Evaluation of the Impact of Meibomian Gland Dysfunction Using a Novel Patient-Reported Outcome Instrument.

Purpose: This study was intended to characterize the impact of meibomian gland dysfunction (MGD) on patients' quality of life. Methods: In this prospective, multicenter, noninterventional clinical study (NCT01979887), eligible individuals (age ≥40 years; absence of uncontrolled ocular/systemic disease) were categorized, based on composite grading of ocular symptoms, Schirmer score, and meibum quality, into (1) non-MGD, (2) mild/moderate MGD, or (3) severe MGD cohorts. The MGD Impact Questionnaire (MGD IQ), a 10-item patient-reported outcome measure, was self-administered at clinic visit on day 1, and readministered on day 22 to assess intervisit agreement regarding MGD IQ responses. Results: In total, 75 subjects were assigned to the study cohorts (25 per cohort). Across cohorts, MGD IQ item scores rose incrementally with increasing MGD severity. The severe MGD cohort experienced greater difficulty with reading and performance of leisure activities, greater time on eye care, and greater bother with eye care and eye appearance than the mild/moderate MGD cohort (all P < 0.05). Compared with the non-MGD cohort, the mild/moderate MGD cohort had greater difficulty working on computer, whereas the severe MGD cohort had greater difficulty reading, driving, and performing leisure activities, more frequent difficulty with outdoor activities, more time on eye care, and greater bother with eye care (all P < 0.05). Intervisit agreement between MGD IQ responses was fair to moderate (weighted kappa statistic 0.33‒0.58). Conclusions: Vision-related activities are negatively impacted by increasing severity of MGD. The MGD IQ instrument can help characterize disease severity and amplify the patient's voice in patient-centric clinical research. ClinicalTrials.gov NCT01979887.

Impact of presbyopia treatment pilocarpine hydrochloride 1.25% on night-driving performance.

CLINICAL RELEVANCE: Patients prescribed pilocarpine ophthalmic solution are advised to be cautious when driving at night, but studies evaluating the effects of pilocarpine hydrochloride ophthalmic solution 1.25% (pilo), approved to treat presbyopia, on driving at night are lacking. BACKGROUND: This double-masked, crossover, phase 3b study evaluated night-driving performance with pilo or the placebo once daily. METHODS: Forty-three adults (40-55 years) with presbyopia impacting daily activities and mesopic, high-contrast, binocular distance-corrected near vision 6/12-6/30 were randomised to bilateral treatment with pilo followed by placebo or placebo followed by pilo (with a ≥7-day washout between interventions). Night-driving performance was evaluated at twilight at a closed-circuit course. Primary efficacy endpoint: overall composite night-driving performance Z score at the end of the 7-14-day intervention period, 1 hour post-instillation. Pilo was considered non-inferior if the lower limit of the 95% confidence interval (CI) for the least squares mean difference (LSMD, pilo minus placebo) was >-0.25. Other efficacy endpoints: individual components of the night-driving performance test (hazard avoidance rate; road sign recognition rate and distance; pedestrians recognition distance; overall driving and lane-keeping times) and night-driving experience questionnaire. Safety included treatment-emergent adverse events (TEAEs). RESULTS: The mean overall composite Z scores were -0.121 (pilo) and 0.118 (placebo). The LSMD (pilo minus placebo) was -0.224 (95% CI, -0.346, -0.103), with 3 of the 7 individual tasks being significantly better with the placebo. The questionnaire did not reveal significant differences between pilo and the placebo. There were no serious or severe TEAEs and no TEAE-related discontinuations. The most common ocular TEAEs were headache and visual impairment with pilo (both 27.9%), and dry eye (7.0%) with the placebo. CONCLUSION: The overall performance of night driving was inferior with pilo, compared with placebo. The study findings are consistent with the current class labelling and provide evidence to inform regulators and assist clinicians considering prescribing pilo to adults who seek treatment of presbyopia symptoms and drive at night.ClinicalTrials.gov identifier: NCT04837482.

Exploring Signs and Symptoms Associated with Meibomian Gland Dysfunction for Use as Clinical Trial Endpoints.

Purpose: Dry eye disease is attributed to impaired tear production and/or evaporative dry eye. Evaporative dry eye is frequently associated with meibomian gland dysfunction (MGD). The objective of this study was to identify clinical study endpoints related to MGD. Methods: This 22-day, noninterventional, case-control clinical study involved three cohorts with increasing MGD severity: no MGD, mild/moderate MGD, and severe MGD. Symptoms were assessed with an ocular symptom questionnaire grading blurred vision, eye burning, eye dryness, eye pain, light sensitivity, eye itching, eye foreign body sensation, and overall ocular discomfort. Sign assessments included the maximum meibum quality score (MMQS), tear breakup time, Schirmer tear tests, biomicroscopy, and corneal staining. Signs and symptoms were compared between cohorts and study visits. Results: Seventy-five study participants were assigned to the cohorts (25 per cohort). MMQS scores increased with increasing MGD severity, reflecting the selection criteria for the cohorts. Between-visit scores showed a weighted kappa statistic of 0.72 indicating substantial agreement. Mean scores of all assessed symptoms increased with increasing MGD severity. Scores for symptoms showed moderate (κ = 0.41-0.60) to substantial (κ = 0.61-0.80) agreement between visits. Overall ocular discomfort demonstrated the strongest correlation with the MMQS. Conclusion: The MMQS was a reproducible sign of MGD showing good agreement with ocular symptoms. Overall ocular discomfort was well correlated with typical dry eye symptoms and could potentially be used as a single measure of MGD symptoms. The findings from this observational study may inform endpoints for future clinical trials. ClinicalTrials.gov NCT01979887.

Relationship Between Human Meibum Lipid Composition and the Severity of Meibomian Gland Dysfunction: A Spectroscopic Analysis.

Purpose: Information on the relationship between meibum lipid composition and severity of meibomian gland dysfunction (MGD) is limited. The purpose of this study was to analyze the molecular components of meibum collected from individuals with no MGD, mild-to-moderate MGD, and severe MGD. Methods: Adults with and without MGD were enrolled in a prospective, multicenter, exploratory clinical trial (ClinicalTrials.gov Identifier: NCT01979887). Molar ratios of cholesteryl ester to wax ester (RCE/WE) and aldehyde to wax ester (Rald/WE) in meibum samples were measured with 1H-NMR spectroscopy. Results were evaluated for participants grouped by MGD disease status and severity (non-MGD, mild-to-moderate MGD, and severe MGD), as defined by maximum meibum quality scores, Schirmer test results, and Subject Ocular Symptom Questionnaire responses. Results: Sixty-nine meibum samples from 69 individuals were included in the analysis: 24 non-MGD, 24 mild-to-moderate MGD, and 21 severe MGD. Mean RCE/WE was 0.29 in non-MGD, 0.14 in mild-to-moderate MGD (P = 0.038 vs. non-MGD, 51% lower), and 0.07 in severe MGD (P = 0.16 vs. mild-to-moderate MGD, 52% lower; P = 0.002 vs. non-MGD, 76% lower). Mean Rald/WE was 0.00022 in non-MGD, 0.00083 in mild-to-moderate MGD (P = 0.07 vs. non-MGD, 277% higher), and 0.0024 in severe MGD (P = 0.003 vs. mild-to-moderate MGD, 190% higher; P < 0.001 vs. non-MGD, 992% higher). Conclusions: RCE/WE was lowest and Rald/WE was highest in the severe MGD cohort, suggesting that these meibum constituent molar ratios may result from the pathophysiology associated with MGD and can impact ocular surface lipid and tear film homeostasis. These findings may potentially help identify targets for MGD treatment.

Acute Vulvar Aphthous Ulceration After COVID-19 Vaccination: 3 Cases.

OBJECTIVE: We present a case series of acute vulvar aphthosis immediately following COVID-19 vaccination. MATERIALS AND METHODS: We describe 3 cases of acute vulvar aphthosis following Pfizer Comirnaty BNT162b2 mRNA and AstraZeneca (Vaxzevria) ChAdOx1 nCoV-19 COVID-19 vaccination in adolescent girls. RESULTS: All patients developed vulvar aphthosis within a few days after receiving COVID-19 vaccination. The onset of vulvar aphthosis was observed to correlate with the dosing schedule known to produce the highest likelihood of adverse effects, first dose in AstraZeneca (Vaxzevria) ChAdOx1 nCoV-19 and second dose in Pfizer Comirnaty BNT162b2 mRNA COVID-19 vaccine. Two patients required oral prednisolone and hospital admission for indwelling urinary catheterization due to urinary retention. Full disease resolution with no sequalae was achieved in all three patients. CONCLUSIONS: Clinicians should be aware of the possible risk of vulvar aphthosis after COVID-19 vaccine administration. Nevertheless, its occurrence should not prevent affected patients from receiving future doses of COVID-19 vaccines, as the mortality and morbidity of COVID-19 infection significantly outweigh the risk of vulvar aphthosis recurrence.

Clinicopathological characteristics of new primary melanomas in patients receiving immune checkpoint inhibitor therapy for metastatic melanoma.

BACKGROUND: Immune checkpoint inhibitors have improved survival in advanced stage melanoma patients. Rates of new primary melanomas (NPM) in patients with prior melanoma have been reported to be as high as 12%. Little is currently known regarding the frequency or characteristics of NPMs occurring in melanoma patients treated with immune checkpoint inhibitors. AIM: To determine the frequency and describe clinicopathologic characteristics of NPMs diagnosed in patients during or after treatment with immune checkpoint inhibitors for metastatic melanoma. METHODS: A retrospective analysis of prospectively collected data from the Melanoma Institute Australia and Westmead Hospital Dermatology databases. Clinicopathological data for the initial primary melanoma (IPM) and NPM were compared. RESULTS: Between 2013-2017, 14 NPMs in 13 patients (out of a total of 1047) treated with checkpoint inhibitors were identified. NPMs were significantly thinner than the IPM (median Breslow thickness 0.35 mm vs 2.0 mm, P = 0.0003), less likely to be ulcerated (0/14 vs 6/13, P = 0.004) and less likely to have nodal metastases (0/14 vs 6/13, P = 0.004). NPMs were significantly more likely to be detected in the in-situ stage (6/14 vs 0/13, P = 0.0016). CONCLUSION: NPMs are infrequent in patients treated with checkpoint inhibitors. When they occur, they are usually detected at an early stage and have features associated with a favourable prognosis, most likely reflecting close surveillance. Further study is required to determine long-term risk in patients achieving a durable response to immune checkpoint inhibitors, and to determine whether the immunotherapy itself influences both their development and biology.

Survey Report on Complaints Related to the Interconnectivity between Vial Containers and Transfer Devices.

To address the challenges related to the interconnectivity between vial container closure systems and vial transfer devices, pharmaceutical, elastomer, and transfer device manufacturers have formed a working group under the Product Quality Research Institute (PQRI) to establish best practices for the evaluation of the assembly of vial transfer devices and vial systems. As part of the project, the first activity was to quantify the nature and frequency of issues (complaints). To this end, the working group conducted a survey with questionnaires related to categories and numbers of complaints, regions/countries where complaints were received, and the nature of the manufacturers who received the complaints. The survey was distributed to the 16 companies participating in the working group, and 11 companies submitted a response. Besides quantifying and ranking the frequency of issues, the survey determined what issues are common across all companies and what issues may be product-specific or specific by manufacturer. In this article, the analysis and outcomes of the survey will be presented, and the next steps will be discussed.

Stewart-Bluefarb syndrome following traumatic arteriovenous malformation.

Stewart-Bluefarb syndrome is a rare angioproliferative disorder that presents as violet plaques on the extremities, due to an underlying arteriovenous malformation (AVM). We report the case of a 12-year-old boy who developed a traumatic AVM in a bicycle accident and presented seven years later with exophytic, violet plaques. This is the first instance of a traumatic AVM preceding Stewart-Bluefarb syndrome in a pediatric patient in the literature. Given the typically long period required to establish this diagnosis, it is crucial for clinicians to actively interrogate a history of preceding trauma in patients presenting with acroangiodermatitis.

An Investigation to Examine the Effect of the Elastomeric Surface Treatment on Protein Stability.

Various kinds of treatments on the surface of the elastomeric components can have negative impacts on the quality of protein therapeutics. We compared the effects of bare (non-siliconized and nonlaminated), siliconized, and fluoropolymer-laminated elastomeric components on the stability of ß-lactoglobulin, human serum albumin, adalimumab, abatacept, and immunoglobulin antibodies. The study was conducted in two main parts. Part I was to evaluate the stability of proteins under agitation-induced stress. Protein aggregate formation, turbidity, and protein recovery were analyzed using dynamic FI, absorbance at 350 nm, and size-exclusion high-performance liquid chromatography, respectively. Proteins were found to be more stable with laminated stoppers as compared with bare or siliconized stoppers. Part II was to identify the chemical modifications when the proteins were stored in contact with the same three stoppers. Capillary isoelectric focusing analysis of the adalimumab samples showed formation of acidic variants in siliconized and bare stoppers. Reverse-phase high-performance liquid chromatography suggested chemical changes to the human serum albumin. Analysis of tryptic digest of human serum albumin by liquid chromatography/mass spectrometry/mass spectrometry indicated that the amino acids most susceptible to oxidation (cysteine, tryptophan, and methionine) were also the ones that were modified. Part III of this study investigated the barrier property of the fluoropolymer film with no drug product. Our results were consistent with the suggestion that the fluoropolymer lamination provides a barrier that prevents leachables from the elastomeric components into the protein therapeutics. Our work provided an in-depth understanding of the effects of elastomeric surface treatments on the biophysical and chemical stability of protein drugs.

Drug Formulation Impact on Prefilled Syringe Functionality and Autoinjector Performance.

Given the surging interest in developing prefilled syringe and autoinjector combination products, investment in an early compatibility assessment is critical to prevent unwarranted drug/container closure interactions and avoid potential reformulation during late stages of drug development. In addition to the standard evaluation of drug stability, it is important to consider container closure functionality and overall device performance changes over time because of drug-container closure component interaction. This study elucidated the mechanisms that cause changes in syringe glide force over time and the impact on the injection duration. It was an expansion of the previous work, which indicated that drug formulation variables such as formulation excipients and pH affect syringe functionality over time. The current study described an investigative process for troubleshooting prolonged and variable autoinjector injection time caused by an increased syringe glide force variability over time. This increase in glide force variability stems from two root causes, namely plunger dimensional variation and syringe silicone oil change over time. The results demonstrated (a) the underlying factors of silicone oil change in the presence of drug formulation matrices, (b) accelerated stability of syringe glide force as a good indicator of long-term, real-time stability, and (c) that buffer matrix-filled syringes can be used to predict the syringe functionality and stability of drug product-filled syringes. Based on the experimental findings of a variety of orthogonal characterization techniques including contact angle, interfacial tension, and calculation of Hansen solubility parameters, it is proposed that silicone oil change is caused by formulation excipients and a complex set of phenomena summarized as "wet, wash, and delube" processes.

Symptomatic stability with aripiprazole once-monthly: efficacy analyses from acute and long-term studies.

Objective: To evaluate the effect of aripiprazole once-monthly 400 mg (AOM 400; Abilify Maintena®) on symptom stability in acute treatment and maintenance therapy settings in patients with schizophrenia. Methods: Results were analyzed from two pivotal maintenance studies (Studies 246 and 247), a long-term (52 weeks), open-label extension of these studies (Study 248), an open-label, mirror-image study in patients switching from oral to long-acting injectable antipsychotic therapy (Study 283), and a study of AOM 400 in the acute setting (Study 291). Symptom stability was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression (CGI) scale (CGI-Severity of Illness and CGI-Improvement). Results are reported for the total study population and in subgroups stratified by age. Results: In Study 246, AOM 400 resulted in significantly greater improvements from baseline vs placebo on all measures of symptom stability, with improvements maintained through 52 weeks. In Study 247, a non-inferiority study, AOM 400 resulted in improvements in PANSS and CGI scores comparable or significantly greater at all timepoints vs oral aripiprazole. In Study 248, AOM 400 resulted in the long-term stability of symptom improvements from the earlier studies. In Study 283, AOM 400 resulted in significant improvements from baseline in PANSS and CGI scores over 24 weeks. In Study 291, AOM 400 resulted in significantly greater improvements from baseline in PANSS and CGI scores vs placebo at all post-baseline timepoints. In post hoc analyses, AOM 400 showed similar efficacy in symptom improvement in adult patients aged ≤35 years and >35 years, with some evidence of a larger treatment effect on PANSS negative symptoms among younger patients in the acute treatment setting. Conclusion: In acute treatment and maintenance therapy settings, AOM 400 was effective in the rapid stabilization and long-term maintenance of symptoms in patients with schizophrenia.

Modeling the Permeation Rates of Organic Migrants through a Fluoropolymer Film.

Polymer films have been widely used as barriers for blocking certain organic molecules (such as leachables and extractables) in both food and parenteral pharmaceutical packaging applications. However, a good understanding of the barrier properties of those polymer films is still lacking for combination drug product manufacturers to make practical risk-based assessments regarding the effectiveness of the barrier films against potential leachables. The present work addressed this issue by a combined theoretical/experimental approach-a new mathematical model based on Hansen Solubility Parameters, the size and shape of organic molecules, was developed to quantitatively estimate the Steady-State Permeation Rate of organic migrants through a model ethylene-tetrafluoroethylene fluoropolymer film by considering contributions from both solubility and diffusivity. This model facilitates expedited screening of potential leachables, allowing for experimental focus on higher-risk leachables and ultimately enabling rapid combination drug product development.LAY ABSTRACT: Currently, there is a shortage of simple mathematical models that can accurately estimate the effectiveness of the barrier properties of polymer films; therefore, practical assessment of the barrier properties of these materials is mainly realized by experimental measurements of the permeation rates of interested migrants. These measurements can be time-consuming, costly, and inaccurate. Sometimes these measurements are even impossible if the migrant molecules are not commercially available (although we might know their molecular structures). Thus, there is a need for a practical and easy-to-use mathematical model that can estimate/predict the permeation rate through these barrier materials. To satisfy this need, we developed a new model based on the molecular polarity, size, and shape of migrant molecules to quantitatively estimate the permeation rate of the migrant molecules through these barrier materials. This model will be useful for applications in both food and drug packaging. Additionally, this model will be useful for medical devices or containers that will hold or store organic drug molecules, such as medical tubing or IV bags. Finally, organic compounds used in inks and adhesives that will permeate through packaging materials could also be modeled in the same fashion.