Research into the suitability of the NeuroKit test method in measuring drug effects

Central nervous system (CNS) function in humans can be assessed in groups of neurophysiological, neuroendocrine and neuropsychological effects. Drugs acting on the CNS will usually influence more than one of these groups and affect several different functional domains within each group. This offers numerous possibilities to measure drug-induced changes in CNS-activity. In general, several different complementary tests are applied in early CNS-drug research, with the aim of covering all relevant CNS-functional domains that can be responsive to drug effects such as sedation, stimulation or consciousness. 

CHDR has developed a CNS test battery called NeuroCart, consisting of validated neurophysiological and neuropsychological assessments to quantify PD drug effects. The most sensitive assessments include (among others) saccadic eye movement as a measure of arousal, adaptive tracking of visuomotor coordination and sustained attention, finger tapping of visuomotor coordination, smooth pursuit eye movements and body sway of motor coordination, visual analogue scales (VAS) for subjective drug effects, and N-Back for working memory. Additionally, several other tests can be included depending on the research question and study treatment.

In previous CHDR studies, NeuroCart has been shown to be sensitive to the acute effects of the sedative lorazepam, the stimulant modafinil, and the dissociative S-ketamine, with significant dose and concentration dependent effects on multiple NeuroCart endpoints. As such, NeuroCart represents a useful non-invasive tool to characterize the acute PD profile of several CNS active compounds with distinct mechanisms of action and to relate these to its respective PK profile. One limitation of the NeuroCart, however, is that the current set-up is confined to study execution at CHDR and specific study rooms. 

NeuroKit has been developed by CHDR as a portable and scalable version of NeuroCart. It comprises a subset of eight NeuroCart tests, namely saccadic eye movements, smooth pursuit eye movements, adaptive tracking, body sway, N-Back, finger tapping, VAS Bond & Lader, and VAS Bowdle. To facilitate portability, NeuroKit’s hardware setup has been adapted, with virtual reality goggles and a touchscreen tablet respectively replacing NeuroCart’s computer screen and keyboard, and an accelerometer replacing the potentiometer in the implementation of body sway. Evaluation of the technical performance of individual NeuroKit measurements compared to NeuroCart has been concluded by CHDR, and preliminary analysis showed positive results that warrant the next step in the validation process. However, it remains uncertain whether and to what extent the implemented modifications could affect NeuroKit’s performance compared to NeuroCart.

Primary Objectives:

• Quantify the PD effects of CNS active compounds with distinct mechanisms of action (lorazepam, modafinil and S-ketamine) with NeuroKit and NeuroCart in healthy male and female participants.

   

• Estimate the ratio of PD effects of NeuroKit and NeuroCart for CNS active compounds with distinct mechanisms of action (lorazepam, modafinil and S-ketamine) in healthy male and female participants.

   

Secondary Objectives:

• Quantify the pharmacokinetic profiles of lorazepam, modafinil and S-ketamine during PD measurements on NeuroKit and NeuroCart in healthy male and female participants. 

   

• Evaluate the feasibility of Virtual Reality (VR) to perform NeuroKit saccadic eye movements, smooth pursuit eye movements and adaptive tracking assessment under influence of a compound with dissociative effects (S-ketamine) in healthy male and female participants. 

This is a single centre, randomized, double blind, double-dummy, placebo-controlled, four-way crossover pharmacological validation study to investigate the ability of the newly developed CNS test battery NeuroKit to reliably quantify the pharmacodynamic effects (PD) of CNS-penetrant drugs by comparing PD effects of drugs with distinctly different mechanisms of actions to NeuroCart in healthy male and female volunteers.

The study consists of a medical screening period (from 42 days prior to visit 1) to ensure subjects meet eligibility criteria, including a training on NeuroCart and NeuroKit in a period up to 21 days before first drug administration, followed by four occasions of three days in-clinic each, separated by a wash-out period of 7 to 10 days. A final follow-up visit takes place 7-10 days after last dose, resulting in a total study duration of 82 – 94 days for each subject. This study design will allow for adequate PD assessments of both CNS test batteries.

Three study drugs or placebo will be administered to the subjects. S-ketamine 0.475 mg/kg for 75 min + 0.275 mg/kg for 75 min IV, modafinil 200 mg PO, and lorazepam 2 mg PO will be prepared with matching placebo formulations, including capsules and a NaCl 0.9% solution. For modafinil, two 100 mg tablets will be encapsulated for blinding, resulting in two administered capsules for the total dose of 200 mg. For lorazepam, two 1 mg tablets will be encapsulated for blinding, resulting in two administered capsules for the total dose of 2 mg. Administration will occur in a double-dummy fashion, thus, subjects will each time receive four capsules PO and one IV administration. IV S-ketamine or placebo will be administered for 150 minutes at two different infusion rates. Subjects will rinse and swallow all orally administered capsules with a total of 240 mL of water.

Matching placebo will consist of a saline solution or encapsulated placebo capsule. S-ketamine dosing will be individually prepared based on the subject weight at screening. Prior to each dosing the subject will be weighed again. If the change in weight is 15% or more relative to the weight at screening, the dose must be adjusted to the new weight.

Lorazepam, modafinil and S-ketamine are registered drugs with well-characterized pharmacological and safety profiles in humans. Nonetheless since side effects might occur, the study drug administrations will be performed under medical supervision during admission to CHDR’s clinic research unit. Subjects will be closely monitored and will only be discharged from the unit if their medical condition allows this. Furthermore, single doses of lorazepam 2 mg, modafinil 200 mg and S-ketamine reaching plasma exposures similar to those targeted in the current study (~ 150 ng/mL) administered in previous CHDR studies, were safe as no serious adverse effects occurred, and those that did occur, were anticipated based on the respective drugs’ pharmacological profiles. NeuroCart is a validated CNS-battery that quantifies various pharmacodynamic drug effects including CNS suppression (sedation), stimulation and changes in consciousness and perception. Previously, Neurocart has previously been shown to be sensitive to single doses of lorazepam 2 mg, modafinil 200 mg and S-ketamine reaching plasma exposures similar to those targeted in the current study (~ 150 ng/mL). The key objective of this study is to validate the ability of NeuroKit, as a portable and scalable version of NeuroCart, to reliably quantify the PD effects of CNS-penetrant drugs by comparing the effects of drugs with distinctly different mechanisms of action on NeuroKit to NeuroCart in healthy male and female volunteers. Together therefore, the potential risks to participants are considered minimal and weigh up to the scientific objectives of the study.