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Long-term safety of once-daily, dual-release hydrocortisone in patients with adrenal insufficiency: a phase 3b, open-label, extension study.

ABSTRACT: OBJECTIVE:To investigate the long-term safety and tolerability of a once-daily, dual-release hydrocortisone (DR-HC) tablet as oral glucocorticoid replacement therapy in patients with primary adrenal insufficiency (AI). DESIGN:Prospective, open-label, multicenter, 5-year extension study of DR-HC conducted at five university clinics in Sweden. METHODS:Seventy-one adult patients diagnosed with primary AI who were receiving stable glucocorticoid replacement therapy were recruited. Safety and tolerability outcomes included adverse events (AEs), intercurrent illness episodes, laboratory parameters and vital signs. Quality of life (QoL) was evaluated using generic questionnaires. RESULTS:Total DR-HC exposure was 328 patient-treatment years. Seventy patients reported 1060 AEs (323 per 100 patient-years); 85% were considered unrelated to DR-HC by the investigator. The most common AEs were nasopharyngitis (70%), fatigue (52%) and gastroenteritis (48%). Of 65 serious AEs reported by 32 patients (20 per 100 patient-years), four were considered to be possibly related to DR-HC: acute AI (n?=?2), gastritis (n?=?1) and syncope (n?=?1). Two deaths were reported (fall from height and subarachnoid hemorrhage), both considered to be unrelated to DR-HC. From baseline to 5 years, intercurrent illness episodes remained relatively stable (mean 2.6-5.4 episodes per patient per year), fasting plasma glucose (0.7?mmol/L; P?

SUBMITTER: Nilsson AG

PROVIDER: S-EPMC5425941 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Long-term safety of once-daily, dual-release hydrocortisone in patients with adrenal insufficiency: a phase 3b, open-label, extension study.

Nilsson Anna G AG Bergthorsdottir Ragnhildur R Burman Pia P Dahlqvist Per P Ekman Bertil B Engström Britt Edén BE Ragnarsson Oskar O Skrtic Stanko S Wahlberg Jeanette J Achenbach Heinrich H Uddin Sharif S Marelli Claudio C Johannsson Gudmundur G

European journal of endocrinology 20170314 6

<h4>Objective</h4>To investigate the long-term safety and tolerability of a once-daily, dual-release hydrocortisone (DR-HC) tablet as oral glucocorticoid replacement therapy in patients with primary adrenal insufficiency (AI).<h4>Design</h4>Prospective, open-label, multicenter, 5-year extension study of DR-HC conducted at five university clinics in Sweden.<h4>Methods</h4>Seventy-one adult patients diagnosed with primary AI who were receiving stable glucocorticoid replacement therapy were recruit ...[more]

PMID: 28292927

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Project description:BackgroundPatients with adrenal insufficiency (AI) require life-long glucocorticoid (GC) replacement therapy. Within tissues, cortisol (F) availability is under the control of the isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD). We hypothesize that corticosteroid metabolism is altered in patients with AI because of the nonphysiological pattern of current immediate release hydrocortisone (IR-HC) replacement therapy. The use of a once-daily dual-release hydrocortisone (DR-HC) preparation, (Plenadren®), offers a more physiological cortisol profile and may alter corticosteroid metabolism in vivo.Study design and methodsProspective crossover study assessing the impact of 12 weeks of DR-HC on systemic GC metabolism (urinary steroid metabolome profiling), cortisol activation in the liver (cortisone acetate challenge test), and subcutaneous adipose tissue (microdialysis, biopsy for gene expression analysis) in 51 patients with AI (primary and secondary) in comparison to IR-HC treatment and age- and BMI-matched controls.ResultsPatients with AI receiving IR-HC had a higher median 24-hour urinary excretion of cortisol compared with healthy controls (72.1 µg/24 hours [IQR 43.6-124.2] vs 51.9 µg/24 hours [35.5-72.3], P = .02), with lower global activity of 11β-HSD2 and higher 5-alpha reductase activity. Following the switch from IR-HC to DR-HC therapy, there was a significant reduction in urinary cortisol and total GC metabolite excretion, which was most significant in the evening. There was an increase in 11β-HSD2 activity. Hepatic 11β-HSD1 activity was not significantly altered after switching to DR-HC, but there was a significant reduction in the expression and activity of 11β-HSD1 in subcutaneous adipose tissue.ConclusionUsing comprehensive in vivo techniques, we have demonstrated abnormalities in corticosteroid metabolism in patients with primary and secondary AI receiving IR-HC. This dysregulation of pre-receptor glucocorticoid metabolism results in enhanced glucocorticoid activation in adipose tissue, which was ameliorated by treatment with DR-HC.

Project description:INTRODUCTION:Different prolonged-release formulations of tacrolimus are available. To date, the pharmacokinetic (PK) profile of LCP-tacrolimus (LCPT; Envarsus®) has not been compared with PR-Tac (Advagraf®) in de novo kidney transplant recipients. These profiles will guide clinical recommendations for the initiation and dose titration strategies of once-daily tacrolimus formulations. METHODS:This randomized, parallel-group, open-label, multicenter PK study randomized 75 de novo, adult, white kidney transplant recipients to LCPT 0.17 mg/kg/day (n = 37) or PR-Tac 0.20 mg/kg/day (n = 38) for 4 weeks. Dose adjustments were permitted to target a pre-defined therapeutic range based on measured trough blood concentrations. RESULTS:PK analysis (days 1, 3, 7 and 14) included 68 patients (LCPT, n = 33; PR-Tac, n = 35). Similar proportions of patients were within the pre-defined therapeutic tacrolimus trough blood concentration range, with < 12% in each group having below-target trough levels over the study period. LCPT demonstrated ~ 30% greater relative bioavailability [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 1.32 (p = 0.007); day 7, 1.25 (p = 0.051); day 14, 1.43 (p = 0.002)] and ~ 30% lower peak-to-trough percentage fluctuation of blood concentration [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 0.70 (p < 0.001); day 7, 0.68 (p < 0.001); day 14, 0.73 (p = 0.004)] in addition to longer time to maximum blood concentration (tmax), lower maximum concentration (Cmax) and a consistently lower daily dose (~ 40% dose reduction with LCPT vs. PR-Tac by day 28). Safety profiles were similar. CONCLUSION:In de novo kidney transplant recipients, prolonged-release formulations of tacrolimus can reach therapeutic concentrations in the immediate post-transplant period. LCPT has greater relative bioavailability and lower peak-to-trough fluctuation compared with PR-Tac. TRIAL REGISTRATION:Registered at ClinicalTrials.gov; study number NCT02500212. FUNDING:Chiesi Farmaceutici S.p.A.

Project description:Baclofen, a racemic γ-aminobutyric acid B receptor agonist, is commonly used for the management of multiple sclerosis-related spasticity but is associated with frequent dosing and poor tolerability. Arbaclofen, the active R-enantiomer of baclofen, exhibits 100- to 1000-fold greater specificity for the γ-aminobutyric acid B receptor compared with the S-enantiomer and ∼5-fold greater potency compared with racemic baclofen. Arbaclofen extended-release tablets allow a dosing interval of 12 h and have shown a favourable safety and efficacy profile in early clinical development. A 12-week, randomized, placebo-controlled Phase 3 trial in adults with multiple sclerosis-related spasticity demonstrated that arbaclofen extended-release 40 mg/day significantly reduced spasticity symptoms compared with placebo and was safe and well tolerated. The current study is an open-label extension of the Phase 3 trial designed to evaluate the long-term safety and efficacy of arbaclofen extended-release. In a 52-week, open-label, multicentre study, adults with a Total Numeric-transformed Modified Ashworth Scale score ≥2 in the most affected limb received oral arbaclofen extended-release titrated over 9 days up to 80 mg/day based on tolerability. The primary objective was assessment of arbaclofen extended-release safety and tolerability. Secondary objectives included an assessment of efficacy using the Total Numeric-transformed Modified Ashworth Scale-most affected limb, the Patient Global Impression of Change and Expanded Disability Status Scale. Of 323 patients enrolled, 218 (67.5%) completed 1 year of treatment. Most patients (74.0%) achieved an arbaclofen extended-release maintenance dose of 80 mg/day. At least one treatment-emergent adverse event was reported by 278 patients (86.1%). The most common adverse events were [n patients (%)]: urinary tract disorder [112 (34.7)], muscle weakness [77 (23.8)], asthenia [61 (18.9)], nausea [70 (21.7)], dizziness [52 (16.1)], somnolence [41 (12.7)], vomiting [29 (9.0)], headache [24 (7.4)] and gait disturbance [20 (6.2)]. Most adverse events were of mild-moderate severity. Twenty-eight serious adverse events were reported. One death occurred during the study, a myocardial infarction that was considered by investigators as unlikely to be related to treatment. Overall, 14.9% of patients discontinued due to adverse events, primarily muscle weakness, multiple sclerosis relapse, asthenia and nausea. Evidence of improvement in multiple sclerosis-related spasticity was observed across arbaclofen extended-release dosages. Arbaclofen extended-release treatment (up to 80 mg/day) was well tolerated and reduced symptoms of spasticity in adult patients with multiple sclerosis for 1 year. Clinical Trial Identifier: ClinicalTrials.gov, NCT03319732.

Dataset Information

Long-term safety of once-daily, dual-release hydrocortisone in patients with adrenal insufficiency: a phase 3b, open-label, extension study.

Publications

Long-term safety of once-daily, dual-release hydrocortisone in patients with adrenal insufficiency: a phase 3b, open-label, extension study.

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