这项审查的目的是描述承诺的理由和主要根本原因,在临床发展过程中,单独使用和/或与其他技术结合使用的候选药物的研究。为了轻松理解,将参考SpinalonTM的情况,由左旋多巴/卡比多巴/丁螺环酮组成的新型固定剂量组合(FDC)产品。这种药物能够触发,在单次口服给药后几分钟内,截瘫动物的基本非自愿“反射”行走45分钟。一个月内的每日给药被证明会随着时间的推移而导致表现增加,对肌肉骨骼和心血管系统有健康益处。双盲,剂量递增,对45名脊髓损伤受试者进行的随机I/IIa期研究成功提供了最大耐受剂量(MTD)和疗效的初步证据.为了探索如何优化疗效,我们设计了一项包含150名受试者的IIb期研究,以比较不同条件下重复给药的效果(组).用电动跑步机测试,用于体重支撑的安全带,提出了经皮脊髓刺激器和/或外骨骼,因为:1)这些设备不太可能改变安全性,但2)合理预期它们会增加脊髓运动神经元的激活,反射式步行感应,和肌肉骨骼/心血管的好处。这种方法通常会让第三阶段的研究清楚地证明,以更少的科目和更低的成本,在优化的条件和设置中使用SpinalonTM对健康的长期益处。这种药物开发的创新策略可能有助于进一步描述作用机制以及患者的最佳使用条件。适应其他产品的发展,这种方法可以提高安全性,功效,下一代CNS药物的临床实用性和依从性。
The aim of this review is to describe the rationale and main underlying reasons for undertaking, during clinical development, the study of drug candidates used separately and/or in combination with other technologies. To ease comprehension, reference will be made to the
case of SpinalonTM, a new fixed-dose combination (FDC) product composed of levodopa/carbidopa/buspirone. This drug is capable of triggering, within minutes after a single administration orally, 45 minute- episodes of basic involuntary \'reflex\' walking in paraplegic animals. Daily administration during one month was shown to lead to increased performance over time, with health benefits onto musculoskeletal and cardiovascular systems. A double-blind, dose-escalation, randomized phase I/IIa study with 45 spinal cord-injured subjects successfully provided the maximal tolerated dose (MTD) and preliminary evidence of efficacy. As an attempt to explore how efficacy may be optimized, a phase IIb study with 150 subjects was designed to compare the effects of repeated administration in different conditions (arms). Tests with a motorized treadmill, a harness for body weight support, a transdermal spinal cord stimulator and/or an exoskeleton were proposed because: 1) these devices are unlikely to alter safety but, 2) they are reasonably expected to increase spinal locomotor neuron activation, reflex walking induction, and musculoskeletal/cardiovascular benefits. This approach would normally allow the phase III study to demonstrate clearly, with fewer subjects and at lower costs, long-term benefits on health of SpinalonTM used in optimized conditions and settings. This innovative strategy in drug development may contribute to further describe the mechanisms of action as well as optimized conditions of use for patients. Adapted to the development of other products, such an approach may enable greater safety, efficacy, clinical utility and compliance to be sought for next-generation CNS drugs.