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Iontophoretic delivery of dexamethasone phosphate for non-infectious, non-necrotising anterior scleritis, dose-finding clinical trial.

ABSTRACT: Currently available treatment options for non-infectious scleritis, including non-steroidal anti-inflammatory drugs, systemic corticosteroids and immunosuppressive therapies, have both efficacy and side effect limitations. Iontophoretic delivery of corticosteroids has been demonstrated to be effective for anterior uveitis and represents a potential new approach to scleritis therapy. We hypothesised that iontophoretic delivery would provide effective and precise medication delivery to the sclera, while limiting systemic exposure and side effects. This first-in-human randomised, double-masked, dose-escalating study of iontophoretic administration of dexamethasone phosphate for scleritis suggests the treatment to be well tolerated and safe (within the limitations of the 18 patients sample size). There was a suggestion of efficacy in the lowest (1.2 mA/min at 0.4 mA) dose group (corresponding to the superficial location of scleritis compared with anterior uveitis), with 5/7 eyes meeting the primary efficacy outcome within 28 days. Our results suggest iontophoretic delivery of corticosteroids is a promising potential treatment for scleritis, with favourable safety and preliminary efficacy results in this phase 1 trial. TRIAL REGISTRATION NUMBER:NCT01059955.

SUBMITTER: O'Neil EC

PROVIDER: S-EPMC6092316 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Iontophoretic delivery of dexamethasone phosphate for non-infectious, non-necrotising anterior scleritis, dose-finding clinical trial.

O'Neil Erin C EC Huang Jiayan J Suhler Eric B EB Dunn James P JP Perez Victor L VL Gritz David C DC McWilliams Kathy K Peskin Ellen E Ying Gui-Shuang GS Bunya Vatinee Y VY Maguire Maureen G MG Kempen John H JH

The British journal of ophthalmology 20180417 8

Currently available treatment options for non-infectious scleritis, including non-steroidal anti-inflammatory drugs, systemic corticosteroids and immunosuppressive therapies, have both efficacy and side effect limitations. Iontophoretic delivery of corticosteroids has been demonstrated to be effective for anterior uveitis and represents a potential new approach to scleritis therapy. We hypothesised that iontophoretic delivery would provide effective and precise medication delivery to the sclera, ...[more]

PMID: 29666122

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Project description:BackgroundNon-infectious scleritis is a potentially sight-threatening condition in which the sclera, the white outer layer of the eye, becomes inflamed. Whilst scleritis can be infective, the majority of cases are due to non-infectious causes, often occurring in association with an underlying systemic autoimmune or auto-inflammatory condition. Thorough systemic work-up is crucial to identify disease aetiology and exclude infection; however, a significant proportion of disease remains idiopathic with the underlying cause unknown. Non-infectious scleritis is normally managed with systemic corticosteroid and immunosuppression, yet there is no widely agreed consensus on the most appropriate therapy, and no national or international guidelines exist for treatment of non-infectious scleritis.MethodsStandard systematic review methodology will be used to identify, select and extract data from comparative studies of pharmacological interventions used to treat patients with non-infectious scleritis. Searches of bibliographic databases (Cochrane Library, MEDLINE, CINAHL and EMBASE) and clinical trial registers will be employed. No restrictions will be placed on language or date of publication. Non-English articles will be translated where necessary. The primary outcome of interest will be disease activity measured by reduction in scleritis grading according to standardised grading systems. Secondary outcomes will include change in best corrected visual acuity, reduction in concurrent dose of systemic corticosteroid, time to treatment failure, adverse events and health-related quality of life. Risk of bias assessment will be conducted appropriate to each study design. Study selection, data extraction and risk of bias assessment will be completed by two reviewers independently. Data will be presented in a table and a narrative synthesis will be undertaken. Meta-analysis will be performed where methodological and clinical homogeneity exists. Subgroup and sensitivity analysis will be undertaken if appropriate.DiscussionMany studies have investigated the effectiveness of pharmacological agents used in the management of non-infectious scleritis. A systematic review is needed to collate and analyse this evidence. Findings of this systematic review will help guide ophthalmologists managing patients with non-infectious scleritis and may form the basis for evidence-based recommendations for future clinical practice and encourage standardisation of treatment protocols.Systematic review registrationPROSPERO CRD42019125198.

Project description:PurposeTo evaluate the safety and potential efficacy of gevokizumab, an anti-interleukin 1β (IL-1β) monoclonal antibody, in the treatment of active, noninfectious, non-necrotizing anterior scleritis.DesignPhase 1/2, open label, nonrandomized, prospective, single-arm pilot trial.MethodsEight patients with active, noninfectious, non-necrotizing anterior scleritis with a scleral inflammatory grade of +1 to +3 in at least 1 eye were enrolled. In 1 patient both eyes were enrolled, for a total of 9 eyes (4 eyes with +1, 1 eye with +2, and 4 eyes with +3). Patients received 1 subcutaneous injection of 60 mg gevokizumab at baseline and then every 4 weeks for 12 weeks. Complete physical and ocular examinations were performed at each visit. The primary outcome was at least a 2-step reduction or reduction to grade 0 in scleral inflammation on a 0 to +4 scale according to a standardized photographic scleritis grading system by 16 weeks in the study eye compared to baseline. Secondary outcomes included changes in visual acuity, intraocular pressure, and trends in scleral grading. Participants who met the primary outcome were eligible to continue in the study for up to 52 weeks and received additional gevokizumab injections every 4 weeks until week 36, followed by 2 safety visits at weeks 40 and 52.ResultsSeven eyes from 7 patients met the primary outcome within a median time of 2 weeks following the first gevokizumab injection. No definitive changes in visual acuity or intraocular pressure were identified. There were no serious adverse events related to the study drug. A total of 43 adverse effects were reported, with 93% described as mild, 95% as nonocular, and only 14% deemed possibly caused by the investigational treatment.ConclusionsThe results of this small study suggest that blockage of IL-1β using gevokizumab may be beneficial in treating active, noninfectious anterior scleritis and that gevokizumab is well tolerated. Larger randomized trials are warranted to assess the true efficacy of gevokizumab in the treatment of non-necrotizing anterior scleritis.

Project description:BackgroundThe symptom of heavy menstrual bleeding (HMB) diminishes quality-of-life for many mid-age women and imposes substantial societal burden. We investigated our hypothesis that HMB reflects impaired endometrial vasoconstriction due to endometrial glucocorticoid deficiency. Does reversing this deficiency, by short-term luteal-phase treatment with exogenous glucocorticoid (dexamethasone), ameliorate HMB?MethodsIn our Bayesian response-adaptive parallel-group placebo-controlled randomised trial, five pre-planned interim analyses used primary outcome data to adjust randomisation probabilities to favour doses providing most dose-response information. Participants with HMB, recruited from Lothian (Scotland) NHS clinics and via community invitations/advertisements, were aged over 18 years; reported regular 21-42 day menstrual cycles; and had measured menstrual blood loss (MBL) averaging ≥ 50 mL over two screening periods. Identically encapsulated placebo, or one of six Dexamethasone doses (0·2 mg, 0·4 mg, 0·5 mg, 0·6 mg, 0·75 mg, 0·9 mg), were taken orally twice-daily over five days in the mid-luteal phase of three menstrual cycles. Participants, investigators, and those measuring outcomes were masked to group assignment. Primary outcome, change in average MBL from screening to 'treatment', was analysed by allocated treatment, for all with data.Trial registrationClinicalTrials.gov NCT01769820; EudractCT 2012-003,405-98 FINDINGS: Recruitment lasted 29/01/2014 to 25/09/2017; 176 were screened, 107 randomised and 97 provided primary outcome data (n = 24,5,9,21,8,14,16 in the seven arms, placebo to 1·8 mg total daily active dose). In Bayesian normal dynamic linear modelling, 1·8 mg dexamethasone daily showed a 25 mL greater reduction in MBL from screening, than placebo (95% credible interval 1 to 49 mL), and probability 0·98 of benefit over placebo. Adverse events were reported by 75% (58/77) receiving dexamethasone, 58% (15/26) taking placebo. Three serious adverse events occurred, two during screening, one in a placebo participant. No woman withdrew due to adverse effects.InterpretationOur adaptive trial in HMB showed that dexamethasone 1·8 mg daily reduced menstrual blood loss. The role of dexamethasone in HMB management deserves further investigation.FundingUK MRC DCS/DPFS grant MR/J003611/1.

Project description:IntroductionHeavy menstrual bleeding (HMB) diminishes individual quality-of-life and poses substantial societal burden. In HMB endometrium, inactivation of cortisol (by enzyme 11β hydroxysteroid dehydrogenase type 2 (11βHSD2)), may cause local endometrial glucocorticoid deficiency and hence increased angiogenesis and impaired vasoconstriction. We propose that 'rescue' of luteal phase endometrial glucocorticoid deficiency could reduce menstrual bleeding.Methods and analysisDexFEM is a double-blind response-adaptive parallel-group placebo-controlled trial in women with HMB (108 to be randomised), with active treatment the potent oral synthetic glucocorticoid dexamethasone, which is relatively resistant to 11βHSD2 inactivation. Participants will be aged over 18 years, with mean measured menstrual blood loss (MBL) for two screening cycles ≥50 mL. The primary outcome is reduction in MBL from screening. Secondary end points are questionnaire assessments of treatment effect and acceptability. Treatment will be for 5 days in the mid-luteal phases of three treatment menstrual cycles. Six doses of low-dose dexamethasone (ranging from 0.2 to 0.9 mg twice daily) will be compared with placebo, to ascertain optimal dose, and whether this has advantage over placebo. Statistical efficiency is maximised by allowing randomisation probabilities to 'adapt' at five points during enrolment phase, based on the response data available so far, to favour doses expected to provide greatest additional information on the dose-response. Bayesian Normal Dynamic Linear Modelling, with baseline MBL included as covariate, will determine optimal dose (re reduction in MBL). Secondary end points will be analysed using generalised dynamic linear models. For each dose for all end points, a 95% credible interval will be calculated for effect versus placebo.Ethics and disseminationDexamethasone is widely used and hence well-characterised safety-wise. Ethical approval has been obtained from Scotland A Research Ethics Committee (12/SS/0147). Trial findings will be disseminated via open-access peer-reviewed publications, conferences, clinical networks, public lectures, and our websites.Trial registration numberClinicalTrials.gov NCT01769820; EudractCT 2012-003405-98.

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Iontophoretic delivery of dexamethasone phosphate for non-infectious, non-necrotising anterior scleritis, dose-finding clinical trial.

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Iontophoretic delivery of dexamethasone phosphate for non-infectious, non-necrotising anterior scleritis, dose-finding clinical trial.

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