European Adrenal Insufficiency Registry (EU-AIR): a comparative observational study of glucocorticoid replacement therapy

Abstract

BackgroundIncreased morbidity and mortality associated with conventional glucocorticoid replacement therapy for primary adrenal insufficiency (primary AI; estimated prevalence 93–140/million), secondary AI (estimated prevalence, 150–280/million, respectively) or congenital adrenal hyperplasia (estimated prevalence, approximately 65/million) may be due to the inability of typical glucocorticoid treatment regimens to reproduce the normal circadian profile of plasma cortisol. A once-daily modified-release formulation of hydrocortisone has been developed to provide a plasma cortisol profile that better mimics the daytime endogenous profile of cortisol. Here, we describe the protocol for the European Adrenal Insufficiency Registry (EU-AIR), an observational study to assess the long-term safety of modified-release hydrocortisone compared with conventional glucocorticoid replacement therapies in routine clinical practice (ClinicalTrials.gov identifier: NCT01661387).MethodsPatients enrolled in EU-AIR have primary or secondary AI and are receiving either modified-release or conventional glucocorticoid replacement therapy. The primary endpoints of EU-AIR are the incidence of intercurrent illness, adrenal crisis and serious adverse events (SAEs), as well as the duration of SAEs and dose changes related to SAEs. Data relating to morbidity, mortality, adverse drug reactions, dosing and concomitant therapies will be collected. Patient diaries will record illness-related dose changes between visits. All decisions concerning medical care are made by the registry physician and patient. Enrolment is targeted at achieving 3600 patient-years of treatment (1800 patient-years per group) for the primary analysis, which is focused on determining the non-inferiority of once-daily modified-release replacement therapy compared with conventional glucocorticoid therapy.ResultsRecruitment began in August 2012 and, as of March 2014, 801 patients have been enrolled. Fifteen centres are participating in Germany, the UK and Sweden, with recruitment soon to be initiated in the Netherlands.ConclusionsEU-AIR will provide a unique opportunity not only to collect long-term safety data on a modified-release preparation of glucocorticoid but also to evaluate baseline data on conventional glucocorticoid replacement. Such data should help to improve the treatment of AI.

Circadian disruption: New clinical perspective of disease pathology and basis for chronotherapeutic intervention

“…-Delayed sleep phase syndrome (Skene et al, 1999) -Sleep-onset insomnia (Wang-Weigand et al, 2009) -Non-24 h sleep/wake disorder -SW schedule disorder (Roth, 2012) -Smith-Magenis syndrome (Chen et al, 2015) -Delirium (Furuya et al, 2012) -Peptic ulcer disease (Moore & Merki, 1997) -Depression, mania, seasonal affective disorder and seasonal affective bipolar disorder (Dallaspezia et al, 2015;Geoffroy et al, 2015;Klemfuss & Kripke, 1989;Melrose, 2015;Salgado-Delgado et al, 2011) -Nocturnal asthma (Smolensky & D'Alonzo, 1997;) -AI (Chan & Debono, 2010;Debono et al, 2009;Ekman et al, 2014;Johannsson et al, 2009;Quinkler et al, 2015) -Nocturia (Bliwise et al, 2014;Ebell et al, 2014;Miller, 2000;Moon et al, 2004) -Sleep-time non-dipping and rising 24 h BP patterns, that is nocturnal hypertension Hermida et al, 2011aHermida et al, , b, c, 2013cPortaluppi & Smolensky, 2010;Smolensky et al, 2015b).…”

“…In contrast, unequal temporal distribution of the daily oral tablet dose of hydrocortisone as a chronotherapeutic substitution schedule -two-third or threefourth of the daily dose ingested upon awakening from nighttime sleep in the morning at 07:00 h and the remaining amount before bedtime at 23:00 h -with the aim of re-establishing typical cortisol circadian rhythmicity -improved the CTS toward normal (Figure 2). More recently explored AI chronotherapies include circadian configured subcutaneous or intravenous hydrocortisone infusion strategies (Løvås & Husebye, 2007;Merza et al, 2006) as well as thrice daily unequal morning, afternoon and evening (Debono & Ross, 2013) and once daily bedtime-dosed dual-release (combination immediate-release and extended-release) oral tablet schedules (Chan & Debono, 2010;Debono et al, 2009;Ekman et al, 2014;Johannsson et al, 2009;Quinkler et al, 2015). Nonetheless, it does not appear that any of these trials, including the currently ongoing multicenter evaluation of the newest bedtime-dosed dual combination immediate release/extended-release hydrocortisone tablet formulation, specifically entails chronobiological assessment of the potential corrective effect upon the inherent and characteristic CD of AI (Ekman et al, 2014).…”

Prednisolone is associated with a worse lipid profile than hydrocortisone in patients with adrenal insufficiency

“…EU-AIR is an observational, open-ended study (ClinicalTrials.gov identifier: Nbib1661387) in patients with primary AI (PAI), secondary AI (SAI) or congenital adrenal hyperplasia (CAH) who are undergoing long-term treatment with modified-release hydrocortisone or other glucocorticoid replacement therapies (21). The primary objective of the EU-AIR is to monitor the safety of long-term treatment with once-daily modified-release hydrocortisone and other glucocorticoid replacement therapies in patients with AI.…”

“…All medical care decisions, including those relating to treatment choice, are entirely at the discretion of the patient and registry physician. Patient data, including laboratory assessments, were collected by means of an electronic case report form at enrolment and thereafter at routine clinic visits (every 6–12 months) (21). …”

Insuficiência suprarrenal primária de etiologia tuberculosa

“…Embora a hidrocortisona seja o glicocorticóide de primeira escolha na idade pediátrica, pela sua curta duraç ão de aç ão e baixa potência que permitem uma ótima titulaç ão da dose, optou--se pela prednisolona numa administraç ão diária, com o intuito de melhorar a adesão terapêutica, já que se tratava de um adolescente de 16 anos. Está em curso um estudo clínico comparativo entre a terapêutica de substituiç ão clássica com hidrocortisona e a hidrocortisona de libertaç ão modificada (Plenadren ® ) em dose única diária, recentemente aprovada na terapêutica da ISR em adultos, com um perfil plasmático mais próximo do padrão circadiano normal do cortisol 13 Em relaç ão aos tuberculostáticos, é importante referir que a rifampicina acelera o metabolismo do cortisol e da maioria dos glicocorticóides sintéticos, o que pode precipitar uma crise de ISR aguda num doente com adrenalite tuberculosa ainda não diagnosticada ou condicionar ajustes terapêuticos em doentes conhecidos 1,4,5 .…”