Introducing Palliative Care within the Treatment of End-Stage Liver Disease: The Study Protocol of a Cluster Randomized Controlled Trial.

Introduction: Patients with end-stage liver disease (ESLD) suffer from myriad symptoms due to the systemic effects of the disease and unpredictable acute episodes, which contribute to progressive deterioration in quality of life (QOL). Despite clear evidence that palliative care (PC) improves QOL in other serious illnesses, PC is underutilized and delayed for ESLD patients. Through a comparative effectiveness trial of specialist led consultative PC (Model 1) versus trained hepatologist led PC (Model 2), we aim to build evidence on introducing PC into the routine outpatient care of ESLD patients. Objective: We hypothesize that trained hepatologist led PC model will have a better improvement in QOL compared to consultative PC model. Methods: This two-arm, multicenter cluster-randomized trial assesses the effectiveness of two PC models for patients with ESLD. Fourteen clinical centers will recruit 1260 patient-caregiver dyads. Each center is the unit of randomization. Hepatologists at sites randomized to the Model 2 have undergone web-based training in the principles of PC as pertained to ESLD. PC intervention is delivered over four visits (initial, one, two, and three months). Follow-up assessments occur at 6, 9, and 12 months. Eligible patients are those with new onset or ongoing complications of ESLD with a caregiver willing to participate. Outcomes: The primary outcome is change in patients' QOL from baseline to three months. Secondary outcomes include symptom burden, depression, distress, satisfaction with care, caregiver burden and QOL, goal concordant care, and health care utilization. Challenges and Contributions Engagement: A research advisory board has been developed with representatives from the participating centers, who have provided active feedback on the protocol, outcomes, study methods, and training program. Intervention Fidelity: Intervention fidelity will be maintained by adherence to a visit agenda and providers in both models completing a PC checklist after each study visit.

Economic evaluation of a fluocinolone acetonide intravitreal implant for patients with DME based on the FAME study.

INTRODUCTION: Diabetic macular edema (DME) is the most common cause of visual impairment in patients with diabetes. DME is a complex disease characterized by the deposition of fluid and proteins within the intraretinal layers, and the disease is recognized as being mediated by multiple cytokines, requiring a multifactorial therapeutic approach. Iluvien (fluocinolone acetonide intravitreal implant) 0.19 mg contains a corticosteroid, fluocinolone acetonide [FAc], and is indicated for the treatment of DME in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure. METHODS: A Markov model was constructed in Microsoft Excel with a 15-year time horizon comparing the healthcare and productivity costs with health outcomes from treatment. The model was structured around 13 best corrected visual acuity states using Early Treatment Diabetic Retinopathy Study scores. Observations and extrapolations from the Fluocinolone Acetonide for Diabetic Macular Edema study were applied to determine observed and ongoing treatment effects. RESULTS: The expected incremental cost-effectiveness ratio for treatment with an FAc implant is $38,763, assuming 40% of patients are treated unilaterally; when 100% of patients receive unilateral treatment with an FAc implant, it is cost-saving. CONCLUSION: Administering an FAc implant to patients with DME previously treated with a corticosteroid is a cost-effective treatment option for ophthalmologists.

Shear effects on aluminum phosphate adjuvant particle properties in vaccine drug products.

Adjuvant-containing drug products can be exposed to high levels of interfacial shear during manufacture. This may affect the integrity of the adjuvant, alter its interaction with the drug substance or change the physical characteristics of the drug product. In this study, a solid-liquid interfacial shear device was used to investigate the shear response of aluminum phosphate adjuvant alone and two adjuvant containing vaccine drug products (DP1 and DP2). The relationship between the shear sensitivity of each and its resuspension properties was determined. Changes in the particle dimensions of the bulk adjuvant were minimal at shear strain rates of 10,900 s(-1) . However, at 25,500 s(-1) , the median particle diameter was reduced from 6.2 to 3.5 µm and was marked by the presence of sub-micron fines. A formulation without drug substance and DP2 produced similar shear responses but with less impact on particle diameter. The behavior of DP1 was less predictable. Sheared DP1 was characterized by prolonged sedimentation because of the presence of fine particulates and required in excess of 300 rotations to resuspend after extended storage. The study confirms that the solid-liquid interfacial shear device may be applied to understand product shear sensitivity associated with vaccine manufacturing.

Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema.

OBJECTIVE: To assess long-term efficacy and safety of intravitreal inserts releasing 0.2 µg/d (low dose) or 0.5 µg/d (high dose) fluocinolone acetonide (FAc) in patients with diabetic macular edema (DME). DESIGN: Two randomized, sham injection-controlled, double-masked, multicenter clinical trials. PARTICIPANTS: Subjects with persistent DME despite ≥1 macular laser treatment were randomized 1:2:2 to sham injection (n = 185), low-dose insert (n = 375), or high-dose insert (n = 393). METHODS: Subjects received study drug or sham injection and after 6 weeks were eligible for rescue laser. Based on retreatment criteria, additional study drug or sham injections could be given after 1 year. MAIN OUTCOME MEASURES: Percentage of patients with improvement of ≥15 letters from baseline. Secondary outcomes included other parameters of visual function and foveal thickness. RESULTS: At month 36, the percentage of patients who gained ≥15 in letter score using the last observation carried forward method was 28.7% (low dose) and 27.8% (high dose) in the FAc insert groups compared with 18.9% (P = 0.018) in the sham group, and considering only those patients still in the trial at month 36, it was 33.0% (low dose) and 31.9% (high dose) compared with 21.4% in the sham group (P = 0.030). Preplanned subgroup analysis demonstrated a doubling of benefit compared with sham injections in patients who reported duration of DME ≥3 years at baseline; the percentage who gained ≥15 in letter score at month 36 was 34.0% (low dose; P<0.001) or 28.8% (high dose; P = 0.002) compared with 13.4% (sham). An improvement ≥2 steps in the Early Treatment Diabetic Retinopathy Study retinopathy scale occurred in 13.7% (low dose) and 10.1% (high dose) compared with 8.9% in the sham group. Almost all phakic patients in the FAc insert groups developed cataract, but their visual benefit after cataract surgery was similar to that in pseudophakic patients. The incidence of incisional glaucoma surgery at month 36 was 4.8% in the low-dose group and 8.1% in the high-dose insert group. CONCLUSIONS: In patients with DME FAc inserts provide substantial visual benefit for up to 3 years and would provide a valuable addition to the options available for patients with DME.

Iluvien: a new sustained delivery technology for posterior eye disease.

Iluvien (fluocinolone acetonide intravitreal insert, Alimera Sciences, Inc.), a novel injectable intravitreal insert, is being studied to deliver a very low dose of a corticosteroid to the retina for up to 3 years as a treatment for diabetic macular edema. Using a proprietary 25-gauge injector system, an ophthalmologist injects the Iluvien insert, which uses the Medidur (Alimera Sciences, Inc.) technology, into the vitreous through a minimally invasive procedure in an out-patient setting. The placement of the device in the inferior vitreous has the potential to maximize drug at the retina while reducing exposure of the anterior chamber. Phase III studies are underway to test the safety and efficacy of Iluvien. This article offers a specific review of the Iluvien technology rather than an overview of the various intravitreal methods of treating posterior eye disease.