| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Attentional deficits and impulsive behaviour. These symptoms are common in attention deficit hyperactivity disorder, but also other conditions affecting the central nervous system such as Alzheimer's disease, schizophrenia, or depression and anxiety. |
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| E.1.1.1 | Medical condition in easily understood language |
| Attention Deficit Hyperactivity Disorder and other conditions affecting attention and impulsivity |
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| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Behaviours [F01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10022891 |
| E.1.2 | Term | Investigations |
| E.1.2 | System Organ Class | 10022891 - Investigations |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The aim of this study is to investigate in young, healthy participants whether and to what degree single doses of methylphenidate, atomoxetine, amphetamine, and modafinil:
a) enhance the TVA visual speed (C) and Visual Short Term Memory (VSTM) storage capacity (K) parameters,
b) produce a reduction on commission and omission errors, and improvements in d’, reaction times and correct responses on the Conners CPT, and
c) whether objectively measured changes in visual perceptual speed are associated with changes in subjective alertness and pleasantness of the task.
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| E.2.2 | Secondary objectives of the trial |
We want to correlate the results on our primary endpoints with a number of tests providing different measures of different aspects of arousal. The visual analogue scale (VAS) test will estimate the subjective rating of arousal of the participants, whereas the pupillometry, heart rate variability, and the motor activity will provide physiological and behavioral aspects of changes in arousal.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Healthy young male and female adults (age 20-35) will be recruited from the Copenhagen area and will potentially be included after medical screening. Subjects must understand spoken and written English.
A summary of the eligibility criteria is provided below in form of a list:
- 20-35 years old
- No history of psychiatric illness (e.g. schizophrenia, depression)
- No neurological illness (e.g. autism spectrum disorder, dyslexia)
- No cardiovascular illness (e.g. high blood pressure, stroke)
- No history of drug addiction
- No recreational use of psychostimulants in the last 3 months
- No major vision or motor impairments
- No pregnancy or breastfeeding, and following approved contraception methods
- No lactose intolerance or allergies to excipients/active ingredients
- Body Mass Index between 18-30
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| E.4 | Principal exclusion criteria |
| Participants will have no history of psychiatric, neurological or cardiovascular illness, no history of drug addiction, and will have no major vision or motor impairments. No pregnant or breastfeeding woman will be included. In addition, subjects who are lactose intolerant or show any allergies to the excipients/active ingredients used in the administered drugs will be excluded from the study. Participants will have had no recreational use of psychostimulants in the last 3 months. Subject with a body mass index smaller than 18 or larger than 30 will be excluded for pharmacological safety and efficacy concerns. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoints
TVA test:
• Visual processing speed (C)
• Efficacy of Selection (α)
Conners CPT:
• Reaction time (RT)
• Efficacy of Selection (d')
Our focus will be on the parameters that tap into the processing speed of VSTM, since recent research has shown how this parameter seems to be affected by DAT- and NET-inhibitor intervention (Finke et al 2010). We will utilize both a reaction time paradigm (Conners CPT) and an accuracy-based paradigm (TVA). Reaction time paradigms are traditionally by far the most used. Introducing it to this project enables us to ensure the comparability of our study with the present body of work, as well as it ensures translatability of our accuracy-based results with the reaction time measures. Moreover, it ties our data to that of a mouse-population in a previously conducted project of a similar design (Caballero-Puntiverio et al. 2018).
The parameter denoting the speed of VSTM processing in the TVA, (C), describes the speed of visual processing, measured in letters processed per second. In the Conners CPT, this is reflected in the reaction time measure (RT).
In order to ensure whether e.g. an improvement in speed is exclusive to that one parameter, or whether it may stem from a more liberal decision criteria, and hence a speed/accuracy trade off, we are also interested in investigating the quality of their decision making. Hence, we want to evaluate the efficacy of their selection, reflected in the (α) parameter for the TVA, and the (d') parameter for the Conners CPT. This could reveal potential changes in the impulsivity and the response profile of the participants.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After all six visits have been completed |
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| E.5.2 | Secondary end point(s) |
Secondary Endpoints
TVA test:
• Visual short term memory capacity (K)
• Threshold for Visual Processing (t0)
Others:
• Plasma Concentration of the drug
• VAS – subjective alertness rating
• Heart Rate Variability
• Pupillometry
• Motor Activity
The secondary endpoints are measures which we want to correlate with the primary, in order to get a more nuanced picture of the changes in performance.
Any potential changes in the speed of visual processing (C and RT) could potentially stem from an increase in the initial perceptual processes, rather than the speed of the visual short term memory. Hence, we want to correlate potential improvements in these measures with the estimations of the threshold for visual processing (t0), which is defined as the longest ineffective exposure duration in ms, below which the participant neither has perceived nor can report any letters.
Since previous research has indicated that modafinil has the potential to increase the VSTM storage capacity (K), we also want to examine potential differences in performance in this project.
We have also included the measure of plasma concentration of the drug. The purpose for this is two-fold. Firstly, we want to be able to validate that the drug has been ingested and absorbed, and secondly, we want to evaluate the significance of drug concentration, since recent research has suggested that the degree of improvement in attentional performance is correlated with the plasma concentration of the drug.
Any change in performance in the tests measuring attention may stem from an increase in arousal. Hence, we want to correlate the results on our primary endpoints with a number of tests providing different measures of different aspects of arousal. The visual analogue scale (VAS) test will estimate the subjective rating of arousal of the participants, whereas the pupillometry, heart rate variability, and the motor activity will provide physiological and behavioral aspects of changes in arousal.
Refer to section 3.2 to obtain more details about the assessment tools.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After all six visits have been completed |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
The effect of ADHD medication in healthy human volunteers performing the Conners CPT and the Combi-TVA will be assessed to learn more about the processes and networks involved in attentional function and impulsivity. Moreover, effects of ADHD medication in inattention and impulsivity measures observed in mice will be now assessed in healthy human volunteers and translatability of the rodent assays discussed.
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| within subject, counter-balanced, Latin Square design (each subject is their own control) |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of the trial is defined as 96 hours after the last subject undergoing the trial has attended the last scheduled visit. 96 hours are provided from the last visit to record any adverse reactions related to treatment. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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