Primary Efficacy Variable
The mean change in IOP at D84 was −0.49±1.80 mm Hg for T2347 and −0.49±2.25 mm Hg for BPLT in the mITT set (Table 2). Noninferiority was demonstrated at D84, as the upper limit of the 95% CI for the difference between treatments (T2347 minus BPLT) was <1.5 mm Hg (0.50 mm Hg, MMRM). Noninferiority was confirmed by the PP and ITT analyses.
The sensitivity analysis using ANCOVA also supported the result of noninferiority (upper 95% CI: 0.54 mm Hg).
Secondary Efficacy Variables
In the contralateral eye, the change in IOP from baseline at D84 was 0.08±2.06 mm Hg for T2347 and 0.14±2.25 mm Hg for BPLT, with an upper 95% CI for the treatment difference of 0.43 mm Hg (MMRM), supporting the primary analysis. The sensitivity analysis for the contralateral eye (ANCOVA) also supported the primary analysis (upper 95% CI: 0.44 mm Hg).
Similar results were seen at D42 in the worse eye, with a change in IOP of −0.65±1.86 mm Hg for T2347 and −0.49±2.24 mm Hg for BPLT (upper 95% CI: 0.31 mm Hg) (Table 2). Results for the contralateral eye also showed no difference between groups at D42, supporting the results for the worse eye, with a change in IOP of 0.05±2.41 mm Hg for T2347 and 0.05±2.18 mm Hg for BPLT (upper 95% CI: 0.52 mmHg).
Investigators assessed the global efficacy as satisfactory or very satisfactory with no statistically significant difference between treatments at D42 (≥94.6%; P=0.850, CMH) and D84 (≥97.5%; P=0.862).
Safety and Tolerability
In the T2347 group, 12 (9.4%) patients experienced treatment-related ocular AEs versus 8 (7.0%) patients in the BPLT group (P=0.482). The most common treatment-related ocular AEs were eye irritation (2 and 5 patients in the T2347 and BPLT groups, respectively) and conjunctival hyperemia (3 and 1 patients) (Table 3). The incidence of treatment-related systemic AEs was similar in both treatment groups (P=0.686), reported by 4 (3.1%) patients in the T2347 group and 2 (1.7%) patients in the BPLT group (Table 3).
Most treatment-related ocular and systemic AEs were mild or moderate in severity. No patient in either group experienced an ocular SAE; one patient experienced a systemic SAE (cerebral artery occlusion in the BPLT group), but this was not considered to be treatment related, and the patient recovered without sequelae. Three patients were withdrawn because of treatment-related ocular AEs of eye pain (one patient in the T2347 group) and eye irritation (one patient in each group).
The median (range) total severity score of ocular symptoms upon instillation was similar at baseline in the T2347 group and the BPLT group (1.0 [0-9] for both), and it was consistently lower for T2347 than for BPLT on D42 (0.0 [0-9] vs. 1.0 [0-6]) and D84 (0.0 [0-6] vs. 0.5 [0-7]). A statistically significant between-group difference was shown for the change from baseline in the total score of symptoms upon instillation on D42 (P=0.007), as well as on D84 (P=0.021) (Table 4). No statistically significant between-group difference was shown for ocular symptoms throughout the day on D42 (P=0.155) and D84 (P=0.129) (Table 4).
There were no statistically significant differences between treatments in individual ocular symptoms of tearing, foreign body sensation, and eye dryness sensation on D42 or D84, either upon instillation or throughout the day (Fig. 2 and Table, Supplemental Digital Content 1, http://links.lww.com/IJG/A245). However, irritation/burning/stinging was significantly less severe in the worse eye for T2347 than for BPLT upon instillation on D42 (P=0.003) and D84 (P<0.001) (Fig. 2A), but there was no difference between treatments throughout the day on D42 (P=0.612) or D84 (P=0.094) (Fig. 2B). Itching in the worse eye on D84 was significantly less severe for T2347 than for BPLT, both upon instillation (P=0.01) (Fig. 2A) and throughout the day (P<0.001) (Fig. 2B).
Other Safety Parameters
There were no clinically important differences between groups for any slit-lamp examination, including conjunctival hyperemia and global ocular staining (Table 4), nor for corneal thickness, fundoscopy, visual field examinations, best-corrected far visual acuity, blood pressure, or heart rate during the study.
Satisfaction with regard to local tolerance assessed by the investigator and patient was similar for each group at both D42 (≥96.4% very satisfactory/satisfactory, P=0.442 and P=0.110, respectively) and at D84 (≥93.6% very satisfactory/satisfactory, P=0.058 and P=0.089). Of note, the percentage of patients who were very satisfied was higher in the T2347 group than in the BPLT group on both D42 (57.0% vs. 45.0%) and D84 (65.3% vs. 50.0%).
In this phase III randomized, investigator-masked, and multicenter study, noninferiority of efficacy for a preservative-free latanoprost-timolol fixed combination (T2347) compared with BPLT was demonstrated at D84 in patients suffering from OAG/OHT who were previously receiving the preserved formulation. Although the overall safety profile was comparable between the 2 groups, T2347 induced improvements in some ocular symptoms.
Although an increased bioavailability of BAK-preserved drugs has been reported,26–28 a growing body of evidence indicates no difference between BAK-preserved and BAK-free formulations. Comparable penetration of both tafluprost formulations has been shown in the aqueous humor of rabbits.29 Furthermore, numerous clinical trials have assessed the impact on efficacy of the removal of BAK from latanoprost,25 bimatoprost,30 tafluprost,31 timolol,32 or bimatoprost/timolol fixed combination33,34 formulations and concluded that the efficacy of the BAK-free formulation was noninferior (or equivalent) to that obtained with the BAK-preserved formulation. Recently, Bhagat and colleagues performed a randomized, parallel-group, active-controlled study in patients with OAG or OHT to compare the IOP-lowering efficacy of a novel fixed-dose combination of latanoprost 0.005%/timolol 0.5%, preserved with zinc chloride and boric acid, with latanoprost (BAK-preserved, Xalatan; Pfizer Inc., New York, NY) or timolol (BAK-preserved, Timoptic; Merck & Co Inc., Whitehouse Station, NJ) administered as monotherapy or concomitantly.23 The IOP-lowering efficacy of this new BAK-free latanoprost/timolol fixed combination was similar to BAK-preserved latanoprost plus timolol administered concomitantly, and better than preserved latanoprost or timolol administered alone. Our results are consistent with the literature and add to these previous findings in terms of IOP control. Of note, the slight IOP reduction in patients who continued on the same treatment during the study (BPLT group) could be explained by the lack of reproducibility in diurnal IOP pattern over time35,36 or by the Hawthorne effect, that is, better patient management and overall compliance in a clinical trial setting.37,38
Formulations without preservatives have previously been shown to have improved tolerability compared with those containing BAK.25 In the present study, however, preservative-free T2347 showed a similar overall safety profile to the BAK-preserved comparator. At least 4 possible explanations can be put forward for this observation. First, an 84-day treatment period may not be sufficient to observe real differences in objective ocular signs. For instance, in another 3-month study, a BAK-preserved formulation of travoprost showed a similar safety profile to a BAK-free formulation.39 In clinical practice, glaucoma treatment is usually given over a period of years, and the toxic effects of BAK may require regular use over a long period of time before adverse ocular signs are clinically identifiable.20,40 Second, although the combination of 2 ocular therapies might be expected to result in a safety profile reflecting the sum of side effects due to the individual components, clinical studies and meta-analyses have shown fixed combinations containing a β-blocker to be better tolerated than individual components.15,16,41,42 In this context, it is noteworthy that local tolerance, including moderate to severe conjunctival hyperemia, has been shown to be significantly improved by the same preservative-free formulation as T2347 but without timolol (Monoprost; Laboratoires Théa, Clermont-Ferrand, France) compared with BPLT without timolol (Xalatan) after 3 months of treatment.25 The presence of timolol in the latanoprost formulations, therefore, could reduce the between-group difference in tolerability in the present study that would otherwise be expected due to the preservative. Third, patients with a more severe ocular surface disease were not included in the present study. Exclusion of these potentially more sensitive patients could have further limited the differences observed between groups over the 84-day study period. Finally, only patients already successfully treated with a preserved latanoprost-timolol fixed combination were included, and, by definition, these patients tolerated it well.
A potential limitation of the present study was the choice of a single morning IOP assessment for comparing T2347 to the preserved comparator. However, this approach is supported by several arguments: (1) peak IOP generally occurs in the morning in most POAG and OHT patients, (2) the 24-hour efficacy on IOP of the latanoprost-timolol fixed combination administered once daily in the evening in glaucoma and OHT patients is well established, (3) on the basis of preclinical data in monkeys, T2347 was shown as effective as BPLT in reducing IOP in the morning, as well as over 24 hours, after once-daily repeat dosing in the evening.43 In the preclinical study, the morning time point was shown to be the most challenging time to demonstrate noninferiority of T2347 to the reference treatment. This is consistent with the results from a cross-over clinical trial that showed a similar diurnal IOP-lowering effect (measured at 8 AM, 12 noon, 4 PM, and 8 PM) of the same preservative-free formulation as T2347 but without timolol (Monoprost) in comparison with BPLT without timolol (Xalatan).44 Thus, it was considered that the IOP-lowering effect of T2347 compared with the reference BPLT could be relevantly extrapolated from the single morning IOP assessment.
Other potential limitations of the study included a double-masked design not being feasible due to the different packaging of T2347 and BPLT (single-dose units vs. multidose vials, respectively). Although the study procedures ensured that single-masking was maintained and controlled by assigning personnel other than the investigator to dispense treatments and by instructing patients not to disclose treatment information to the investigator, patients could have known which treatment was assigned, which could have led to bias in the reporting of subjective assessments. Also, for ethical purposes, a washout period was deemed not to be appropriate for these patients already treated and IOP controlled by preserved fixed combination at study entry. Moreover, the primary endpoint was evaluated at D84, allowing sufficient time to eliminate any carry-over effect of previous treatment. With regard to the statistical tests, an upper 95% CI limit of 1.5 mm Hg for the treatment difference at D84 was used to show noninferiority for the IOP change from baseline for T2347 compared with BPLT. While 1.5 mm Hg is a common limit for studies with participants with uncontrolled IOP at baseline,15,45 using it for participants already medicated at study entry and therefore with lower IOP at baseline, such as in the present study, could be considered a less rigorous standard. However, the noninferiority of T2347 would still have been demonstrated using the more stringent limit of 1 mm Hg,46,47 and even using 0.5 mm Hg. In addition, similar results were observed at D42, although the study was not designed for a formal noninferiority assessment at this time point.
In conclusion, the preservative-free latanoprost-timolol fixed combination T2347 showed noninferior efficacy compared with the preserved comparator in patients who were previously receiving the preserved formulation at study entry. T2347 was well tolerated and demonstrated improvements in some of the ocular symptoms. It could potentially confer a therapeutic advantage for OAG/OHT patients on long-term treatment.
The authors acknowledge the patients for their participation in this study and all study site personnel.
The authors thank Dr Andrew Lane (Lane Medical Writing) who provided professional medical writing assistance in the preparation and development of this manuscript in accordance with the European Medical Writers Association guidelines and Good Publication Practice.
The research contribution from Dr Clarke was supported by the NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust, UCL Institute of Ophthalmology, and the NIHR Moorfields Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.
The authors acknowledge the T2347 Study Group, composed of: Belgium: Dr Nathalie Collignon, Dr Marc Goethals, Prof Ingeborg Stalmans; Estonia: Dr Tiia Jugaste, Dr Kuldar Kaljurand, Dr Krista Turman; France: Prof Béatrice Cochener, Dr Laurent Coupier, Prof Bruno Mortemousque, Prof Jean-Philippe Nordmann, Prof Jean-François Rouland, Dr Marie-Claude Veschambre; Germany: Dr Philipp Franko Zeitz, Prof Norbert Pfeiffer, Dr Stefanie Schmickler, Dr Bogomil Voykov, Dr Joachim Watchlin; Hungary: Dr Adrienne Csutak, Dr Alexis Tsorbatzoglou, Prof Péter Vámosi, Dr L. Balázs Varsányi; Latvia: Dr Lasma Volksone; Poland: Prof Bartlomiej Kaluzny, Prof Ewa Mrukwa-Kominek, Dr Joanna Konopinska, Prof Wojciech Lubinski, Dr Jaroslaw Marek, Prof Jerzy Szaflik, Prof Tomasz Zarnowski; Russia: Prof Yury S. Astakhov, Prof Valeriy P. Erichev, Dr Andrey Zolotarev; Spain: Prof Alfonso Antón-López, Dr Elena Arrondo, Prof Javier Benítez-Del-Castillo, Dr Rafael A. Giménez-Gómez, Prof Noemi Güerri, Prof Enrique Mencía-Gutiérrez, Dr Jesús Hernández-Barahona Palma, Dr Jerónimo J. Lajara-Blesa, Dr Cosme Lavín-Dapena, Prof Javier Moreno-Montañés, Dr Ignacio Vinuesa-Silva; UK: Prof David C. Broadway, Dr Jonathan Clarke, Dr Mohammed Hassan, Dr James Kirwan, Dr Donald Montgomery.
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