Controlled-ileal-release nicotinic acid (CIR-NA) for a targeted gut microbiome interventionfor remission of prediabetes

控制回肠释放烟酸（CIR-NA）用于靶向肠道微生物组干预以缓解糖尿病前期

• 批准号: 424470129
• 负责人: Professor Dr. Matthias Laudes
• 金额: --
• 依托单位: Institut für Klinische Molekularbiologie
• 依托单位国家: 德国
• 项目类别: Clinical Trials
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/424470129?language=en
• 关键词: Controlled; ileal; release; nicotinic; acid

Changes in the gut microbiome are associated with common western-world diseases like obesity and type 2 diabetes mellitus (T2DM). The gut microbiome therefore represents a novel target for innovative metabolic therapies. However, compared to novel Diabetes medications like SGLT2 Inhibitors and GLP1 analogues, therapeutic effects of the microbiome are supposed to be rather mild making usage as a diabetic drug unlikely. In contrast, microbiome might be of special interest for prediabetic patients in which the metabolic disturbances are rather mild and for which classical pharmacological agents are not approved in Germany. Furthermore, the Diabetes Prevention Program (DPP) follow-up analysis has shown that the risk for the development of diabetic microvascular complications is already increased in subjects with prediabetes. In addition, prediabetes is very common (in 2035 estimated ½ Billion worldwide), and transformation into manifest type 2 diabetes is very common (annual conversion rate 5-10%), suggesting this pre-disease to be an ideal target for an innovative microbiome-based therapy.In the past using animal experiments and human studies our group has developed a microbiome intervention using microencapsulated niacin, which is able to induce both, changes in the microbiome as well as improvement of systemic insulin sensitivity. The microencapsulation procedure thereby inhibits systemic resorption in the upper GI tract (to avoid side effects like flushing) and delivers the niacin into the terminal ileum/colon, where most of the microbiota are localized (=controlled ileac release). In the past we performed a proof-of-concept study in human subjects in a period of 6 weeks showing beneficial effects of the treatment on gut microbiome and systemic insulin sensitivity of liver and skeletal muscle. This proof-of-concept study reflects the rational for the proposed intervention trial.The aim of the proposed intervention trial is to examine in 520 human subjects if treatment with controlled-ileac release nicotinic acid (CIR-NA) is able to induce a remission of prediabetes (=primary end-point). For that, 3 different intervention groups (100 mg, 200 mg and 500 mg CIR-NA) will be compared to a placebo group (130 prediabetic subjects each) in a time period of 6 month at 3 different centers in Germany.

肠道微生物群的变化与西方世界常见的疾病有关，如肥胖症和2型糖尿病(T2 DM)。因此，肠道微生物组代表了创新代谢疗法的新靶点。然而，与SGLT2抑制剂和GLP1类似物等新型糖尿病药物相比，微生物组的治疗效果被认为是相当温和的，因此不太可能作为糖尿病药物使用。相比之下，微生物组可能对糖尿病前期患者特别感兴趣，因为他们的代谢障碍相当轻微，而且德国没有批准传统的药理药物。此外，糖尿病预防计划(DPP)的后续分析表明，在糖尿病前期患者中，发生糖尿病微血管并发症的风险已经增加。此外，糖尿病前期非常常见(2035年全球估计有50亿人)，转化为显性2型糖尿病非常常见(年转换率为5-10%)，这表明这种疾病前期是基于微生物组创新疗法的理想靶点。在过去，我们团队利用动物实验和人体研究开发了一种使用微囊化烟酸的微生物组干预，它能够诱导微生物组的变化以及改善全身胰岛素敏感性。因此，微囊化过程抑制了上消化道的全身吸收(以避免冲洗等副作用)，并将烟酸输送到末端回肠/结肠，大部分微生物区系在那里定位(=受控回肠释放)。在过去，我们在人类受试者身上进行了为期6周的概念验证研究，显示了该治疗对肝脏和骨骼肌的肠道微生物群和全身胰岛素敏感性的有利影响。这项概念验证研究反映了拟议的干预试验的合理性。拟议的干预试验的目的是在520名受试者中检查回肠控释烟酸(CIR-NA)治疗是否能够诱导糖尿病前期的缓解(=主要终点)。为此，3个不同的干预组(100毫克、200毫克和500毫克CIR-NA)将在德国的3个不同中心与安慰剂组(各130名糖尿病前期受试者)在6个月的时间内进行比较。