Travoprost/timolol fixed combination shows promising results in phase 3 clinical trials

Testing of concomitant travoprost/timolol suggests statistically clinical equivalence with once-daily combination therapy.

ByPhilippe Denis, MD, PhD

Philippe Denis

In a series of phase-3 trials, a fixed combination of travoprost 0.004%/timolol 0.5% proved to be safe and well tolerated as a new treatment option for the management of IOP in patients with open-angle glaucoma and ocular hypertension. Results from the clinical trial were presented at the International Glaucoma Symposium in Athens, Greece, in March 2007.

Fixed-combination therapy

DuoTrav (travoprost 0.004%/timolol 0.5%; Alcon) is a once-daily fixed-combination ocular solution that provides the efficacy of two medications in one dose to simplify administration. The drug includes both the prostaglandin agonist travoprost and the beta-blocker timolol. Travoprost, a full FP receptor agonist, increases outflow through both the uveoscleral and conventional (trabecular) routes. Timolol inhibits the rate of aqueous humor production in the ciliary epithelium, thereby decreasing aqueous humor inflow. The combination drop is more effective in reducing IOP than the two agents taken alone, separately. DuoTrav also reduces IOP at the same rate as concomitant therapy and is more convenient for the patient, encouraging compliance and helping to eliminate potential wash-out effects caused by taking multiple medications sequentially.

Posology study

In the first of several phase 3 trials establishing the safety and efficacy of DuoTrav, identical dosages of the fixed-combination therapy were studied in a 6-week European posology analysis to determine whether a.m. (48 patients) or p.m. (44 patients) dosage was superior. Patients were required to have baseline IOP of >24 mm Hg at 9 a.m., >21 mm Hg at 11 a.m., and >21 mm Hg at 4 p.m. IOP was then measured at the same three time points at weeks 2 and 6.¹ Demographic parameters (gender, ethnicity, iris color, and diagnosis) were similar in both treatment arms.

Both a.m. and p.m. dosing of DuoTrav produced similar mean IOP reductions, most significantly at 9 a.m. when IOP decreased by 10 mm Hg. The diurnal curve was slighter flatter for the a.m. dose, although, as with other efficacy differences between the arms, did not reach statistical significance. Minimal hyperemia was reported in both treatment arms.

Clinically, these results may suggest that the fixed combination may be administered either in the morning or in the evening, and probably at any time of the day, with no clinical consequences.

DuoTrav vs. Travatan and timolol alone

Another phase 3 trial² was conducted to assess the safety and efficacy of DuoTrav (85 patients; once-daily dosing in a.m. with placebo in the p.m.) compared with single-agent Travatan (travoprost 0.004%; Alcon) (86 patients; once-daily dosing in p.m. with placebo in a.m.) and timolol 0.5% (92 patients; twice-daily dosing). To be eligible, patients had to have baseline IOP measurements of >26 mm Hg at 8 a.m., >24 mm Hg at 10 a.m., and >22 mm Hg at 4 p.m. IOP measurements were then taken at weeks 2 and 6 and month 3 during the study.

Results from the trial indicated that DuoTrav reduced IOP more effectively than either of the monotherapy components.²

At 8 a.m., exactly 1-day postdose, patients who received DuoTrav experienced significant reductions in IOP of up to 12 mm Hg (38%) compared with patients taking either of the other two study drugs. Similarly, patients receiving DuoTrav showed IOP reductions from baseline of up to 11 mm Hg at 10 a.m. compared with patients taking either Travatan or timolol. At 4 p.m., DuoTrav produced improved IOP measurements compared with the drugs used in the other two study arms, with reductions from baseline of up to 10 mm Hg. In total, IOP reductions with DuoTrav were 1.9 to 3.3 mm Hg greater than with timolol and 1.0 to 2.4 mm Hg greater than with Travatan.

DuoTrav also proved safe and well tolerated, with an incidence of adverse events comparable with both Travatan and timolol.

DuoTrav vs. concomitant administration of Travatan and timolol

In 2005, results from two pivotal phase 3 trials were published that further supported the safety and efficacy profiles of once-daily DuoTrav compared with concomitant Travatan and timolol in patients with open-angle glaucoma and ocular hypertension. Eligibility criteria for both studies required patients to have a baseline IOP of >22 mm Hg at 8 a.m. during two separate visits. Patients were then monitored for IOP at 8 a.m., 10 a.m., and 4 p.m. at weeks 2 and 6 and month 3.

DuoTrav produced statistically significant reductions in IOP from baseline measurements at the 8 a.m. time point, 24 hours following the last dose.

—Philippe Denis, MD, PhD

In the first trial, 151 patients received DuoTrav and 142 patients received concomitant Travatan and timolol.³ The two study groups had no significant demographic differences in terms of gender, ethnicity, iris color, or diagnosis. Considering the relatively high baseline IOP levels required for study entry, a greater number of the participants had open-angle glaucoma than ocular hypertension in both studies.

DuoTrav produced statistically significant reductions in IOP from baseline measurements at the 8 a.m. time point, 24 hours following the last dose. DuoTrav and concomitant Travatan and timolol resulted in mean IOP reductions from baseline of up to 9.1 and 9.3 mm Hg, respectively, at the 24-hour postdose time point.

Significant and equivalent reductions for both arms were also noted at the 10 a.m. and 4 p.m. time points. Noninferiority analysis conducted at the 10 a.m. time point revealed a similar efficacy profile for both arms. At the 4 p.m. time point, treatment with DuoTrav produced reductions in IOP of 7.4 to 7.8 mm Hg, statistically similar to the 8.4- to 8.6-mm Hg range observed with concomitant dosing.

Overall, DuoTrav resulted in mean IOP reductions from baseline of 7.4 to 9.4 mm Hg, compared with 8.4 to 9.4 mm Hg for concomitant eye drops, a difference of 0 to 1.0 mm Hg, indicating therapeutic equivalence between the two arms.

An additional group of patients receiving twice-daily timolol 0.5% (81 patients) was added in the second phase 3 trial comparing DuoTrav (155 patients) with concomitant Travatan and timolol (151 patients).⁴

DuoTrav proved noninferior to concomitant thercapy at all study time points. However, DuoTrav did produce superior reductions compared with twice-daily timolol. Treatment with DuoTrav, as well as with the other two study drugs, resulted in consistent and significant reductions in IOP from baseline throughout the trial.

Treatment with the fixed-combination therapy resulted in a lower rate of hyperemia than that observed with concomitant treatment throughout phase 3 testing (Figure).

Figure: Hyperemia Summary Acorss 5 Studies

Figure. Pooled data of reported ocular adverse events taken from 5 clinical trials.

Enhancing convenience

None of the phase 3 studies noted in this article measured patient compliance; although reducing IOP is attributed to the convenience of dosing with fixed-combination DuoTrav. By combining two separate medications into a once-daily fixed formulation, DuoTrav is potentially able to improve patient compliance, leading to better treatment outcomes.

The Ocular Hypertension Treatment Study revealed that approximately 40% of patients with glaucoma or ocular hypertension takes two or more IOP-lowering medications after 5 years of therapy.⁵ Factors contributing to noncompliance in glaucoma include intolerance of medication, forgetfulness, and physical incapacity to use eye drops. In addition, because glaucoma is primarily asymptomatic, some patients will resist acknowledging the condition and will feel less like they have a disease if they do not take their drops. Intolerance to the medication and the wash-out effect caused by failure to wait the indicated time between using different eyedrops are two other factors contributing to noncompliance.

Results of these phase 3 trials indicate that DuoTrav fixed-combination therapy effectively reduces IOP and is well tolerated. The efficacy of DuoTrav fixed-combination therapy will be established over time and through patient feedback and follow-up analyses. DuoTrav also provides greater reduction in IOP than either of its components and provides efficacy similar to that with concomitant travoprost plus timolol.

DuoTrav can be administered once a day in either the morning or the evening and should be prescribed to patients with open-angle glaucoma or ocular hypertension whose IOP is not sufficiently controlled by beta blocker or prostaglandin analog therapy.

References

Denis P, Andrew R, Wells D, Friren B. A comparison of morning and evening instillation of a combination travoprost 0.004%/timolol 0.5% ophthalmic solution. Eur J Ophthalmol. 2006;16:407-415.
Barnebey HS, Orengo-Nania S, Flowers BE, et al. The safety and efficacy of travoprost 0.004%/timolol 0.5% fixed combination ophthalmic solution. Am J Ophthalmol. 2005;140:1-7.
Hughes BA, Bacharach J, Craven ER, Kaback MB, Mallick S, Landry TA, Bergamini MV. A three-month, multicenter, double-masked study of the safety and efficacy of travoprost 0.004%/timolol 0.5% ophthalmic solution compared to travoprost 0.004% ophthalmic solution and timolol 0.5% dosed concomitantly in subjects with open angle glaucoma or ocular hypertension. J Glaucoma. 2005;14:392-399.
Schuman JS, Katz GJ, Lewis RA, et al. Efficacy and safety of a fixed combination of travoprost 0.004%/timolol 0.5% ophthalmic solution once daily for open-angle glaucoma or ocular hypertension. Am J Ophthalmol. 2005;140:242-250.
Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:701-713.

Philippe Denis, MD, PhD, is the Division Head of Ophthalmology and Professor of Medicine at University Hospital Complex of Lyon, France.