Phase â /â ¡, Double-Masked, Randomized, Vehicle-Controlled Study of H-1337 Ophthalmic Solution for Glaucoma and Ocular Hypertension.

PURPOSE: To perform a phase Ⅰ/Ⅱ evaluation of an H-1337 ophthalmic solution in subjects with primary open-angle glaucoma (POAG) or ocular hypertension (OHT). DESIGN: This was a phase I/II, randomized, double-masked, vehicle-controlled, dose-response study conducted at 6 private practice sites in the United States. The study was registered with clinicaltrials.gov as NCT03452033. PARTICIPANTS: Eighty-seven subjects with bilateral POAG or OHT were enrolled. METHODS: After washout of ocular hypotensive medications as required, the subjects were randomized to receive either the H-1337 ophthalmic solution at 0.06%, 0.2%, and 0.6% or its vehicle twice daily unilaterally in the study eye for the first 3 days and then twice daily in both eyes from day 4 to 28. MAIN OUTCOME MEASURES: The primary efficacy end point was the mean change in intraocular pressure from baseline (day 0) for each group on day 28 at hour 4 compared with the vehicle. RESULTS: In the primary efficacy end point, i.e., mean change from the baseline on day 28 at hour 4, the mean change from the baseline was - 4.45 ± 3.801, - 5.16 ± 3.114, - 4.93 ± 3.110, and - 0.39 ± 2.355 in the 0.06%, 0.2%, and 0.6% H-1337 and vehicle groups, respectively. The difference between each active group and the vehicle group was statistically significant (P < 0.0001). Treatment-emergent adverse events (TEAEs) occurred in 49% of subjects who received H-1337 (range, 41% [0.2% arm]-64% [0.6% arm] across the H-1337 arms) and 18% of subjects who received the vehicle. The majority of TEAEs were mild in severity; 3 subjects who received H-1337 had a TEAE of moderate intensity (instillation site erythema, blurred vision, and muscle strain). CONCLUSIONS: The H-1337 ophthalmic solution showed clinically and statistically significant ocular hypotensive activity and was well tolerated, with a relatively low incidence of hyperemia. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Ophthalmic community perception of new medication needs.

AIM: To survey ophthalmologists (who have participated previously in clinical research) and ophthalmic industry professionals (who have been involved in ocular research and development) to indicate perceived needs for new pharmaceuticals in various ophthalmic subspecialties. METHODS: A prospective, industry-based survey was sent to ophthalmologists and ophthalmic industry professionals about the perceived needs for new pharmaceutical products. RESULTS: This survey was sent to 559 ophthalmic pharma professionals and ophthalmologists. We received 82 (15%) responses. The results showed that the most commonly perceived need for new pharmaceuticals were dry and wet age-related macular degeneration, glaucoma, diabetic macular edema and dry eye. There was a statistical difference found between response groups (P<0.0001). Respondents indicated they would express their commitment to a new product they perceived as needed by recommending to colleagues (63%), prescribing (60%), participating as principle investigator in a related clinical trial (52%), advising the company (52%), lecturing on behalf of the product (43%), investing in the product (38%), taking no action (7%) or obtain a position in the company (1%). CONCLUSION: Ophthalmic pharma professionals and ophthalmologists perceive the greatest need for new medicines in ophthalmology to be in dry and wet age-related macular degeneration, glaucoma, diabetic macular edema and dry eye.

Ophthalmic Start-Up Chief Executive Officers' Perceptions of Development Hurdles.

PURPOSE: To identify current challenges facing ophthalmic pharmaceutical start-ups in developing new products. METHODS: Surveys were distributed to the chief executive officer (CEO) or president of ophthalmic start-ups. RESULTS: The survey attracted 24 responses from 78 surveys distributed (31%). The CEOs stated that a lack of financial capital (n = 18, 75%), FDA regulations (n = 6, 25%), and failure to meet clinical endpoints (n = 6, 25%) were their greatest development hurdles. Risk aversion to medicines in early development (n = 18, 75%), mergers and acquisitions reducing corporate choice for licensing agreements (n = 7, 29%), the emergence of large pharmaceutical-based venture capital funding groups (n = 12, 50%), and the failure of many large pharmaceutical companies to develop their own medicines (n = 10, 42%) were noted as recent prominent trends affecting fundraising. CONCLUSION: The study suggests that development funding, regulatory burden, and meeting clinical endpoints are the greatest development challenges faced by ophthalmic start-up CEOs.

What data sources do ophthalmologists trust?

To survey ophthalmologists regarding sources they trust when incorporating new medical knowledge into their practice. The survey was distributed primarily to US-based ophthalmologists. Questions were derived based on the lead author's research experience from congresses and discussions and from mentions in the medical literature. In total, 77 physicians completed the survey of 1886 sent (4% response rate). Regarding study design, physicians preferred a well-controlled, randomised, double-masked trial (99%) with multicentred investigational site across a wide geographical area (80%). Authorship of a research article was most desired from a well-known key opinion leader (KOL) (75%) or any KOL leader at a university (75%). The most selected journal type was a subspecialty publication (86%) and second a multispecialty high impact journal (77%). Study sponsorship was most desired from the NIH or other government agencies (71%) or a university (71%). Doctors preferred clinical opinions from an ophthalmic medical society (75%). For the source of new clinical data, physicians indicated an unsponsored peer-reviewed journal article (77%) or a lecture at a large ophthalmic congress (74%) as the preferred source. Ophthalmologists generally desire sponsors, study designs and opinions that appear free of bias on which to base their clinical practice decisions.

The Source and Impact of Specific Parameters that Enhance Well-Being in Daily Life.

The purpose of this study was to review four parameters (forgiveness, gratitude, hope and empathy) frequently noted when evaluating well-being. We reviewed clinical studies from 1966 to present. We included 63 articles. All four of the parameters were shown to generally improve an individual's well-being. These parameters demonstrated a positive influence within more specific societal issues including improvement in social relationships, delinquent behavior and physical health. These parameters were generally derived from training and religion. This study suggests that these parameters may improve either one of general well-being, pro-social and positive relational behavior and demonstrate positive health effects.

Fitness to stand trial, human rights and possibilities from England and Wales.

The capacity of individuals with disability, including cognitive or mental health impairments, to access justice on an equal basis has been considered recently in several Australian jurisdictions. Impairments can render individuals vulnerable in the legal system, affecting their reliability as a witness or their fitness to be tried, especially when limited support is available to help these individuals meet the test and criteria for fitness to stand trial. This article considers the situation in Australia in light of human rights perspectives and compares it with the England and Wales approach where special support measures have been introduced to help individuals access justice. The article recommends that better support measures be introduced in Australia that would be consistent with a human rights framework calling for support to enable individuals with disability to access justice. In particular, the introduction of intermediaries, as used in England and Wales, would go some way towards helping vulnerable individuals to access justice.

Description of Ophthalmic Pharmaceutical and Device Start-Up Companies.

AIMS: To describe the number, type and location of ophthalmic companies and their associated product areas and indications. METHODS: A retrospective, non-patient-based, observational review of ophthalmic pharmaceutical and device companies with a new product in development. Data was compiled by Internet searches. RESULTS: We identified 190 companies currently developing ophthalmic products: 134 (71%) were privately held and 56 (29%) publicly held, while 136 (72%) were in the United States and 53 (28%) were outside the United States. There were 436 total products of which 338 (78%) were pharmaceuticals and 98 (22%) devices. With pharmaceuticals we identified 46 separate indications with age-related macular degeneration (n = 75), glaucoma (n = 52) and dry eye (n = 46) as most common; anti-vascular endothelial growth factor, hormone therapy and anti-inflammatory products were also common classes. With devices there were 30 indications with glaucoma (n = 26), age-related macular degeneration (n = 19) and dry eye (n = 6) as most common; drug delivery, ocular implants and prostheses were less common classes. CONCLUSIONS: Ophthalmology as a specialty is benefited by a wide effort in new medicine and device development. However, a concentration of effort into relatively few indications suggests a potential lack of market analysis and possible difficulty for many companies in commercializing their product.

Techniques to Reduce the Placebo Effect in Glaucoma Clinical Trials.

AIM: To evaluate techniques used to reduce the placebo effect in prior well-controlled, single or double-masked placebo-controlled glaucoma trials. METHODS: This study was a retrospective, non-patient-based, observational review of phase I-III trials with a placebo arm for glaucoma medicines available after 1977. RESULTS: This study included 20 articles with 20 placebo control arms consisting of 458 patients evaluating 10 different glaucoma medications with 58 treatment arms. There was no statistical difference across the evaluated types of study designs to limit the placebo effect either for the morning trough or diurnal curve. The average reduction of the intraocular pressure in the placebo groups was 1.6 ± 1.5 mm Hg for the morning trough and 1.3 ± 1.3 mm Hg for the diurnal curve across all studies. CONCLUSION: The results of this study suggest that current design techniques described in the literature to limit the placebo effect appear ineffective compared to no additional techniques.

The placebo effect in early-phase glaucoma clinical trials.

PURPOSE: To analyze the extent and prevalence of the placebo effect in prior early-phase glaucoma clinical studies. METHODS: Articles were evaluated on phase I and II trials of glaucoma medicines that became commercially available after 1977 with a placebo arm that involved glaucoma patients. RESULTS: We included 23 studies with 23 treatment arms with a total of 1703 patients in articles evaluating 10 different glaucoma medications. This study showed that at 8 AM (n = 18), the average decrease in placebo from untreated baseline was 2.3 ± 1.6 mm Hg (9%), while for the diurnal curve (n = 17), the mean decrease was 1.4 ± 1.1 mm Hg (6%). At 8 AM, 8/18 treatment arms had greater than 2 mm Hg intraocular pressure (IOP) decrease, and all had at least some reduction in IOP. For the diurnal curve, 4 of 17 studies had reduced IOP greater than 2 mm Hg. One treatment arm had no placebo effect. CONCLUSIONS: This study suggests that a placebo effect is common in glaucoma clinical trials and potentially could limit the ability to evaluate the efficacy of a new medicine.

A neuropsychological comparison of siblings with neurological versus hepatic symptoms of Wilson's Disease.

Wilson's Disease (WD) (also known as hepatolenticular degeneration) is a rare inherited autosomal recessive disorder of abnormal copper metabolism, with an estimated prevalence of approximately 1 in 30,000. The clinical features associated with WD are highly varied. However, subtypes generally reflect neurological, hepatic, and psychiatric symptoms. The present case study reports two brothers with a recent diagnosis of WD. Neurological symptoms and cognitive deficits were exhibited in one brother (BL) in the form of extrapyramidal features, while the other brother (AL) only exhibited hepatic symptoms. Extensive neuropsychological testing was conducted on both siblings to compare cognitive profiles. Results for BL indicated significantly impaired motor functioning and information processing speed, which impacted him significantly at school. Aspects of executive dysfunction were also apparent in addition to reduced visual and verbal memory, working memory, and attention. Results for AL revealed evidence of verbal memory difficulties and aspects of executive dysfunction. Comparison is made of the distinct and common cognitive characteristics of the cases presented in terms of implications for early intervention and management of cognitive difficulties.

Glaucoma clinical trial design: A review of the literature.

The purpose of this article is to review the prior research evaluating design techniques for glaucoma clinical trials to help ophthalmologists and pharmaceutical sponsors better develop literature-based studies that are cost- and time-efficient. We performed this study using known published articles by the authors and literature found on Pub Med. We included 24 articles that analyzed specifically the results of clinical trial methods and/or interpretation. This review found that studies have evaluated glaucoma specific aspects of glaucoma clinical trials including: Predicting the results of later phase clinical trials based on early phase clinical trials and animal studies; protocol design parameters such as intraocular pressure, inclusion criteria, method of pressure measurement, study population, and side effect evaluation; and study planning issues such as number of clinical sites as well as subjects, dropout rates, estimated serious adverse events, and protocol violations. This review suggests that the medical literature supports some aspects of glaucoma clinical trial study design. Additional design features might be derived from government regulations, guidance, as well as agency contacts, consultants, and clinical community standards. Study design decisions that must be made beyond the aforementioned resources should be made carefully, with appropriate consultation as needed, considering the risk/benefit ratio to the study. However, more research is needed to better evaluate the design procedures and methods involved in glaucoma clinical trials to best provide a cost- and time-efficient study while achieving quality efficacy and safety results.

Review of the impact of presbyopia on quality of life in the developing and developed world.

PURPOSE: To examine the public health impact of presbyopia regarding its effect on quality of life (QoL) and society in both the developed and developing worlds. METHODS: A database was created from articles found on PubMed, the Cochrane Library and Science Direct using the following search terms: presbyopia, QoL, accommodation, impact, cost, prevention, treatment and public health. Articles were accepted into the database if they addressed presbyopia and public health. RESULTS: This study showed in the developed world presbyopic subjects treated with reading glasses suffered a reduction in QoL parameters compared with those who were younger and emmetropic. A small minority of subjects were assessed to be a candidate for additional non-spectacle treatment measures. In undeveloped areas, the manifestations of presbyopia were similar to the developed world in symptoms, age and reduced QoL. However, there was inadequate treatment of this condition, even with reading glasses. The availability of reading glasses ranged from 6 to 45%. Activities of daily living could not be accomplished as easily without near correction of reading. Reasons described for the lack of correction included: lack of access to medical care, poor awareness of decreased near vision, lack of motivation and cost. Overall scant data exist regarding presbyopia and its impact and how treatment affects QoL. CONCLUSIONS: This review suggests that the effect of presbyopia and its treatments on QoL remain poorly described and incompletely treated, especially in developing areas of the world.

Lower limits of intraocular pressure in glaucoma clinical trials.

PURPOSE: To determine the association of the lower limit of intraocular pressure (IOP) specified in the inclusion criteria to baseline and active treatment visit IOPs for monotherapy treatments. METHODS: A review of clinical trial articles evaluating currently used topical glaucoma medicines. Articles were published between January 1995 and December 2011. RESULTS: This study included 37 monotherapy treatment arms from 15 studies. There were 18 prostaglandin analogs, 8 ß-blockers, 8 carbonic anhydrase inhibitors, 2 α-agonists, and 1 unoprostone. For all studies included generally there was a stepwise increase in the baseline 8 AM and diurnal IOP of approximately 1 mm Hg for each 1 mm Hg increase in entry criteria. This was true for all treatment arms together, with or without a PM entry criterion (P<0.0001). However, the inclusion of an afternoon entry criterion time point did not seem to affect average IOP at baseline for the 8 AM and diurnal IOP. The treated reductions from baseline were not statistically different based on morning or afternoon entry criteria for either the 8 AM or diurnal IOPs (P≥0.07). CONCLUSIONS: Progressively higher 8 AM entry criteria IOPs at untreated baseline may influence, depending on design, in a linear manner the 8 AM and diurnal baseline IOPs of glaucoma studies at baseline. However, this effect was not observed in the treated reductions from baseline. Further, the addition of an afternoon entry criterion time point does not seem to change baseline 8 AM and diurnal IOPs.

Association of strength of community service to personal wellbeing.

To assess the impact of community service on personal wellbeing in a mid-west church-based population. A prospective survey evaluating: self-reported community service, the perceived benefit of the service and its association to personal wellbeing. 309 participants were included of whom 92 % were employed full or part time, homemakers or students. Those who served in some capacity had better scores on five Wellbeing questions including: contentment, peace, joy, purpose and community acceptance (P < 0.02), but not better self-perceived mental or physical health (P > 0.05). People who served had a better combined Wellbeing score than those who could not serve (P = 0.03). A higher number of hours served/week was associated with better Global Wellbeing (P = 0.02). The greatest perceived benefit of service was related to enhancing wellbeing of others and the service organization itself (P < 0.0001). Church going adults, who are serving in some capacity in their church or community, may demonstrate heightened personal wellbeing compared to those who are not assisting others.

Association of strength of religious adherence to quality of life measures.

PURPOSE: The purpose of this study is to evaluate, in a mid-west, religiously conservative church-population, the impact upon a subject's Biblically based depth of religious adherence on quality of life. METHODS: A survey evaluating self-reported adherence to basic activities and knowledge of faith and perceived well-being. Subjects were divided into 'adherent' or 'less-adherent' and these groups were used to analyze differences. RESULTS: Of 303 included subjects we found differences between adherent and less-adherent groups in each of 7 questions (P ≤ 0.01). The strongest separation between groups resulted from: if they met the needs of another Christian, studied the Holy Scriptures or praised God. CONCLUSION: Religious adherence may promote a sense of well-being in those who profess Christian faith.

Long-term cost and efficacy analysis of latanoprost versus timolol in glaucoma patients in Germany.

AIM: To evaluate 5-year effectiveness and cost between latanoprost or timolol monotherapy in a pilot trial. METHODS: A retrospective, multi-center trial performed at 6 sites in Germany of patients who had a diagnosis of primary open-angle or pigmentary glaucoma, in at least one eye, initiated on monotherapy with latanoprost or timolol maleate. Qualified consecutive charts were reviewed in which 5-year efficacy, safety and cost data was abstracted. RESULTS: Seventy-seoen latanoprost and 49 timolol patients were included, at the final visit no difference existed between the two groups in disc parameters including: rim area, rim area/disc area ratio, cup volume or vertical cup/disc ratio (P>0.05). There was no difference in intraocular pressure (IOP) between the initial latanoprost (17.4±2.6) and timolol (16.3±2.8mmHg) groups. There was less change in medicines over the follow-up period (0.1 vs 0.8) and fewer medications at the final visit (1.2 vs 1.8) with latanoprost compared to timolol. No patient treated with latanoprost discontinued therapy during follow-up, while 12% discontinued timolol mostly due to inadequate IOP control. Cost/year was less with initial timolol ($458±236) as compared to latanoprost ($552±202). CONCLUSION: Patients begun on latanoprost or timolol and followed over 5 years may have similar clinical outcomes. However, timolol patients may require more medicines and medicine changes to control IOP for long-term, but at a lower cost.

Review of clinical medicine and religious practice.

The purpose was to evaluate faith-based studies within the medical literature to determine whether there are ways to help physicians understand how religion affects patients' lives and diseases. We reviewed articles that assessed the influence of religious practices on medicine as a primary or secondary variable in clinical practice. This review evaluated 49 articles and found that religious faith is important to many patients, particularly those with serious disease, and patients depend on it as a positive coping mechanism. The findings of this review can suggest that patients frequently practice religion and interact with God about their disease state. This spiritual interaction may benefit the patient by providing comfort, increasing knowledge about their disease, greater treatment adherence, and quality of life. The results of prayer on specific disease states appear inconsistent with cardiovascular disease but stronger in other disease states.