Tissue-specific genotype-phenotype correlations among USH2A-related disorders in the RUSH2A study.

We assessed genotype-phenotype correlations among the visual, auditory, and olfactory phenotypes of 127 participants with Usher syndrome (USH2) (n =80) or nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) (n = 47) due to USH2A variants, using clinical data and molecular diagnostics from the Rate of Progression in USH2A Related Retinal Degeneration (RUSH2A) study. USH2A truncating alleles were associated with USH2 and had a dose-dependent effect on hearing loss severity with no effect on visual loss severity within the USH2 subgroup. A group of missense alleles in an interfibronectin domain appeared to be hypomorphic in ARRP. These alleles were associated with later age of onset, larger visual field area, better sensitivity thresholds, and better electroretinographic responses. No effect of genotype on the severity of olfactory deficits was observed. This study unveils a unique, tissue-specific USH2A allelic hierarchy with important prognostic implications for patient counseling and treatment trial endpoints. These findings may inform clinical care or research approaches in others with allelic disorders or pleiotropic phenotypes.

Auditory and olfactory findings in patients with USH2A-related retinal degeneration-Findings at baseline from the rate of progression in USH2A-related retinal degeneration natural history study (RUSH2A).

Sensorineural hearing loss (SNHL) is characteristic of Usher syndrome type 2 (USH2), but less is known about SNHL in nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) and olfaction in USH2A-associated retinal degeneration. The Rate of Progression of USH2A-related Retinal Degeneration (RUSH2A) is a natural history study that enrolled 127 participants, 80 with USH2 and 47 with ARRP. Hearing was measured by pure-tone thresholds and word recognition scores, and olfaction by the University of Pennsylvania Smell Identification Test (UPSIT). SNHL was moderate in 72% of USH2 participants and severe or profound in 25%, while 9% of ARRP participants had moderate adult-onset SNHL. Pure-tone thresholds worsened with age in ARRP but not in USH2 participants. The degree of SNHL was not associated with other participant characteristics in either USH2 or ARRP. Median pure-tone thresholds in ARRP participants were significantly higher than the normative population (p < 0.001). Among 14 USH2 participants reporting newborn hearing screening results, 7 reported passing. Among RUSH2A participants, 7% had mild microsmia and 5% had moderate or severe microsmia. Their mean (±SD) UPSIT score was 35 (±3), similar to healthy controls (34 [±3]; p = 0.39). Olfaction differed by country (p = 0.02), but was not significantly associated with clinical diagnosis, age, gender, race/ethnicity, smoking status, visual measures, or hearing. Hearing loss in USH2A-related USH2 did not progress with age. ARRP patients had higher pure-tone thresholds than normal. Newborn hearing screening did not identify all USH2A-related hearing loss. Olfaction was not significantly worse than normal in participants with USH2A-related retinal degeneration.

Efficacy and tolerability of an investigational nitric oxide-releasing topical gel in patients with molluscum contagiosum: A randomized clinical trial.

BACKGROUND: Although a variety of ablative, topical, and systemic therapies are used for molluscum contagiosum (MC), none has been well studied or approved by the US Food and Drug Administration. OBJECTIVES: To compare the efficacy and tolerability of topical SB206 (berdazimer sodium gel coadministered with hydrogel) with vehicle. METHODS: A 12-week, phase 2, multicenter, randomized, double-blind, vehicle-controlled clinical trial of topical SB206. RESULTS: A total of 256 patients (mean age, approximately 7 years) participated. Of patients who completed 12 weeks of treatment (n = 217), all MC lesions cleared in 20.0% of patients who received vehicle compared with 13.2%, 41.0%, and 35.1% of patients treated with twice daily SB206 4%, 8%, and 12%, respectively, and 41.9% of patients treated with once daily SB206 12%. Application-site erythema occurred in 10.6% of patients treated with SB206. Application-site reactions were the most common adverse events leading to treatment discontinuation, affecting 2 patients (approximately 4%) in each of the SB206 4%, 8%, and 12% twice daily groups and 0 patients in the vehicle or SB206 12% once daily groups. LIMITATIONS: A larger study is needed to confirm the efficacy of SB206 12% once daily and provide additional safety assessments. CONCLUSION: Of the doses studied, SB206 12% applied once daily provided the best balance between MC lesion clearance and tolerability for evaluation in a larger study.

A Phase 2 Controlled Study of SB206, a Topical Nitric Oxide-Releasing Drug for Extragenital Wart Treatment.

BACKGROUND: Nitric oxide (NO), a free radical gas, is endogenously produced in human cells. In high concentration, NO neutralizes many disease-causing microbes. The topical investigational drug SB206 releases NO and has the potential to treat skin diseases caused by viruses. Genital warts (condyloma acuminata) are primarily caused by human papillomavirus (HPV) types 6 and 11. Available treatments have low tolerability and efficacy rates and are inconvenient for the patient. Genital warts can recur if HPV is incompletely eradicated during treatment. OBJECTIVE: Topical SB206 (berdazimer sodium plus carboxymethyl cellulose hydrogel) was assessed for tolerability, safety, and efficacy for up to12 weeks in patients with external genital and/or perianal warts (EGW/PAW) in a phase 2, double-blind, randomized, dose-escalation study. METHODS: Patients (N=108) were randomly assigned to SB206 or vehicle in a 3:1 ratio: SB206 4% once (QD) or twice daily (BID), 8% QD, 12% QD, or corresponding vehicle. Treatment duration was up to 84 days. The primary efficacy endpoint was complete clearance of baseline EGW/PAW at or before week 12. Pearson's Chi Square tests compared the efficacy of active vs vehicle treatments. Safety was assessed through adverse event and tolerability reports, physical examination findings, and clinical laboratory test results. RESULTS: In the Intent-to-Treat population, the percentage of patients with complete clearance of baseline EGW/PAW at or before week 12 was higher for SB206 groups than for vehicle groups, with the greatest difference between SB206 12% QD (33.3%; P=0.010) and vehicle QD (4.3%). CONCLUSION: Berdazimer sodium (SB206) plus hydrogel was efficacious and well tolerated in the treatment of EGW/PAW. J Drugs Dermatol. 2018;17(10):1100-1105.

A Phase 2, Controlled, Dose-Ranging Study of SB208, an Investigational Topical Nitric Oxide-Releasing Drug, for the Treatment of Tinea Pedis.

BACKGROUND: Tinea pedis, or athlete's foot, is a superficial, skin infection caused by dermatophytes. It is usually topically treated. Nitric oxide is endogenously produced in humans and has a variety of physiologic and antimicrobial properties. SB208 is a novel topical treatment comprising berdazimer sodium (a nitric oxide-storing macromolecule) and a hydrogel. Admixing these two components releases nitric oxide to the application site. METHODS: A phase 2, double-blind, randomized trial evaluated the safety and efficacy of 3 doses of SB208 (2%, 4%, and 16%) vs matching vehicle, administered once daily for 14 days, in subjects with culture-confirmed interdigital tinea pedis. The primary efficacy outcome was the proportion of subjects with negative fungal cultures at end of treatment (day 14). Secondary outcomes at days 14 and 42 were the proportion of subjects with mycological cure (negative potassium hydroxide wet mount skin test and culture), clinical cure (reduced signs and symptoms from baseline graded on a 4-point scale). Safety was monitored through physical examinations, adverse events, and hemoglobin and methemoglobin levels. Efficacy outcomes were analyzed using a two-sided Cochran-Mantel-Haenszel test for general association, stratified by site. RESULTS: At day 14, a higher proportion of patients had negative fungal cultures in the pooled SB208-treated group (62%; P=0.04) than the vehicle-treated group (43%). Of SB208 groups, the 4% group had higher incidence of negative fungal cultures vs the vehicle group (67.6% vs 42.9%; P=0.03). At day 42, pooled SB208-treated groups had significantly more mycological cure vs vehicle group (47% vs 31%, respectively; P=0.08), and clinical cure was maintained in 23% of pooled SB208-treated patients vs 14% of vehicle-treated patients. No safety concerns were reported. Adverse events were mild, not serious, and considered unrelated to study medications. CONCLUSIONS: Topical SB208 was effective and well tolerated in the treatment of tinea pedis. J Drugs Dermatol. 2018;17(8):888-893.

Cost-Effectiveness Analysis of Four Simulated Colorectal Cancer Screening Interventions, North Carolina.

INTRODUCTION: Colorectal cancer (CRC) screening rates are suboptimal, particularly among the uninsured and the under-insured and among rural and African American populations. Little guidance is available for state-level decision makers to use to prioritize investment in evidence-based interventions to improve their population's health. The objective of this study was to demonstrate use of a simulation model that incorporates synthetic census data and claims-based statistical models to project screening behavior in North Carolina. METHODS: We used individual-based modeling to simulate and compare intervention costs and results under 4 evidence-based and stakeholder-informed intervention scenarios for a 10-year intervention window, from January 1, 2014, through December 31, 2023. We compared the proportion of people living in North Carolina who were aged 50 to 75 years at some point during the window (that is, age-eligible for screening) who were up to date with CRC screening recommendations across intervention scenarios, both overall and among groups with documented disparities in receipt of screening. RESULTS: We estimated that the costs of the 4 intervention scenarios considered would range from $1.6 million to $3.75 million. Our model showed that mailed reminders for Medicaid enrollees, mass media campaigns targeting African Americans, and colonoscopy vouchers for the uninsured reduced disparities in receipt of screening by 2023, but produced only small increases in overall screening rates (0.2-0.5 percentage-point increases in the percentage of age-eligible adults who were up to date with CRC screening recommendations). Increased screenings ranged from 41,709 additional life-years up to date with screening for the voucher intervention to 145,821 for the mass media intervention. Reminders mailed to Medicaid enrollees and the mass media campaign for African Americans were the most cost-effective interventions, with costs per additional life-year up to date with screening of $25 or less. The intervention expanding the number of endoscopy facilities cost more than the other 3 interventions and was less effective in increasing CRC screening. CONCLUSION: Cost-effective CRC screening interventions targeting observed disparities are available, but substantial investment (more than $3.75 million) and additional approaches beyond those considered here are required to realize greater increases population-wide.

Multicenter Study of a Novel Topical Interleukin-1 Receptor Inhibitor, Isunakinra, in Subjects With Moderate to Severe Dry Eye Disease.

OBJECTIVES: Isunakinra, formerly known as EBI-005, is a novel interleukin (IL)-1 receptor inhibitor developed for topical treatment of patients with dry eye disease (DED). This phase 1b/2a multicenter, double-masked, randomized, vehicle controlled environmental trial assessed the safety and biological activity of isunakinra in patients with moderate to severe DED. METHODS: Subjects (N=74) were randomized to vehicle (placebo) or isunakinra (5 or 20 mg/mL) 3×/daily for 6 weeks. Evaluations included safety, tolerability, biological activity for signs (corneal fluorescein staining [CFS]), symptoms (pain or sore eyes and total Ocular Surface Disease Index [OSDI]), and reduction in rescue artificial tear use. RESULTS: Topical administration of isunakinra (5 and 20 mg/mL) was safe and well tolerated and resulted in clinically relevant improvements in symptoms (OSDI score, painful/sore eye component of OSDI) and signs (total CFS) compared with baseline with no dose response. OSDI scores improved from baseline by 38% (18.9 points) at 6 weeks and CFS scores improved by 33% (3 points) in the isunakinra groups. These changes were not statistically significant compared with the vehicle. Use of artificial rescue tears was significantly reduced in the isunakinra treatment groups (mean=9 vials) compared with vehicle (mean=31 vials). The differences between isunakinra and vehicle treatments were more pronounced in subjects with OSDI scores less than 50 at baseline. CONCLUSIONS: Isunakinra was safe, well tolerated and showed clinically meaningful improvements in signs and symptoms of DED. These results encouraged the design of an adequately powered study to characterize the safety and efficacy of isunakinra in ocular surface diseases.

Functional Vision in Patients With Biallelic USH2A Variants.

PURPOSE: To describe functional vision (FV) and investigate the relationship between FV, visual acuity (VA), and hill of vision (VTOT) at baseline in patients with biallelic USH2A variants. DESIGN: Multicenter, international, cross-sectional study. METHODS: In individuals with biallelic disease-causing variants in USH2A, clinical diagnosis of Usher syndrome type 2 (USH2) or autosomal recessive nonsyndromic retinitis pigmentosa (ARRP) was based on history of hearing loss and audiology examinations. The VALVVFQ-48 was administered verbally to participants ≥18 years old. VA was measured in both eyes; VTOT was determined from static perimetry in the study eye (better VA). FV scores were calculated using Rasch analysis. RESULTS: Median age of 121 participants (76 with USH2, 45 with ARRP) was 41 years (range: 19-80); 54% were female. FV scores varied from -2.0 to 7.6 logits (median [interquartile range (IQR)]: 2.8 [1.5-3.8]). ARRP and USH2 participants had similar FV scores, both before [mean (95% CI): 2.8 (2.3-3.4) and 2.7 (2.3-3.2), respectively], and after [mean (95% CI): 2.5 (2.1-3.0) and 2.9 (2.6-3.3), respectively; P = .24] adjusting for age, VA, disease duration, and VTOT. VA and VTOT accounted for 29% and 26% of the variance in FV scores, respectively (P < .001 for each). Together, they accounted for 36% of variance observed. CONCLUSIONS: Biallelic USH2A variants were associated with a large range of FV, yet similar in ARRP and USH2, despite hearing loss in USH2. The modified VALVVFQ-48 we evaluated is not ideal for detecting the impact of USH2A-associated retinal degenerations on activities of daily living.

Self-Reported Functional Vision in USH2A-Associated Retinal Degeneration as Measured by the Michigan Retinal Degeneration Questionnaire.

Purpose: The purpose of this study was to evaluate self-reported functional vision (FV) and the impact of vision loss in patients with USH2A-associated retinal degeneration using a patient-reported outcome (PRO) measure, the Michigan Retinal Degeneration Questionnaire (MRDQ), to correlate MRDQ scores with well-established visual function measurements. Design: An observational cross-sectional study (n = 93) of participants who had Usher Syndrome Type 2 (USH2, n = 55) or autosomal recessive non-syndromic retinitis pigmentosa (ARRP; n = 38) associated with biallelic variants in the USH2A gene. Methods: The study protocol was approved by all ethics boards and informed consent was obtained from each participant. Participants completed the MRDQ at the 48-month study follow-up visit. Disease duration was self-reported by participants. One-way ANOVA was used to compare subgroups (clinical diagnosis, age, disease duration, and full-field stimulus threshold [FST] Blue-Red mediation) on mean scores per domain. Spearman correlation coefficients were used to assess associations between MRDQ domains and visual/retinal function assessments. Results: Of the study sample, 58% were female participants and the median disease duration was 13 years. MRDQ domains were sensitive to differences between subgroups of clinical diagnosis, age, disease duration, and FST Blue-Red mediation. MRDQ domains correlated with static perimetry, microperimetry, full-field stimulus testing, and best-corrected visual acuity (BCVA). Conclusions: Self-reported FV measured by the MRDQ, when applied to USH2 and ARRP participants, had good distributional characteristics and correlated well with visual function tests. MRDQ adds a new dimension of understanding on vision-related functioning and establishes this PRO tool as an informative measure in evaluating USH2A outcomes.

The Importance of Natural History Studies in Inherited Retinal Diseases.

Natural history studies of inherited retinal diseases (IRDs) play a critical role in the design and implementation of treatment trials. Study objectives ideally encompass (1) understanding the time course and pattern of disease progression, (2) within genotypic and phenotypic subtypes of patient populations, and (3) characterizing a range of measures of vision function, retinal structure, and functional vision that may serve as endpoints. In rare disease, data quality standards are paramount to optimizing smaller sample sizes, including a prospective, standardized, and longitudinal approach to data collection. Multicenter studies additionally facilitate strength in numbers and generalizability, and multidisciplinary collaboration ensures a holistic approach to study design and knowledge-building. Dissemination of natural history study results, data sets, and lessons learned will stimulate further innovation and progress in IRD therapeutic research, including setting up future trial designs for their best chance of success.

Beyond the NEI-VFQ: Recent Experience in the Development and Utilization of Patient-Reported Outcomes for Inherited Retinal Diseases.

Patient-reported outcome measures (PROMs) are tools designed to capture how a patient feels or functions, without the input or interpretation of anyone else. The earliest PROMs used in studies of inherited retinal diseases (IRDs) lack the validity required for therapy development today. The NEI-VFQ was one of the earliest PROMs developed using concept elicitation and cognitive debriefing of patients, but it lacks items that are common to patients with IRDs and it has poor measurement properties. Recent advances in PROM development include the Michigan Retinal Degeneration Questionnaire (MRDQ) and the ViSIO-PRO for nonsyndromic retinitis pigmentosa (RP), both of which have been qualitatively and quantitatively validated. As these new tools are used in clinical studies, they will generate additional evidence about their measurement characteristics. With the latest advances in PROM development for IRDs, it is now possible to move beyond the NEI-VFQ to measure what is truly important to patients.

Identifying and Overcoming Challenges in Developing Effective Treatments for Usher 1B: A Workshop Report.

Purpose: To identify challenges and opportunities for the development of treatments for Usher syndrome (USH) type 1B. Methods: In September 2021, the Foundation Fighting Blindness hosted a virtual workshop of clinicians, academic and industry researchers, advocates, and affected individuals and their families to discuss the challenges and opportunities for USH1B treatment development. Results: The workshop began with insights from individuals affected by USH1B. Presentation topics included myosin VIIA protein function in the ear and eye and its role in disease pathology; challenges with the USH1B mouse model most used in disease research to date; new investigations into alternative disease models that may provide closer analogues to USH1B in the human retina, including retinal organoids and large animal models; and learnings from and limitations of available disease natural history data. Participants discussed the need for an open dialogue between researchers and regulators to design USH1B clinical trials with appropriate outcome measures of vision improvement, along with multimodal imaging of the retina and other testing approaches that can help inform trial designs. The workshop concluded with presentations and a roundtable reviewing emerging treatments, including USH1B-targeted genetic augmentation therapy and gene-agnostic approaches. Conclusions: Initiatives like this workshop are important to foster all stakeholders in support of achieving the shared goal of treating and curing USH1B. Translational Relevance: Presentations and discussions focused on overcoming disease modeling and clinical trial design challenges to facilitate development, testing, and implementation of effective USH1B treatments.

Psychometric Validation of the ViSIO-PRO and ViSIO-ObsRO in Retinitis Pigmentosa and Leber Congenital Amaurosis.

INTRODUCTION: Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA) are rare inherited retinal degenerative disorders. The Visual Symptom and Impact Outcomes patient-reported outcome (ViSIO-PRO) and observer-reported outcome (ViSIO-ObsRO) instruments were developed in this population to assess visual function symptoms and impacts on vision-dependent activities of daily living (ADL) and distal health-related quality of life (HRQoL). This study aimed to explore the psychometric properties of the ViSIO-PRO and ViSIO-ObsRO in RP/LCA. METHODS: The 49-item ViSIO-PRO and 27-item ViSIO-ObsRO instruments were completed by 83 adult and adolescent patients and 22 caregivers of child patients aged 3-11 years with RP/LCA, respectively, at baseline and 12-16-day follow-up. Concurrent measures were also administered at baseline. Psychometric analyses assessed item (question) properties, dimensionality, scoring, reliability, validity, and score interpretation. RESULTS: Item responses were mainly evenly distributed across the response scale, and inter-item correlations were mostly moderate to strong (> 0.30) at baseline within hypothesized domains. Item deletion was informed by item properties, qualitative data, and clinical input and supported retention of 35 ViSIO-PRO items and 25 ViSIO-ObsRO items. Confirmatory factor analysis in line with pre-hypothesized domains supported a four-factor model assessing visual function symptoms, mobility, vision-dependent ADL, and distal HRQoL. A bifactor model supported calculation of total scores and four domain scores. Internal consistency was high for domain and total scores (Cronbach's alpha > 0.70) and test-retest reliability for total scores was strong between baseline and 12-16-day follow-up (intraclass correlation coefficients 0.66-0.98). Convergent validity was supported by strong correlations in a logical pattern with concurrent measures. Mean baseline scores differed significantly between severity groups. Distribution-based methods provided initial insights to guide interpretation of scores. CONCLUSIONS: Findings supported item reduction and established scoring of the instruments. Evidence of reliability and validity as outcome measures in RP/LCA was also reported. Further research is ongoing to explore responsiveness of the ViSIO-PRO and ViSIO-ObsRO instruments and interpretation of change scores.

Qualitative exploration of the visual function impairments and impacts on vision-dependent activities of daily living in Retinitis Pigmentosa and Leber Congenital Amaurosis: content validation of the ViSIO-PRO and ViSIO-ObsRO measures.

BACKGROUND: Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA) are rare inherited retinal degenerative disorders. The associated visual impairments have significant impacts on patients' vision-dependent activities of daily living (ADL), mobility, and distal health-related quality of life (HRQoL). To adequately capture patient and caregiver perspectives in clinical trials, patient and observer-reported outcome instruments must demonstrate sufficient evidence of content validity in the target population. This study aimed to explore the patient experience of RP/LCA and assess the content validity of the Visual Symptom and Impact Outcomes PRO (ViSIO-PRO) and ObsRO (ViSIO-ObsRO) instruments in RP/LCA. METHODS: A total of 66 qualitative, combined concept elicitation (CE) and cognitive debriefing (CD) interviews were conducted (33 adults, 10 adolescents, 8 children and 15 caregivers of children) in the US, France, Germany, and Canada. Patients had a clinical and genetic diagnosis of RP/LCA from a range of genotypes. CE results were used to further inform the development of a conceptual model and CD interviews assessed the relevance and understanding of the 44-item ViSIO-PRO and 26-item ViSIO-ObsRO instruments. Interviews were conducted across two iterative rounds to allow item modifications. RESULTS: Findings were consistent across RP/LCA genotypes. Night blindness, reduced peripheral vision, vision in very bright lighting and light/dark adaptation were the most frequently reported visual function symptoms impacting vision-dependent ADL and mobility. Impacts on distal HRQoL domains were also reported. The ViSIO-PRO and ObsRO items were well understood by participants and relevant across genotypes. The instructions, 7-day recall period and response scales were well understood and endorsed. Participant and expert clinician feedback supported modifications to item wording, the addition of six new ViSIO-PRO items and one new ViSIO-ObsRO item, and the removal of one ViSIO-PRO item due to lack of relevance. CONCLUSIONS: Findings support the content validity of the ViSIO-PRO and ViSIO-ObsRO instruments for use across RP/LCA genotypes. Ongoing research to evaluate the psychometric validity of the instruments will support future use of the instruments as efficacy endpoints in clinical trials and in general clinical practice to track disease severity and impact of disease on functioning.

Development of Novel Patient-Reported Outcome (PRO) and Observer-Reported Outcome (ObsRO) Instruments in Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA): ViSIO-PRO and ViSIO-ObsRO.

INTRODUCTION: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are rare inherited retinal degenerative disorders resulting in visual impairments and impacts on patients' vision-dependent activities of daily living (ADL), mobility and distal health-related quality of life (HRQoL). This study aimed to conduct qualitative research to understand the patient experience of RP/LCA across genotypes and inform development of patient- and observer-reported outcome (PRO/ObsRO) instruments in RP/LCA. METHODS: Research activities included a qualitative literature review and review of existing visual function PRO instruments in RLBP1 RP, and concept elicitation (CE) and cognitive debriefing (CD) interviews of existing PRO instruments with patients with RLBP1 RP, expert clinicians, and payers. In wider RP/LCA, a social media listening (SML) study and a qualitative literature review was conducted, while psychometric evaluation of a PRO instrument in LCA was performed. Input from expert clinicians was sought at key stages. RESULTS: Findings from the qualitative literature reviews identified a range of visual function symptoms which had significant impacts on patients' vision-related ADL and distal HRQoL. Patient interviews identified additional visual function symptoms and impacts not previously reported in published literature. These sources informed development and refinement of a conceptual model displaying the patient experience of RP/LCA. Review of existing visual function PRO instruments, and CD interviews evaluating their content validity, confirmed that no existing instrument provides a comprehensive assessment of all concepts relevant to patients with RP/LCA. This highlighted the need for development of the Visual Symptom and Impact Outcomes PRO and ObsRO instruments to adequately assess the patient experience of RP/LCA. CONCLUSIONS: Results informed and supported development of the instruments to assess visual functioning symptoms and vision-dependent ADL, mobility and distal HRQoL in RP/LCA, in accordance with regulatory standards. Next steps to further support use in RP/LCA clinical trials/practice includes content and psychometric validation of the instruments in this population.

Static Perimetry in the Rate of Progression in USH2A-related Retinal Degeneration (RUSH2A) Study: Assessment Through 2 Years.

PURPOSE: To evaluate disease progression using static perimetry (SP) in patients with USH2A-related retinal degeneration, including Usher syndrome type 2 (USH2) and nonsyndromic autosomal recessive retinitis pigmentosa. DESIGN: Prospective, observational cohort study. METHODS: A total of 102 patients with biallelic disease-causing sequence variants in USH2A with baseline best-corrected visual acuity (BCVA) letter score ≥54 were recruited from 16 clinical sites in Europe and North America. SP, BCVA, full-field stimulus thresholds, spectral domain optical coherence tomography macular scans, and fundus-guided mesopic microperimetry were performed at baseline and annually. The main outcome measures were total hill of vision (VTOT), hill of vision in the central 30° (V30), VTOT minus V30 (VPERIPH), and mean sensitivity. RESULTS: The average decline (95% CI) was 2.05 (1.40, 2.70) decibel-steradian (dB-sr)/y for VTOT, 0.48 (0.32, 0.65) dB-sr/y for V30, 1.53 (0.97, 2.08) dB-sr/y for VPERIPH, and 0.55 (0.40, 0.71) dB/y for mean sensitivity. Average percentage decline per year was 8.3 (5.5, 11.1) for VTOT, 5.2 (3.0, 7.4) for V30, 16.0 (9.5, 22.0) for VPERIPH, and 5.1 (3.5, 6.7) for mean sensitivity. Changes from baseline to year 2 in all SP measures were highly correlated (r's ranging from 0.52 [V30 vs VPERIPH] to 0.98 [VTOT vs VPERIPH]). CONCLUSIONS: Quantitative measures of SP declined significantly over 2 years in USH2A-related retinal degeneration. The annual percentage rate of change was greatest for VTOT and VPERIPH, whereas V30 and mean sensitivity changed least, reflecting earlier and more severe peripheral degeneration compared with central loss.

Denufosol tetrasodium in patients with cystic fibrosis and normal to mildly impaired lung function.

RATIONALE: Intervention for cystic fibrosis lung disease early in its course has the potential to delay or prevent progressive changes that lead to irreversible airflow obstruction. Denufosol is a novel ion channel regulator designed to correct the ion transport defect and increase the overall mucociliary clearance in cystic fibrosis lung disease by increasing chloride secretion, inhibiting sodium absorption, and increasing ciliary beat frequency in the airway epithelium independently of cystic fibrosis transmembrane conductance regulator genotype. OBJECTIVES: To evaluate the efficacy and safety of denufosol in patients with cystic fibrosis who had normal to mildly impaired lung function characteristic of early cystic fibrosis. METHODS: A total of 352 patients greater than or equal to 5 years old with cystic fibrosis who had FEV(1) greater than or equal to 75% of predicted normal were randomized to receive inhaled denufosol, 60 mg, or placebo three times daily in a Phase 3, randomized, double-blind, placebo-controlled, 24-week trial. MEASUREMENTS AND MAIN RESULTS: Main outcome measures included change in FEV(1) from baseline to Week 24 endpoint and adverse events. Mean change from baseline to Week 24 endpoint in FEV(1) (primary efficacy endpoint) was 0.048 L for denufosol (n = 178) and 0.003 L for placebo (n = 174; P = 0.047). No significant differences between groups were observed for secondary endpoints including exacerbation rate and other measures of lung function. Denufosol was well tolerated with adverse event and growth profiles similar to placebo. CONCLUSIONS: Denufosol improved lung function relative to placebo in cystic fibrosis patients with normal to mildly impaired lung function. Clinical trial registered with www.clinicaltrials.gov (NCT00357279).

The RUSH2A Study: Dark-Adapted Visual Fields in Patients With Retinal Degeneration Associated With Biallelic Variants in the USH2A Gene.

Purpose: To measure visual fields using two-color dark-adapted chromatic perimetry in a subset of participants in the Rate of Progression of USH2A-related Retinal Degeneration (RUSH2A), a study of USH2A-mediated syndromic (USH2) and autosomal recessive nonsyndromic retinitis pigmentosa, determine percentage retaining rod function, and explore relationships between dark-adapted visual fields (DAVF) and rod function from ERG and full-field stimulus thresholds (FST). Methods: Full-field rod mean sensitivity, number of rod loci, maximum sensitivity, DAVF full-field hill of vision (DAVF VTOT), and 30° hill of vision (DAVF V30) were measured in one eye for DAVF ancillary study participants (n = 49). Loci where cyan relative to red sensitivity was more than 5 dB on dark-adapted chromatic perimetry were considered rod mediated. Correlation coefficients between the DAVF measures and standard clinical measures were estimated, as were kappa statistics (κ) for agreement between DAVF and other measures of rod function. Results: Of 49 participants tested with DAVF, 38 (78%) had evidence of rod function, whereas 15 (31%) had measurable rod ERGs. DAVF maximum sensitivity was highly correlated with FST white thresholds (r = -0.80; P < .001). Although not statistically significant, the number of rod loci and DAVF VTOT were lower in eyes with longer disease duration by 0.82 (95% confidence interval, -1.76, 0.12) loci/year and 0.59 (95% confidence interval, -1.82, 0.64) dB-steradians/year, respectively. Conclusions: Rod-mediated function on FST and DAVF is present in many patients with symptomatic USH2A-related retinal degeneration, including some without measurable rod ERGs. RUSH2A longitudinal data will determine how these measures change with disease progression and whether they are useful for longitudinal studies in inherited retinal degenerations.

Baseline Microperimetry and OCT in the RUSH2A Study: Structure-Function Association and Correlation With Disease Severity.

PURPOSE: To investigate baseline mesopic microperimetry (MP) and spectral domain optical coherence tomography (OCT) in the Rate of Progression in USH2A-related Retinal Degeneration (RUSH2A) study. DESIGN: Natural history study METHODS: Setting: 16 clinical sites in Europe and North AmericaStudy Population: Participants with Usher syndrome type 2 (USH2) (N = 80) or autosomal recessive nonsyndromic RP (ARRP) (N = 47) associated with biallelic disease-causing sequence variants in USH2AObservation Procedures: General linear models were used to assess characteristics including disease duration, MP mean sensitivity and OCT intact ellipsoid zone (EZ) area. The associations between mean sensitivity and EZ area with other measures, including best corrected visual acuity (BCVA) and central subfield thickness (CST) within the central 1 mm, were assessed using Spearman correlation coefficients. MAIN OUTCOME MEASURES: Mean sensitivity on MP; EZ area and CST on OCT. RESULTS: All participants (N = 127) had OCT, while MP was obtained at selected sites (N = 93). Participants with Usher syndrome type 2 (USH2, N = 80) and nonsyndromic autosomal recessive Retinitis Pigmentosa (ARRP, N = 47) had the following similar measurements: EZ area (median (interquartile range [IQR]): 1.4 (0.4, 3.1) mm2 vs 2.3 (0.7, 5.7) mm2) and CST (median (IQR): 247 (223, 280) µm vs 261 (246, 288), and mean sensitivity (median (IQR): 3.5 (2.1, 8.4) dB vs 5.1 (2.9, 9.0) dB). Longer disease duration was associated with smaller EZ area (P < 0.001) and lower mean sensitivity (P = 0.01). Better BCVA, larger EZ area, and larger CST were correlated with greater mean sensitivity (r > 0.3 and P < 0.01). Better BCVA and larger CST were associated with larger EZ area (r > 0.6 and P < 0.001). CONCLUSIONS: Longer disease duration correlated with more severe retinal structure and function abnormalities, and there were associations between MP and OCT metrics. Monitoring changes in retinal structure-function relationships during disease progression will provide important insights into disease mechanism in USH2A-related retinal degeneration.

The Impact of Inherited Retinal Diseases in the United States of America (US) and Canada from a Cost-of-Illness Perspective.

OBJECTIVE: To estimate the annual cost of inherited retinal diseases (IRDs) in the United States of America (US) and Canada from a societal perspective - including costs to the health system, individual and family productivity costs, lost wellbeing and other societal economic costs - by setting and payer. Findings will inform the need for policy action to mitigate the impact of IRDs. METHODS: The costs of IRDs were estimated using a cost-of-illness methodology, based on the prevalence of IRDs in each country. Intangible costs of reduced wellbeing were also estimated using disability-adjusted life years which were then converted to monetary values using the value of a statistical life. RESULTS: Using base prevalence rates, total costs attributable to IRDs in the US were estimated to range between US$13,414.0 and US$31,797.4 million in 2019, comprising both economic costs (between US$4,982 and US$11,753.9 million; 37% of total costs) and wellbeing costs (between US$8,431.7 and US$20,043.6 million; 63%). Total costs attributable to IRDs in Canada were estimated to range between CAN$1637.8 and CAN$6687.5 million in 2019, comprising both economic costs (between CAN$566.6 and CAN$2,305.7 million; 34%) and wellbeing costs (between CAN$1,071.4 and CAN$4,381.9 million; 66% of total costs). CONCLUSION: The impact of IRDs in the US and Canada is substantial when considering both economic costs and reduced wellbeing. The wellbeing costs due to IRDs in the US and Canada are considerable, accounting for over 60% of total costs. Vision loss from IRDs often manifests in childhood, meaning some people live with vision impairment and blindness for their whole lives. Further research into current and emerging cost-effective therapies and interventions is required given the substantial economic burden faced by those living with vision loss.