Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
BMJ Open. 2024 Aug 21;14(8):e087983. doi: 10.1136/bmjopen-2024-087983.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that presents with a progressive movement disorder along with cognitive and psychiatric problems. It is caused by a Cytosine-adenin-guanine (CAG) expansion in exon 1 of the huntingtin gene which codes for mutant huntingtin (mHTT) that over time accumulates in cells, causing dysfunction and then death through new toxic gain-of-function mechanisms. Autophagy has been shown to be critical for the degradation of diverse intracytoplasmic aggregate-prone proteins that cause neurodegenerative disease, including mHTT. From a screen of a library enriched in approved drugs, felodipine was selected as the most suitable candidate showing strong autophagy-inducing effects in preclinical models of HD. We are, therefore, conducting a trial to assess the safety and tolerability of felodipine in people with early HD.
FELL-HD is a phase II, single-centre, open-label, dose-finding trial in people with early HD. 18 participants with early clinical features of the disease will be treated with felodipine for 58 weeks, with a further 4-week follow-up. The primary outcome measure is the number of adverse events attributable to felodipine. Exploratory outcomes include additional measures of motor and cognitive function, non-motor symptoms and quality of life scales, as well as peripheral and central disease biomarkers assessed through brain MRI. Analysis of blood and cerebrospinal fluid will also be performed through an associated sample study, FELL HD-s.
The study was approved by the London-Brent Research Ethics Committee (reference 22/LO/0387) and has been accepted by the Medicines and Healthcare products Regulatory Agency for clinical trials authorisation (reference CTA 12854/0256/001-0001). A lay summary of the results of the trial will be uploaded to our research group website which is publicly accessible. A webinar or in-person open day, to present results of the trial to participants and our wider cohort of patients who attend our centre, will be held once the trial is completed. The results of the trial will also be published in scientific journals and presented at national and international conferences.
EudraCT-2021-000897-27, ISRCTN56240656.
亨廷顿病（HD）是一种常染色体显性神经退行性疾病，表现为进行性运动障碍，伴有认知和精神问题。它是由亨廷顿基因外显子 1 中的胞嘧啶-腺嘌呤-鸟嘌呤（CAG）扩展引起的，该基因编码突变型亨廷顿蛋白（mHTT），随着时间的推移，mHTT 在细胞中积累，通过新的毒性获得功能机制导致功能障碍和细胞死亡。自噬对于降解引起神经退行性疾病的各种细胞内聚集倾向蛋白至关重要，包括 mHTT。从富含已批准药物的文库中筛选，非洛地平被选为最适合的候选药物，在 HD 的临床前模型中显示出强烈的自噬诱导作用。因此，我们正在进行一项试验，以评估早期 HD 患者使用非洛地平的安全性和耐受性。
FELL-HD 是一项在早期 HD 患者中进行的 II 期、单中心、开放性、剂量发现试验。18 名早期具有疾病临床特征的患者将接受非洛地平治疗 58 周，随后进行 4 周随访。主要结局指标是归因于非洛地平的不良事件数量。探索性结局包括运动和认知功能、非运动症状和生活质量量表的额外测量，以及通过脑 MRI 评估的外周和中枢疾病生物标志物。通过相关样本研究 FELL HD-s 还将对血液和脑脊液进行分析。
该研究获得了伦敦布伦特研究伦理委员会（参考号 22/LO/0387）的批准，并已被药品和医疗产品监管局接受用于临床试验授权（参考号 CTA 12854/0256/001-0001）。试验结果的通俗摘要将上传到我们的研究小组网站，该网站对公众开放。一旦试验完成，将举行网络研讨会或现场开放日，向参与者和我们中心的更广泛的患者群体介绍试验结果。试验结果还将发表在科学期刊上，并在国内外会议上发表。
EudraCT-2021-000897-27，ISRCTN56240656。
