of 49.5% and 33%

respectively.

CONCLUSION

Zaditen 2 times a day was significantly more effec-

tive than sodium Cromolyn four times a day in alleviating

symptoms and signs of moderate VKC. The faster onset

action (within 15 minutes) and better symptoms relief

observed with Ketotifen during the initial 2 hours, along

with favourable safety and tolerability profile make Zaditen

a new valuable treatment option for patients with moder-

ate VKC.

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Correspondence:

Mohammad Reza Shoja

Shahed Beheshty Post. Po Box 583,

Yazd, IRAN.

e-mail: [email protected]