A multicenter,randomized, parallel-group,clinical trial comparing the safety and efficacy of loteprednol etabonate 0.5%/tobramycin 0.3% with dexamethasone 0.1%/tobramycin 0.3% in the treatment of Chinese patients with blepharokeratoconjunctivitis

Abstract

Objective:

To compare the efficacy and safety of loteprednol etabonate 0.5%/tobramycin 0.3% (LE/T) and dexamethasone 0.1%/tobramycin 0.3% (DM/T) ophthalmic suspensions in a Chinese population with ocular inflammation associated with blepharokeratoconjunctivitis (BKC).     

Tolerability of loteprednol/tobramycin versus dexamethasone/tobramycin in healthy volunteers: results of a 4-week,randomized, double-masked,parallel-group study

ABSTRACT

Objective: To compare the ocular comfort and tolerability of loteprednol etabonate 0.5%/tobramycin 0.3% (LE/T; Zylet^*) with dexamethasone 0.1%/tobramycin 0.3% (DM/T; TobraDex^?) in healthy volunteers.

Research design and methods: In this multicenter, randomized, double-masked, parallel-group study, healthy volunteers (n?=?306) were randomized to receive LE/T or DM/T four times per day for 28 days. Subjects recorded subjective ratings for seven comfort/tolerability parameters using an electronic patient diary (EPD). The primary endpoint was the difference at week 4 from the ratings of an artificial tear at baseline in comfort/tolerability parameters between treatment groups, using a noninferiority paradigm.

Clinical trials registration: ClinicalTrials.gov, NCT 00532961.

Results: The 97.5% confidence intervals for the lower bound were within –10 for all of the seven comfort/tolerability parameters evaluated (pain, stinging/burning, irritation, itchiness, foreign-body sensation, dryness, and light sensitivity). Secondary analysis revealed small but significant within-treatment differences in pain favoring LE/T over tears and in light sensitivity favoring tears over DM/T (p?<?0.01). Small between-treatment differences in the changes from baseline tear ratings to individual study visits favored LE/T for pain, stinging/burning, irritation, itchiness, foreign-body sensation, and light sensitivity at visit 4 (p?≤?0.04); for pain, stinging/burning, and foreign-body sensation at visit 5 (p?≤?0.03), and for dryness and light sensitivity at visit 6 (p?≤?0.05).

Conclusions: LE/T satisfied all conditions of noninferi-ority to DM/T in comfort and tolerability. Subjects receiving LE/T were more likely to report better ocular comfort/tolerability ratings relative to baseline artificial tears than subjects receiving DM/T.

Limitations: The study population consisted of healthy volunteers.     

Loteprednol and tobramycin in combination: a review of their impact on current treatment regimens

Importance of the field: The treatment of ocular inflammation continues to be a challenge. Topical corticosteroids are effective in reducing ocular inflammation but are limited by adverse events including elevation of intraocular pressure, development of cataracts, glaucoma and inhibition of wound healing with associated risk of infection. Loteprednol etabonate (LE) is a unique C-20 ester corticosteroid designed to produce a predictable therapeutic effect with a low incidence of side effects. Zylet^® (LE/T) a combination of LE and tobramycin (T) is indicated for the treatment of steroid-responsive ocular inflammatory conditions in which there exists either superficial bacterial ocular infection or a potential risk of bacterial infection.

Areas covered in this review: The current review of the literature (Medline and the Cochrane Library, 1996 – 2009) examines the safety and efficacy of LE/T in the treatment of ocular inflammation.

What the reader will gain: Studies with either LE or LE/T indicate that LE has a lower risk of IOP elevation compared with C-20 ketone corticosteroids owing to its rapid de-esterification to inactive metabolites. LE also lacks the ability to form Schiff base intermediates with lens proteins, a common first step in cataractogenesis. LE/T was noninferior to dexamethasone 0.1%/tobramycin 0.3% in the treatment of blepharokeratoconjunctivitis.

Take home message: LE/T may be a safer treatment option for ocular inflammation in which there is risk of superficial bacterial infections.     

Circadian IOP-lowering efficacy of travoprost 0.004% ophthalmic solution compared to latanoprost 0.005%*

ABSTRACT

Purpose: The primary objective of this study was to determine the intraocular pressure- (IOP) lowering efficacy over two consecutive 24-h periods of travoprost 0.004% ophthalmic solution (Travatan^?) compared to latanoprost 0.005% (Xalatan^?) dosed once daily in patients with primary open-angle glaucoma or ocular hypertension.

Methods: This was a double-masked trial conducted at the Hospital Clínico San Carlos, Madrid, Spain. The primary objective of this study was to determine the IOP lowering efficacy of travoprost and latanoprost. During the eligibility visit, patients’ IOP was measured throughout two consecutive 24‐h periods every 4?h. Patients were then randomized to travoprost or latanoprost (one drop at 8 p.m. daily for 2 weeks). Sixty-two patients were randomized (travoprost n = 32; latanoprost n = 30). IOP was measured at week 2 every 4?h throughout two 24‐h periods. All measurements were taken in both supine and sitting positions with the aid of Perkins applanation tonometry. Limitations of the study include a small sample size (due to the difficulty in recruiting patients in a study of this type) which enrolled only Caucasian patients and a short study duration. However, with 25 subjects per group, there was at least 90% power to detect a mean IOP change from baseline of 2.9?mmHg and 80% power to detect a difference of 2.5?mmHg between treatments.

Results: Patients on travoprost therapy showed lower mean IOP levels than those on latanoprost. This difference was statistically significant (?p < 0.05) at 12, 16, 20, 24, 36, 40, and 48?h after the last dose for the supine position. The mean IOPs in the supine position throughout the first and the second 24‐h period of the week 2 visit as well as for the 48‐h visit were statistically lower (?p < 0.05) for the travoprost group. Adverse events were mild and included hyperemia and corneal staining. Travoprost and latanoprost were both well tolerated.

Conclusion: Mean IOP values were significantly lower for patients on travoprost for the majority of time points in the supine position.     

Comparison of morning versus evening dosing and 24-h post-dose efficacy of travoprost compared with latanoprost in patients with open-angle glaucoma

ABSTRACT

Objective: To compare the IOP-lowering efficacy of a.m.-dosed travoprost and latanoprost at 24-h post-dose.

Research design and methods: Open-angle glaucoma patients not naïve to prostaglandin therapy and currently controlled on p.m.-dosed (2100) latanoprost (n?=?21) or travoprost (n?=?30) had baseline IOPs measured at 0900. In a randomized, single-masked, crossover design, patients received travoprost (Travatan) or latanoprost (Xalatan) at 0900 for 4?weeks, then were crossed over to receive the second prostaglandin for another 4?weeks. Treatment IOP was measured at 0900 prior to morning dose at both 4 and 8?week visits. Patient dosing preference (a.m./p.m.) was surveyed on exit.

Main outcome measure: Intraocular pressure (IOP).

Results: The mean IOP in the first period when all patients were dosed in the evening was assessed 12?h after dosing at 09:00 and it was similar in the two treatment groups (mean?±?standard deviation: 17.9?±?2.7?mmHg for travoprost versus 17.7?±?2.5?mmHg for latanoprost, p?=?0.812). In the a.m.-dosing crossover comparison, the 24-h post-dose IOP was significantly lower (?p?<?0.001) on travoprost (16.9?±?3.1?mmHg) compared to latanoprost (18.6?±?3.3?mmHg). In the exit survey, 51% of patients preferred a.m.-dosing.

Conclusions: a.m.-dosed travoprost is superior to a.m.-dosed latanoprost by 1.7?mmHg at 24-h post-dose.     

Evaluation of the effects on choroidal thickness of bimatoprost 0.03% versus a brinzolamide 1.0%/timolol maleate 0.5% fixed combination

Objective: To investigate the effects of two different medical treatment options on choroidal thickness (CT) in cases of open-angle glaucoma (OAG).

Methods: Sixty-seven eyes newly diagnosed with OAG and 52 healthy eyes constituting the control group were included in the study. Glaucomatous eyes were randomly divided into two subgroups; Group I was started on bimatoprost 0.03% and Group II on a brinzolamide 1.0%/timolol maleate 0.5% fixed combination (BTFC). Intraocular pressure (IOP), ocular pulse amplitude (OPA) and subfoveal CT measurements were performed in all eyes in the study before treatment and on weeks 2, 4 and 8 after treatment.

Results: Mean initial IOP values in groups I and II and the control group were 25.5?±?4.7, 25.1?±?5.2 and 16.1?±?2.9?mmHg, mean OPA values were 3.7?±?1, 3.6?±?1.4 and 2.4?±?0.6?mmHg and mean CT values were 269.4?±?83, 264.5?±?84.4 and 320.1?±?56.6?μm, respectively. Eight weeks after treatment, mean IOP values in Groups I and II and the control group were 18.3?±?2.6, 18.1?±?3.4 and 15.7?±?2.9?mmHg, mean OPA values were 2.9?±?1.2, 2.8?±?1.5 and 2.3?±?0.8?mmHg and mean CT values were 290.2?±?87.3, 271.8?±?82.5 and 319.3?±?56.8?μm, respectively. No significant difference was determined in terms of the decrease in IOP and OPA obtained after treatment in Group I and Group II. However, a significant difference was observed between the two groups in terms of choroidal thickening after treatment.

Conclusion: The use of topical ocular hypotensive medication in eyes with OAG results in an increase in CT. This increase is relatively greater with bimatoprost 0.03% therapy compared to BTFC.     

Evaluation of clinical efficacy and safety of tobramycin/dexamethasone ophthalmic suspension 0.3%/0.05% compared to azithromycin ophthalmic solution 1% in the treatment of moderate to severe acute blepharitis/blepharoconjunctivitis

Abstract

Objective:

To evaluate the clinical efficacy and safety of tobramycin/dexamethasone (TobraDex ST^*; ‘ST’) ophthalmic suspension 0.3%/0.05% compared to azithromycin (Azasite^?) ophthalmic solution (1%) in the treatment of moderate to severe blepharitis/blepharoconjunctivitis.     

Brimonidine-purite 0.1% versus brimonidine-purite 0.15% twice daily in glaucoma or ocular hypertension: a 12-month randomized trial*

ABSTRACT

Objective: To compare the safety and intraocular pressure (IOP)-lowering effects of brimonidine-purite^? 0.1% with the marketed formulation of brimonidine-purite 0.15% (Alphagan P^§ 0.15%) when used twice daily (BID) by patients with glaucoma or ocular hypertension previously treated with brimonidine-purite 0.15% for at least 6 weeks.

Methods: In a 12-month, randomized, double-masked, multicenter, parallel group, non-inferiority study, patients with glaucoma or ocular hypertension who were treated with brimonidine-purite 0.15% BID were randomly assigned to continue brimonidine-purite 0.15% (n = 102) or to administer brimonidine-purite 0.1% (n = 105) BID for 12 months. IOP was measured at approximately 8 a.m. (hour 0) and 10 a.m. (hour 2).

Main outcome measures: Mean change from baseline IOP and adverse events.

Results: Demographics and baseline characteristics were similar between treatment groups. Treated-baseline mean IOPs at both timepoints were similar between groups (p ≥ 0.606). Brimonidine-purite 0.1% provided IOP-lowering that was non-inferior to brimonidine-purite 0.15% at each of the 12 follow-up timepoints, and there were no statistically significant between-group differences at any timepoint. The most commonly reported adverse event was conjunctival hyperemia (13.5% for brimonidine-purite 0.1%; 10.8% for brimonidine-purite 0.15%). No significant differences in the incidence of adverse events were noted between the two formulations.

Conclusions: Brimonidine-purite 0.1% BID is as effective as brimonidine-purite 0.15% BID in lowering IOP in patients with glaucoma or ocular hypertension who were previously treated with brimonidine-purite 0.15%, and both formulations are well tolerated. Limitations of the study include enrollment of only patients who were already on treatment with brimonidine-purite 0.15%. The 0.1% formulation of brimonidine-purite allows for decreased exposure to brimonidine while providing an IOP-lowering effect comparable to that of the 0.15% formulation. Clinical trial registered at clinicaltrials.gov; identifier: NCT00168363.     

Treatment of patients with primary open-angle glaucoma with a fixed combination of brimonidine 0.2%/timolol 0.5%: multicenter,open-label,observational study in Germany*

ABSTRACT

Objective: At the introduction of the fixed-combination of brimonidine/timolol in Germany in 2006, a non-interventional, multicenter, observational, open-label study was initiated to evaluate efficacy, tolerability, and safety of this preparation in a broad patient population.

Methods: The study population comprised patients with bilateral primary open-angle glaucoma or ocular hypertension with insufficient intraocular pressure (IOP) control who participating physicians determined required a change of medication, and who switched to exclusive use of the new fixed-combination brimonidine 0.2%/timolol 0.5%. Patient demographics and information on specific risk factors were collected. IOP readings were recorded for each eye at treated baseline (previous therapy), 4 to 6 weeks, and 12 weeks after changing to twice-daily brimonidine/timolol. Tolerability was measured using a four-step scale ranging from excellent to poor. All adverse events were recorded.

Results: Mean treated baseline IOP (±SD) for all patients (N?=?861) was 20.8?±?3.5?mmHg. Five hundred sixty-five patients switched from monotherapy, 138 patients switched from other fixed combinations, and 158 patients had been using non-fixed combinations of up to four different active agents. The brimonidine/timolol fixed combination provided an additional IOP decrease in most pretreatment subgroups, with an overall reduction to 16.9?±?2.6?mmHg after 4 to 6 weeks and to 16.5?±?2.7?mmHg after 12 weeks. Both of these values were significantly lower than baseline IOP (p?<?0.001). A target pressure of <18?mmHg was achieved in 79.5% of all eyes at week 12. Tolerability of fixed-combination brimonidine/timolol was rated excellent or good by the physicians for 97.1% of patients, and by 93.4% of the patients themselves. Few adverse events occurred during the treatment period.

Conclusions: Although this study was limited by its observational design, our results show that the fixed combination of brimonidine 0.2%/timolol 0.5% was effective, well tolerated, and safe in a broad POAG patient population.     

Efficacy,tolerability and safety of the fixed combination of bimatoprost 0.03% and timolol 0.5% in a broad patient population: multicenter,open-label observational study*

ABSTRACT

Objective: To evaluate intraocular pressure (IOP)-lowering efficacy, tolerability, and safety of the fixed combination of bimatoprost 0.03% and timolol 0.5% (Ganfort^?) among German patients.

Methods: Multicenter, observational, open-label study of patients with primary open angle glaucoma or ocular hypertension (n?=?606). As determined by participating physicians, patients had insufficient IOP control and required a medication change. They were switched to once-daily fixed-combination bimatoprost/timolol with no wash-out period. IOP was recorded at treated baseline, 4–6 weeks and 12 weeks after switching. Tolerability was measured using a 4-step scale (excellent, good, moderate, poor) and all adverse events were recorded.

Results: A total of 405 patients switched from monotherapy, 97 switched from other fixed combinations, and 104 switched from non-fixed combinations. Among all patients, 32.5% had used prostaglandin analog (PGA) monotherapy, 8.7% had been using a fixed combination that included a PGA, and 6.9% had been using an adjunctive combination of a PGA and a β-blocker. Mean treated baseline IOP (±SD) for all patients was 20.7?±?3.5?mmHg. Overall, changing medication to fixed-combination bimatoprost/timolol lowered IOP to 16.6?±?2.7?mmHg (p?<?0.001 vs. baseline) after 4–6 weeks and to 16.1?±?2.6?mmHg (p?<?0.001) after 12 weeks; reductions of 19.8% and 22.2%, respectively. Combined bimatoprost/timolol provided an additional IOP reduction versus baseline in most subgroups based on prior treatment. At week 12, patients who had previously used a β-blocker achieved an additional 25.8% decrease from baseline and IOP was reduced by 22.6% in former PGA monotherapy patients. At week 12, 84.6% of all eyes reached a target pressure less than or equal to 18?mmHg. Tolerability of bimatoprost/timolol was rated excellent or good by the physicians for 98.7% of patients and by 96.7% of the patients themselves. Few adverse events occurred during the treatment period.

Conclusions: Although this study was limited by its observational design, our results show that the fixed combination of bimatoprost 0.03%/timolol 0.5% was effective, well tolerated, and safe in a broad patient population.     

Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus from Latin America

Objective:

This post hoc analysis evaluated the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) from Latin America.

Research design and methods:

Analyses were performed in subgroups of patients from Latin America based on data from three individual, 26-week, placebo-controlled studies of canagliflozin (monotherapy [n?=?116/584], add-on to metformin [n?=?199/918], and add-on to metformin plus sulfonylurea [n?=?76/469]) and three individual, 52-week, active-controlled studies of canagliflozin (add-on to metformin versus sitagliptin [n?=?240/1101], add-on to metformin versus glimepiride [n?=?155/1450], and add-on to metformin plus sulfonylurea versus sitagliptin [n?=?156/755]).

Main outcome measures:

Changes from baseline in HbA_1c, body weight, and systolic blood pressure (BP) with canagliflozin 100 and 300?mg versus placebo or active comparator (i.e., sitagliptin or glimepiride) were evaluated in the overall study populations and Latin American subgroups. Safety was assessed based on adverse event (AE) reports.

Results:

Canagliflozin 100 and 300?mg provided reductions in HbA_1c, body weight, and systolic BP across studies in patients from Latin America that were generally similar to those seen in the overall populations of patients with T2DM. The AE profile in patients from Latin America was equivalent to that in the overall populations; higher rates of genital mycotic infections and osmotic diuresis–related AEs were seen with canagliflozin versus comparators. Limitations of this study include the post hoc analysis of data and the small sample size of patients from Latin America.

Conclusion:

Canagliflozin improved glycemic control, reduced body weight and systolic BP, and was generally well tolerated in patients with T2DM from Latin America.

Clinical trial registration:

NCT01081834; NCT01106677; NCT01106625; NCT00968812; NCT01137812.     

A comparison of the fourth-generation fluoroquinolones gatifloxacin 0.3% and moxifloxacin 0.5% in terms of ocular tolerability

SUMMARY

Purpose: To compare the ocular tolerability of the commercially available ophthalmic solutions of the fourth-generation fluoroquinolones, gatifloxacin 0.3% (Zymart, Allergan, Inc., Irvine, CA) with benzalkonium chloride (BAK) and moxifloxacin 0.5% (Vigamoxt) without BAK.

Methods: A baseline evaluation was conducted on 30 healthy volunteers for conjunctival hyperemia, conjunctival vascularity, pupil size, and anterior chamber (AC) cell and flare. Pupils were measured under scotopic conditions with a Colvard pupillometer. Conjunctival hyperemia and vascularity, and AC reaction were measured on a Likert-like scale of 0-3. Subjects then received drops in both eyes from masked bottles of gatifloxacin ophthalmic solution 0.3% with BAK (in one eye determined randomly) and moxifloxacin ophthalmic solution 0.5% without BAK (in the contralateral eye) in a double-masked fashion. Subjects graded pain and ocular irritation in each eye on a scale of 1-10 after 5min with their eyes closed. The examination was then repeated.

Results: The average age of this study population was 34.4years. The groups of eyes receiving moxifloxacin 0.5% demonstrated an increase in mean conjunctival hyperemia (0.21 [range: 0-1] at baseline to 1.52 [range: 0-3] at 5min.)

that was significantly greater (p?=?0.0005) compared with that of the group receiving gatifloxacin 0.3% (0.22 [range: 0-1] at baseline to 0.45 [range: 0-2] at 5min). The group receiving moxifloxacin 0.5% showed an increase in conjunctival vascularity (0.55 [range: 0-1] at baseline to 1.61 [range: 0.5-3] at 5?min.) that was significantly greater (p?=?0.0005) compared with that of the group receiving gatifloxacin 0.3% (0.52 [range: 0-1] at baseline to 0.68 [range: 0-2] at 5?min.). Significantly less pain (1.2 vs. 3.2, p?=?0.001) and irritation (0.64 vs. 3.42, p?=?0.001) occurred with gatifloxacin 0.3% than with moxifloxacin 0.5%. Pupil size was significantly reduced (5.65mm-5.05mm) in eyes receiving moxifloxacin 0.5% (p?=?0.004) and no significant change occurred in pupil size (5.60mm-5.65mm) in eyes that received gatifloxacin 0.3% (p?=?0.878). No AC reaction was noted with either medication.

Conclusions: The group of eyes receiving gatifloxacin 0.3% with BAK demonstrated greater ocular tolerability in comparison to the group receiving moxifloxacin 0.5% without BAK. Moxifloxacin-induced pupillary miosis may be due to prostaglandin release in the anterior chamber. A limitation of this study is the relatively young age of the study population.     

Brimonidine purite 0.1% versus brinzolamide 1% as adjunctive therapy to latanoprost in patients with glaucoma or ocular hypertension

ABSTRACT

Objective: To evaluate the efficacy and tolerability of brimonidine purite 0.1% in comparison to brinzolamide 1% when used as adjunctive therapy to latanoprost 0.005% in patients with glaucoma or ocular hypertension.

Methods: Randomized, single-center, investigator-masked, parallel-group clinical study. Patients with IOP?≥?18?mmHg while on once-daily latanoprost were randomized to adjunctive treatment with brimonidine purite TID (n?=?20) or brinzolamide TID (n?=?20) for 3 months. Intraocular pressure (IOP) was measured at 8 a.m., 10 a.m., and 4 p.m. at latanoprost-treated baseline and after 1 and 3 months of latanoprost and adjunctive therapy. A patient questionnaire was administered to evaluate the tolerability of eye drop instillation.

Results: Baseline mean diurnal IOP (± standard deviation, mmHg) on latanoprost was comparable between groups (brimonidine purite: 19.6?±?2.94; brinzolamide: 19.8?±?3.25; p = 0.846). Mean diurnal IOP at Month 3 was 16.3?±?2.63?mmHg with brimonidine purite and 17.8?±?2.19?mmHg with brinzolamide (?p = 0.028). Adjunctive use of brimonidine purite provided greater IOP lowering than brinzolamide at 10 a.m. (?p < 0.001) and 4 p.m. (?p = 0.050) and equivalent IOP lowering to brinzolamide at 8 a.m. (?p = 0.716). Blurred vision at Month 1 and bitter taste at Months 1 and 3 were more common upon instillation of brinzolamide eye drops.

Conclusion: Brimonidine purite 0.1% provided significantly lower IOP compared with brinzolamide 1% when used as adjunctive therapy to latanoprost. Both adjunctive therapies were well tolerated. Limitations of this study include the use of a single site and the sample size. Additional studies are needed to further evaluate these drugs as adjunctive therapy to prostaglandin analogs.     

Pioglitazone versus rosiglitazone treatment in patients with type 2 diabetes and dyslipidemia: cost-effectiveness in the US

ABSTRACT

Objectives: Pioglitazone hydrochloride (Actos) and rosiglitazone maleate (Avandia) are members of the thiazolidinedione (TZD) class of oral anti-diabetic drugs (OADs) and are used to treat type 2 diabetes mellitus (T2DM). Greater beneficial effects on lipids have been demonstrated with pioglitazone, however. Study objectives were to evaluate the long-term cost-effectiveness of pioglitazone compared to rosiglitazone in treating patients with T2DM and dyslipidemia, and determine the extent to which reported beneficial lipid effects of pioglitazone would improve clinical and economic outcomes through reduced macrovascular complications.

Research design and methods: The validated CORE Diabetes Model (CDM) was used to simulate changes in glycosylated hemoglobin (HbA_1c), complications, and direct medical costs. Baseline parameters came from a multi-center, double-blind trial comparing lipid and glycemic effects of pioglitazone (n?=?400) and rosiglitazone (n?=?402) among individuals with T2DM and untreated dyslipidemia. Sensitivity analyses examined the impact of cohort, clinical, and cost inputs on incremental cost effectiveness ratios (ICERs).

Results: In the base case, pioglitazone was associated with mean (standard deviation [SD]) quality-adjusted life years (QALYs) of 7.476 (0.123) vs. 7.326 (0.128) for rosiglitazone. Pioglitazone had $3038 higher total direct costs, but $580 lower complication costs. Risks of four cardiovascular complications were reduced with pioglitazone (relative risks 0.860–0.942), while risks of 17 other complications were slightly higher (relative risks 1.001–1.056). The ICER for pioglitazone treatment was $20?171/QALY. Results were most sensitive to the effects of HbA_1c, high-density lipoprotein-cholesterol, overall lipid effects, and pioglitazone acquisition costs.

Conclusions: Study limitations include issues of generalizability of the trial patient population, as well as inability to capture non-adherence and variation in ‘real-world’ treatment patterns. Nevertheless, pioglitazone (when compared to rosiglitazone) was found to have long-term value as a treatment option for T2DM patients with dyslipidemia treated within the US payer setting.     

From dorzolamide 2%/timolol 0.5% to brinzolamide 1%/timolol 0.5% fixed combination: a 6-month,multicenter, open-label tolerability switch study

Purpose: To assess ocular surface status and tolerability after switching glaucoma patients from dorzolamide/timolol to brinzolamide/timolol fixed combination (FC).

Methods: Six-month, multicenter, open-label, prospective study that switched 72 patients from dorzolamide/timolol to brinzolamide/timolol FC. Intraocular pressure (IOP), tear film break-up-time (TF-BUT), fluorescein staining and Glaucoma Symptom Scale (GSS) questionnaire were recorded at baseline and after 6 months.

Results: Median interquartile range (IQR) IOP was 16 (IQR 15 – 18) mmHg at baseline and 16 (15 – 17) mmHg and 6 months. TF-BUT significantly improved (p < 0.0001); the regression analysis found a negative association between TF-BUT changes and age at baseline and at month 6 (r = ?0.32; p = 0.0082 and r = ?0.31; p = 0.0085). Patients with no corneal fluorescein staining statistically increased after substitution (p = 0.04). Quality of life – as examined by the GSS symptoms (SYMP) score – statistically improved (p < 0.0001), revealing an association between GSS SYMP score and age [coefficient ?0.67, 95% confidence interval (CI) ?1.13 to ?0.21, p = 0.0005), superficial keratitis (coefficient ?8.26, 95% CI ?15.73 to ?0.80, p = 0.031) and TF-BUT (coefficient 4.94, 95% CI 1.71 to 8.17, p = 0.003).

Conclusion: Brinzolamide/timolol FC is associated with reduced topical discomfort and improved signs of ocular surface disease. The good tolerability and comfort of this FC might contribute to good patient adherence.     

Once-daily insulin detemir in a cohort of insulin-naïve patients with type 2 diabetes: a sub-analysis from the PREDICTIVE study

ABSTRACT

Objective: PREDICTIVE^* is a large, observational study of the empirical use of insulin detemir in patients with type 1 or type 2 diabetes (T1DM/T2DM). This post hoc analysis evaluates insulin-naïve patients with T2DM uncontrolled on oral antidiabetic drugs (OADs) who were initiated and remained on once-daily insulin detemir for 12 weeks.

Research design and methods: This observational, multinational, multi-center, open-label prospective study evaluated the efficacy and safety of insulin detemir in 1653 insulin-naïve patients with T2DM (mean age 60.8?±?10.9 years, BMI 29.8?±?4.8?kg/m², and HbA_1C 8.82?±?1.50%). Statistical comparisons were made between baseline and 12-week follow up data. Our study was subject to the usual limitations of observational studies.

Main outcome measures: Endpoints were: incidence of serious adverse drug reactions, including number of hypoglycemic events (total, major, and nocturnal), glycemic parameters, and weight change.

Results: Following insulin initiation, no significant change occurred in the number of nocturnal hypoglycemic events or total hypoglycemic events (p?=?0.4513), and no serious adverse drug reactions were observed during the 12 weeks of treatment. HbA_1C decreased by a mean 1.25% (SD?±?1.25%; p?<?0.0001), with 30% of patients (n?=?383) achieving HbA_1C <7% at 12 weeks. Mean changes in fasting blood glucose and fasting blood glucose variability were –3.62?mmol/L (SD?±?2.93; p?<?0.0001) and ?0.48?mmol/L (SD?±?1.03; p?<?0.0001), respectively. Body weight decreased by a mean 0.5?kg (SD?±?3.3; p?<?0.0001), with weight loss or no weight change occurring in a substantial percentage of patients in each BMI category (<25, 25–30, 30–35, and >35?kg/m²). Patients with higher baseline BMI lost the most weight, with the greatest weight loss (–1.20?kg) reported in those with BMI >35?kg/m².

Conclusions: Empirical use of insulin detemir as an insulin initiation strategy can improve glycemic control with good tolerability, including a low risk of hypoglycemia and a weight benefit, in a majority of insulin-naïve patients uncontrolled on OADs.     

Short-term pharmacokinetic comparison of a novel testosterone buccal system and a testosterone gel in testosterone deficient men

SUMMARY

Objective: The primary objective of the study was to compare the percentage of men with mean serum total T (Cave(0–24)) within normal range during the 24-h pharmacokinetic (PK) sampling period on Days 14 and 15.

Methods: Treatment with a new testosterone (T) buccal system, (Striant), 30mg twice daily was compared to a transdermal gel delivery system, (T-gel) [AndroGel 5?g containing 1% (50?mg) T] daily for 14days in T-deficient men. Safety parameters included laboratory assessments and collection of adverse events. Patients were otherwise healthy T-deficient men with total T?<?8.7 nmol/L (< 2.5?ng/mL).

Results: Twenty-six of the 28 patients enrolled completed the 24-h PK assessment. Of the evaluable patients, 92.3% of T buccal system and 83.3% of T-gel patients had Cave(0–24) within the normal range of 10.4-36.4 nmol/L (3.0–10.5?ng/mL). Mean total T values were not different in the T buccal system group (Cave(0–24) 16.7?±?4.7?nmol/L; 4.8?±?1.4?ng/mL) compared to the T-gel group (Cave(0–24) 15.9?±?4.8?nmol/L; 4.6?±?1.4?ng/mL). All T values returned to baseline levels after the study drug was stopped. Serum LH and FSH levels decreased, and E2 increased as expected following T administration. Differences in DHT concentrations between treatment groups were significant (p?=?0.012) with mean DHT levels on Day 14 of 1.9?±?1.4 nmol/L (0.55?±?0.42?ng/mL) for the T buccal system and 3.2?±?1.3?nmol/L (0.93?±?0.38ng/mL) for T-gel, which was greater than the upper level of normal (2.9?nmol/L; 0.85?ng/mL). Statistically significant differences were seen in the mean T/DHT ratio on Days 14     

Assessment of the drug loading,in vitro and in vivo release behavior of novel pH-sensitive hydrogel

Context: As a glucocorticoid drug, dexamethasone has good therapeutic effects for ulcerative colitis. pH-sensitive hydrogels could make conventional changes of volume in response with different pH values. Meanwhile, they could load drugs depending on its internal three-dimensional network structure.

Objective: Appropriate methods were used to improve the drug-loading capacity of hydrogel and exploring the colon-targeting character of dexamethasone hydrogel.

Materials and methods: Different solvents (ethanol and 1,2-propanediol) were employed to dissolve dexamethasone as well as hydrogel monomer materials (poly(ethylene glycol) methyl ether (MPEG)–poly(lactide acid)–acryloyl chloride macromonomer, itaconic acid (IA) and MPEG–methacrylate), then mixing them together to prepare hydrogel through the heat-initiated free radical polymerization method. Differential scanning calorimetry and X-ray diffraction methods were used to verify whether dexamethasone was loaded into hydrogels. In vitro drug release behavior and in vivo pharmacokinetic study were also investigated in detail.

Results: Dexamethasone was successfully loaded into hydrogel, and its loading capacity was improved (5?mg/g). Both the in vitro release study and the in vivo pharmacokinetic study showed the good colon-targeting character of the pH-sensitive P(LE–IA–MEG) hydrogel (T_max?=?1.0?h, C_max?=?2.16?µg/ml of dexamethasone; T_max?=?3.9?h, C_max?=?0.43?µg/ml of dexamethasone hydrogel).

Discussion: Dexamethasone could be targeted to the colon site by P(LE–IA–MEG) hydrogel, thereby improving its therapeutic effect and reduce its side effects.

Conclusion: P(LE–IA–MEG) hydrogel might have great potential application in colon-targeted drug delivery systems.     

A randomized,double-blind,non-inferiority trial evaluating the efficacy and safety of omarigliptin,a once-weekly DPP-4 inhibitor,or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy

Objective: To evaluate the efficacy and safety of adding the once-weekly DPP-4 inhibitor omarigliptin or the sulfonylurea glimepiride to the treatment regimen of patients with type 2 diabetes (T2DM) and inadequate glycemic control on metformin monotherapy.

Methods: Patients with T2DM and HbA1c ≥6.5% to ≤9.0% while on a stable dose of metformin (≥1500?mg/day) were randomized to omarigliptin 25?mg once-weekly (n?=?376) or glimepiride up to 6?mg once daily (n?=?375) for 54 weeks. The primary hypothesis was that omarigliptin is non-inferior to glimepiride in reducing HbA1c at week 54.

Results: The mean baseline HbA1c was 7.5% in the omarigliptin group and 7.4% in the glimepiride group. After 54 weeks, the least squares (LS) mean change from baseline in HbA1c was –0.30% in the omarigliptin group and –0.48% in the glimepiride group, with a between-group difference (95% CI) of 0.18% (0.06, 0.30), which met the pre-specified criterion for declaring non-inferiority. The incidence of symptomatic hypoglycemia was 5.3% in the omarigliptin group and 26.7% in the glimepiride group. With the exception of hypoglycemia, the incidences of adverse events and discontinuations were similar between treatment groups. Relative to baseline, omarigliptin was associated with a mean weight loss (?0.4?kg) and glimepiride a mean weight gain (+1.5?kg).

Conclusions: After 54 weeks, as add-on therapy to metformin, once-weekly omarigliptin was generally well tolerated and non-inferior to glimepiride in improving glycemic control, with a lower incidence of hypoglycemia and with weight loss vs weight gain.     

Phase III efficacy and safety study of besifloxacin ophthalmic suspension 0.6% in the treatment of bacterial conjunctivitis

ABSTRACT

Objective: To compare the clinical and antimicrobial efficacy of besifloxacin ophthalmic suspension 0.6% with that of vehicle in the treatment of bacterial conjunctivitis.

Research design and methods: This was a randomized, multicenter, double-masked, vehicle-controlled study. A total of 957 patients aged 1 year and older with bacterial conjunctivitis were randomized to treatment with besifloxacin ophthalmic suspension 0.6% or vehicle applied topically three times daily for 5 days.

Main outcome measures: Primary endpoints were clinical resolution and microbial eradication of baseline bacterial infection at Visit 2 (Day 5?±?1). Secondary endpoints included clinical resolution and microbial eradication at Visit 3 (Day 8 or 9), individual clinical outcomes at follow-up visits, and safety.

Clinical trial registration: NCT number, NCT00347932.

Results: Three hundred and ninety patients had culture-confirmed bacterial conjunctivitis. Clinical resolution and microbial eradication were significantly greater with besifloxacin ophthalmic suspension than with vehicle at Visit 2 (45.2% vs. 33.0%, p?=?0.0084; and 91.5% vs. 59.7%, p?<?0.0001, respectively) and Visit 3 (84.4% vs. 69.1%, p?=?0.0011; and 88.4% vs. 71.7%, p?<?0.0001, respectively). Results for secondary endpoints of individual clinical outcomes were consistent with primary endpoints. Fewer eyes receiving besifloxacin ophthalmic suspension experienced adverse events than those receiving vehicle (9.2% vs. 13.9%; p?=?0.0047).

Conclusions: Besifloxacin ophthalmic suspension produces clinical resolution and microbial eradication rates significantly better than vehicle and is safe for the treatment of bacterial conjunctivitis.

Limitations: A limitation of this study is the lack of a non-treatment control group.