Title: Safety and Efficacy of Prednisolone in Adrenal Insufficiency Disease (PRED-AID).
Funder: Department of Health and Social Care

Abstract: Background There are approximately 27,000 individuals with Adrenal Insufficiency (AI) in the UK with an annual incidence 3140 new cases (1,2). Untreated, the 2-year mortality is 85%(3). AI is treated by replacing endogenous steroids using oral glucocorticoids, with the goal of mimicking the physiological diurnal cortisol rhythm. Although life expectancy has improved since the introduction of treatment (4), there is still increased mortality with AI, associated with over-replacement (5,6). Over-replacement increases the long-term risks of malignancy, diabetes, cardiovascular disease and osteoporosis (4,7). If under-replaced, patients experience symptoms such as lethargy, depression, nausea and are exposed to the risk of life-threatening Addisonian crises (8). It is important to strike the correct balance with steroid replacement to optimize quality of life and prevent acute crises but without increasing the long-term risk of mortality and morbidity.The most commonly prescribed therapy is hydrocortisone. With a short half-life of 2 hours (9), hydrocortisone requires thrice-daily administration, which reduces patient compliance. Moreover, hydrocortisone is expensive at 186 per month for 20mg daily. Although modified release versions of hydrocortisone like Plenadren allow for once-daily dosing, these are costlier at 240 per month.Prednisolone is an alternative to hydrocortisone that is structurally similar to hydrocortisone but has a longer half-life (2-4 hours), permitting it to be given once-daily. Prednisolone is recommended as an alternative in the Endocrine Society's Clinical Practice Guidelines (10). In addition to the benefit of once-daily administration, prednisolone is 35-60 times cheaper than hydrocortisone at 3.21-5.35 per month.In the past, prednisolone was used for replacement at a dose of 7.5 mg daily, in a one-size-fits-all fashion, and this practice was associated with the development of osteoporosis and diabetes, i.e. the dose was too high (11-14). However, two developments make low-dose prednisolone a viable choice for replacement in AI: (1) new evidence that the appropriate dose is much lower (3-5mg) (15); (2) a new assay that I have developed at Imperial College Healthcare NHS Trust, used to identify patients as slow versus fast metabolisers, allowing us to customise doses to individual patients.There is currently a vacuum of evidence supporting the use of prednisolone at lower doses (5mg or less) in AI, with the exception of a few case reports of AI patients doing well on doses of 3 mg (16). There have been no prospective studies comparing low-dose prednisolone to established hydrocortisone therapy assessing patient satisfaction, bone or glycaemic outcomes. This study aims to address this dearth of evidence, by showing that prednisolone is equivalent to hydrocortisone in replacing the steroid requirements of patients with AI.Question addressed by this research Is low-dose prednisolone safe for the treatment of AI?Plan of investigation Participants with AI will be recruited to this randomised, double-blind, cross-over study. Participants will be randomly assigned to one of two treatment arms, either (a) 4 months of prednisolone therapy, followed by two weeks of usual treatment, then 4 months of hydrocortisone therapy; or (b) 4 months of hydrocortisone, followed by 2 weeks of usual treatment, then 4 months of prednisolone. The prednisolone and hydrocortisone during the 4-month treatment periods will be supplied in indistinguishable capsules, given three times a day during the prednisolone phase, the first dose will be prednisolone, and the lunchtime/afternoon doses, placebo. I will assess the effects of each treatment on patient wellbeing (using validated subjective health surveys: SF36 and Addi-QoL), patient safety, and biological observations (heart rate, blood pressure, weight and waist-hip circumference ratio). I will investigate the effects of each treatment on the markers of bone turnover (osteocalcin, P1NP and NTX) and glycaemic control (fasting glucose, HbA1c and insulin resistance, assessed by HOMA-IR).

Lay abstract: Background In Adrenal Insufficiency (AI), the body is unable to produce vital steroid hormones, the chief of these being cortisol. There are approximately 27,000 individuals in the UK with AI, with up to 3140 new cases per year. Untreated, the condition kills patients.The main treatment is replacement of the absent hormone with tablets. This is commonly done using hydrocortisone, taken 3 times daily. Correctly replacing the hormones is a significant challenge. If an individual is given too much hydrocortisone, they risk long term complications including diabetes, osteoporosis (weakened bones) and cardiovascular disease (heart attacks). If, however they are given too little, patients can feel tired, unwell and may collapse as there is insufficient steroid hormone to cope with stress.As hydrocortisone is eliminated by the body very quickly, it must be taken three times a day to maintain adequate levels, and omitting a dose can be dangerous. Hydrocortisone is very expensive, costing 186 for a month's supply. As patients take hydrocortisone for the rest of their lives, with the average age of diagnosis at 52 years, this is a total lifetime cost of 69,000. The NHS spent 70 million on hydrocortisone in 2015.This study will look at an alternative steroid hormone for replacement called prednisolone. Prednisolone is similar to hydrocortisone but is eliminated more slowly, requiring only once daily administration. Prednisolone replacement costs between 3.21-5.35 per month meaning that it is more economical than the other available options. In comparison, the projected lifetime treatment cost using prednisolone would be just 1200-2000. Prednisolone might also be safer, as once daily administration results in adequate replacement. There is currently no data demonstrating superiority of any particular steroid including hydrocortisone or prednisolone in patients with AI.For the purposes of hormone replacement, prednisolone should be used in much smaller doses than typically used for conditions like rheumatoid arthritis. In the past, prednisolone was used in one-size-fits-all doses of 7.5 mg daily but this caused side effects such as weakening of the bones (osteoporosis) and high blood sugar (diabetes). We now know that we can prevent these problems by the following plan: (1) we can reduce the dose required for replacement to 3-5 mg a day; (2) by using a blood test to measure the amount of prednisolone remaining in the blood 8 hours after a given dose of prednisolone, we can confirm the right dose of prednisolone for each patient: 3, 4 or 5 mg. Using this plan, we can ensure that patients get the right dose of prednisolone, and minimise any side effects.Aim of the Study The aim of this study, therefore, is to compare low-dose prednisolone with standard hydrocortisone replacement to ensure that low-dose prednisolone is equivalent to standard hydrocortisone treatment in terms of replacing the steroid hormone needs of patients with AI, and in terms of maintaining their overall health.Study Plan I will study patients with AI. I will give each participant a test dose of prednisolone and measure the level of prednisolone at 8 hours after the test dose. Using this result, I will decide on the exact dose of prednisolone to be used for each participant. Some participants may require more than one test dose. The participants will then be randomised to treatment with (a) 4 months of once daily prednisolone (at the determined dose with placebo at midday and the afternoon) followed by a 2 week washout period followed by 4 months of standard thrice daily hydrocortisone, or (b) 4 months of standard thrice daily hydrocortisone followed by the same washout period and then 4 months of prednisolone (at the determined dose with placebo as previously described). Patients and doctors will not know whether they are taking prednisolone in the first 4 months or the second 4 months as the prednisolone and the hydrocortisone will be supplied in identical-looking capsules. During each of these 4 month periods, I will check that participants are safe on their treatment, that they are feeling well, and will obtain blood samples to assess bone health and blood sugar levels.Patient and public involvement This study has been designed with input from the Association for Multiple Endocrine Neoplasia Disorders (AMEND). AMEND represents many patients who have AI, and they will help in dissemination of the findings.Impact Prednisolone will improve the experience of patients with AI as it is more convenient to take once a day. Prednisolone is also much cheaper than hydrocortisone, and this will reduce the financial burden on the NHS in the years to come.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE