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.
Keywords: Fixed-dose combination products, combinatorial approaches, chronic spinal cord injury, phase I/IIa, phase IIb, pivotal phase III,
comorbid problems, symptomatic treatments, central pattern generator, CPG, SpinalonTM, treadmill training, transcutaneous spinal cord
stimulation, body weight supported treadmill training, exoskeleton, dermoskeleton, KeeogoTM, bioengineering, biomedical, devices
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