Latanoprost and Dorzolamide for the Treatment of Pediatric Glaucoma: The Glaucoma Italian Pediatric Study (Gipsy), Design and Baseline Characteristics

Introduction

To investigate the efficacy of a treatment strategy with latanoprost and dorzolamide in primary pediatric glaucoma patients partially responsive to surgery.

Methods

Single arm, prospective, interventional multicenter study. Primary pediatric glaucoma patients younger than 13 years after a single surgical procedure with IOP between 22 and 26 mmHg were considered eligible. At baseline, patients were allocated to latanoprost monotherapy once daily. Depending on intraocular pressure (IOP) reduction at first visit, the patients were allocated to one of three groups: continuation of latanoprost monotherapy, addition of dorzolamide twice daily, or switch to dorzolamide three times daily. The same approach for allocation in medication groups was used in all subsequent visits. Patients in the dorzolamide monotherapy group with IOP reduction <20% from baseline were considered non-responders and withdrawn. Study treatment and patient follow-up will continue for 3 years or until treatment failure. The primary endpoint is the percentage of responders. Secondary endpoints are time to treatment failure and frequency of adverse events.

Results

A total of 37 patients (69 eyes) were enrolled. The mean age was 4.0 ± 3.8 years, the female/male ratio was 1/1.7, and the majority of patients were Caucasian. Eighty percent of patients had bilateral glaucoma. Goniotomy was the most frequently performed surgery (38.6%), followed by trabeculotomy (22.8%), trabeculectomy (21.1%), and trabeculectomy plus trabeculotomy (17.5%). The baseline IOP was 23.6 ± 1.5 mmHg.

Conclusion

The study population is representative of patients frequently encountered after the first surgery for primary pediatric glaucoma. The study will produce evidence on the medium-term efficacy of a defined pharmacological approach.

     

24-Hour Efficacy and Ocular Surface Health with Preservative-Free Tafluprost Alone and in Conjunction with Preservative-Free Dorzolamide/Timolol Fixed Combination in Open-Angle Glaucoma Patients Insufficiently Controlled with Preserved Latanoprost Monotherapy

Introduction

The aim of the present study was to evaluate the 24-h efficacy, tolerability, and ocular surface health with preservative-free (PF) tafluprost and a PF triple drug regimen comprising tafluprost and dorzolamide/timolol fixed combination (DTFC) in open-angle glaucoma patients who were insufficiently controlled with preserved branded or generic latanoprost monotherapy and who exhibited signs or symptoms of ocular surface disease (OSD).

Methods

Prospective, observer-masked, crossover, comparison. Eligible consecutive open-angle glaucoma patients were randomized to either PF tafluprost or the triple PF regimen for 3 months. They were then crossed over to the opposite therapy for another 3 months. At the end of the latanoprost run-in period and after each PF treatment period, patients underwent habitual 24-h intraocular pressure (IOP) monitoring with Goldmann tonometry in the sitting position (at 10:00, 14:00, 18:00, and 22:00) and Perkins tonometry in the supine position (at 02:00 and 06:00). Tolerability and selected ocular surface parameters were evaluated at baseline and the end of each treatment period.

Results

Forty-three open-angle glaucoma patients completed the trial. Mean 24-h IOP on preserved latanoprost was 22.2 ± 3.9 mmHg. Compared with latanoprost monotherapy, PF tafluprost obtained a greater reduction in mean, peak, and fluctuation of 24-h IOP including the 02:00 and 06:00 time points (P < 0.05). With the exception of 24-h fluctuation, the triple PF regimen provided significantly lower IOP parameters than latanoprost or PF tafluprost (P < 0.001). Finally, PF tafluprost therapy displayed significantly improved tear film break-up times (6.7 vs 6.0 s), corneal staining (1.3 vs 2.2), and Schirmer I test results (9.1 vs 8.2 mm) compared with the preserved latanoprost baseline (all P < 0.01). The triple PF regimen demonstrated similar tear film break-up times (6.1 vs 6.0 s) and Schirmer I test results (8.2 vs 8.2 mm) to latanoprost, but revealed a significant improvement in the corneal stain test (1.7 vs 2.2; P < 0.001).

Conclusions

In this trial PF tafluprost therapy provided statistically greater 24-h efficacy and improved tolerability compared with preserved latanoprost. The combination of PF tafluprost and PF dorzolamide/timolol fixed combination was statistically and clinically more efficacious than both monotherapies and demonstrated similar ocular surface characteristics to preserved latanoprost monotherapy.

Trial registration

ClinicalTrials.gov (NCT02802137).

Funding

Santen.

     

Outcomes Following Implantation of Two Second-Generation Trabecular Micro-Bypass Stents in Patients with Open-Angle Glaucoma on One Medication: 18-Month Follow-Up

Introduction

The study objective was to evaluate the intraocular pressure (IOP) and medication-lowering effect of 2 second-generation trabecular micro-bypass stents in eyes with open-angle glaucoma (OAG) on one preoperative medication.

Methods

Fifty-seven qualified phakic eyes with OAG on 1 medication, preoperative medicated IOP of 18–30 mmHg, and preoperative unmedicated (post-washout) IOP of 22–38 mmHg underwent implantation of 2 second-generation trabecular micro-bypass stents in a standalone procedure. Evaluations included IOP, best-corrected visual acuity, medication use, fundus and slit lamp examinations, visual field, cup to disc ratio, pachymetry, and complications and interventions. Subjects have been followed for 18 months, and follow-up is ongoing.

Results

At Month 12 postoperative, 100% of eyes had achieved an IOP reduction ≥20% (100% had IOP ≤18 mmHg and 67% had IOP ≤15 mmHg) without medication versus preoperative unmedicated IOP, and 75% had IOP reduction ≥20% without medication versus preoperative medicated IOP. The Month 12 mean unmedicated IOP had decreased by 42%, to 14.2 ± 1.9 mmHg vs 24.4 ± 1.3 mmHg preoperatively, and this reduction was maintained through 18 months (14.4 ± 2.1 mmHg). A high safety profile was observed.

Conclusion

In this prospective, open-label, single-arm study, the standalone implantation of two second-generation trabecular micro-bypass stents in OAG patients on 1 preoperative medication resulted in IOP reduction to ≤15 mmHg and elimination of medication through 18 months, with favorable safety.

Trial Registration

ClinicalTrials.gov identifier, NCT02868190.

Funding

Glaukos Corporation, San Clemente, CA.

     

Multicenter,Randomized, Investigator-Masked Study Comparing Brimonidine Tartrate 0.1% and Timolol Maleate 0.5% as Adjunctive Therapies to Prostaglandin Analogues in Normal-Tension Glaucoma

Introduction

This study compared the efficacy and safety of adjunctive brimonidine tartrate 0.1% ophthalmic solution (brimonidine) and timolol maleate 0.5% ophthalmic solution (timolol) in prostaglandin analogue (PGA)-treated normal-tension glaucoma (NTG), assessing the non-inferiority of brimonidine in terms of intraocular pressure (IOP) reduction.

Methods

In this multicenter, randomized, investigator-masked, parallel-group, clinical study, adjunctive brimonidine or timolol was administered twice daily for 12 weeks in eyes with NTG that had been treated with PGA for at least 90 days and required additional treatment despite an IOP of 16 mmHg or less. IOP was measured on at least three visits before add-on therapy (mean baseline IOP), and at weeks 4, 8, and 12 after adjunctive administration. Systolic/diastolic blood pressure, pulse rate, and adverse events (AEs) were recorded at each visit.

Results

A total of 152 individuals were enrolled and 128 (84.2%) were eligible for efficacy analyses. IOP in both groups at each visit decreased significantly from baseline (P < 0.001). However, the difference in the change from baseline IOP at week 12 between the brimonidine (?1.05 ± 1.81 mmHg) and timolol (?1.41 ± 1.40 mmHg) groups was 0.36 mmHg (95% confidence interval [CI] [?0.21, 0.92]), which exceeded the value of the non-inferiority margin (0.75 mmHg). Baseline systolic/diastolic blood pressure decreased significantly in both groups at certain visits (P < 0.05), while baseline pulse rates decreased significantly in the timolol group (P < 0.001), with no significant differences in the brimonidine group. AE-related treatment discontinuation occurred in 2/71 (2.8%) and 2/75 (2.7%) patients in the brimonidine and timolol groups, respectively.

Conclusion

This study demonstrated an add-on effect of brimonidine to PGAs, although non-inferiority of brimonidine to timolol as adjunctive therapy in PGA-treated NTG in terms of IOP reduction was not observed. Brimonidine was associated with no adverse effects on pulse rate.

Funding

Senju Pharmaceutical Co., Ltd.

Trial registration

UMIN Clinical Trials Registry identifier, UMIN000014810.

     

12-Month Outcomes of Goniotomy Performed Using the Kahook Dual Blade Combined with Cataract Surgery in Eyes with Medically Treated Glaucoma

Introduction

To describe the 12-month efficacy and safety of goniotomy performed using the Kahook Dual Blade (KDB) in combination with cataract surgery in eyes with medically treated open-angle glaucoma (OAG).

Methods

This was a prospective, interventional case series conducted at seven centers in North America. Consecutive patients with medically treated OAG and visually significant cataract underwent phacoemulsification combined with goniotomy (PE?+?goniotomy) using KDB. Indications for glaucoma surgery included reduction of intraocular pressure (IOP) and reduction of IOP-lowering medications. De-identified data were collected and included pre-, intra-, and postoperative data on IOP, the use of IOP-lowering medications, and adverse events through 12 months of follow-up.

Results

Among 52 eyes undergoing surgery, mean IOP was reduced from 16.8?±?0.6 mmHg at baseline to 12.4?±?0.3 mmHg at month 12 (P?<?0.001), a 26.2% reduction. Mean IOP across time points ranged from 12.4–13.3 mmHg during follow-up. The mean number of topical IOP-lowering medications was reduced from 1.6?±?0.2 at baseline to 0.8?±?0.1 at month 12 (P?<?0.05), a 50.0% reduction. At month 12, 57.7% of eyes had IOP reduction ≥?20% from baseline, and 63.5% were on ≥?1 fewer IOP-lowering medications. In subgroup analysis, 84.6% of eyes with lower mean baseline IOP were using ≥?1 fewer medications at month 12, and 100% of eyes with higher mean baseline IOP had IOP reductions ≥?20%. The most common postoperative adverse events were pain/irritation (n?=?4, 7.7%), opacification of the posterior lens capsule (n?=?2, 3.8%), and IOP spike >?10 mmHg (n?=?2, 3.8%).

Conclusion

PE?+?goniotomy using the KDB significantly lowers both IOP and dependence on IOP-lowering medications in eyes with OAG. Adverse events were not sight-threatening and typically resolved spontaneously.

Funding

New World Medical, Inc.

     

Effects of Brinzolamide,a Topical Carbonic Anhydrase Inhibitor,on Corneal Endothelial Cells

Introduction

This clinical study aimed to investigate the effect of brinzolamide, a topical carbonic anhydrase inhibitor, on corneal endothelial cells (CECs) in patients with glaucoma using a follow-up clinical study design.

Methods

Patients with primary open-angle glaucoma or ocular hypertension were administrated an ophthalmic solution of either latanoprost alone (LT) as a control (n = 18) or latanoprost plus brinzolamide (LT + BR; n = 16). CECs were examined at baseline and at 4, 12, 24, and 48 weeks in 18 and 16 eyes of the LT and LT + BR groups, respectively, using a non-contact specular microscope. CECs were evaluated by parameters, including cell density (CD), coefficient of variation (CV) in cell size, and percentage hexagonality (Hex).

Results

Compared with the baseline intraocular pressure (IOP), the mean IOP in the LT group was significantly reduced at 12 and 24 weeks, whereas that in the LT + BR group was significantly reduced at all time points (P < 0.01). The mean CD, CV, and Hex at baseline were not significantly different between the two groups. No significant time-course changes in CD, CV, or Hex were observed in either group. At 48 weeks, there was no significant difference in the mean CD, CV, or Hex between the two groups.

Conclusion

Patients treated with LT + BR showed significant IOP reduction. However, the use of brinzolamide in addition to latanoprost had no influence on CECs during the one-year follow-up period.

     

Sustainability of Intraocular Pressure Reduction of Travoprost Ophthalmic Solution in Subjects with Normal Tension Glaucoma

Introduction

We examined the sustainability of the intraocular pressure (IOP)-lowering efficacy of travoprost (0.004%) ophthalmic solution in subjects with normal tension glaucoma (NTG).

Methods

Travoprost ophthalmic solution was given once daily at 9 PM to subjects with newly diagnosed NTG or with NTG who had not received any ocular hypotensives within the previous 30 days. IOP was measured at three time points (9 AM, 1 PM, and 5 PM) at baseline and week 12 visits, and at one time point (9 AM) at week 4 and week 8 visits. Conjunctival hyperemia, superficial punctate keratopathy, and other adverse events were evaluated during the observation period.

Results

Thirty subjects (12 males and 18 females; mean age 65.6 years) from 32 subjects enrolled were included in the efficacy analysis. The mean IOPs (±standard deviation) of 16.6 ± 1.4, 15.7 ± 1.8, and 15.7 ± 2.2 mmHg at 9 AM, 1 PM, and 5 PM, respectively, at baseline reduced significantly to the mean IOPs of 13.0 ± 1.8, 12.7 ± 1.8, and 12.8 ± 1.6 mmHg, respectively, at week 12 (P < 0.0001 for every time point). Together with the mean IOPs of 13.4 ± 1.9 mmHg at week 4 and 13.2 ± 1.9 mmHg at week 8, the pooled IOP during the observation period for up to 12 weeks showed a statistically and clinically significant reduction of IOP at 9 AM. (3.4 mmHg or 20.3% reduction from baseline, P < 0.0001). There were no adverse events leading to treatment discontinuation.

Conclusion

This multi-center collaborative study suggests that IOP-lowering efficacy of travoprost ophthalmic solution persists during the day at the clinically relevant level in subjects with NTG.

Funding

Alcon Japan Ltd.

Trial registration

University Hospital Medical Information Network, UMIN ID: 000011621.

     

Multicenter,Randomized, Controlled Study Comparing Tafluprost/Timolol Fixed Combination with Latanoprost/Timolol Fixed Combination in Primary Open-Angle Glaucoma and Ocular Hypertension

Introduction

This was the first exploratory randomized controlled study to compare the efficacy and safety of a preserved tafluprost/timolol fixed combination (TAF/TIM) with a preserved latanoprost/timolol fixed combination (LAT/TIM).

Methods

This prospective, randomized, open-label study was conducted in Japanese patients with primary open-angle glaucoma, including normal-tension glaucoma or ocular hypertension. Following a 4-week LAT/TIM run-in period, eligible patients entered a 12-week treatment period, during which they received either LAT/TIM or TAF/TIM. The efficacy endpoint was the change in intraocular pressure (IOP) from baseline to week 12 and the safety endpoints included the changes from baseline to week 12 in superficial punctate keratopathy (SPK) score, tear breakup time (TBUT), and hyperemia score, as well as adverse events (AEs). At week 6, ocular symptoms were evaluated using a questionnaire.

Results

In total, 131 patients provided informed consent. Of these, 115 completed the run-in period and were assigned to receive TAF/TIM (n?=?60) or LAT/TIM (n?=?55). At week 12, there were no significant differences between the TAF/TIM and LAT/TIM groups in the change from baseline in trough IOP and IOP at 4–6 h after instillation. There were no significant differences between the two groups in the change from baseline to week 12 in SPK score, TBUT, and hyperemia score. However, only in the TAF/TIM group, the total SPK score and the inferior cornea SPK score were significantly lower at week 12 compared with baseline. Eye irritation and eye pain were significantly decreased in the TAF/TIM group compared with the LAT/TIM group. Two treatment-related AEs were reported in the TAF/TIM group (3.3%) and none in the LAT/TIM group, while no serious AEs were reported in either group.

Conclusion

TAF/TIM is as effective as LAT/TIM in terms of IOP-reducing effect, with fewer ocular symptoms. TAF/TIM was associated with a significant improvement in SPK scores.

Trial Registration

UMIN Clinical Trials Registry Identifier, UMIN000023862.

Funding

Santen Pharmaceutical Co., Ltd., Osaka, Japan.

     

Long-term Safety and Efficacy of Latanoprostene Bunod 0.024% in Japanese Subjects with Open-Angle Glaucoma or Ocular Hypertension: The JUPITER Study

Introduction

Latanoprostene bunod (LBN) is a novel nitric oxide (NO)-donating prostaglandin F2α analog. We evaluated the long-term safety and intraocular pressure (IOP)-lowering efficacy of LBN ophthalmic solution 0.024% over 1 year in Japanese subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT).

Methods

This was a single-arm, multicenter, open-label, clinical study. Subjects aged 20 years and older with a diagnosis of OAG or OHT instilled 1 drop of LBN ophthalmic solution 0.024% in the affected eye(s) once daily in the evening for 52 weeks and were evaluated every 4 weeks. Safety assessments included vital signs, comprehensive ophthalmic exams, and treatment-emergent adverse events (AEs). Absolute and percent reductions from baseline in IOP were also determined.

Results

Of 130 subjects enrolled, 121 (93.1%) completed the study. Mean age was 62.5 years, and mean (standard deviation) baseline IOP was 19.6 (2.9) and 18.7 (2.6) mmHg in study eyes and treated fellow eyes, respectively. Overall, 76/130 (58.5%) and 78/126 (61.9%) subjects experienced ≥1 AEs in study eyes and treated fellow eyes, respectively. In both study eyes and treated fellow eyes, the most common AEs were conjunctival hyperemia, growth of eyelashes, eye irritation, and eye pain. At 52 weeks, 9% of treated eyes had an increase in iris pigmentation compared with baseline based on iris photographs. No safety concerns emerged based on vital signs or other ocular assessments. Mean reductions from baseline in IOP of 22.0% and 19.5% were achieved by week 4 in study and treated fellow eyes, respectively. These reductions were maintained through week 52 (P < 0.001 vs. baseline at all visits).

Conclusion

Once daily LBN ophthalmic solution 0.024% was safe and well-tolerated in Japanese subjects with OAG or OHT when used for up to 1 year. Long-term treatment with LBN ophthalmic solution 0.024% provided significant and sustained IOP reduction.

Trial registration

ClinicalTrials.gov identifier, NCT01895972.

Funding

Bausch & Lomb, Inc. a division of Valeant Pharmaceuticals International Inc.

     

Prospective Evaluation of Two iStent<Superscript>®</Superscript> Trabecular Stents,One iStent Supra<Superscript>®</Superscript> Suprachoroidal Stent,and Postoperative Prostaglandin in Refractory Glaucoma: 4-year Outcomes

Introduction

This study evaluates long-term outcomes of two trabecular micro-bypass stents, one suprachoroidal stent, and postoperative prostaglandin in eyes with refractory open angle glaucoma (OAG).

Methods

Prospective ongoing 5-year study of 80 eligible subjects (70 with 4-year follow-up) with OAG and IOP ≥ 18 mmHg after prior trabeculectomy and while taking 1–3 glaucoma medications. Subjects received two iStent^® trabecular micro-bypass stents, one iStent Supra^® suprachoroidal stent, and postoperative travoprost. Postoperative IOP was measured with medication and annually following medication washouts. Performance was measured by the proportion of eyes with ≥ 20% IOP reduction on one medication (the protocol-specified prostaglandin) versus preoperative medicated IOP (primary outcome); and the proportion of eyes with postoperative IOP ≤ 15 and ≤ 18 mmHg on one medication (secondary outcome). Additional clinical and safety data included medications, visual field, pachymetry, gonioscopy, adverse events, visual acuity, and slit-lamp and fundus examinations.

Results

Preoperatively, mean medicated IOP was 22.0 ± 3.1 mmHg on 1.2 ± 0.4 medications, and mean unmedicated IOP was 26.4 ± 2.4 mmHg. Postoperatively, among eyes without later cataract surgery, mean medicated IOP at all visits through 48 months was ≤ 13.7 mmHg (≥ 37% reduction), and annual unmedicated IOP was ≤ 18.4 mmHg (reductions of ≥ 30% vs. preoperative unmedicated IOP and ≥ 16% vs. preoperative medicated IOP). At all postoperative visits among eyes without additional surgery or medication, ≥ 91% of eyes had ≥ 20% IOP reduction on one medication versus preoperative medicated IOP. At month 48, 97 and 98% of eyes achieved IOP ≤ 15 and ≤ 18 mmHg, respectively, on one medication. Six eyes required additional medication, no eyes required additional glaucoma surgery, and safety measurements were favorable throughout follow-up.

Conclusion

IOP control was achieved safely with two trabecular micro-bypass stents, one suprachoroidal stent, and postoperative prostaglandin. This microinvasive, ab interno approach introduces a possible new treatment option for refractory disease.

Trial Registration

NCT01456390.

Funding

Glaukos Corporation.

     

Additive Intraocular Pressure Lowering Effects of the Rho Kinase Inhibitor,Ripasudil in Glaucoma Patients Not Able to Obtain Adequate Control After Other Maximal Tolerated Medical Therapy

Introduction

The aim of this study is to investigate the additive intraocular pressure (IOP)-lowering effects and safety of the selective Rho kinase inhibitor, 0.4% ripasudil, in patients with glaucoma not adequately controlled by other maximal tolerated medical therapies.

Methods

We retrospectively reviewed 92 glaucoma patients who received ripasudil as an additive glaucoma treatment. In spite of receiving prior maximal tolerated medical therapies, all patients had uncontrolled glaucoma before receiving ripasudil. IOP was recorded at all follow-up dates.

Results

The study population consisted of 43 primary open-angle glaucoma (POAG), 28 normal-tension glaucoma (NTG), ten secondary glaucoma, seven exfoliation glaucoma, and four developmental glaucoma patients. After ripasudil administration, there was a significant decrease in the IOP. The mean pre-administration IOP and % IOP reduction at the last follow-up were 19.7 ± 4.9 mmHg and 6.5 ± 17.0% for POAG, 15.5 ± 2.0 mmHg and 2.3 ± 10.4% for NTG, 22.8 ± 8.3 mmHg and 19.1 ± 13.5% for secondary glaucoma, 22.5 ± 4.4 mmHg and 2.1 ± 14.5% for exfoliation glaucoma, and 20.2 ± 8.9 mmHg and 11.4 ± 23.1% for developmental glaucoma, respectively. Side effects led to ripasudil discontinuation in 13 patients, with five exhibiting an allergic reaction, six developing blepharitis, and two having a burning sensation.

Conclusions

Use of ripasudil as an adjunctive therapy resulted in lowering of the IOP. Ripasudil was well tolerated.

Funding

Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (26462689).

     

The Effect of Phacoemulsification on Intraocular Pressure in Eyes with Hyperfiltration Following Trabeculectomy: A Prospective Study

Introduction

The aim of this study was to evaluate the effect of visually non-significant cataract extraction in patients with hypotony maculopathy and reduced visual acuity due to over-filtering blebs after trabeculectomy.

Methods

Patients with intraocular pressure (IOP) < 6 mmHg and documented hypotony maculopathy due to over-filtering blebs after trabeculectomy were prospectively recruited. Eligible patients underwent visually non-significant cataract phacoemulsification, no earlier than 12 weeks from the diagnosis of hypotony maculopathy. IOP and visual acuity before and after phacoemulsification were compared at 1 and 3 months from surgery. Correlations between age, time interval between surgeries, baseline IOP, bleb type and IOP and visual acuity changes at 3 months after phacoemulsification were investigated.

Results

From January 2010 to September 2014, 20 consecutive adult patients met the inclusion criteria. Before phacoemulsification, mean IOP was 3.1 ± 1.6 mmHg. Following phacoemulsification, mean IOP increased to 8.6 ± 4.1 mmHg at 1 month (p < 0.01) and to 9.1 ± 4.3 mmHg at 3 months (p < 0.01). IOP elevation following phacoemulsification was observed in 16 of 20 eyes (80%). Mean visual acuity improved from Snellen 0.5 ± 0.1 to 0.6 ± 0.1 at 1 month (p < 0.01) to 0.7 ± 0.2 at 3 months (p < 0.01) after phacoemulsification. In 4 eyes in which the IOP was not elevated, surgical revision of the previous trabeculectomy was performed. No significant correlations between investigated variables, visual acuity and IOP changes at 3 months after phacoemulsification were found.

Conclusion

Phacoemulsification of visually non-significant cataract appears to be a safe and effective technique for managing chronic ocular hypotony with deep anterior chamber due to over-filtering blebs.

     

Prospective Observational Post-Marketing Study of Tafluprost for Glaucoma and Ocular Hypertension: Effectiveness and Treatment Persistence

Introduction

The aim of this study was to investigate the long-term intraocular pressure (IOP)-lowering effect and safety of tafluprost, a prostaglandin analogue, in actual clinical practice and to determine persistency of tafluprost as an indicator of its benefit–risk balance.

Methods

This was a large-scale, post-marketing, multicenter, non-interventional, open-label, long-term study. Patients with glaucoma or ocular hypertension who initiated tafluprost treatment were registered and prospectively observed over a 2-year period in the real-world setting in Japan. Long-term IOP and safety data were collected.

Results

Of the 4502 patients registered from 553 medical institutions, 4265 patients were analyzed. The majority of patients had normal-tension glaucoma (44.4%) and primary open-angle glaucoma (37.8%), and patients with ocular hypertension constituted 7.0%. Treatment patterns with tafluprost during the study period were as follows: naïve monotherapy (48.1%), switching monotherapy (18.4%), and concomitant therapy (33.5%). In all patients analyzed, mean IOP was significantly reduced from 18.6 ± 5.9 mmHg (month 0) to 15 mmHg or below throughout the 2-year observation period after initiation of tafluprost. Significant IOP-lowering effects were shown in various treatment patterns and disease types. Adverse reactions were observed in 795 patients (18.64%). Major adverse reactions included eyelid pigmentation, ocular hyperemia, eyelash changes, eyelid hypertrichosis, and iris hyperpigmentation. Kaplan–Meier curves showed that 84.6% and 76.1% of patients were persistent on tafluprost for 1 and 2 years, respectively, when discontinuation due to insufficient efficacy or adverse events was defined as a treatment failure event. Furthermore, among treatment-naïve patients (n = 2304), the persistency rates on tafluprost monotherapy were 77.0% for 1 year and 67.0% for 2 years.

Conclusion

Tafluprost showed significant long-term IOP-lowering effects regardless of treatment patterns or diagnosis, with minimum safety concerns in the actual clinical practice. The observed treatment persistence suggests that tafluprost can be used long term owing to its benefit–risk profile.

Funding

Santen Pharmaceutical Co., Ltd., Osaka, Japan.

     

Muscle Relaxants as a Risk Factor for Vis-à-tergo During Penetrating Keratoplasty: A Prospective Interventional Study

Introduction

This study aimed to investigate the influence of three muscle relaxants on intraocular pressure (IOP), ocular pulse amplitude (OPA), and vis-à-tergo (VAT) in patients undergoing penetrating keratoplasty (PKP) under general anesthesia.

Methods

Ninety-five patients undergoing PKP were included in this prospective single-center interventional study. IOP and OPA were measured with a dynamic contour tonometer before and 5 min after onset of general anesthesia. Mivacurium (n = 30), atracurium (n = 35), and rocuronium (n = 30) were administered as nondepolarizing muscle relaxants. VAT was assessed 15 min after surgery had begun.

Results

When mivacurium was used, IOP decreased by 2.2 mmHg [standard deviation (SD) ±2.2 mmHg; p < 0.001]. Atracurium decreased the IOP by an average of 5.8 mmHg (SD ±1.8 mmHg; p < 0.001) and rocuronium caused an IOP reduction of 7.2 mmHg (SD ±2 mmHg; p < 0.001). The relative IOP decrease was 12% with mivacurium, 29% with atracurium, and 37% with rocuronium (p < 0.001). OPA decreased by 0.6 mmHg with mivacurium (SD ±0.6 mmHg; 26%; p < 0.001), 1.3 mmHg with atracurium (SD ±1.3 mmHg; 40%; p < 0.001), and 1.2 mmHg with rocuronium (SD ±0.7 mmHg; 42%; p < 0.001). The relative OPA decrease was 26% with mivacurium, 40% with atracurium, and 42% with rocuronium (p < 0.001). VAT occurred in 36% of cases. Mivacurium was used in 77% of these cases, atracurium in 26%, and rocuronium in 6.6% (p < 0.001).

Conclusions

Mivacurium is associated with a higher risk of VAT during PKP. Therefore, atracurium or rocuronium may minimize complications in ocular surgery with large incisions.

     

Pharmacokinetics,Pharmacodynamics, and Safety of MEDI4212, an Anti-IgE Monoclonal Antibody,in Subjects with Atopy: A Phase I Study

Introduction

The anti-IgE therapy omalizumab is currently licensed for the treatment of moderate to severe allergic asthma and chronic idiopathic urticaria. Owing to limitations in the use of omalizumab, a need exists for optimized anti-IgE therapies to broaden clinical indications and patient populations, and to improve dosing schedules. The objective of this phase I, randomized, placebo/omalizumab-controlled, first-in-human, dose-escalation study was to evaluate the pharmacokinetics, pharmacodynamics, and safety of the high-affinity, anti-IgE therapy MEDI4212 in non-Japanese and Japanese subjects with atopy and/or diagnostic IgE ≥30 IU/mL.

Methods

Subjects with atopy and/or baseline IgE ≥30 IU/mL were randomized to a single dose of subcutaneous (5, 15, 60, 150, or 300 mg) or intravenous (300 mg) MEDI4212, subcutaneous omalizumab, or placebo. Following administration, pharmacokinetic, pharmacodynamic [IgE (free and total), and cellular FcεRI expression], and safety assessments were made.

Results

MEDI4212 rapidly suppressed free serum IgE to a greater extent than omalizumab; however, recovery of free IgE to baseline in MEDI4212-dosed subjects was rapid when compared with the slow and gradual recovery seen in omalizumab-dosed individuals. The loss of IgE suppression corresponded with a rapid decrease of serum MEDI4212. FcεRI expression on dendritic cells and basophils was reduced following MEDI4212 dosing. MEDI4212 was well tolerated by subjects; adverse events were generally of low severity and no subjects discontinued due to adverse events.

Conclusions

The increased potency of MEDI4212 may be of clinical interest for individuals with high-diagnostic IgE levels where more extensive IgE suppression is required for clinical response. However, the modest duration of free IgE suppression below the target concentration noted with MEDI4212 in this study suggests limited potential for dosing schedule advantages over omalizumab.

Funding

MedImmune.

Trial registration

ClinicalTrials.gov identifier, NCT01544348.

     

Systematic review including re-analyses of 1148 individual data sets of central venous pressure as a predictor of fluid responsiveness

Purpose

Central venous pressure (CVP) has been shown to have poor predictive value for fluid responsiveness in critically ill patients. We aimed to re-evaluate this in a larger sample subgrouped by baseline CVP values.

Methods

In April 2015, we systematically searched and included all clinical studies evaluating the value of CVP in predicting fluid responsiveness. We contacted investigators for patient data sets. We subgrouped data as lower (<8 mmHg), intermediate (8–12 mmHg) and higher (>12 mmHg) baseline CVP.

Results

We included 51 studies; in the majority, mean/median CVP values were in the intermediate range (8–12 mmHg) in both fluid responders and non-responders. In an analysis of patient data sets (n = 1148) from 22 studies, the area under the receiver operating curve was above 0.50 in the <8 mmHg CVP group [0.57 (95 % CI 0.52–0.62)] in contrast to the 8–12 mmHg and >12 mmHg CVP groups in which the lower 95 % CI crossed 0.50. We identified some positive and negative predictive value for fluid responsiveness for specific low and high values of CVP, respectively, but none of the predictive values were above 66 % for any CVPs from 0 to 20 mmHg. There were less data on higher CVPs, in particular >15 mmHg, making the estimates on predictive values less precise for higher CVP.

Conclusions

Most studies evaluating fluid responsiveness reported mean/median CVP values in the intermediate range of 8–12 mmHg both in responders and non-responders. In a re-analysis of 1148 patient data sets, specific lower and higher CVP values had some positive and negative predictive value for fluid responsiveness, respectively, but predictive values were low for all specific CVP values assessed.

     

Effects of benzalkonium chloride- and polyquad-preserved combination glaucoma medications on cultured human ocular surface cells

Introduction

The aim of this study is to investigate potential adverse effects of fixed combination glaucoma medications preserved with either benzalkonium chloride (BAK) or Polyquad® (PQ; Alcon Research Ltd., Fort Worth, TX, USA) on cultured ocular epithelial cells.

Methods

Confluent cultures of human cornea and conjunctival cell lines were exposed for 25 minutes to different glaucoma medications as well as a range of concentrations of BAK (0.001%–0.050%). Balanced salt solution was used as the “live” control and a solution containing 70% methanol and 0.2% saponin was used as a “dead” control. The number of dead and live cells were determined via ethidium homodimer (Eth-1) and calcein acetoxymethyl ester (AM) fluorescence, respectively.

Results

The toxicity of the prostaglandin analog with beta-blocker timolol fixed-combination formulations preserved with BAK was different from that observed in the respective BAK concentrations. Travoprost plus timolol fixed combination with BAK performed better than its respective BAK concentration alone, while the latanoprost plus timolol fixed combination performed worse than its respective BAK concentration. Travoprost plus timolol fixed combination preserved with PQ had greater corneal and conjunctival cell survival than either the travoprost plus timolol fixed combination preserved with BAK or the latanoprost plus timolol fixed combination.

Conclusion

Ocular surface side effects have previously been demonstrated with chronic, long-term exposure to intraocular-pressure-lowering medications containing the common preservative BAK. BAK alone has significant in-vitro cytotoxicity to cultured ocular epithelial cells. Substitution of BAK with PQ resulted in significantly higher percentages of live conjunctival and corneal cells. Further studies are needed to understand the clinical implications of these findings.

     

Does severe obstructive sleep apnea syndrome alter retrobulbar blood flow? A color Doppler ultrasound study

Purpose

To evaluate extraocular orbital vessels with color Doppler ultrasound (CDU) and investigate the effects of severe obstructive sleep apnea (OSA) on retrobulbar blood flow.

Methods

Between February 2014 and September 2015, 30 patients with severe OSA (apnea–hypopnea index (AHI) > 30) and 28 controls were prospectively included in this study. Intraocular pressure (IOP) was measured with a Goldmann applanation tonometer, and CDU was used to evaluate the retrobulbar vessels.

Results

The mean AHI score for the OSA group was 63.2 ± 21.5 per hour. The IOP values were significantly higher in the severe OSA group (p < 0.05). The central retinal artery peak systolic velocity (PSV) (p < 0.05) and end-diastolic velocity (EDV) (p < 0.02), and the ophthalmic artery (OA) PSV and EDV, were found to be significantly lower in the OSA group (p < 0.05).

Conclusion

Severe OSA causes an increase in IOP and a decrease in flow velocity in the retrobulbar circulation.

     

Efficacy and Tolerability of Fixed-Dose Combination Perindopril/Indapamide in Hypertensive Patients with a History of Stroke or Transient Ischemic Attack: PICASSO Trial

Introduction

In everyday medical practice, physicians often need to manage patients whose blood pressure is not well controlled. Those with a history of cerebrovascular disease are a high-risk group in need of rapid blood pressure control.

Methods

The PICASSO study was a real-life, observational trial involving 9257 inadequately treated hypertensive patients who were switched from previous therapy to the fixed-dose combination of perindopril 10 mg/indapamide 2.5 mg (PI) for 3 months. A subanalysis of data of 1117 hypertensive patients who met the clinical criteria of previous stroke or transient ischemic attack was performed. Twenty-four hour ambulatory blood pressure measurements (ABPMs) were also done in a small group of patients (n:38).

Results

At baseline, mean systolic/diastolic blood pressure (SBP/DBP) was 161.5?±?15.2/93.1?±?9.9 mmHg. After 1 month with the fixed dose of PI, average office SBP/DBP decreased to 140.0?±?11.9/83.5?±?7.7 mmHg. After 3 months, SBP/DBP had dropped to 132.9?±?9.8/80.0?±?6.2 mmHg, by 28.6?±?15.5/13.1?±?10.0 mmHg (p?<?0.001). Blood pressure control rate (<?140/90 mmHg) was 67.3% after 3 months. When data were stratified by baseline blood pressure, decreases in SBP/DBP were statistically significant in patients with all grades (1–3) of hypertension. In patients previously treated with an angiotensin-converting enzyme inhibitor?±?hydrochlorothiazide (n?=?677), blood pressure decreased by 29.8?±?15.5/13.3?±?10.2 mmHg (p?<?0.001). Decreases in 24-h ABPM values were also significant (n?=?38). Treatment was well tolerated; only a few adverse events were recorded.

Conclusion

This study suggests that fixed combination perindopril 10 mg/indapamide 2.5 mg is an effective and well-tolerated treatment for patients with a history of stroke or transient ischemic attack.

Funding

EGIS Pharmaceuticals Plc.

     

Biodistribution Study of Intravenously Injected Cetuximab-IRDye700DX in Cynomolgus Macaques

Purpose

The use of receptor-targeted antibodies conjugated to photosensitizers is actively being explored to enhance treatment efficacy. To facilitate clinical testing, we evaluated cetuximab conjugated to IRDye700DX (IR700) in cynomolgus macaques.

Procedures

Total IR700 and intact cetuximab-IR700 were measured in 51 tissues at 2 and 14 days after intravenous injection of 40 and 80 mg/kg cetuximab-IR700, respectively, and compared with an unlabeled cetuximab-dosed control group (two each per sex per time point per group).

Results

The IR700 retrieved from all tissues at 2 and 14 days after dosing was estimated at 34.9?±?1.8 and 2.53?±?0.67 % of the total dose, respectively. The tissues with the highest levels of intact cetuximab-IR700 at 2 days after dosing were the blood, lung, and skin. Formalin-fixed paraffin-embedded tissue sections at 2 days after dosing showed the highest IR700 signals in the axillary lymph node, mammary gland, and gall bladder.

Conclusions

Both IR700 and intact cetuximab-IR700 biodistributions were consistent with known epidermal growth factor receptor (EGFR) expression, and changes between 2 and 14 days were consistent with rapid metabolism and excretion of the cetuximab-IR700.