Evaluation of Atomoxetine on Noradrenergic System's Role in Learning Dynamics in Healthy Subjects

The primary objective of this study is to **characterize** the role of the **noradrenergic system** in the regulation of learning dynamics in healthy subjects. This is achieved by comparing the behavior of subjects during learning tasks, their pupil diameter, and their electroencephalographic (EEG) responses after administration of a single dose of **atomoxetine** (40 mg) and placebo. Understanding the noradrenergic system's influence on learning dynamics is clinically relevant as it may provide insights into cognitive processes and potential therapeutic targets for cognitive impairments.

Secondary objectives include:

• Determining the cerebral and pupillary correlates of latent computational variables during the task.
• Checking the effect of atomoxetine on participants' emotional state, specifically depression and anxiety.
• Assessing the tolerance of the investigational medicinal products (IMPs).
• Exploring the genetic basis of individual differences in learning rate.

The clinical trial involves **healthy subjects** aged 18 to 39 years, with no neurological or psychiatric disorders. Both male and female participants are included, and the study does not involve any vulnerable populations. The total number of participants is not provided by the sponsor. Participants were selected based on specific criteria, including being right-handed as assessed by the Edinburgh scale, providing written signed informed consent, and being covered by the social security system. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as a **Phase IV**, single-center, double-blind, randomized, placebo-controlled, cross-over study. The primary objective is to evaluate the role of the noradrenergic system in the regulation of learning dynamics in healthy subjects. Participants will be administered a single dose of **atomoxetine** (40 mg) or a placebo, with the primary endpoint being the paired difference in computational model parameters characterizing the learning process under both conditions. The trial is expected to commence recruitment on May 19, 2025, and conclude by July 9, 2027.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility criteria are assessed. Key inclusion criteria include being aged 18 to 39 years, right-handed as per the Edinburgh scale, and providing written informed consent. The study excludes individuals with neurological or psychiatric disorders. Following the inclusion visit, participants will attend two main study visits (V1 and V2), during which neuropsychological tests will be conducted, and **EEG** and **ECG** recordings will be taken. Pupil diameter will be measured using an eye-tracking device, and salivary cortisol levels will be assessed as an indirect marker of noradrenaline function. Psychometric scales will be administered to evaluate anxiety and depression levels.

The expected duration of participant involvement is approximately one day, as the study involves a single-dose administration. However, participants may be withdrawn from the study if they experience significant adverse effects or if they do not comply with study procedures. The end-of-study visit will involve a final assessment of side effects, vital signs, and ECG findings. The study aims to provide insights into the noradrenergic system's role in learning dynamics, with secondary endpoints including correlations between physiological measures and learning process variables.

The clinical trial involves the administration of **Atomoxetine**, marketed as Atomoxetin STADA 40 mg Hartkapseln, as the experimental medication. Atomoxetine is a selective **noradrenaline reuptake inhibitor** and is provided in the form of a hard capsule. Each capsule contains 40 mg of the active substance, atomoxetine, and is intended for **oral use**. The maximum daily dose and total dose for the treatment period is 40 mg, administered as a single dose. The treatment period is limited to one day. Atomoxetine is chemically synthesized and is not a paediatric formulation. The trial aims to evaluate the effects of atomoxetine on learning dynamics in healthy subjects by assessing behavioral changes, pupil diameter, and electroencephalographic responses.

The study also includes a non-experimental treatment in the form of a placebo, which consists of empty hard gelatin capsules. These capsules are identical in appearance to the atomoxetine capsules but contain no active pharmaceutical ingredient. The placebo is also administered orally and serves as a comparator to assess the effects of atomoxetine. The placebo capsules are chemically derived from gelatin and are used to ensure blinding in the study. The administration of the placebo follows the same dosing schedule as the experimental medication, with a single dose given during the one-day treatment period.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints designed to evaluate the impact of a single dose of **atomoxetine** compared to a placebo. The primary endpoint involves the paired difference in the parameters of computational models that characterize the learning process during stable and dynamic accumulation tasks. This comparison will be made between the selective noradrenaline reuptake inhibitor (sNRI) condition and the control condition.

Secondary endpoints include several measures: continued electroencephalographic (EEG) recording during neuropsychological tests at two visits (V1 and V2) and its correlation with latent variables of the learning process; paired differences in pupil diameter recorded using an eye-tracking device; paired differences in electrocardiogram (ECG) readings; and paired differences in salivary cortisol concentration as an indirect marker of noradrenaline function. Additionally, psychometric scales will be used at the end of neuropsychological tests at V1 and V2, including the State Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI), and Visual Analog Scales (VAS) for anxiety, sadness, and fatigue intensity. Side effects, including vital signs worsening and ECG findings, will be monitored between study drug administration and V2. Genotyping for three single nucleotide polymorphisms (SNPs) in genes affecting noradrenergic function will also be conducted.