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

MICA：使用比较药效学等效性对肾上腺功能不全的非侵入性诊断测试进行临床验证

• 批准号: MR/W029502/1
• 负责人: Charlotte Elder
• 金额: $ 125.66万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW029502%2F1
• 关键词: MICA; Clinical; validation; non; invasive

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.

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），盐和水的平衡（醛固酮）和雄激素（性类固醇，如睾酮）。肾上腺功能不全（AI）是指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被释放出来。如果不进行治疗（替代皮质醇），人工智能会通过低血压导致严重疾病和死亡，导致循环衰竭（肾上腺危机）。导致人工智能的原因有很多，包括成人和儿童。在高收入国家，免疫系统破坏肾上腺、脑肿瘤和开具类固醇药物治疗炎症（如关节炎、哮喘、癌症）是最常见的原因，但全球主要原因是结核病和艾滋病。AI通常是永久性的，但特别是那些服用类固醇药物的患者，它可能不是永久性的，可能需要反复检测。短Synacthen试验（SST）是世界上最流行的肾上腺功能不全诊断试验。Synacthen是一种结构与脑激素ACTH非常相似的药物，它刺激肾上腺产生皮质醇。在SST中，在给予Synacthen之前和30-60分钟后进行血液测试，以测量肾上腺产生的皮质醇的上升。如果皮质醇上升不足，则诊断为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和对类固醇可能引起的肾上腺功能不全的认识的提高，SSTs的需求也在增加。SST需要静脉插管和采血。因此，它是侵入性的、资源密集型的（需要住院日托和训练有素的人员来进行检查），而且对病人，特别是儿童来说不愉快；导致成本和要求测试的门槛都上升。我们已经开发了一种无创、无针、替代SST的方法，使用药物四糖苷（Synacthen），通过鼻腔喷雾给药，并在唾液样本上测量产生的皮质醇反应。这种新药是四糖苷和壳聚糖的混合物，壳聚糖是一种鼻腔药物增强剂，可以帮助四糖苷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），并发现我们的新药Nasacthin在健康成年男性和儿童中具有可靠的吸收和良好的耐受性。我们已经向MHRA（英国药品监管机构）寻求建议，了解下一步要做哪些研究，以便获得在临床实践中使用Nasacthin的许可，以诊断患者的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Nasacthin Test与SST相比不会产生更低的皮质醇反应，然后在患者群体中进行测试，以确保它能像SST一样准确地诊断人工智能。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）患者额外的医院就诊，从而降低医疗保健提供者的成本，并重要地改善患者的整体体验。新测试在住院，门诊和社区设置的效用；农村和难以到达的全球社区；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群体中肾上腺对类固醇的反应提供重要的研究工具。