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Ocular hypotensive efficacy and safety of once daily carteolol alginate
  1. Philippe Demaillya,
  2. Catherine Allaireb,
  3. Claude Trinquand for the Once-daily Carteolol Study Groupb
  1. aHôpital St Joseph, Institut du Glaucome, Paris, France, bScientific and Medical Affairs Department, Laboratoire Chauvin, Montpellier, France
  1. Claude Trinquand, MD, Laboratoire Chauvin, Scientific and Medical Affairs Department, Le Millenaire, BP 1174, F-34009 Montpellier cedex, Francectrinqua{at}chauvingroup.com

Abstract

BACKGROUND/AIM Carteolol is a β adrenoceptor antagonist used topically to reduce intraocular pressure, typically twice daily. In an effort to provide a once daily dosing regimen, carteolol was formulated with 1% alginic acid. The objective of this study was to evaluate the efficacy and safety of carteolol alginate solution in comparison with standard carteolol solution.

METHODS This was a double masked, parallel group, multicentre study. Patients with ocular hypertension or open angle glaucoma (n=235) were randomly assigned to receive either carteolol alginate four times daily or standard carteolol solution, twice daily. The masking was maintained through the use of a vehicle in the evening for the alginate group. Patients were evaluated at baseline, 15, 60, and 120 days.

RESULTS At 0900 (presumed trough) on day 60, mean reductions in intraocular pressure (IOP) from baseline were 6.09 (SD 2.97) and 6.09 (3.18) mm Hg for the standard carteolol and alginate, respectively. At 1100 (presumed peak), mean reductions were 6.51 (2.53) and 6.47 (2.76) mm Hg, respectively. Results were similar at other times (day 15 and day 120). The most common side effect was transient stinging on instillation of drops, which did not differ significantly between groups. There were no differences of note in other ocular or systemic signs or symptoms.

CONCLUSION The new alginate formulation of carteolol 2% given once daily was as effective as standard carteolol 2% given twice daily with no meaningful differences regarding safety.

  • carteolol alginic acid
  • eye drops
  • ocular hypertension

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Carteolol is a β adrenoceptor antagonist with intrinsic sympathomimetic activity. Applied topically in patients with elevated intraocular pressure (IOP), it elicits a dose related decrease in IOP, with a maximum at 2%.12 Applied twice daily, its ocular hypotensive efficacy has been reported to be similar to that of timolol.34

Glaucoma is for the most part an asymptomatic disease, and the treatments may elicit both local and systemic untoward effects. Thus, it is a classic disease for which patient adherence with a medication regimen may be low.5 In an effort to reduce the dosing frequency for topical carteolol from the standard twice daily to once daily, carteolol was formulated with alginic acid. Alginate solution exhibits a viscosity low enough to be compatible with topical administration without blurring effect. Sodium alginate is a natural polymer product with bioadhesive properties,6 used in many pharmaceutical preparations including those for reflux oesophagitis.7 In animals, an alginate formulation of carteolol 1% and 2% provides good intraocular delivery of carteolol, enhanced relative to standard solution.8 In a water loaded rabbit model of aqueous humour dynamics, the alginate formulation of carteolol had a longer duration of action than the standard solution.8 In a short term study in normal volunteers, the alginate formulation was found to be of similar comfort as the standard solution, with a possible longer duration of ocular hypotensive action.

The objective of this study was to evaluate the efficacy and safety of carteolol alginate administered once daily in comparison with standard carteolol solution administered twice daily in a long term study.

Methods

This was a double masked, randomised, multicentre study, comparing two parallel treatment groups. Enrolled were adult patients with open angle glaucoma or ocular hypertension in one or both eyes. Patients using ocular hypotensive medication were required to undergo a washout as follows: β adrenoceptor antagonists or sympathomimetics (3 weeks); latanoprost (1 week), pilocarpine, apraclonidine, or topical or oral carbonic anhydrase inhibitors (72 hours). For entry into the study the “study” eye(s) was (were) required to have an unmedicated IOP ⩾ 23 at 0900 or 1100 and < 32 mm Hg at 0900 and 1100. This study was reviewed by an institutional review board, and all patients provided written informed consent. Excluded from the study were patients with angle closure, congenital, secondary glaucoma, or advanced glaucoma; contact lens wear during the study; any intraocular infection or inflammation, ocular trauma, ocular surgery, or laser trabeculoplasty within the previous 3 months; previous intolerance to carteolol; or contraindications to the use of β adrenoceptor antagonists (for example, asthma, chronic obstructive pulmonary disease, moderate to severe atrioventricular block unless a pacemaker was implanted, or bradycardia <45 bpm, etc). Ocular corticosteroid use during the study was prohibited. Patients who were using systemic medications such as adrenergic hypotension agents were allowed to participate if the condition and dosing regimen were stable. Also excluded were pregnant and lactating women.

A baseline examination was conducted, including measurements of heart rate and blood pressure, visual acuity, automated threshold visual field (if not performed within the previous 6 months), biomicroscopy, IOP measurement by Goldmann applanation at 0900 and 1100. After the last baseline IOP measurement, patients were assigned to receive, in a double masked fashion, either 2% carteolol alginate four times daily (∼0900) or standard 2% carteolol solution (Carteol, Laboratories Chauvin, Montpellier, France), twice daily (∼0900 and 2100). The randomisation code was prepared using the proc ranuniprocedure (pc-sas Version 6.12, SAS Institute, Cary, NC, USA) with a block size of four.

The composition of carteolol-alginate was identical to that of market carteolol, with the exception of the addition of 1% alginate. The formulations were identical in tonicity and viscosity. The pH of the solutions was similar. The vehicle for the carteolol-alginate group was formulated the same as the carteolol-alginate formulation, with the exception of carteolol. Patients used the medication in one or both eyes. The masking was maintained through the use of a vehicle in the evening for the alginate group. Patients were evaluated at baseline, 15, 60, and 120 days, with IOP measurements just before instillation of medication (0900) and 2 hours after in-office instillation of medication (1100). Slit lamp examinations were performed at each follow up examination, together with measurement of heart rate and blood pressure (1000) and ocular tolerance of the medication (1100). At day 120, visual acuity was assessed with the Snellen or decimal Monoyer scale, and visual fields were performed.

Statistical analysis of ocular hypotensive efficacy was performed on the eye with the higher IOP at a mean of the 0900 and 1100 baseline, or, if equal, the right eye. With a sample size of 105 patients per treatment group, this study was planned for 95% power to detect a difference in treatments on IOP of 2 mm Hg, assuming a standard deviation of 4 mm Hg,9 and a two tailed alpha of 0.05. The study also had 80% power to detect a treatment difference of 1.5 mm Hg. An overenrolment of approximately 5% was planned to account for any premature withdrawals or disqualifications. Both intent to treat and per protocol analyses were planned. Continuous measures were analysed using t test or Wilcoxon rank sum test depending on the distribution and ANOVA, and categorical measures were evaluated using the χ2 test (proc ttest, proc npar1way, proc glm and proc freq, pc-sas). A priori, the primary efficacy criterion was defined as the change from time relevant baseline IOP on day 60, a period by which the IOP on the new treatment should have stabilised. Equivalence tests were carried out following the methodology described by Grouin and Coste.10 Two one sided t tests were performed. If both p values were inferior to 0.05, then equivalence between the two formulations was the conclusion.

Results

Entered into the study were 235 patients (115 standard and 120 alginate), plus one subject who did not return after day 0. In the standard group, five patients did not complete the study: lost to follow up (one), adverse events (two, dizziness, thorax pain and sweats of moderate intensity; and mild ocular irritation), worsening of disease (one), and cancellation of consent (one). In the alginate group a similar number of patients did not complete the trial: adverse events (three, tinnitus and watering of the eye; bradycardia; and dizziness—all judged mild or moderate), cancellation of consent (one), and poor compliance (one).

Patient demographics are shown in Table 1. The population was 58% male with a mean age of 61 years, with iris colour distributed among blue-green-grey, hazel, and brown irides. Most patients were white. Approximately two thirds of the patients were diagnosed with primary open angle glaucoma (63.4%, 149/235), including three patients with pigmentary glaucoma (one in standard group and two in the alginate group). There were no statistically significant differences between treatment groups (p ⩾0.22). Most (87%; 204/235) patients received treatment in both eyes. Also, most (64%, 151/235) patients were using at least one systemic medication. Before study entry, 51% of patients (120/235) were using an ocular hypotensive medication. For 102 of these patients, this medication was a topical β adrenoceptor antagonist.

Table 1

Demographics

Mean intraocular pressure at 0900 and 1100 is shown in Figures 1 and 2respectively, and mean change from baseline in intraocular pressure in Tables 2 and3.

Figure 1

Mean intraocular pressure (IOP) at 0900 (SD).

Figure 2

Mean intraocular pressure (IOP) at 1100 (SD).

Table 2

Intraocular pressure at 0900 (mm Hg): mean (SD) change from day 0 baseline

Table 3

Intraocular pressure at 1100 (mm Hg): mean (SD) change from day 0 baseline

From a baseline of approximately 24–25 mm Hg, mean reductions ranged from 5.5 to 6.5 mm to an IOP of approximately 18 mm Hg in both treatment groups. The ocular hypotensive efficacy of carteolol was slightly greater at 1100, 2 hours after the last instillation, relative to 0900, approximately 24 or 12 hours after the last instillation of alginate or standard, respectively. The IOP course was statistically significant within time (time effect: p=0.0001 in the repeated measures analysis). There was no evidence of drift with either treatment. In the equivalency analyses, all measures were within the plus or minus 2 mm Hg interval for equivalence and the two unilateralt tests were highly significant (p <0.005) at each time of evaluation.

A per protocol analysis was performed on the 210 patients (102 in standard and 108 in alginate groups) without major protocol violations. Results were similar to the intent to treat analysis. The confidence intervals were (−0.57, +0.80) and (−0.46, 0.66) mm Hg for day 60 at 0900 and 1100, respectively.

No change was noted in distance visual acuity for 78.3% (90/115) of standard treated patients and in 70.0% (84/120) of alginate treated patients, without any statistically significant difference between the two treatment groups (χ2, p = 0.20). Similar results were seen with fellow eye.

At day 120, visual fields were unchanged for 78.3% (90/115) of standard carteolol treated patients and 67.5% (81/120) of alginate treated patients for the study eye (p = 0.12 by χ2).

Adverse events were reported by 59 patients. Fifteen adverse events were assessed as drug related. Among these, four affected the eye and adnexa: two in the standard group (one irritation and one worsening of dry eye) and two in the alginate group (one ocular irritation and one superficial punctate keratitis). Eleven non-ophthalmic adverse events were assessed as drug related: five in the standard carteolol group and six in the alginate group. These adverse events were known possible β blocker side effects.

Two serious adverse events were reported during the study: unilateral worsening of existing age related macular degeneration (standard group) and hospitalisation for repair of hiatal hernia (alginate group). Neither was judged as drug related.

Subjective tolerance upon instillation was judged good or very good by 99% of alginate patients and by 98% of standard patients evaluated on day 120 (Table 4). Discomfort was reported by approximately 10% to 15% of patients in each treatment group at each visit (Table 5). These reports were similar in incidence in each group. The most frequent discomfort in both groups was a stinging sensation which generally lasted for a few seconds or a few minutes. The blurred vision sensation was recorded in 3/120 patients of the alginate group and 2/115 patients of the standard group.

Table 4

Number and percentage of patients with very good or good tolerance upon instillation

Table 5

Description of discomfort upon instillation

At baseline, mean heart rate, systolic and diastolic blood pressure was approximately 73–74 bpm, 141–144 mm Hg, and 81–82 mm Hg, respectively. Slight decreases in means were observed at follow up visits (up to 6 bpm, 8 mm Hg, and 3 mm Hg, respectively). There were no statistically significant differences between treatment groups (p = 0.607 to 0.852).

Discussion

Evaluated at both peak and trough, at an initial, middle, and long term stage, the new alginate formulation once daily was equivalent in ocular hypotensive efficacy to the standard solution formulation given twice daily. While a vehicle control would have been desirable, it is not possible to use in a chronic glaucoma study for ethical reasons. The positive control, standard carteolol solution, was similarly effective in the present study (reduction of ∼ 6 mm Hg, or ∼25%) to that observed in previous studies.2411 Thus, the efficacy of the positive control, and the high power of the study (95% to detect a 2 mm Hg difference) supports the statement of equivalency.

Special attention is directed towards the 0900 hour measurement. This is ∼24 hours after the last dose of carteolol alginate, and yet the mean IOP is similar to the standard solution given 12 hours previously.

The ocular tolerance of the alginate was good. Again, it was similar to the standard formulation, which itself has been reported to be well tolerated.1213 Thus, the finding of no substantial comfort problems is also a positive attribute of the alginate. In particular, the incidence of blurred vision (less than 3% in each group) is much lower than what has been reported with timolol in gel forming solution.13

With regard to safety, there was no significant difference between both treatment groups for all studied safety variables.

Both treatment groups experienced a slight decrease in mean heart rate and blood pressure. The intrinsic sympathomimetic activity of carteolol could explain the relatively small impact of carteolol on the cardiovascular function: carteolol has been shown to cause less bradycardia than timolol at night.14 In our study, cardiovascular parameters were measured only once per visit, 1 hour after the morning instillation. Thus, it is not possible to discuss what occurred at other times for the 24 hours.

The relatively few adverse events were similar to those previously reported for this class of compounds.1516

In conclusion, the new alginate formulation of carteolol 2% given once daily was as effective as standard carteolol given twice daily with no meaningful differences regarding safety.

Acknowledgments

Conflict of interest: Professor Demailly serves as a consultant to Laboratories Chauvin, but has no proprietary interest. Drs Allaire and Trinquand are employees of Laboratories Chauvin.

The Once-daily Carteolol Study Group consisted of 23 French clinical centres and one Swiss clinical centre: Y Lachkar, MD, H Graciès, MD, Hôpital St Joseph, Paris (Study Coordinator: Pr Ph Demailly); J P Adenis, MD, Ph Bertin, MD, CHRU Dupuytren, Limoges; JC Dascotte, MD, Loos; J Flament, MD, J Szwarcberg, MD, Hospices Civils, Strasbourg; T Hoang-Xuan, MD, N Belayachi, MD, Hôpital Bichat, Paris; G Kretz, MD, Paris; MJ Le Rebeller, MD, Ph Cousin, MD, GH Pellegrin-Tripode, Bordeaux; G Lesieur, MD, Albi; M Montard, MD, F Majo, MD, CHR Jean Minjoz, Besançon; A Raspiller, MD, L Mala, MD, X Portrat, MD, Hôpital Central, Nancy; Ph Renard, MD, P Delacour, MD, Institut Arthur Vernes, Paris; D Sirbat, MD, Strasbourg; C Bouat, MD, S Vitte, MD, JP Ghipponi, MD, Hôpital Militaire Laveran, Marseille; L Pernod, MD, P Héliès, MD, CHA René Le Bas, Cherbourg; C Rousse, MD, C Chopin, MD, Hôpital Louis Pasteur, Dôle; JL George, MD, P Lesure, MD, Hôpital de Brabois, Vandoeuvre-les-Nancy; J Ferraton, MD, Clinique Charcot, Ste-Foy-les-Lyon; A Brézin, MD, ORivoal, MD, A Lefrançois, MD, Hôpital Cochin, Paris; G Arrouas, MD, Dijon; JD Grange, MD, L Kodjikian Hôpital de la Croix Rousse, Lyon; JL Kovalski, MD, Y Dordain MD, R Macarez MD, D Salabert MD, HIA ‘’Clermont-Tonnerre'‘, Brest; P Daubas MD, G Filliard MD, Hôpital Sainte-Anne, Toulon; AGarrec, MD, Polyclinique Sévigné, Cesson-Sevigné; A Mermoud, MD, F Achache MD, A Chabari MD, Hôpital Jules Gonin, Lausanne (Suisse).

Statistician: Alice Huntsman, PhD, Clinica and Statistica (Issy les Moulineaux, France).

Coordinating centre: Catherine Allaire, MD, Sandrine George, MS, Anne Combe, MS, Florence Bernard, MS, Ghéziel El Hamdi, PhD, Scientific and Medical Affairs Department, Laboratoire Chauvin, Montpellier, France.

Medical writer: Gary D Novack, PhD (San Rafael, CA, USA).

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