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荷尔蒙；涉及新陈代谢(皮质醇)、盐分和水分平衡(醛固酮)和雄激素(性类固醇，如睾酮)。肾上腺功能不全(AI)描述的是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，并作为身体压力反应的一部分被释放。如果不进行治疗(替代皮质醇)，人工智能可通过低血压导致循环衰竭(肾上腺危象)而导致严重疾病和死亡。无论是成人还是儿童，人工智能的原因都有很多。在高收入国家，免疫系统对肾上腺的破坏、脑瘤以及针对炎症性疾病(如关节炎、哮喘、癌症)开出的类固醇药物处方是最常见的，但在全球范围内，主要原因是结核病和艾滋病。人工智能通常是永久性的，但特别是在那些服用类固醇药物的患者中，可能不是，可能需要重复检测。短突触试验(SST)是目前世界上最流行的肾上腺功能不全诊断试验。Synacten是一种结构非常类似于大脑激素ACTH的药物，ACTH刺激肾上腺产生皮质醇。在SST试验中，在给药前和给药后30-60分钟进行血液测试，以测量肾上腺产生的皮质醇的增加。如果皮质醇升高不足，患者被诊断为AI，需要补充皮质醇(氢化可的松)。近年来，随着类固醇药物处方的增加和对类固醇可能导致的肾上腺功能不全的认识的提高，对SSTs的需求也有所增加。SST需要静脉插管和采血。因此，这是侵入性的、资源密集型的(需要日托医院入院和训练有素的人员来提供测试)，并使患者，特别是儿童感到不快；导致要求测试的成本和门槛都上升了。我们已经开发出一种非侵入性的，无针的，替代SST的药物，通过喷雾鼻腔给药，产生的皮质醇反应在唾液样本上测量。这种新药是四天冬氨酸和壳聚糖的组合，壳聚糖是一种鼻用药物增强剂，它有助于四天冬氨酸从鼻子吸收到血液中。到目前为止，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)，并发现我们的新药Nasachim在健康的成年男性和儿童中可以可靠地吸收并具有良好的耐受性。我们已经征求了MHRA(英国药品监管机构)的建议，关于下一步要做什么研究，以便获得能够在临床实践中使用Nasachim的许可证，以便诊断患者的AI。他们建议我们在健康的男性、女性和儿童中进行研究，以验证Nasachim测试不会产生比SST更低的皮质醇反应，然后在患者群体中进行测试，以确保它可以像SST一样准确地诊断AI。我们的非侵入性测试将消除对针头的需求，并减少(实际上在某些情况下完全避免)患者额外的住院次数，从而降低医疗保健提供者的成本，并重要地改善整体患者体验。这项新颖的测试在住院、门诊和社区环境中具有实用价值；在农村和全球难以接触到的社区中；在成人和儿童中；并将为未来研究包括儿童在内的许多不同患者队列中肾上腺对类固醇的反应提供重要的研究工具。

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.