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Clinical safety and acceptability of a catalase tablet for hydrogen peroxide neutralization
Clinical Articles
Clinical Safety and Acceptability of a Catalase Tablet for Hydrogen Peroxide Neutralization Richard C. Courtney,
OD, Nicholas Tarantino,
In a 6-month, open-label, pan&l comparison study, the safety, efficacy, and patient acceptability of a new caraI.asecontaining tablet fur hydrogen peroxide neutralization was evaluated. Subjects wearing knses on a DW or EW basis used regimens including oxidutive disinfection, cat&se neutralization, and enrymutic cleaning. Subjects wearing lenses on a DW basis were assigned to either a IO-minute neutralization group (Group I, n = 56) or an overnight neutralization group (Group 2, n = 52). Similarly, subjects wearing lenses on an EW basis were assigned to either a IO-minute neutralization group (Group 3, n = 58) or an overnight neutralization group (Group 4, n = 63). There were few clinically significant slitlamp findings in the four groups, and the only regimen-related slit-lamp findings were confined to one subject. There were no clinically significant, regimen-related decreases in visual acuity in the four groups. The results of this study demonstrate that the cat&se-neurraliting tablet, when dissolved in hydrogen peroxide disinfecting solution and used in conjunction with enzymatic cleaning, is safe and acceptable for use with daily- and extendedwear hydrogel contact lenses. Results a/so indicate that the use of cat&se-containing tablets fur hydrogen peroxide neutralization offers increased patient convenience. Keywords:
Hydrogel contact
lenses; hydrogen peroxide
Introduction Hydrogen peroxide disinfection has been proved to be a safe and effective means of disinfecting hydrogel lenses, l-3
OD, and Patricia Brown, MS
with the added advantage that it can easily accommodate simultaneous enzymatic cleaning.4’5 Inherent in hydrogen peroxide disinfection, however, is the need for neutralization. ‘J Effective neutralization removes the risk of ocular irritation due to residual hydrogen peroxide.7 Catalase, a naturally occurring enzyme, has been shown to be a highly effective means of neutralizing hydrogen peroxide used for contact lens disinfection.8 Since catalase, a biocatalyst, is highly specific for hydrogen peroxide, small concentrations of catalase are able to efficiently perform neutralization. Overall, catalase neutralization is rapid, thorough, and safe. A newly developed catalase tablet, which is added directly to the hydrogen peroxide solution, provides a simplified means of neutralizing the disinfectant. With this new system, the catalase tablet is dropped into the disinfection solution at the end of the hydrogen peroxide disinfection cycle, rendering the solution harmless to ocular tissue. Neutralization is complete within 10 minutes.9 By simplifying the neutralization process, the catalase tablet should contribute to better patient compliance. This study, involving subjects wearing both daily-wear (DW) and extended-wear (EW) lenses, was conducted to evaluate the safety and patient acceptability of this form of catalase neutralization of hydrogen peroxide.
Materials and Methods Subjects
Address reprint requests to Dr. Richard C. Courtney at Allergan Optical, 2525 DuPont Drive, Irvine, CA 927151599. Accepted
for publication
0 1990 Butterworth
December
Publishers
1989.
After giving informed consent, healthy subjects with eyes free of pathology were enrolled into this multicenter study. Each subject had been adapted to a schedule of dailyor extended-wear for at least 1 month.
ICLC, Vol. 17, MarlApr
1990
67
Clinical Articles pending on the assigned treatment group. Rub and rinse with sterile saline solution and apply lenses directly to eyes.
Lens Cure Regimen Subjects wearing lenses on a DW basis were dispensed new lenses and randomly assigned to one of two DW groups: a lo-minute neutralization group (Group 1) and an overnight neutralization group (Group 2). Subjects wearing lenses on an EW basis were dispensed new lenses and assigned to one of two EW groups: a lo-minute neutralization group (Group 3) and an overnight neutralization group
Once a week, the subjects in the two EW groups removed their lenses and treated them as follows: Rinse lenses with sterile saline solution. Clean lenses with surfactant cleaner, rinsing thoroughly with sterile saline solution. Deliver one enzymatic cleaning tablet into the lens cup containing the hydrogen peroxide disinfecting solution. Soak lenses in the hydrogen peroxide/enzymatic cleaning solution for either 15 minutes or overnight, depending on the assigned treatment group. Deliver one catalase-neutralizing tablet into the disinfecting/enzymatic cleaning solution. Soak lenses in the neutralizing solution either overnight or 10 minutes, depending on the assigned treatment group. Rub and rinse with sterile saline solution and apply lenses directly to eyes.
(Group 4). Each night, subjects wearing lenses on a DW basis removed their lenses and cleaned them as follows: ??Rinse
lenses with sterile saline solution. * lenses with surfactant cleaner,? rinsing thoroughly with sterile saline solution. ??Soak lenses in hydrogen peroxide disinfecting solution$ either 10 minutes or overnight, depending on the assigned treatment group. ??Deliver one catalase-neutralizing tablets into the lens cup containing the hydrogen peroxide disinfecting solution and allow lenses to soak either overnight or 10 minutes, depending on the assigned treatment group. ??Rinse lenses with the sterile saline solution and then apply lenses directly to eyes. ??Once a week, deliver one enzymatic cleaning tabled’ into the lens cup containing the hydrogen peroxide disinfecting solution, soaking lenses for either 15 minutes or overnight, depending on the assigned treatment group. Deliver one catalase-neutralizing tablet into the disinfecting/enzymatic cleaning solution. Soak lenses in the neutralizing solution either overnight or 10 minutes, de, ??Clean
The lens care regimens are summarized
in Table 1.
examination Methods
Each subject was examined at eight office visits: baseline, 1 day and 1 week after starting the regimen, and 30,60, 90, 135, and 180 days after starting the regimen. Slit-lamp examination findings and visual acuity were recorded at each visit. At each follow-up visit, subjects reported any symptoms of eye discomfort, and at the final visit subjects evaluated their overall eye comfort during the study and the acceptability of the study regimen. During the slit-lamp examination, observations of corneal staining, edema, and injection were graded based on severity (grades l-4). Tarsal conjunctival findings were also graded on a similar scale. These parameters were considered clinically significant if they were both greater than 1 + (minimal) and more severe than reported at baseline. Any increase from baseline in cornea1 vascularization or iritis was considered clinically significant regardless of severity. The following were also considered to be clinically
* LENS PLUS@ Sterile Saline Solution, Allergan, Inc., Irvine, CA. t LENS PLUS@ Daily Cleaner, Allergan, Inc. $ LENS PLUS’s’ Oxysept” 1 Disinfecting Solution, Allergan, Inc. 0 LENS PLUS@ Oxysept@ 2 Neutralizing tablets, Allergan, Inc. ‘IUltrazymeTH Enzymatic Cleaner, Allergan, Inc.
Table 1. Lens Care Regimens’
Wz Surfactant Group 1 lo-minute Group 2 Overnight Group 3 lo-minute Group 4 Overnight
Disinfection
H,O, Disinfection + Enzymatic Cleaning
Catalase Neutralization
DW (n = 56)
Overnight
Overnight
10 minutes
DW (n = 52)
10 minutes
15 minutes
Overnight
EW (n = 58)
Overnight
Overnight
10 minutes
EW (n = 63)
10 minutes
15 minutes
Overnight
EW groups used the specified regimen once a week, and DW groups used the specified regimens daily except enzymatic cleaning, was done once a week. ??
68
ICLC, Vol. 17, Mar/Apr 1990
which
Cat&se
tab/et for hydrogen peroxide neutralization:
Courtney et al.
be related to some component of the study regimen. Because we were unable to rechallenge this subject, the actual cause can only be presumed.
significant: 1) moderate and severe symptoms of eye discomfort; 2) visual acuity decreases of two lines or more on the Snellen chart; and 3) decreases from baseline of 4 or more hours of wearing time with DW and decreases of 2 or more days with EW. Data are reported separately for DW and EW subjects because the two modes require different lens care regimens and because lenses are on the eye for a much longer time in EW. Analysis of data pooled from both wear modes was therefore considered inappropriate.
Slit-Lamp Findings Clinically significant slit-lamp findings from all causes were reported as follows: five reports among five subjects in Group 1, five reports among three subjects in Group 2, 14 reports among 10 subjects in Group 3, and 24 reports among 11 subjects in Group 4 (Table 4). There were no clinically significant, regimen-related findings in Groups 1, 3, or 4. In Group 2, one subject, in a single visit, accounted for all three of the clinically significant, regimen-related slit-lamp findings. All of the clinically significant findings noted resolved by the end of the study without altering the regimen.
Results Study Population
Demographic data of the 229 subjects are given in Table 2. All available data from 108 DW and 121 EW subjects were evaluated. Sixteen subjects did not complete the study for the reasons listed in Table 3. Two DW and two EW subjects were disqualified from the data analysis because of deviations from the subject entry criteria (see Table 3). Two DW subjects were discontinued, one for reasons unrelated to the regimen and one for allergic symptoms, the cause of which was uncertain. Ten EW subjects were discontinued, of which only one was for a reason believed to
Visual Acuity There were no clinically significant, regimen-related decreases in visual acuity. Clinically significant decreases in visual acuity from all causes were reported as follows: five reports among four subjects in Group 1, 10 reports among five subjects in Group 3, and seven reports among four
Table 2. Study Population DW Group 1 (lo-Minute Neutralization) Subjects Age (vr) Mean f SD Range Sex Female Male Lens Materials Low water, nonionic (FDA Group 1) Crofilcon A (39% H,O) Ocufilcon A (46% H,O) Tefilcon (38% H,O) Tetrafilcon (43% H,O) Polymacon (38% H,O) High water, nonionic (FDA Group 2) Lidofilcon A (70% H,O) Ofilcon A (74% H,O) Surfilcon A (74% H,O) Vifilcon A (55% H,O) Low water, ionic (FDA Group 3) Bufilcon A (45% H,O) Etafilcon (43% H,O) High water, ionic (FDA Group 4) Bufilcon A (55% H,O) Etafilcon A (58% H,O) Methafilcon A (55% H,O) Perfilcon A (71% H,O) Phemfilcon A (55% H,O)
EW Group 2 (Overnight Neutralization)
Group 3 (lo-Minute Neutralization)
Group 4 (Overnight Neutralization)
56
52
58
63
32.7 2 8.0 14-54
29.2 k 8.1 IQ-52
33.4 k 7.4 18-51
33.1 + 8.1 5-56
45 (80%) 11 (20%)
39 (75%) 13 (25%)
39 (67%) 19 (33%)
41 (65%) 22 (35%)
15 0 9 3 10
18 2 13 0 8 0 0 0 0
0 2 11 5
11 2
11 0
1 0
3 0 2 0 1
0 0 0 0 0
/UC,
14 0
12 1
: 12
: 12
Vol. 17, Mar/Apr 1990
69
Clinical Articks Table 3. Subjects Failing to Complete
the Study DW
EW
Group 1 (IO-Minute Neutralization) Reason Non-regimen-related Disqualified ’ Lens related Missed visits Moved Unable to complete scheduled Personal reasons Regimen-related Allergy symptoms Discomfort/itching
Group 2 (Overnight Neutralization)
Group 3 (lo-Minute Neutralization
Group 4 (Overnight Neutralization)
0 0 0 0
2 0 0 1
2 0 3 0
0
0 0
0 0
0 0
1 1
1 0
0 0
0 0
0 1
1
3
5
7
: 0
as
Total
Two DW subjects from the overnight neutralization group were disqualified for wearing the improper lens type for the regimens assigned (FDA Group 4 hydrogen lenses were assigned to the lo-minute neutralization group). One EW subject decided at Visit 1, prior to any exposure to the study products, not to participate in the study. A second EW subject was disqualified at the baseline visit due to wearing lenses on a DW basis. ??
Table 4. No. Clinically
Significant
Slit-Lamp Findings (Regimen-Related
Causes/All
Causes)
DW Group 1 (IO-Minute Neutralization)
Finding *
EW Group 2 (Overnight Neutralization)
Group 3 (lo-Minute Neutralization)
Group 4 (Overnight Neutralization)
Cornea1 staining Injection Tarsal papillae Tarsal follicles Cornea1 edema “Other” findingst
o/3 o/2 o/o o/o o/o o/o
l/2 l/l o/o o/o l/l O/l
O/5 015 o/2 o/2 o/o o/o
017 017 O/l o/2 o/4 o/3
Total findings
o/5
315
0114
O/24
No. subjects
o/5
l/3
0110
o/11
The numbers shown represent regimen-related causes/all causes. More than one finding was reported for some subjects in each treatment group. t Other findings include acute hordeolum, chemosis, exudate, and limbakcleral impression. ??
subjects
in Group
related. visual
There acuity
4. Most
of these
were no clinically in Group
2. Visual
reports
significant acuity
were
lens-
decreases
in
for all subjects
re-
turned to baseline, or within one line of baseline, lenses or at a subsequent, follow-up visit.
with new
Comfurt There
were no clinically
significant,
regimen-related
re-
ports of eye discomfort in Groups 1 and 3. The four reports of clinically significant, regimen-related eye discomfort by two subjects in Group 2 were as follows: Both subjects experienced burning and stinging, and, in addition, one subject reported redness and excessive tearing. The two reports of clinically significant, regimen-related eye dis70
ICLC, Vol. 17, Mar/Apr 1990
comfort
by one subject
blurred
vision
symptoms
and
in Group
cloudy
of eye discomfort
4 were as follows:
lenses.
Clinically
bilateral
significant
from all causes were reported
as
follows: 22 reports among nine subjects in Group 1, 11 reports among six subjects in Group 2, 19 reports among six subjects in Group 3, and 47 reports among 18 subjects in
Group 4. Data concerning the subjects with clinically sig nificant (i.e., moderate and severe) symptoms of ocular discomfort are presented in Table 5. All clinically significant signs of irritation resolved at a subsequent follow-up visit. Subjects’ Evaluation of Regimen Acceptability At the end of the study, subjects were given a questionnaire in order to evaluate overall eye comfort and regimen
Catalase tablet for hydrogen peroxide neurralization: Table 5. No. Clinically
Significant
Reports of Eye Discomfort
(Regimen-Related
Causes/All
Courtney et al.
Causes)
DW
EW
Symptoms
Group 1 (lo-Minute Neutralization)
Group 2 (Overnight Neutralization)
Burning/stinging Increased lens awareness Dry eye feeling Itching Photophobia/sensitivity to light Excessive tearing Blurring of vision Redness General irritation Other?
o/4 O/3 o/2 o/2 O/l 012 013 O/3 O/l 011
213 o/o O/l o/o O/l 113 o/o l/2 O/O O/l
Total reports
0122
No. subjects
o/9
Group 3 (IO-Minute Neutralization)
Group 4 (Overnight Neutralization)
o/3 O/6 o/o o/3 O/O o/o o/3 o/3 o/o O/l
O/3 o/13 014 O/5 014 o/2 115 017 O/l l/3
4/11
o/19
2147
216
O/6
l/18
* The numbers shown represent regimen-related causes/all causes. More than one symptom was reported by some subjects in each treatment group. t Other symptoms include cloudy lenses, headaches, sty, mucus, and swollen eye. Symptoms include all occurrences reported by subjects, but not necessarily verified by investigators.
Group (DW
I
IO-Minute
Neutralization) (1~56)
Group
2
(DW Overnlqhl Neutrollzotlon) (ll~51)
Group
3
(EW IO-Minute Neutrolizotlon) (n=55)
Group4 (EW Overnight Neutrollzation) lnz5t3)
Figure 1. Subjects reporting good or excellent overall eye comfort during lens wear.
acceptability. The majority of the subjects in the four treatment groups reported good or excellent overall eye comfort during lens wear (Figure 1). One hundred percent of the subjects in both DW groups reported that their overall eye comfort throughout the study had been good or excellent. Ninety-eight percent and 88% of the subjects in the EW lo-minute and overnight groups, respectively, reported that their eye comfort throughout the study had been good or excellent. In addition, the majority of subjects in all four treatment groups reported that the study regimen was an equally or more acceptable method of contact lens care compared with their previous regimen (Figure 2). Eightyeight percent and 96%, respectively, of the subjects in Groups 1 and 2 reported that the study regimen provided an equally or more acceptable method of contact lens care. Eighty-nine percent and 88%, respectively, of the subjects in Groups 3 and 4 reported that the study regimen provided an equally or more acceptable method of contact lens care.
Group
I
IDW IO-Minute Neutrallzotion) (nz56)
Group
More
m
Equally
Group
2
(DW OvernIght Neutralization)
IZZd
3
(EW IO-Minute Neutratizatlon) (nz55)
(n=51)
acceptable acceptable
Group4 (EW Overnight Neutralization) in:581
Figure 2. Subjects reporting that study regimen provided an equally or more acceptable method of contact lens care compared to their previous regimen. Previous regimens included oxidative (53.6%), chemical (25%), and thermal (21.4%) disinfection
Discussion Overall, the results of this study demonstrated the safety and efficacy of this regimen among the 108 subjects wearing lenses on a daily-wear basis and the 121 subjects wearing lenses on an extended-wear
basis.
The very low incidence of signs and symptoms of irritation observed among the subjects in both DW groups during the course of the study was indicative of the safety of this regimen. For 99% of the eye examinations in Groups 1 and 2, there were either no positive slit-lamp findings or the findings were not clinically significant. One subject accounted for all three of the clinically significant, regimen-related slit-lamp findings, and all the clinically significant signs and symptoms of irritation resolved at a subsequent follow-up visit without alteration of the regimen. Signs and symptoms of irritation observed among the ICLC, Vol. 17, Mar/Apr 1990
71
Clinical Articks EW subjects during the course of the study were also indicative of the safety of this regimen. There were no clinically significant slit-lamp findings or reports of symptoms of discomfort that were judged by the investigators to be probably regimen-related. For 98% of the eye examinations in Groups 3 and 4, there were either no positive slit-lamp findings or the findings were not clinically significant. All clinically significant signs and symptoms of irritation resolved at a subsequent follow-up visit. The low incidence of signs and symptoms in this study is also indicative of the efficacy of the catalase tablet in the study regimen. Catalase is a very effective agent for neutralizing hydrogen peroxide and, as such, contributed to regimen safety in terms of a low incidence of symptoms of discomfort and other complaints. Visual acuity was well maintained during the study, which also indicated safety and acceptability of the regimen. None of the clinically significant decreases in visual acuity was attributed to the study regimen in any of the treatment groups, and visual acuity for all subjects returned to baseline, or within one line of baseline, with new lenses or at a subsequent follow-up visit. The total number of reports of clinically significant eye discomfort from all causes was also low. There were 66 such reports in the two EW groups, compared with 33 for the DW groups. Increased lens awareness accounted for the greatest disparity, being considerably higher in the EW groups. These differences may be due to the modality of extended wear, which can lead to a decrease in the amount of oxygen available to the cornea and a reduced tolerance to contact lens wear.” Also, since subjects in the EW groups were wearing a higher proportion of highwater-content lenses, and were using surfactant cleaners only once a week, they may have been more vulnerable to irritation due to intraweekly deposit buildup. Previous studies have reported similar findings.4p5 When introduced at the end of the disinfection cycle, the catalase tablet effectively neutralizes the hydrogen peroxide solution. By removing the need for a second, neutralization-specific solution, the catalase tablet simplifies the disinfection/neutralization component of the lens care regimen. The use of catalase-containing tablets for hydrogen peroxide neutralization offers increased patient conve-
Clinical
nience and should lead to better compliance with regimens and, consequently, a lower risk of contact lens-related complications. Conclusions The results of this study indicate that the catalasecontaining hydrogen peroxide-neutralizing tablet dissolved in LENS PLUS@ Oxysept@ 1 Disinfecting Solution, with weekly inclusion of UltrazymeTN Enzymatic Cleaner, is safe and acceptable for use with both daily-wear and extendedwear hydrogel contact lenses when used in neutralization procedures as short as 10 minutes to as long as overnight. Acknowledgments The authors gratefully acknowledge the clinical participation of Gayle N. Amemiya, OD, Ronald M. Cedrone, OD, Robert L. Davis, OD, Richard D. Ebling, OD, Victor M. Finnemore, OD, Steven S. Grant, OD, Edward J. Kienast, OD, William C. Lee, OD, S. Victor Stella, OD, and Jack J. Yager, OD; the technical assistance of Debra Kono; and the editorial assistance of Stephen Rutledge. References 1. Gasset AR, Ramer RM, Katzin D: Hydrogen peroxide sterilization of hydrophilic contact lenses. Arch Opthulmol 1975;93:412-415. 2. Janoff LE: The effective disinfection of soft contact lenses using hydrogen peroxide. Contact0 1979;23:37-40. 3. Penley CA, Llabr& C, Wilson LA, Aheam DG: Efficacy of hydrogen peroxide disinfection systems for soft contact lenses contaminated with fungi. CLAO J 1985;11:65-68. 4. Tarantino N, Courtney RC, Lasswell LA, Kono D, Frank J: Simultaneous enzymatic cleaning and hydrogen peroxide disinfection of hydrogel lenses. ICLC 1988;15:25-32. 5. Courmey RC, Tarantino N, Stubblefield D: Clinical evaluation of Ultrazyme Enzymatic Cleaner used with AOSept. ICLC 1989;16:40-47. 6. Knopf HLS: Reaction to hydrogen peroxide in contact-lens wear. Am J OphMmol 1984;97:796. 7. Paugh JR, Brennan NA, Efron N: Ocular response to hydrogen peroxide. Am J Optom Physiol Opt 1988;65:91-98. a. Gyulai P, Dziabo A, Kelly W, Kiral R: Efficacy of catalase as a neutralizer of a hydrogen peroxide disinfecting solution for soft contact lenses. ICLC 1986;2:41&422. 9. Data on file, Allergan, Inc., 1988. 10. Holden BA: Cornea1 requirements for extended wear: an update. CLAO J 1988;14:22C-222.
Implications
This paper describes a clinical investigation designed to gauge the efficacy and safety of a new method of neutralization for use with hydrogen peroxide disinfection. The biocatalyst “catalase,” with which we are familiar as a neutralizing solution, is presented here in tablet form. The tablet is added directly to the peroxide solution following a IO-minute or overnight disinfection period. By avoiding the need for a second, neutralization-specific solution, the tablet offers increased convenience-patient compliance with the lens care regimen is expected to improve accordingly. Despite these gains, this is still a two-step system and as such may not be as popular with some lens wearers as one-step peroxide or overnight soaking solutions. We still await a tablet that can be added at the start of the disinfection procedure and that has a slowly dissolving outer layer that prevents the initiation of neutralization 72
ICLC, Vol. 17, Mar/Apr
1990
Cat&se
tablet fur hydrogen peroxide neutralization:
Courtney et al.
until an adequate period of disinfection has elapsed. Nonetheless, this disinfection system offers both the antimicrobial efficacy of 3% hydrogen peroxide (hence, the option of long and short disinfection periods) together with a very simple means of achieving neutralization. Russell Lowe, OD Cornea1 Biophysics Laboratory Department of Optometry University of Melbourne Parkville, Victoria 3052, Australia
Richard C. Courtney graduated from Northwestern University in 1969 with a BA degree in biological sciences. He subsequently served for 3 years as a commissioned officer in the United States Navy. He received his OD degree from the Southern California College of Optometry in 1977, where he was valedictorian of his class. Courtney was a clinical instructor in the Special Testing-Disease Detection Department there for 2 years. In 1979 he joined Contact Lens Clinical Research at Allergan Optical, where he now serves as senior director. Courtney’s current research interests include methodologies for evaluating the safety and efficacy of contact lens care products. Nicholas Tarantino graduated with honors in 1980 from the Southern California College of Optometry. In private practice he conducted clinical research for several industry leaders before joining Clinical Research at Allergan Optical in 1983, where he now serves as director of contact lens clinical research. Tarantino is a member of the American Optometric Association, the California Optometric Association, the American Academy of Optometry, and the International Society of Dakryology.
Patricia Brown graduated from Ohio State University in 1981 with an MS degree in nursing. After working in various nursing positions, she joined Allergan Optical’s Product Information Services group in 1983. Since 1988, she has served as coordinator of contact lens clinical research. Brown is a member of the Drug Information Association and the American Society of Ophthalmic Registered Nurses.
ICLC, Vol. 17, Mar/Apr 1990
73
Clinical Safety and Acceptability of a Catalase Tablet for Hydrogen Peroxide Neutralization Richard C. Courtney,
OD, Nicholas Tarantino,
In a 6-month, open-label, pan&l comparison study, the safety, efficacy, and patient acceptability of a new caraI.asecontaining tablet fur hydrogen peroxide neutralization was evaluated. Subjects wearing knses on a DW or EW basis used regimens including oxidutive disinfection, cat&se neutralization, and enrymutic cleaning. Subjects wearing lenses on a DW basis were assigned to either a IO-minute neutralization group (Group I, n = 56) or an overnight neutralization group (Group 2, n = 52). Similarly, subjects wearing lenses on an EW basis were assigned to either a IO-minute neutralization group (Group 3, n = 58) or an overnight neutralization group (Group 4, n = 63). There were few clinically significant slitlamp findings in the four groups, and the only regimen-related slit-lamp findings were confined to one subject. There were no clinically significant, regimen-related decreases in visual acuity in the four groups. The results of this study demonstrate that the cat&se-neurraliting tablet, when dissolved in hydrogen peroxide disinfecting solution and used in conjunction with enzymatic cleaning, is safe and acceptable for use with daily- and extendedwear hydrogel contact lenses. Results a/so indicate that the use of cat&se-containing tablets fur hydrogen peroxide neutralization offers increased patient convenience. Keywords:
Hydrogel contact
lenses; hydrogen peroxide
Introduction Hydrogen peroxide disinfection has been proved to be a safe and effective means of disinfecting hydrogel lenses, l-3
OD, and Patricia Brown, MS
with the added advantage that it can easily accommodate simultaneous enzymatic cleaning.4’5 Inherent in hydrogen peroxide disinfection, however, is the need for neutralization. ‘J Effective neutralization removes the risk of ocular irritation due to residual hydrogen peroxide.7 Catalase, a naturally occurring enzyme, has been shown to be a highly effective means of neutralizing hydrogen peroxide used for contact lens disinfection.8 Since catalase, a biocatalyst, is highly specific for hydrogen peroxide, small concentrations of catalase are able to efficiently perform neutralization. Overall, catalase neutralization is rapid, thorough, and safe. A newly developed catalase tablet, which is added directly to the hydrogen peroxide solution, provides a simplified means of neutralizing the disinfectant. With this new system, the catalase tablet is dropped into the disinfection solution at the end of the hydrogen peroxide disinfection cycle, rendering the solution harmless to ocular tissue. Neutralization is complete within 10 minutes.9 By simplifying the neutralization process, the catalase tablet should contribute to better patient compliance. This study, involving subjects wearing both daily-wear (DW) and extended-wear (EW) lenses, was conducted to evaluate the safety and patient acceptability of this form of catalase neutralization of hydrogen peroxide.
Materials and Methods Subjects
Address reprint requests to Dr. Richard C. Courtney at Allergan Optical, 2525 DuPont Drive, Irvine, CA 927151599. Accepted
for publication
0 1990 Butterworth
December
Publishers
1989.
After giving informed consent, healthy subjects with eyes free of pathology were enrolled into this multicenter study. Each subject had been adapted to a schedule of dailyor extended-wear for at least 1 month.
ICLC, Vol. 17, MarlApr
1990
67
Clinical Articles pending on the assigned treatment group. Rub and rinse with sterile saline solution and apply lenses directly to eyes.
Lens Cure Regimen Subjects wearing lenses on a DW basis were dispensed new lenses and randomly assigned to one of two DW groups: a lo-minute neutralization group (Group 1) and an overnight neutralization group (Group 2). Subjects wearing lenses on an EW basis were dispensed new lenses and assigned to one of two EW groups: a lo-minute neutralization group (Group 3) and an overnight neutralization group
Once a week, the subjects in the two EW groups removed their lenses and treated them as follows: Rinse lenses with sterile saline solution. Clean lenses with surfactant cleaner, rinsing thoroughly with sterile saline solution. Deliver one enzymatic cleaning tablet into the lens cup containing the hydrogen peroxide disinfecting solution. Soak lenses in the hydrogen peroxide/enzymatic cleaning solution for either 15 minutes or overnight, depending on the assigned treatment group. Deliver one catalase-neutralizing tablet into the disinfecting/enzymatic cleaning solution. Soak lenses in the neutralizing solution either overnight or 10 minutes, depending on the assigned treatment group. Rub and rinse with sterile saline solution and apply lenses directly to eyes.
(Group 4). Each night, subjects wearing lenses on a DW basis removed their lenses and cleaned them as follows: ??Rinse
lenses with sterile saline solution. * lenses with surfactant cleaner,? rinsing thoroughly with sterile saline solution. ??Soak lenses in hydrogen peroxide disinfecting solution$ either 10 minutes or overnight, depending on the assigned treatment group. ??Deliver one catalase-neutralizing tablets into the lens cup containing the hydrogen peroxide disinfecting solution and allow lenses to soak either overnight or 10 minutes, depending on the assigned treatment group. ??Rinse lenses with the sterile saline solution and then apply lenses directly to eyes. ??Once a week, deliver one enzymatic cleaning tabled’ into the lens cup containing the hydrogen peroxide disinfecting solution, soaking lenses for either 15 minutes or overnight, depending on the assigned treatment group. Deliver one catalase-neutralizing tablet into the disinfecting/enzymatic cleaning solution. Soak lenses in the neutralizing solution either overnight or 10 minutes, de, ??Clean
The lens care regimens are summarized
in Table 1.
examination Methods
Each subject was examined at eight office visits: baseline, 1 day and 1 week after starting the regimen, and 30,60, 90, 135, and 180 days after starting the regimen. Slit-lamp examination findings and visual acuity were recorded at each visit. At each follow-up visit, subjects reported any symptoms of eye discomfort, and at the final visit subjects evaluated their overall eye comfort during the study and the acceptability of the study regimen. During the slit-lamp examination, observations of corneal staining, edema, and injection were graded based on severity (grades l-4). Tarsal conjunctival findings were also graded on a similar scale. These parameters were considered clinically significant if they were both greater than 1 + (minimal) and more severe than reported at baseline. Any increase from baseline in cornea1 vascularization or iritis was considered clinically significant regardless of severity. The following were also considered to be clinically
* LENS PLUS@ Sterile Saline Solution, Allergan, Inc., Irvine, CA. t LENS PLUS@ Daily Cleaner, Allergan, Inc. $ LENS PLUS’s’ Oxysept” 1 Disinfecting Solution, Allergan, Inc. 0 LENS PLUS@ Oxysept@ 2 Neutralizing tablets, Allergan, Inc. ‘IUltrazymeTH Enzymatic Cleaner, Allergan, Inc.
Table 1. Lens Care Regimens’
Wz Surfactant Group 1 lo-minute Group 2 Overnight Group 3 lo-minute Group 4 Overnight
Disinfection
H,O, Disinfection + Enzymatic Cleaning
Catalase Neutralization
DW (n = 56)
Overnight
Overnight
10 minutes
DW (n = 52)
10 minutes
15 minutes
Overnight
EW (n = 58)
Overnight
Overnight
10 minutes
EW (n = 63)
10 minutes
15 minutes
Overnight
EW groups used the specified regimen once a week, and DW groups used the specified regimens daily except enzymatic cleaning, was done once a week. ??
68
ICLC, Vol. 17, Mar/Apr 1990
which
Cat&se
tab/et for hydrogen peroxide neutralization:
Courtney et al.
be related to some component of the study regimen. Because we were unable to rechallenge this subject, the actual cause can only be presumed.
significant: 1) moderate and severe symptoms of eye discomfort; 2) visual acuity decreases of two lines or more on the Snellen chart; and 3) decreases from baseline of 4 or more hours of wearing time with DW and decreases of 2 or more days with EW. Data are reported separately for DW and EW subjects because the two modes require different lens care regimens and because lenses are on the eye for a much longer time in EW. Analysis of data pooled from both wear modes was therefore considered inappropriate.
Slit-Lamp Findings Clinically significant slit-lamp findings from all causes were reported as follows: five reports among five subjects in Group 1, five reports among three subjects in Group 2, 14 reports among 10 subjects in Group 3, and 24 reports among 11 subjects in Group 4 (Table 4). There were no clinically significant, regimen-related findings in Groups 1, 3, or 4. In Group 2, one subject, in a single visit, accounted for all three of the clinically significant, regimen-related slit-lamp findings. All of the clinically significant findings noted resolved by the end of the study without altering the regimen.
Results Study Population
Demographic data of the 229 subjects are given in Table 2. All available data from 108 DW and 121 EW subjects were evaluated. Sixteen subjects did not complete the study for the reasons listed in Table 3. Two DW and two EW subjects were disqualified from the data analysis because of deviations from the subject entry criteria (see Table 3). Two DW subjects were discontinued, one for reasons unrelated to the regimen and one for allergic symptoms, the cause of which was uncertain. Ten EW subjects were discontinued, of which only one was for a reason believed to
Visual Acuity There were no clinically significant, regimen-related decreases in visual acuity. Clinically significant decreases in visual acuity from all causes were reported as follows: five reports among four subjects in Group 1, 10 reports among five subjects in Group 3, and seven reports among four
Table 2. Study Population DW Group 1 (lo-Minute Neutralization) Subjects Age (vr) Mean f SD Range Sex Female Male Lens Materials Low water, nonionic (FDA Group 1) Crofilcon A (39% H,O) Ocufilcon A (46% H,O) Tefilcon (38% H,O) Tetrafilcon (43% H,O) Polymacon (38% H,O) High water, nonionic (FDA Group 2) Lidofilcon A (70% H,O) Ofilcon A (74% H,O) Surfilcon A (74% H,O) Vifilcon A (55% H,O) Low water, ionic (FDA Group 3) Bufilcon A (45% H,O) Etafilcon (43% H,O) High water, ionic (FDA Group 4) Bufilcon A (55% H,O) Etafilcon A (58% H,O) Methafilcon A (55% H,O) Perfilcon A (71% H,O) Phemfilcon A (55% H,O)
EW Group 2 (Overnight Neutralization)
Group 3 (lo-Minute Neutralization)
Group 4 (Overnight Neutralization)
56
52
58
63
32.7 2 8.0 14-54
29.2 k 8.1 IQ-52
33.4 k 7.4 18-51
33.1 + 8.1 5-56
45 (80%) 11 (20%)
39 (75%) 13 (25%)
39 (67%) 19 (33%)
41 (65%) 22 (35%)
15 0 9 3 10
18 2 13 0 8 0 0 0 0
0 2 11 5
11 2
11 0
1 0
3 0 2 0 1
0 0 0 0 0
/UC,
14 0
12 1
: 12
: 12
Vol. 17, Mar/Apr 1990
69
Clinical Articks Table 3. Subjects Failing to Complete
the Study DW
EW
Group 1 (IO-Minute Neutralization) Reason Non-regimen-related Disqualified ’ Lens related Missed visits Moved Unable to complete scheduled Personal reasons Regimen-related Allergy symptoms Discomfort/itching
Group 2 (Overnight Neutralization)
Group 3 (lo-Minute Neutralization
Group 4 (Overnight Neutralization)
0 0 0 0
2 0 0 1
2 0 3 0
0
0 0
0 0
0 0
1 1
1 0
0 0
0 0
0 1
1
3
5
7
: 0
as
Total
Two DW subjects from the overnight neutralization group were disqualified for wearing the improper lens type for the regimens assigned (FDA Group 4 hydrogen lenses were assigned to the lo-minute neutralization group). One EW subject decided at Visit 1, prior to any exposure to the study products, not to participate in the study. A second EW subject was disqualified at the baseline visit due to wearing lenses on a DW basis. ??
Table 4. No. Clinically
Significant
Slit-Lamp Findings (Regimen-Related
Causes/All
Causes)
DW Group 1 (IO-Minute Neutralization)
Finding *
EW Group 2 (Overnight Neutralization)
Group 3 (lo-Minute Neutralization)
Group 4 (Overnight Neutralization)
Cornea1 staining Injection Tarsal papillae Tarsal follicles Cornea1 edema “Other” findingst
o/3 o/2 o/o o/o o/o o/o
l/2 l/l o/o o/o l/l O/l
O/5 015 o/2 o/2 o/o o/o
017 017 O/l o/2 o/4 o/3
Total findings
o/5
315
0114
O/24
No. subjects
o/5
l/3
0110
o/11
The numbers shown represent regimen-related causes/all causes. More than one finding was reported for some subjects in each treatment group. t Other findings include acute hordeolum, chemosis, exudate, and limbakcleral impression. ??
subjects
in Group
related. visual
There acuity
4. Most
of these
were no clinically in Group
2. Visual
reports
significant acuity
were
lens-
decreases
in
for all subjects
re-
turned to baseline, or within one line of baseline, lenses or at a subsequent, follow-up visit.
with new
Comfurt There
were no clinically
significant,
regimen-related
re-
ports of eye discomfort in Groups 1 and 3. The four reports of clinically significant, regimen-related eye discomfort by two subjects in Group 2 were as follows: Both subjects experienced burning and stinging, and, in addition, one subject reported redness and excessive tearing. The two reports of clinically significant, regimen-related eye dis70
ICLC, Vol. 17, Mar/Apr 1990
comfort
by one subject
blurred
vision
symptoms
and
in Group
cloudy
of eye discomfort
4 were as follows:
lenses.
Clinically
bilateral
significant
from all causes were reported
as
follows: 22 reports among nine subjects in Group 1, 11 reports among six subjects in Group 2, 19 reports among six subjects in Group 3, and 47 reports among 18 subjects in
Group 4. Data concerning the subjects with clinically sig nificant (i.e., moderate and severe) symptoms of ocular discomfort are presented in Table 5. All clinically significant signs of irritation resolved at a subsequent follow-up visit. Subjects’ Evaluation of Regimen Acceptability At the end of the study, subjects were given a questionnaire in order to evaluate overall eye comfort and regimen
Catalase tablet for hydrogen peroxide neurralization: Table 5. No. Clinically
Significant
Reports of Eye Discomfort
(Regimen-Related
Causes/All
Courtney et al.
Causes)
DW
EW
Symptoms
Group 1 (lo-Minute Neutralization)
Group 2 (Overnight Neutralization)
Burning/stinging Increased lens awareness Dry eye feeling Itching Photophobia/sensitivity to light Excessive tearing Blurring of vision Redness General irritation Other?
o/4 O/3 o/2 o/2 O/l 012 013 O/3 O/l 011
213 o/o O/l o/o O/l 113 o/o l/2 O/O O/l
Total reports
0122
No. subjects
o/9
Group 3 (IO-Minute Neutralization)
Group 4 (Overnight Neutralization)
o/3 O/6 o/o o/3 O/O o/o o/3 o/3 o/o O/l
O/3 o/13 014 O/5 014 o/2 115 017 O/l l/3
4/11
o/19
2147
216
O/6
l/18
* The numbers shown represent regimen-related causes/all causes. More than one symptom was reported by some subjects in each treatment group. t Other symptoms include cloudy lenses, headaches, sty, mucus, and swollen eye. Symptoms include all occurrences reported by subjects, but not necessarily verified by investigators.
Group (DW
I
IO-Minute
Neutralization) (1~56)
Group
2
(DW Overnlqhl Neutrollzotlon) (ll~51)
Group
3
(EW IO-Minute Neutrolizotlon) (n=55)
Group4 (EW Overnight Neutrollzation) lnz5t3)
Figure 1. Subjects reporting good or excellent overall eye comfort during lens wear.
acceptability. The majority of the subjects in the four treatment groups reported good or excellent overall eye comfort during lens wear (Figure 1). One hundred percent of the subjects in both DW groups reported that their overall eye comfort throughout the study had been good or excellent. Ninety-eight percent and 88% of the subjects in the EW lo-minute and overnight groups, respectively, reported that their eye comfort throughout the study had been good or excellent. In addition, the majority of subjects in all four treatment groups reported that the study regimen was an equally or more acceptable method of contact lens care compared with their previous regimen (Figure 2). Eightyeight percent and 96%, respectively, of the subjects in Groups 1 and 2 reported that the study regimen provided an equally or more acceptable method of contact lens care. Eighty-nine percent and 88%, respectively, of the subjects in Groups 3 and 4 reported that the study regimen provided an equally or more acceptable method of contact lens care.
Group
I
IDW IO-Minute Neutrallzotion) (nz56)
Group
More
m
Equally
Group
2
(DW OvernIght Neutralization)
IZZd
3
(EW IO-Minute Neutratizatlon) (nz55)
(n=51)
acceptable acceptable
Group4 (EW Overnight Neutralization) in:581
Figure 2. Subjects reporting that study regimen provided an equally or more acceptable method of contact lens care compared to their previous regimen. Previous regimens included oxidative (53.6%), chemical (25%), and thermal (21.4%) disinfection
Discussion Overall, the results of this study demonstrated the safety and efficacy of this regimen among the 108 subjects wearing lenses on a daily-wear basis and the 121 subjects wearing lenses on an extended-wear
basis.
The very low incidence of signs and symptoms of irritation observed among the subjects in both DW groups during the course of the study was indicative of the safety of this regimen. For 99% of the eye examinations in Groups 1 and 2, there were either no positive slit-lamp findings or the findings were not clinically significant. One subject accounted for all three of the clinically significant, regimen-related slit-lamp findings, and all the clinically significant signs and symptoms of irritation resolved at a subsequent follow-up visit without alteration of the regimen. Signs and symptoms of irritation observed among the ICLC, Vol. 17, Mar/Apr 1990
71
Clinical Articks EW subjects during the course of the study were also indicative of the safety of this regimen. There were no clinically significant slit-lamp findings or reports of symptoms of discomfort that were judged by the investigators to be probably regimen-related. For 98% of the eye examinations in Groups 3 and 4, there were either no positive slit-lamp findings or the findings were not clinically significant. All clinically significant signs and symptoms of irritation resolved at a subsequent follow-up visit. The low incidence of signs and symptoms in this study is also indicative of the efficacy of the catalase tablet in the study regimen. Catalase is a very effective agent for neutralizing hydrogen peroxide and, as such, contributed to regimen safety in terms of a low incidence of symptoms of discomfort and other complaints. Visual acuity was well maintained during the study, which also indicated safety and acceptability of the regimen. None of the clinically significant decreases in visual acuity was attributed to the study regimen in any of the treatment groups, and visual acuity for all subjects returned to baseline, or within one line of baseline, with new lenses or at a subsequent follow-up visit. The total number of reports of clinically significant eye discomfort from all causes was also low. There were 66 such reports in the two EW groups, compared with 33 for the DW groups. Increased lens awareness accounted for the greatest disparity, being considerably higher in the EW groups. These differences may be due to the modality of extended wear, which can lead to a decrease in the amount of oxygen available to the cornea and a reduced tolerance to contact lens wear.” Also, since subjects in the EW groups were wearing a higher proportion of highwater-content lenses, and were using surfactant cleaners only once a week, they may have been more vulnerable to irritation due to intraweekly deposit buildup. Previous studies have reported similar findings.4p5 When introduced at the end of the disinfection cycle, the catalase tablet effectively neutralizes the hydrogen peroxide solution. By removing the need for a second, neutralization-specific solution, the catalase tablet simplifies the disinfection/neutralization component of the lens care regimen. The use of catalase-containing tablets for hydrogen peroxide neutralization offers increased patient conve-
Clinical
nience and should lead to better compliance with regimens and, consequently, a lower risk of contact lens-related complications. Conclusions The results of this study indicate that the catalasecontaining hydrogen peroxide-neutralizing tablet dissolved in LENS PLUS@ Oxysept@ 1 Disinfecting Solution, with weekly inclusion of UltrazymeTN Enzymatic Cleaner, is safe and acceptable for use with both daily-wear and extendedwear hydrogel contact lenses when used in neutralization procedures as short as 10 minutes to as long as overnight. Acknowledgments The authors gratefully acknowledge the clinical participation of Gayle N. Amemiya, OD, Ronald M. Cedrone, OD, Robert L. Davis, OD, Richard D. Ebling, OD, Victor M. Finnemore, OD, Steven S. Grant, OD, Edward J. Kienast, OD, William C. Lee, OD, S. Victor Stella, OD, and Jack J. Yager, OD; the technical assistance of Debra Kono; and the editorial assistance of Stephen Rutledge. References 1. Gasset AR, Ramer RM, Katzin D: Hydrogen peroxide sterilization of hydrophilic contact lenses. Arch Opthulmol 1975;93:412-415. 2. Janoff LE: The effective disinfection of soft contact lenses using hydrogen peroxide. Contact0 1979;23:37-40. 3. Penley CA, Llabr& C, Wilson LA, Aheam DG: Efficacy of hydrogen peroxide disinfection systems for soft contact lenses contaminated with fungi. CLAO J 1985;11:65-68. 4. Tarantino N, Courtney RC, Lasswell LA, Kono D, Frank J: Simultaneous enzymatic cleaning and hydrogen peroxide disinfection of hydrogel lenses. ICLC 1988;15:25-32. 5. Courmey RC, Tarantino N, Stubblefield D: Clinical evaluation of Ultrazyme Enzymatic Cleaner used with AOSept. ICLC 1989;16:40-47. 6. Knopf HLS: Reaction to hydrogen peroxide in contact-lens wear. Am J OphMmol 1984;97:796. 7. Paugh JR, Brennan NA, Efron N: Ocular response to hydrogen peroxide. Am J Optom Physiol Opt 1988;65:91-98. a. Gyulai P, Dziabo A, Kelly W, Kiral R: Efficacy of catalase as a neutralizer of a hydrogen peroxide disinfecting solution for soft contact lenses. ICLC 1986;2:41&422. 9. Data on file, Allergan, Inc., 1988. 10. Holden BA: Cornea1 requirements for extended wear: an update. CLAO J 1988;14:22C-222.
Implications
This paper describes a clinical investigation designed to gauge the efficacy and safety of a new method of neutralization for use with hydrogen peroxide disinfection. The biocatalyst “catalase,” with which we are familiar as a neutralizing solution, is presented here in tablet form. The tablet is added directly to the peroxide solution following a IO-minute or overnight disinfection period. By avoiding the need for a second, neutralization-specific solution, the tablet offers increased convenience-patient compliance with the lens care regimen is expected to improve accordingly. Despite these gains, this is still a two-step system and as such may not be as popular with some lens wearers as one-step peroxide or overnight soaking solutions. We still await a tablet that can be added at the start of the disinfection procedure and that has a slowly dissolving outer layer that prevents the initiation of neutralization 72
ICLC, Vol. 17, Mar/Apr
1990
Cat&se
tablet fur hydrogen peroxide neutralization:
Courtney et al.
until an adequate period of disinfection has elapsed. Nonetheless, this disinfection system offers both the antimicrobial efficacy of 3% hydrogen peroxide (hence, the option of long and short disinfection periods) together with a very simple means of achieving neutralization. Russell Lowe, OD Cornea1 Biophysics Laboratory Department of Optometry University of Melbourne Parkville, Victoria 3052, Australia
Richard C. Courtney graduated from Northwestern University in 1969 with a BA degree in biological sciences. He subsequently served for 3 years as a commissioned officer in the United States Navy. He received his OD degree from the Southern California College of Optometry in 1977, where he was valedictorian of his class. Courtney was a clinical instructor in the Special Testing-Disease Detection Department there for 2 years. In 1979 he joined Contact Lens Clinical Research at Allergan Optical, where he now serves as senior director. Courtney’s current research interests include methodologies for evaluating the safety and efficacy of contact lens care products. Nicholas Tarantino graduated with honors in 1980 from the Southern California College of Optometry. In private practice he conducted clinical research for several industry leaders before joining Clinical Research at Allergan Optical in 1983, where he now serves as director of contact lens clinical research. Tarantino is a member of the American Optometric Association, the California Optometric Association, the American Academy of Optometry, and the International Society of Dakryology.
Patricia Brown graduated from Ohio State University in 1981 with an MS degree in nursing. After working in various nursing positions, she joined Allergan Optical’s Product Information Services group in 1983. Since 1988, she has served as coordinator of contact lens clinical research. Brown is a member of the Drug Information Association and the American Society of Ophthalmic Registered Nurses.
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