MICA: Clinical validation of a non-invasive diagnostic test for adrenal insufficiency using comparative pharmacodynamic equivalence

肾上腺位于肾脏上方，是人体内分泌系统的一部分。它们产生许多不同的激素;那些参与新陈代谢（皮质醇），盐和水平衡（醛固酮）和雄激素（性类固醇，如睾酮）。肾上腺功能不全（AI）描述了身体无法产生足够水平的皮质醇。皮质醇有助于控制血压和血糖水平，并作为身体应激反应的一部分释放。如果不治疗（替代皮质醇），AI可能会导致严重的疾病和死亡，通过低血压引起循环衰竭（肾上腺危象）。AI的原因有很多，包括成人和儿童。在高收入国家，免疫系统对肾上腺的破坏、脑肿瘤和为炎症（如关节炎、哮喘、癌症）开具类固醇药物处方是最常见的，但全球主要的病因是结核病和艾滋病。AI通常是永久性的，但特别是在服用类固醇药物的患者中，可能不是，可能需要重复测试。短Synacthen测试（SST）是全球最流行的肾上腺功能不全的诊断测试。Synacthen是一种药物，在结构上与大脑激素ACTH非常相似，ACTH刺激肾上腺产生皮质醇。在SST中，在给予Synacthen之前和之后30-60分钟进行血液测试，以测量肾上腺产生的皮质醇的上升。如果皮质醇升高不充分，患者被诊断为AI，需要替代皮质醇（氢化可的松）。近年来，随着类固醇药物处方的增加以及对类固醇可能导致的肾上腺功能不全的认识提高，对SST的要求也有所增加。SST需要静脉插管和采血。因此，它是侵入性的、资源密集型的（需要日托医院入院和受过训练的人员来进行测试），并且对患者（特别是儿童）来说是不愉快的;导致要求测试的成本和阈值的增加。我们已经开发了一种非侵入性的，无针的，替代SST的药物，tetracosactide（Synacthen），通过喷雾剂鼻腔给药，并在唾液样本上测量所得的皮质醇反应。这种新药是一种由四糖丙交酯和壳聚糖组成的鼻腔药物增强剂，可以帮助四糖丙交酯从鼻子吸收到血液中。迄今为止，我们已经完成了五项临床试验，测试了不同的剂量和配方（混合物），发现我们的新药Nasacthin在健康的成年男性和儿童中可靠地吸收和耐受性良好。我们已经向MHRA（英国药品监管机构）寻求建议，下一步要做什么研究，以便获得许可证，能够在临床实践中使用Nasacthin来诊断患者的AI。他们建议我们在健康男性、女性和儿童中进行研究，以验证Nasacthin测试与SST相比不会产生较低的皮质醇反应，然后在患者人群中进行测试，以确保其诊断AI与SST一样准确。（实际上在某些情况下完全避免）患者的额外医院就诊，从而降低了医疗保健提供者的成本，并且重要地改善了整体患者体验。这种新的测试在住院病人，门诊病人和社区环境中具有实用性;全球农村和难以到达的社区;成人和儿童;并将为未来研究肾上腺对类固醇的反应提供重要的研究工具在许多不同的患者队列中，包括儿童。

The adrenal glands sit above the kidneys and are part of the body's endocrine system. They produce a number of different hormones; those involved in metabolism (cortisol), salt and water balance (aldosterone) and androgens (sex steroids e.g. testosterone). Adrenal insufficiency (AI) describes the inability of the body to produce adequate levels of cortisol. Cortisol helps to control blood pressure and blood sugar levels and is released as part of the body's stress response. Without treatment (replacement cortisol) AI can lead to serious illness and death through low blood pressure causing circulatory collapse (adrenal crisis). There are numerous causes of AI, both in adults and children. In high-income countries destruction of the adrenal gland by the immune system, brain tumours and the prescription of steroid medication for inflammatory conditions (e.g. arthritis, asthma, cancers) are the commonest but globally major causes are TB and AIDS. AI is usually permanent but, especially in those patients taking steroid medication, it may not be and repeated testing may be required. The Short Synacthen Test (SST) is the most popular diagnostic test for adrenal insufficiency worldwide. Synacthen is a drug structurally very similar to the brain hormone, ACTH, which stimulates the adrenal glands to produce cortisol. In the SST blood tests are taken before Synacthen is given and 30-60 minutes after in order to measure the rise in cortisol produced from the adrenal gland. If the cortisol rise is inadequate the patient is diagnosed with AI and requires replacement cortisol (hydrocortisone). Over recent years requests for SSTs have risen in line with the increasing prescription of steroid medication and heightened awareness of the adrenal insufficiency steroids can cause. The SST requires intravenous cannulation and blood sampling. It is thus invasive, resource-intensive (requiring a day care hospital admission and trained personnel to deliver the test) and unpleasant for the patient, especially children; leading to a rise in both the cost and the threshold for requesting the test. We have developed a non-invasive, needle-free, alternative to the SST, with the drug, tetracosactide (Synacthen), given nasally via a spray and the resultant cortisol response measured on saliva samples. The new drug is a combination of tetracosactide with chitosan, a nasal drug enhancer, which helps the tetracosactide be absorbed from the nose into the bloodstream. To date we have completed five clinical trials testing different doses and formulations (mixtures) and found our new drug, Nasacthin, to be reliably absorbed and well tolerated in healthy adult men and children. We have sought advice from the MHRA (UK medicines regulator) as to what studies to do next in order to be granted a licence to be able to use Nasacthin in clinical practice inorder to diagnose AI in patients. They have recommended we perform studies in healthy men, women and children to verify the Nasacthin Test does not produce a lower cortisol response compared to the SST and then to test it in a patient population to ensure confidence that it diagnoses AI as accurately as the SST.Our non-invasive test would negate the need for needles and reduce (indeed in some cases avoid entirely) additional hospital visits for patients, thus reducing costs for the healthcare provider and importantly improving the overall patient experience. The novel test has utility in the inpatient, outpatient and community settings; rural and hard to reach communities globally; in both adults and children; and will provide a vital research tool for future studies on the response of the adrenal gland to steroids in many diverse patient cohorts, including children.