Impact of age, diagnosis, and history of glaucoma surgery on outcomes in pediatric patients treated with latanoprost.

PURPOSE: To evaluate the impact of age, glaucoma-specific diagnosis, and history of prior glaucoma surgery on outcomes in pediatric patients treated with latanoprost monotherapy. PATIENTS AND METHODS: Prospective, randomized, double-masked 12-week, multicenter study included individuals 18 years or younger with glaucoma. Subjects stratified by age (0 to <3, 3 to <12, 12 to 18 y), diagnosis [primary congenital glaucoma (PCG) vs. non-PCG], and baseline intraocular pressure (IOP; 22 to <27, 27 to 31, >31 mm Hg), and randomized (1:1) to latanoprost vehicle (8 AM) and latanoprost 0.005% (8 PM) or timolol 0.5% (or 0.25% for those less than 3 y old; 8 AM/8 PM). IOP and safety assessments performed and adverse events recorded at baseline, weeks 1, 4, 12. Post hoc analyses in age-specific and diagnosis-specific groups of latanoprost-treated subjects were conducted (intent-to-treat population). RESULTS: Sixty-eight subjects were treated with latanoprost (0 to <3, n=17; 3 to <12, n=26; 12 to 18, n=25); 82%, 42%, and 24%, respectively, had a primary diagnosis of PCG. Among Non-PCG subjects, 0% (0/3), 47% (7/15), and 63% (12/19) had a primary diagnosis of juvenile open-angle glaucoma in the 0 to <3, 3 to <12, and 12 to 18 year cohorts, respectively. Mean percent IOP reductions from baseline at week 12 were 22%, 24%, and 30% in the youngest through oldest age groups, respectively (P=0.3600). At week 12, a higher responder rate (≥15% IOP reduction) was observed in the non-PCG than in the PCG group (70% vs. 45%, respectively; P=0.0361). Latanoprost was well tolerated. CONCLUSION: All age and diagnosis subgroups showed clinically relevant (>20%) mean IOP reduction at week 12 with latanoprost monotherapy.

Dose-ranging evaluation of intravitreal siRNA PF-04523655 for diabetic macular edema (the DEGAS study).

PURPOSE: To evaluate the safety and efficacy of three doses of PF-04523655, a 19-nucleotide methylated double stranded siRNA targeting the RTP801 gene, for the treatment of diabetic macular edema (DME) compared to focal/grid laser photocoagulation. METHODS: This multicenter, prospective, masked, randomized, active-controlled, phase 2 interventional clinical trial enrolled 184 DME patients with best corrected visual acuity (BCVA) of 20/40 to 20/320 inclusive in the study eye. Patients were randomly assigned to 0.4-mg, 1-mg, 3-mg PF-04523655 intravitreal injections or laser. The main outcome measure was the change in BCVA from baseline to month 12. RESULTS: All doses of PF-04523655 improved BCVA from baseline through month 12. At month 12, the PF-04523655 3-mg group showed a trend for greater improvement in BCVA from baseline than laser (respectively 5.77 vs. 2.39 letters; P = 0.08; 2-sided α = 0.10). The study was terminated early at month 12 based on predetermined futility criteria for efficacy and discontinuation rates. PF-04523655 was generally safe and well-tolerated, with few adverse events considered treatment-related. By month 12, the discontinuation rates in the PF-04523655 groups were higher than the laser group and were inversely related to dose levels. CONCLUSIONS: PF-04523655 showed a dose-related tendency for improvement in BCVA in DME patients. Studies of higher doses are planned to determine the optimal efficacious dose of PF-04523655. PF-04523655 may offer a new mode of therapeutic action in the management of DME. (ClinicalTrials.gov number, NCT00701181.).

Evaluation of the siRNA PF-04523655 versus ranibizumab for the treatment of neovascular age-related macular degeneration (MONET Study).

OBJECTIVE: To evaluate the efficacy of different dosing paradigms of PF-04523655 (PF) versus ranibizumab (comparator) in subjects with neovascular age-related macular degeneration (AMD). DESIGN: Multicenter, open-label, prospective, randomized, comparator-controlled exploratory study. PARTICIPANTS: A total of 151 patients with subfoveal choroidal neovascularization (CNV) secondary to neovascular AMD who were naive to AMD therapy. METHODS: In this phase 2 study, patients were randomized to 1 of 5 treatment groups with equal ratio. All groups received ranibizumab 0.5 mg at baseline and (a) PF 1 mg every 4 weeks (Q4W) from week 4 to week 12; (b) PF 3 mg Q4W from week 4 to week 12; (c) PF 3 mg every 2 weeks (Q2W) from week 4 to week 12; (d) PF 1 mg + ranibizumab (combination) Q4W from baseline to week 12; and (e) ranibizumab Q4W to week 12. All study treatments were given as intravitreal injections. MAIN OUTCOME MEASURES: The primary end point was the mean change in best-corrected visual acuity (BCVA) from baseline at week 16; secondary end points included the percentage of patients gaining ≥ 10 and ≥ 15 letters in BCVA and mean change in retinal central subfield thickness, lesion thickness, and CNV area. RESULTS: At week 16, the PF 1 mg + ranibizumab combination group achieved numerically greater improvement in mean BCVA from baseline (9.5 letters) than the ranibizumab group (6.8 letters). The difference was not statistically significant. The BCVA improvement in the PF monotherapy groups was less than in the ranibizumab group. Similar trends were observed in the percentage of patients who gained ≥ 10 and ≥ 15 letters. From baseline to week 16 (last observed carried forward), the combination and ranibizumab groups had similar mean reductions in central subfield retinal thickness and total CNV area, which were greater than in all PF monotherapy groups. There were no clinically meaningful differences in reduction of lesion thickness among treatment groups. CONCLUSIONS: In this early, underpowered study evaluating treatments for neovascular AMD, the combination of PF with ranibizumab led to an average gain in BCVA that was more than with ranibizumab monotherapy. No safety concerns were identified.

Comparison of latanoprost and timolol in pediatric glaucoma: a phase 3, 12-week, randomized, double-masked multicenter study.

OBJECTIVE: To compare the efficacy and safety of latanoprost versus timolol in pediatric patients with glaucoma. DESIGN: Prospective, randomized, double-masked, 12-week, multicenter study. PARTICIPANTS: Individuals aged ≤18 years with glaucoma. METHODS: Stratified by age, diagnosis, and intraocular pressure (IOP) level, subjects were randomized (1:1) to latanoprost vehicle at 8 am and latanoprost 0.005% at 8 pm or timolol 0.5% (0.25% for those aged <3 years) twice daily (8 am, 8 pm). At baseline and weeks 1, 4, and 12, IOP and ocular safety were assessed and adverse events were recorded. Therapy was switched to open-label latanoprost pm and timolol am and pm for uncontrolled IOP. MAIN OUTCOME MEASURES: Mean IOP reduction from baseline to week 12. Latanoprost was considered noninferior to timolol if the lower limit of the 95% confidence interval (CI) of the difference was >-3 mmHg. A proportion of responders (subjects with ≥15% IOP reduction at weeks 4 and 12) were evaluated. Analyses were performed in diagnosis subgroups: primary congenital glaucoma (PCG) and non-PCG. RESULTS: In total, 137 subjects were treated (safety population; 12-18 years, n=48; 3-<12 years, n=55; 0-<3 years, n=34). Mean age was 8.8±5.5 years, and mean baseline IOP was 27.7±6.17 mmHg; 125 subjects completed the study, and 107 subjects were in the per protocol population. Mean IOP reductions for latanoprost and timolol at week 12 were 7.2 and 5.7 mmHg, respectively, with a difference of 1.5 mmHg (95% CI, -0.8 to 3.7; P=0.21). Responder rates were 60% for latanoprost and 52% for timolol (P=0.33). Between-treatment differences in mean IOP reduction for PCG and non-PCG subgroups were 0.6 mmHg (95% CI, -2.3 to 3.4) and 2.6 mmHg (95% CI, -0.8 to 6.1), respectively. Responder rates for latanoprost versus timolol were 50% versus 46% for the PCG group and 72% versus 57% for the non-PCG group. Both therapies were well tolerated. CONCLUSIONS: Latanoprost 0.005% is not inferior (i.e., is either more or similarly effective) to timolol and produces clinically relevant IOP reductions across pediatric patients with and without PCG. Both latanoprost and timolol had favorable safety profiles over the duration of this 3-month trial. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Switching immunosuppression medications after renal transplantation--a common practice.

BACKGROUND: The rate of change to immunosuppression discharge regimens over time is unknown. We examined the frequency of changes to initial drug treatment regimens and factors associated with a drug change following renal transplantation. METHODS: Scientific Registry of Transplant Recipients data from adult recipients who underwent primary renal transplantation between January 1998 and December 2002 were analysed. The Kaplan-Meier analysis was used to determine the frequency of regimen changes for the most common immunosuppression discharge regimens, type of change, and to examine switching between the calcineurin inhibitors tacrolimus (Tacro) and ciclosporin United States Pharmacopera (USP) modified (CsA). Cox proportional hazard regression was used to examine recipient, donor and transplant characteristics associated with a drug change. RESULTS: The majority of patients experienced a change to their discharge regimen post-transplantation, and more changes were observed within higher-risk sub-groups of patients. Switching from CsA to Tacro was more common than Tacro to CsA. Significant factors associated with a drug change included those associated with graft loss. CONCLUSIONS: Significant immunosuppression regimen changes occur during the first 4 years post-transplantation. It is possible that early graft survival benefits proven in prospective clinical trials may not translate into long-term success in clinical practice, possibly in part because efficacious regimens are not necessarily maintained long-term.