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Clinical Sciences |

Safety and Efficacy of 2% Pirenzepine Ophthalmic Gel in Children WithMyopia:  A 1-Year, Multicenter, Double-Masked, Placebo-Controlled ParallelStudy FREE

R. Michael Siatkowski, MD; Susan Cotter, OD; Joseph M. Miller, MD; Colin A. Scher, MD; R. Stephens Crockett, PhD; Gary D. Novack, PhD ; US Pirenzepine Study Group
[+] Author Affiliations

Author Affiliations: Department of Ophthalmology,University of Oklahoma, and Dean A. McGee Eye Institute, Oklahoma City (DrSiatkowski); Southern California College of Optomety, Fullerton (Dr Cotter);Departments of Ophthalmology, Optical Sciences, and Public Health, Universityof Arizona, Tucson (Dr Miller); Department of Ophthalmology, Children’sHospital and Health Center, San Diego, Calif (Dr Scher); D.A.T.A., Inc, Mobile,Ala (Dr Crockett); and PharmaLogic Development, Inc, San Rafael, Calif (DrNovack).


Arch Ophthalmol. 2004;122(11):1667-1674. doi:10.1001/archopht.122.11.1667.
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Published online

Objective  To evaluate the safety and efficacy of the relatively selective M1 antagonist pirenzepine hydrochloride in slowing the progression ofmyopia in school-aged children.

Methods  This was a parallel-group, placebo-controlled, double-masked study inhealthy children, aged 8 to 12 years, with a spherical equivalent of −0.75to −4.00 diopters (D) and astigmatism of 1.00 D or less. Patients underwenta baseline complete eye examination and regular examinations during a 1-yearperiod. The setting was 13 US academic clinics and private practices. Patientswere randomized in a 2:1 ratio to receive 2% pirenzepine ophthalmic gel ora placebo control twice daily for 1 year.

Results  At study entry, the spherical equivalent was mean ± SD−2.098 ± 0.903 D for the pirenzepine group (n = 117)and −1.933 ± 0.825 D for the placebo group (n = 57, P = .22). At 1 year, there was a mean increasein myopia of 0.26 D in the pirenzepine group vs 0.53 D in the placebo group(P < .001). No patients in the placebogroup and 13 (11%) of 117 patients in the pirenzepine group discontinued participationin the study because of adverse effects (5 [4%] of 117 due to excessive antimuscariniceffects).

Conclusions  Pirenzepine is effective and relatively safe in slowing the progressionof myopia during a 1-year treatment period.

Figures in this Article

Myopia, one of the most common ocular disorders in the world, is a significantglobal public health problem. It affects at least 25% of the adult populationin the United States.13 Myopiais among the 5 conditions that have been identified as immediate prioritiesby the World Health Organization in its Global Initiative for the Eliminationof Avoidable Blindness.4

Probably the most widely studied pharmacological treatment for myopiahas been the use of atropine, a nonselective muscarinic antagonist. Severalrecent controlled clinical trials have provided evidence that atropine canretard myopia progression in children.57 Animalstudies suggest that this retardation occurs independent of the effect ofatropine on accommodation.812 Pirenzepinehydrochloride, another muscarinic receptor antagonist, has long been usedorally in Europe to treat dyspepsia and pediatric endocrine disorders andhas an extensive clinical history and excellent safety profile.13 Unlikeatropine, which is equipotent in binding to M3 (accommodation andmydriasis) and M1 muscarinic receptors, pirenzepine is relativelyselective for the M1 muscarinic receptor14,15 andthus less likely than atropine to cause mydriasis and cycloplegia. Since Stoneet al12 first suggested study of pirenzepineas an agent to decrease myopic progression, animal research has demonstratedthat it reduced the development of deprivation-induced myopia and axial elongationin animals.1618 Basedon previous phase 1 trials of the safety and tolerability of pirenzepine solutionin adults19 and pirenzepine ophthalmic gelin children,20 we undertook a double-masked,multicenter, placebo-controlled phase 2 trial to evaluate the safety and efficacyof pirenzepine ophthalmic gel in slowing the progression of myopia in school-agedchildren. The maximally tolerated concentration in the previous study, 2%pirenzepine,20 was selected for evaluationin the present study.

STUDY DESIGN

This was a parallel-group, placebo-controlled, double-masked study conductedfrom March 1, 2000, to February 28, 2002, at 13 US sites (academic clinicsand private practices). Children were randomized in a 2:1 ratio to receive2% pirenzepine twice daily or placebo control for 1 year. The 2:1 randomizationschema was used to increase the chance of a patient being randomized to theactive treatment arm, while maintaining sufficient power. A central coordinatingcenter was located at Valley Forge Pharmaceuticals Inc (Irvine, Calif). Clinicalresearch monitors for each site were provided via Clinical Studies ManagementGroup, Tulsa, Okla.

PATIENTS

Eligible patients were healthy children, aged 8 to 12 years, with myopia,defined as a spherical equivalent (SEQ) of −0.75 to −4.00 diopters(D) and astigmatism of 1.00 D or less in each eye as measured by cycloplegicrefraction. Also required were normal pupils and best-corrected visual acuityof 20/25 or better in each eye by Early Treatment Diabetic Retinopathy Study(ETDRS)charts.21 A modified ETDRS procedure was usedto measure visual acuity monocularly at distance and binocularly at near.Starting with the 20/50 line (or 20/100 line when any letter was missed onthe 20/50 line), the child read all 5 letters on each subsequent line untilhe/she missed 3 or more letters on a line. Visual acuity was scored as thelogMAR score for the line plus 0.02 times the total number of letters missedon that line. Ocular exclusion criteria were anisometropia greater than 1.00D in SEQ, any manifest tropia, current use of either contact lenses or bifocals,and a history of ocular surgery, trauma, or chronic ocular disease, includingallergic conjunctivitis. Systemic criteria for exclusion from the study werediseases that required long-term or regular intermittent medication use (eg,asthma, epilepsy); behavioral or neurological disorders that would interferewith the study; participation in any study that involved an investigationaldrug within the month before enrollment; intolerance or hypersensitivity totopical anesthetics, mydriatics, or components of the formulation (eg, benzalkoniumchloride); contraindications to antimuscarinic agents; and pregnancy or plannedpregnancy. Transient pharmacologic therapy for acute diseases was allowed(eg, otitis media, pharyngitis).

The protocol and informed consent and child assent forms were approvedby institutional review boards. The parent or guardian of each study patientgave written informed consent, and the patient provided written assent.

PHARMACOLOGIC AGENTS

We formulated 2% pirenzepine with hydroxypropyl methylcellulose andpreserved it with 0.005% benzalkonium chloride. Both pirenzepine and placebo(identical formulation except for the pirenzepine) were packaged in identicaltubes, the identity of which was masked from the children, parents, and investigators.The product that contained active drug and the vehicle were identical in appearance.Study medications were administered twice daily as an approximately ¼-in(6-mm) strip in the cul-de-sac of the lower eyelid. Approximately 9 monthsafter study began, an electronic monitoring device (MEMS SmartCap system;Aardex, Union City, Calif) was introduced into the trial. The study medicationwas placed into an outer standard medication bottle. To access the medication,the SmartCap had to be removed. The device recorded and stored a bottle openingevent (limit 1 per 15-minute period to reduce double counts). SmartCap datawere retrieved during the patient’s regularly scheduled visit.

STUDY PROCEDURES

Height and weight were recorded, and a baseline, predrug symptom queryfor symptoms that existed before study drug instillation was administered.Monocular and binocular best-corrected visual acuity was measured at distanceand near using the ETDRS charts. A comprehensive eye examination, includingmeasurement of intraocular pressure, was performed to rule out any exclusioncriteria. Autorefraction (Speedy 1; Nikon, Melville, NY) was performed 30to 60 minutes after instillation of 0.5% proparacaine hydrochloride, 1.0%cyclopentolate hydrochloride, and 1.0% tropicamide in each eye with 1 minuteof eyelid closure. A-scan ultrasonography was used to measure axial lengthvia the standard fashion of each site. All qualified patients were providedwith a demonstration by the clinical staff of how to properly instill thestudy medication using a tube of placebo gel. They were then provided witha tube of the placebo gel to take home to practice instillation to ensurethat the child and parents were able to use the gel. The child then returnedwithin 1 week for randomization.

Before randomization, individuals were queried regarding ability toadminister the agent and any potential adverseeffects. No child or parentreported any problems with administration or use of the vehicle gel. Eligiblepatients were randomized either to active or placebo treatment using a sponsor-prepared,computer-generated randomization list stratified by site (PROC PLAN; SAS version8, SAS Institute Inc, Cary, NC). Study medication was administered by studypersonnel, and 10 and 60 minutes later, a symptom query was given and vitalsigns were measured. At 60 minutes, pupil size was recorded and biomicroscopyperformed. Subsequent visits were scheduled at 15 days and 1, 3, 6, 9, and12 months. At each visit, a symptom query was administered and visual acuity,pupil size, anterior segment evaluation, intraocular pressure, heart rate,and blood pressure were measured. At months 3, 6, and 12, cycloplegic autorefractionand A-scan ultrasonography were performed. Autorefraction was also performedat month 9.

STATISTICAL ANALYSIS

The primary outcome measure was SEQ. We assumed that the progressionin the placebo group would be at least −0.3 ± 0.3 D/y(Karla Zadnik, OD, PhD, Orinda Longitudinal Study of Myopia, National Institutesof Health, National Eye Institute, grant 10-EY08893, unpublished data, 1989-2000),with an arbitrary 50% difference between treatments in change from baselinein SEQ cycloplegic refraction. The study had 90% power to detect a mean differencebetween treatment groups of approximately 0.17 D in myopia (α = .05,1-tailed, SD = 0.3 D,t test), assuming144 evaluable children at 1 year (96 pirenzepine patients and 48 placebo patients).The secondary outcome measure was axial length.

In this bilateral treatment study, continuous measures (eg, sphere,pupil size) were averaged between eyes for analysis. Change from baselinerefractive error and axial length was analyzed by a mixed-model analysis ofcovariance with baseline as the covariate; treatment group, site, and theirinteraction as between-patient factors in the model; and the repeated measures(visits and right and left eyes) and their interaction with the between-patientfactors as within-patient factors. Nonsignificant interactions were droppedfrom the model used to estimate treatment effect. Safety measures made oncontinuous scales were analyzed in a manner similar to the efficacy measures.The analysis of safety measures made on categorical or frequency scales wasbased on χ2 statistics. All analyses were performed usingPC-SAS (version 8.1; SAS Institute Inc). A planned interim analysis was conductedwhen 50% of patients reached the primary end point (12 months). The null hypothesisof no treatment effect was tested with a P valueof.005 and not rejected. The criterion P value forstatistical significance in the final analysis was adjusted to.048 to maintainan experiment-wise type I error of less than.05.22

Demographics and baseline characteristics of the 174 patients enrolledare given in Table 1.

Table Graphic Jump LocationTable 1. Demographics and Prestudy Characteristics
PATIENTS

We screened 277 patients and enrolled 174 patients, of which 145 completedthe trial. Twenty-six (22%) of 117 patients randomized to pirenzepine didnot complete the study compared with 3 (5%) of the 57 patients in the placebogroup (Figure 1, P = .005). Thirteen of the 26 pirenzepine-treated patientsstopped participation in the study due to an adverse event: allergic reactionor conjunctivitis, 7; accommodation or blurred vision at near, 5; and stinging,1. Thirteen patients (11%) randomized to pirenzepine did not complete thestudy for reasons other than adverse events: noncompliance with medication, 3;lost to follow-up, 2; and other reasons, 8 (missed visits, withdrew consent,“didn’t like study medication,” moved, use of prohibitedconcomitant systemic medication, or personal reasons). Three patients (5%)randomized to placebo did not complete the study due to the following reasons:noncompliance with medication, 1; and other reasons, 2 (patientunable to accept ultrasound, patient “got tired of using the gel”).For 5 of the 29 patients, discontinuation occurred within the first few daysdue to either intolerance to the study medication or the study procedures.However, for the most part, discontinuation occurred after the patients werein the study for several months or more. When a compliance measurement wasintroduced partway through the study, the mean compliance ratio for each groupwas 79%. No patient’s treatment was unmasked early.

Place holder to copy figure label and caption
Figure 1.

Patient disposition.

Graphic Jump Location
REFRACTIVE STATUS

At study entry, mean ± SD SEQ refraction was −2.098 ± 0.903D for the pirenzepine group and −1.933 ± 0.825 D forthe placebo group (P = .22). As shown in Figure 2, during the 1-year study, the mean SEQrefraction became more myopic in both treatment groups. At 3, 6, 9, and 12months, the mean increase in myopia was significantly higher (P ≤ .006) in the placebo group compared with the pirenzepinegroup (Table 2). At 12 months, therewas a mean increase in myopia of 0.26 D in the pirenzepine group vs 0.53 Din the placebo group for treatment effect in favor of pirenzepine of 0.260D (P < .001). There was no evidencefor a difference among study sites (analysis of variance test for homogeneityacross treatment by investigative site, P = .52at baseline and P = .95 for change frombaseline). Age, sex, iris color, and refraction at entry were not predictiveof treatment difference. Additional methods were used to impute missing valuesdue to patients who discontinued the study. In all 3 methods used (last observationcarried forward, visit-to-visit extrapolation using median of respective treatment,and visit-to-visit extrapolation using median of placebo group), the treatmenteffect was similar to or greater than in the primary analysis method (0.262-0.343D). This is not surprising for the first 2 methods, because they correct forthe dropout of primarily pirenzepine-treated patients, who had, on average,lower rates of myopic progression.

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Figure 2.

Mean spherical equivalent (SEQ) changefrom baseline. Error bars indicate SEM; D, diopters. Between-treatment P values are <.001, .006, <.001, and <.001 at3, 6, 9, and 12 months, respectively.

Graphic Jump Location

The proportion of patients whose myopia progressed by at least 0.75D was 4% (4/99) in the pirenzepine group and 20% (11/56) in the placebo groupat 6 months (P = .004). At 1 year, theproportions were 11% (10/92) vs 31% (17/54), respectively (P = .006, Figure 3).

Place holder to copy figure label and caption
Figure 3.

Proportion of patients with criterionprogression at 12 months calculated on the basis of mean of patients’eyes. P values are.09, .007, .006, and <.001 for0.25, 0.50, 0.75, and 1.00 diopters, respectively.

Graphic Jump Location
AXIAL LENGTH

At study entry, there was no significant difference in mean axial lengthbetween groups (Table 3, 23.88 mm vs23.77 mm, P = .41). At 12 months, therewas a mean increase in axial length of 0.19 mm in the pirenzepine group and0.23 mm in the placebo group. This difference of approximately 0.04 mm, infavor of less myopic progression in the active treatment group, was not statisticallysignificant (P = .60).

Table Graphic Jump LocationTable 3. Mean Axial Length of Patients’ Eyes
SAFETY
Adverse Events

Adverse events for both groups are provided in Table 4. In general, they were mild or moderate in severity. The3 most frequent systemic events were headache, common cold, and flu syndrome.The 3 nonophthalmic adverse events that differed statistically at the conservative P = .15 cutoff level were common cold, rhinitis,and sinusitis, which were actually more frequent in the placebo treatmentgroup. The 3 most frequent ocular events were mydriasis, erythema of the eyelids,and ocular itching. Six ophthalmic adverse events differed at the criterion P value: (1) symptoms of decreased accommodation, (2) increasein papillae and follicles, (3) decreased visual acuity (primarily near), (4)mydriasis and (5) eye discomfort, which were more common in the pirenzepinegroup, and (6) medication residue on eyelids or eyelashes, which was morecommon in the placebo group. Most reports of blurred or decreased vision (primarilynear) and other symptoms of accommodative abnormalities began during the firstmonth of the study. There was 1 serious adverse event reported during thestudy; a patient in the pirenzepine group was thrown from a horse and hospitalizedfor surgical repair of a fractured right arm. During the study, no differencesof note occurred between groups with respect to height, weight, heart rate,or blood pressure.

Table Graphic Jump LocationTable 4. Treatment Emergent Adverse Events by Descending Incidence*
Ocular Signs

At study entry, the mean pupil diameter in room light was 5.0 mm inboth treatment groups (P = .62). Sixtyminutes after the first instillation, the mean mydriasis in pupil diameterwas 1.5 mm in the pirenzepine group and 0.2 mm in the placebo group (P < .001). A similar mydriatic effect wasseen 60 minutes after instillation at month 1. Twelve hours after the lastdose, the mean mydriasis in pupil diameter was approximately 0.5 mm in thepirenzepine group and ±0.2 mm in the placebo group (P ≤ .005, Figure 4).For the most part, there were few reports of abnormal biomicroscopic resultsthat were not present at baseline. Mild conjunctival erythema was noted in4 pirenzepine patients and 1 patient randomized to placebo at 1 or more visits.Conjunctival edema was noted in 2 pirenzepine patients at 6 months, and theseverity was mild and moderate; mild edema was noted in 1 pirenzepine patientat 9 months. No edema was reported in placebo patients.

Place holder to copy figure label and caption
Figure 4.

Mean change from baseline in pupildiameter. Time shown is baseline or approximately 12 hours after last instillation.Error bars indicate standard error of the mean. P valuesare <.001, <.001, <.001, <.001, <.001, and.005 at week 2 andmonths 1, 3, 6, 9, and 12, respectively.

Graphic Jump Location

Medication residue was similar in both treatment groups and was describedas mild to moderate for both groups (45 [38%] of 117 pirenzepine patientsand 30 [53%] of 57 placebo patients). Only one instance of severe conjunctivalerythema was reported during the study; the observation occurred in a pirenzepinepatient at 3 months. No abnormalities of the lens or posterior segment werenoted at any time in any patient. Of the patients with objective conjunctivalpapillae and follicles, few reports of ocular symptoms of discomfort occurred(11 [9%] of 117 pirenzepine patients and 2 [4%] of 57 placebo patients). Ofthe patients found to have increased conjunctival follicles and papillae,9 (19%) of 47 in the pirenzepine group and 2 (20%) of 10 in the placebo groupexperienced an increase of 2 grades or more. From a mean baseline intraocularpressure of 15 mm Hg, there was a mean decrease of up to 1 to 2 mm Hg in eacheye for both treatment groups, with little apparent effect of treatment duration(1 day vs 1 year) or interval from instillation (0 or 60 minutes).

VISUAL ACUITY

At study entry, mean best-corrected distance visual acuity was approximately0.01 logMAR (equivalent to approximately 20/20 Snellen) in both treatmentgroups. During the study, mean changes in distance visual acuity were muchless than 1 line ETDRS, with mean acuity at 12 months similar to entry −0.03 ± 0.089(pirenzepine) and −0.01 ± 0.118 (placebo). Near visualacuity was approximately 0.06 at entry in both groups, and mean changes wereless than 1 line ETDRS. At each visit, the proportion of patients who reportedloss of 3 or more lines in distance or near vision was 0% to 3% (all in thepirenzepine group).

In this large, placebo-controlled study in children 8 to 12 years ofage, pirenzepine was more effective than the placebo gel in retarding boththe mean increase in SEQ and proportion of patients who showed myopic progression.These clinical data are consistent with the efficacy observed in animal models.1618 No serious adverseevents related to drug use occurred, and mydriasis and cycloplegia, as mightbe expected from a nonselective muscarinic antagonist, prompted withdrawalin only 5 (4%) of the 117 pirenzepine-treated patients. Conjunctival allergicreactions were more common in the pirenzepine group but again prompted withdrawalin only 7 (6%) of these 117 patients. Medication residue was frequently observedby the investigator and also reported by patients in the preceding study.20 Conjunctival follicles, observed in both study arms,occur with high frequency in this age group23;it is possible that in many cases both the appearance of follicles and changesin grade are related to environmental and individual immune factors ratherthan to either the study drug or the vehicle. Mydriasis, although expectedand consistent with the pharmacology of pirenzepine, was relatively smallin magnitude (average dilation of 1.3 mm at 15 minutes after dosing and 0.5mm at 12 hours after dosing). As demonstrated in a previous study,20 pupils in children treated with pirenzepine remainreactive to light, unlike what typically occurs with atropine. Therefore,patients in this study were not required to use photochromic spectacles andconcern for lens and/or retinal phototoxicity was minimized.

Potential limitations of the study include lack of formal accommodationtesting and phoria quantification in this protocol. However, accommodationwas measured in the preceding study,20 andno individual with any manifest strabismus was permitted to enroll. Therewas a slight difference in baseline myopia between the pirenzepine and placebogroups. However, this difference was not statistically significant, but myopicprogression between the 2 groups was. Additionally, the entry level of myopiawas not predictive of degree of progression to a statistically significantlevel. Also, there was no difference in family history of myopia between the2 groups. Thus, despite these limitations, we believe that the results ofour study are applicable to the general population.

Although there is little doubt that preventing progression of myopiabeyond 5 or 6 D decreases the risk of retinal detachment, peripheral retinaldegenerations, and glaucoma, preventing even lesser degrees of myopia is alsoof great clinical significance. From a public health standpoint, the incidenceof these myopic complications certainly increases with refractive errors between−1.00 and −5.00 D, although not as significantly as at higherrefractive errors (eg, a patient with −2.00-D myopia has less risk ofdeveloping retinal detachment than a patient with −4.00-D myopia).24,25 Additionally, quality-of-life issuesbecome important with increasing dependence on constant refractive correctionwith higher degrees of myopia. A child with a refractive error of −1.00D may do fine scholastically and athletically with only wearing glasses parttime, but a patient with −2.00-D myopia needs correction all the time.

The magnitude of efficacy seen in the present study, approximately 50%reduction in progression or 0.3 D during 12 months in this US population,is of similar magnitude to that reported by atropine in an Asian population5 and greater than that reported by the use of progressiveaddition lenses.26 The M3 muscarinicantagonistic ocular effects of 0.1% to 0.5% atropine (eg, mydriasis and lossof accommodation) would be expected to be greater than that seen with 2% pirenzepinein the present study. Also, patients in the present study were not allowedto wear bifocals. The apparent ability of long-term pirenzepine treatmentto retard the development of myopia without predominant M3 muscarinicantagonism is contrary to an accommodative basis for the development of pediatricmyopia. Rather, like studies with dopaminergic agonists,2729 theefficacy of muscarinic agents in chicks in which the intraocular muscles arenicotinic in nature, and the Correction of Myopia Evaluation Trial (COMET)using progressive addition lenses,26 this implicatesa muscarinic, cholinergic pathway that does not involve M3 receptoractivation and is supportive of a neural mechanism that may be based in theretina. A scleral-based mechanism, however, is also conceivable; cholinergicamacrine cells may not be required for the progression of form-deprivationmyopia in chicks,9 and muscarinic antagonists(in somewhat high concentrations) inhibit chick scleral chondrocytes.30 Alternatively, both retinal and scleral sites mayplay a role. Regardless of the site(s) of action, the results of this studyand prior work with pirenzepine argue against an accommodative mechanism inthe development of pediatric myopia and also serve to validate the use ofform-deprivation myopia to study this entity.

In conclusion, results of this study serve to establish the safety andefficacy of administration of pirenzepine ophthalmic gel in myopic childrenin slowing the progression of myopia during a 1-year treatment period. Weare continuing to treat and evaluate these patients, because 84 have electedto continue with a second year of controlled evaluation.

Correspondence: R. Michael Siatkowski, MD,Dean A. McGee Eye Institute, 608 Stanton L. Young Blvd, Oklahoma City, OK73104 (Rmichael-Siatkowski@ouhsc.edu).

Submitted for Publication: June 3, 2003; finalrevision received February 12, 2004; accepted May 14, 2004.

Financial Disclosure: This study was supportedby Valley Forge Pharmaceuticals Inc, the developers of pirenzepine ophthalmicgel, and Novartis Ophthalmics AG, its licensee. The study organizers wereemployees of Valley Forge Pharmaceuticals Inc at the time this study was conducted.Drs Crockett and Novack are consultants to Valley Forge Pharmaceuticals Inc.The clinical investigators were contractors to Valley Forge PharmaceuticalsInc for this clinical study. Drs Siatkowski and Miller have received honorariafrom Valley Forge Pharmaceuticals Inc; neither are stockholders nor have anyother investigators received consulting fees from Valley Forge PharmaceuticalsInc.

Previous Presentation: This study was presentedin part as a poster at the Association of Research in Vision and Ophthalmologymeeting; May 8, 2003; Fort Lauderdale, Fla.

Members of the US Pirenzepine Study Group

Study Investigators: Geoffrey E. Bradford,MD (principal investigator), Terry Schwartz, MD (investigator), Kenneth Gainer,MD (investigator), and Paula Fenstermacher (coordinator), West Virginia University(Morgantown); Don L. Bremer, MD (principal investigator), Gary L. Rogers,MD (investigator), Mary Lou McGregor, MD (investigator), Jennifer Fogt, OD(investigator), and Rae Fellows (investigator), Columbus Children’sHospital (Columbus, Ohio); Gerhard W. Cibis, MD (principal investigator),Denise Hug, MD (investigator), Timothy Hug, OD (investigator), Debra Kirk,OD (investigator), Marcia Bray, OD (investigator), Renae Borden, OD (investigator),Dirck DeKeyser, OD (investigator), and Dana Kinney (coordinator) (OverlandPark, Kans); Susan Cotter, OD (principal investigator), Soonsi Kwon, OD (investigator),Raymond H. Chu, OD (investigator), Richard Yardley, OD (investigator), SusanShin, OD (investigator), Jennifer Slutsky, OD (investigator), John Maher,MD (investigator), Sherene Fort, OD (investigator), and Yvonne Flores (coordinator),Southern California College of Optometry (Fullerton); Arlene V. Drack, MD(principal investigator), Scott Lambert, MD (investigator), and Cameile MooreMartin (coordinator), Emory University School of Medicine (Atlanta, Ga); RichardM. Evans, MD (principal investigator), Timothy Dunham, MD (investigator),Lynnell coordinator. Lowry, MD (investigator), and Naomi Quesada (coordinator),Med Center Ophthalmology Associates; Marjean A. Taylor Kulp, OD (principalinvestigator), Michael J. Earley, OD, PhD (investigator), Stephan Katz, MD(investigator), and Tracy Kitts (coordinator), Ohio State University (Columbus);Robert J. Noecker, MD (principal investigator), Joseph M. Miller, MD, MPH(investigator), Rand Siekert OD (investigator), and Toby Aparisi (coordinator),University of Arizona (Tucson); Thomas R. Walters, MD (principal investigator),Douglas Lewis, MD (investigator), James E. Montgomery, MD (investigator),and Cindy Jasek (coordinator), Texan Eye Care (Austin, Tex); Colin A. Scher,MD (principal investigator), Yvette Jockin, MD (investigator), Henry O’Halloran,MD (investigator), and Lynn Nelles (coordinator), Children’s Hospitaland Health Center, San Diego (San Diego, Calif); R. Michael Siatkowski, MD(principal investigator), Dana M. Jones, OD (investigator), and Lisa Ogilbee(coordinator), Dean A. McGee Eye Institute/University of Oklahoma Departmentof Ophthalmology (Oklahoma City); P. Sarita Soni, OD (principal investigator),William Rainey, OD (investigator), James Laughlin, MD (investigator), TracyNguyen, OD (investigator), Brent Shelly, OD (investigator), and Donna Carter(coordinator), Indiana University School of Optometry (Bloomington); JohnH. Sullivan, MD (principal investigator), Douglas R. Fredrick, MD (investigator),Shaku Nagpal, MD (investigator), and Pat Pascoe (coordinator), Eye MedicalClinic of Santa Clara Valley (San Jose, Calif).

Study Organization: Marcia Edmondson, BS, AnneButeyn, BS.

Biostatistics: R. Stephens Crockett, PhD (D.A.T.A.,Inc, Mobile, Ala); the writing committee consisted of Susan Cotter, OD (SouthernCalifornia College of Optometry, Fullerton), Joseph M. Miller, MD, MPH (Universityof Arizona, Tucson), Colin A. Scher, MD (Children’s Hospital and HealthCenter, San Diego, Calif), R. Michael Siatkowski, MD (Dean A. McGee Eye Institute/Universityof Oklahoma, Oklahoma City), R. Stephens Crockett, PhD (D.A.T.A., Inc), andGary D. Novack, PhD (PharmaLogic Development Inc, San Rafael, Calif).

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Norton  TTEssinger  JAMcBrien  NA Lid-suture myopia in tree shrews with retinal ganglion cell blockade. Vis Neurosci 1994;11143- 153
PubMed Link to Article
Stone  RALin  TLaties  AM Muscarinic antagonist effects on experimental chick myopia [letter] Exp Eye Res 1991;52755- 758
PubMed Link to Article
Carmine  AABrogden  RN Pirenzepine: a review of its pharmacodynamic and pharmacokinetic propertiesand therapeutic efficacy in peptic ulcer disease and other allied diseases. Drugs 1985;3085- 126
PubMed Link to Article
Dorje  FWess  JLambrecht  G  et al.  Antagonist binding profiles of five cloned human muscarinic receptorsubtypes. J Pharmacol Exp Ther 1991;256727- 733
PubMed
Buckley  NJBonner  TIBuckley  CMBrann  MR Antagonist binding properties of five cloned muscarinic receptors expressedin CHO-K1 cells. Mol Pharmacol 1989;35469- 476
PubMed
Leech  EMCottriall  CLMcBrien  NA Pirenzepine prevents form deprivation myopia in a dose dependent manner. Ophthalmic Physiol Opt 1995;15351- 356
PubMed Link to Article
Cottriall  CLMcBrien  NA The M1 muscarinic antagonist pirenzepine reduces myopia and eye enlargementin the tree shrew. Invest Ophthalmol Vis Sci 1996;371368- 1379
PubMed
Tigges  MIuvone  PMFernandes  A  et al.  Effects of muscarinic cholinergic receptor antagonists on postnataleye growth of rhesus monkeys. Optom Vis Sci 1999;76397- 407
PubMed Link to Article
Shedden  AHSciberras  DHutzelmann  Jvan Nispen  C Tolerability of pirenzepine ophthalmic solution in adult male volunteers[ARVO abstract] Invest Ophthalmol Vis Sci 1998;39S279
Bartlett  JDNiemann  KHoude  B  et al.  Safety and tolerability of pirenzepine ophthalmic gel in pediatricmyopic patients. J Ocul Pharmacol Ther 2003;19271- 279
PubMed Link to Article
Ferris  FLKassoff  ABresnick  GHBailey  I New visual acuity charts for clinical research. Am J Ophthalmol 1982;9491- 96
PubMed
Fleming  TRHarrington  DPO'Brien  PC Designs for group sequential tests. Control Clin Trials 1984;5348- 361
PubMed Link to Article
Osterlind  G An investigation into the presence of lymphatic tissue in the humanconjunctiva, and its biologic and clinical importance. Acta Ophthalmol (Copenh) 1944;231- 79
Eye Disease Case-Control Study Group, Risk factors for idiopathic rhegmatogenous retinal detachment. Am J Epidemiol 1993;137749- 757
PubMed
Perkins  ES Morbidity from myopia. Sight Sav Rev 1979;4911- 19
PubMed
Gwiazda  JHyman  LHussein  M  et al.  A randomized clinical trial of progressive addition lenses versus singlevision lenses on the progression of myopia in children. Invest Ophthalmol Vis Sci 2003;441492- 1500
PubMed Link to Article
Stone  RALin  TLaties  AMIuvone  PM Retinal dopamine and form-deprivation myopia. Proc Natl Acad Sci U S A 1989;86704- 706
PubMed Link to Article
Iuvone  PMTigges  MStone  RA  et al.  Effects of apomorphine, a dopamine receptor agonist, on ocular refractionand axial elongation in a primate model of myopia. Invest Ophthalmol Vis Sci 1991;321674- 1677
PubMed
Guo  SSSivak  JGCallender  MGDiehl-Jones  B Retinal dopamine and lens-induced refractive errors in chicks. Curr Eye Res 1995;14385- 389
PubMed Link to Article
Lind  GJChew  SJMarzani  DWallman  J Muscarinic acetylcholine receptor antagonists inhibit chick scleralchondrocytes. Invest Ophthalmol Vis Sci 1998;392217- 2231
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Patient disposition.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Mean spherical equivalent (SEQ) changefrom baseline. Error bars indicate SEM; D, diopters. Between-treatment P values are <.001, .006, <.001, and <.001 at3, 6, 9, and 12 months, respectively.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Proportion of patients with criterionprogression at 12 months calculated on the basis of mean of patients’eyes. P values are.09, .007, .006, and <.001 for0.25, 0.50, 0.75, and 1.00 diopters, respectively.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Mean change from baseline in pupildiameter. Time shown is baseline or approximately 12 hours after last instillation.Error bars indicate standard error of the mean. P valuesare <.001, <.001, <.001, <.001, <.001, and.005 at week 2 andmonths 1, 3, 6, 9, and 12, respectively.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Demographics and Prestudy Characteristics
Table Graphic Jump LocationTable 3. Mean Axial Length of Patients’ Eyes
Table Graphic Jump LocationTable 4. Treatment Emergent Adverse Events by Descending Incidence*

References

Sperduto  RDSeigel  DRoberts  JRowland  M Prevalence of myopia in the United States. Arch Ophthalmol 1983;101405- 407
PubMed Link to Article
Wang  QKlein  BEKlein  RMoss  SE Refractive status in the Beaver Dam Eye Study. Invest Ophthalmol Vis Sci 1994;354344- 4347
PubMed
Framingham Offspring Eye Study Group, Familial aggregation and prevalence of myopia in the Framingham OffspringEye Study. Arch Ophthalmol 1996;114326- 332
PubMed Link to Article
Negrel  ADThylefors  B The global impact of eye injuries. Ophthalmic Epidemiol 1998;5143- 169
PubMed Link to Article
Shih  Y-FChen  C-HChou  A-C  et al.  Effects of different concentrations of atropine on controlling myopiain myopic children. J Ocul Pharmacol Ther 1999;1585- 90
PubMed Link to Article
Shih  YFHsiao  CKChen  CJ  et al.  An intervention trial on efficacy of atropine and multi-focal glassesin controlling myopic progression. Acta Ophthalmol Scand 2001;79233- 236
PubMed Link to Article
Yen  MYLiu  JHKao  SCShiao  CH Comparison of the effect of atropine and cyclopentolate on myopia. Ann Ophthalmol 1989;21180- 187
PubMed
McBrien  NAMoghaddam  HOReeder  AP Atropine reduces experimental myopia and eye enlargement via a nonaccommodativemechanism. Invest Ophthalmol Vis Sci 1993;34205- 215
PubMed
Fischer  AJMiethke  PMorgan  IGStell  WK Cholinergic amacrine cells are not required for the progression andatropine-mediated suppression of form-deprivation myopia. Brain Res 1998;79448- 60
PubMed Link to Article
Schaeffel  FTroilo  DWallman  JHowland  HC Developing eyes that lack accommodation grow to compensate for imposeddefocus. Vis Neurosci 1990;4177- 183
PubMed Link to Article
Norton  TTEssinger  JAMcBrien  NA Lid-suture myopia in tree shrews with retinal ganglion cell blockade. Vis Neurosci 1994;11143- 153
PubMed Link to Article
Stone  RALin  TLaties  AM Muscarinic antagonist effects on experimental chick myopia [letter] Exp Eye Res 1991;52755- 758
PubMed Link to Article
Carmine  AABrogden  RN Pirenzepine: a review of its pharmacodynamic and pharmacokinetic propertiesand therapeutic efficacy in peptic ulcer disease and other allied diseases. Drugs 1985;3085- 126
PubMed Link to Article
Dorje  FWess  JLambrecht  G  et al.  Antagonist binding profiles of five cloned human muscarinic receptorsubtypes. J Pharmacol Exp Ther 1991;256727- 733
PubMed
Buckley  NJBonner  TIBuckley  CMBrann  MR Antagonist binding properties of five cloned muscarinic receptors expressedin CHO-K1 cells. Mol Pharmacol 1989;35469- 476
PubMed
Leech  EMCottriall  CLMcBrien  NA Pirenzepine prevents form deprivation myopia in a dose dependent manner. Ophthalmic Physiol Opt 1995;15351- 356
PubMed Link to Article
Cottriall  CLMcBrien  NA The M1 muscarinic antagonist pirenzepine reduces myopia and eye enlargementin the tree shrew. Invest Ophthalmol Vis Sci 1996;371368- 1379
PubMed
Tigges  MIuvone  PMFernandes  A  et al.  Effects of muscarinic cholinergic receptor antagonists on postnataleye growth of rhesus monkeys. Optom Vis Sci 1999;76397- 407
PubMed Link to Article
Shedden  AHSciberras  DHutzelmann  Jvan Nispen  C Tolerability of pirenzepine ophthalmic solution in adult male volunteers[ARVO abstract] Invest Ophthalmol Vis Sci 1998;39S279
Bartlett  JDNiemann  KHoude  B  et al.  Safety and tolerability of pirenzepine ophthalmic gel in pediatricmyopic patients. J Ocul Pharmacol Ther 2003;19271- 279
PubMed Link to Article
Ferris  FLKassoff  ABresnick  GHBailey  I New visual acuity charts for clinical research. Am J Ophthalmol 1982;9491- 96
PubMed
Fleming  TRHarrington  DPO'Brien  PC Designs for group sequential tests. Control Clin Trials 1984;5348- 361
PubMed Link to Article
Osterlind  G An investigation into the presence of lymphatic tissue in the humanconjunctiva, and its biologic and clinical importance. Acta Ophthalmol (Copenh) 1944;231- 79
Eye Disease Case-Control Study Group, Risk factors for idiopathic rhegmatogenous retinal detachment. Am J Epidemiol 1993;137749- 757
PubMed
Perkins  ES Morbidity from myopia. Sight Sav Rev 1979;4911- 19
PubMed
Gwiazda  JHyman  LHussein  M  et al.  A randomized clinical trial of progressive addition lenses versus singlevision lenses on the progression of myopia in children. Invest Ophthalmol Vis Sci 2003;441492- 1500
PubMed Link to Article
Stone  RALin  TLaties  AMIuvone  PM Retinal dopamine and form-deprivation myopia. Proc Natl Acad Sci U S A 1989;86704- 706
PubMed Link to Article
Iuvone  PMTigges  MStone  RA  et al.  Effects of apomorphine, a dopamine receptor agonist, on ocular refractionand axial elongation in a primate model of myopia. Invest Ophthalmol Vis Sci 1991;321674- 1677
PubMed
Guo  SSSivak  JGCallender  MGDiehl-Jones  B Retinal dopamine and lens-induced refractive errors in chicks. Curr Eye Res 1995;14385- 389
PubMed Link to Article
Lind  GJChew  SJMarzani  DWallman  J Muscarinic acetylcholine receptor antagonists inhibit chick scleralchondrocytes. Invest Ophthalmol Vis Sci 1998;392217- 2231
PubMed

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