Treatment with PBI-4050 in patients with Alström syndrome: study protocol for a phase 2, single-Centre, single-arm, open-label trial.
Treatment with PBI-4050 in patients with Alström syndrome: study protocol for a phase 2, single-Centre, single-arm, open-label trial.
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DOI：
10.1186/s12902-018-0315-6
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发表时间：
2018-11-26
影响因子：
2.7
通讯作者：
Geberhiwot T
中科院分区：
文献类型：
--
作者：
Baig S;Veeranna V;Bolton S;Edwards N;Tomlinson JW;Manolopoulos K;Moran J;Steeds RP;Geberhiwot T
Alström综合征（ALMS）是一种非常罕见的常染色体隐性单基因疾病，由ALMS 1基因突变引起，其特征是儿童期发病的肥胖症、血脂异常、晚期非酒精性脂肪肝、糖尿病和极端胰岛素抵抗。有证据表明ALMS中存在多器官纤维化，并且疾病的严重程度通常导致器官衰竭和相关的发病率，从而导致预期寿命缩短。对于这种疾病没有特定的治疗方法，目前的管理仅包括对症治疗。PBI-4050是一种新的分子实体，在临床前模型中具有抗炎和抗纤维化活性，包括以肾脏、心脏、肝脏和肺部进行性纤维化为特征的人类疾病的动物模型。此外，在2型糖尿病合并代谢综合征和特发性肺纤维化中完成的2期研究进一步支持PBI-4050的抗炎和抗纤维化活性。总之，这些数据表明PBI-4050具有治疗ALMS的病理性炎症和纤维化特征的潜力。本研究的目的是评估PBI-4050在ALMS受试者中的安全性和抗炎及抗纤维化活性。这是一项II期、单中心、单组、开放标签试验。总共18名ALMS患者将被招募接受PBI-4050，每日口服总剂量为800 mg，最初24周，再持续36或48周。安全性的标准评估包括不良事件、临床实验室检查、生命体征、体格检查和心电图。疗效评估包括脂肪组织活检、高胰岛素-正常血糖钳夹、脂肪组织微透析、肝脏瞬时弹性成像、肝脏和心脏磁共振成像以及实验室血液检查。这是PBI-4050在ALMS受试者中的首次临床研究。鉴于该疾病的罕见性和复杂性，选择了单中心、单臂、开放标签设计，以最大限度地提高受试者暴露量，并增加实现研究终点的可能性。这些结果将为PBI-4050在ALMS中的作用提供有价值的安全性和初步证据，ALMS是一种与进行性纤维化和过早死亡相关的罕见异质性疾病。该试验在ClinicalTrials.gov（标识符; NCT 02739217，2016年2月）和欧盟药品监管机构临床试验（EudraCT编号2015-001625-16，2015年9月）上注册。本文的在线版本（10.1186/s12902-018-0315-6）包含补充材料，可供授权用户使用。
Alström syndrome (ALMS) is a very rare autosomal recessive monogenic disorder caused by a mutation in the ALMS1 gene and characterised by childhood onset obesity, dyslipidaemia, advanced non-alcoholic fatty liver disease, diabetes and extreme insulin resistance. There is evidence of multi-organ fibrosis in ALMS and severity of the disease often leads to organ failure with associated morbidities, resulting in reduced life expectancy. There are no specific treatments for this disease, and current management consists of only symptomatic therapies. PBI-4050 is a new molecular entity with demonstrated anti-inflammatory and anti-fibrotic activities in preclinical models, including animal models of human diseases characterized by progressive fibrosis in the kidney, heart, liver and lungs. Moreover, completed Phase 2 studies in type 2 diabetes mellitus with metabolic syndrome and idiopathic pulmonary fibrosis further support the anti-inflammatory and anti-fibrotic activity of PBI-4050. Together, these data suggest that PBI-4050 has the potential to treat the pathological inflammatory and fibrotic features of ALMS. The aim of this study is to evaluate the safety and anti-inflammatory & anti-fibrotic activities of PBI-4050 in subjects with ALMS. This is a Phase 2, single-centre, single-arm, open-label trial. A total of 18 patients with ALMS will be enrolled to receive PBI-4050 at a total daily oral dose of 800 mg for an initial 24 weeks with continuation for an additional 36 or 48 weeks. Standard assessments of safety include adverse events, clinical laboratory tests, vital signs, physical examination and electrocardiograms. Efficacy assessments include adipose tissue biopsy, hyperinsulinaemic-euglycaemic glucose clamp, adipose tissue microdialysis, liver transient elastography, liver and cardiac magnetic resonance imaging, and laboratory blood tests. This is the first clinical study of PBI-4050 in subjects with ALMS. Given the rarity and complexity of the disease, a single-centre, single-arm, open-label design has been chosen to maximise subject exposure and increase the likelihood of achieving our study endpoints. The results will provide valuable safety and preliminary evidence of the effects of PBI-4050 in ALMS, a rare heterogeneous disease associated with progressive fibrosis and premature mortality. The trial is registered on ClinicalTrials.gov (Identifier; NCT02739217, February 2016) and European Union Drug Regulating Authorities Clinical Trials (EudraCT Number 2015–001625-16, Sept 2015). The online version of this article (10.1186/s12902-018-0315-6) contains supplementary material, which is available to authorized users.
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