Effects of PF-06412562 on Value-based Decision-making in Healthy Individuals

Study Overview
=================
Brief Summary
-----------------
Numerous psychiatric and neurodegenerative diseases like schizophrenia, dependency on drugs of abuse, depression and Parkinson's disease are related to motivational and cognitive deficits in value-based decision making, which frequently persist even after a successful pharmacological treatment. According to current neurobiologic models, cortical dopamine D1 receptors play a crucial role in taking value-based decisions. In this study, it will be investigated whether value-based decisions in healthy volunteers can be improved by stimulation of D1-receptors. For this purpose, a newly developed dopamine D1-agonist will be used, which selectively increases the activities of frontal D1- and D5-receptors. In this double-blind, randomized, placebo-controlled study, the effects of different single doses of PF-06412562, a not yet licensed D1-agonist, on value-based decision making will be compared with placebo. The use of different dosage strengths will allow to investigate a potential relationship between the extent of activity of the D1-receptor and its influence on behavioral indices. Therefore, four parallel groups will be investigated. Each participant takes in a single dose of either PF-06412562 in different doses or placebo. A screening exam will be carried out 1-3 weeks before the drug intake, and a follow-up examination will be carried out approx. 1 week after the drug intake. At all 3 visits in the study centre, several tests for the investigation of value-based decision making will be carried out.

Official Title
-----------------
Effects of PF-06412562 on Value-based Decision-making in Healthy Individuals: a Mono-center, Randomized, Placebo Controlled, Double-blind Study (Phase I)

Conditions
-----------------
Decision Making

Intervention / Treatment
-----------------
* Drug: PF-06412562
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Informed Consent as documented by signature on the informed consent form Physically and psychiatrically healthy men and women Male and female subjects of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 28 days for females and 90 days for males after the last dose of assigned treatment. A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children. Female subjects of non childbearing potential must meet at least one of the following criteria: Have undergone a documented hysterectomy and/or bilateral oophorectomy; Have medically confirmed ovarian failure or; Achieved post menopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and have a serum follicle stimulating hormone (FSH) level confirming the post menopausal state. All other female subjects (including females with tubal ligations and females that do NOT have a documented hysterectomy, bilateral oophorectomy and/or ovarian failure) will be considered to be of childbearing potential. Aged 18-35 years Negative pregnancy test (see exclusion criteria) Normal or corrected-to-normal vision Exclusion Criteria (selected): Pregnant female subjects; breastfeeding female subjects considered to be healthy based on an extensive pre-study screening including anamnesis, physical examination, laboratory investigations, vital signs, ECG, etc.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active dose 1<br>Single dose of PF-06412562 in low dosage strength | Drug: PF-06412562<br>* double-blind oral intake of single doses of the aforementioned drug or placebo<br>|
| Experimental: Active dose 2<br>Single dose of PF-06412562 in medium dosage strength | Drug: PF-06412562<br>* double-blind oral intake of single doses of the aforementioned drug or placebo<br>|
| Experimental: Active dose 3<br>Single dose of PF-06412562 in higher dosage strength | Drug: PF-06412562<br>* double-blind oral intake of single doses of the aforementioned drug or placebo<br>|
| Placebo Comparator: Placebo<br>Single dose of placebo | Drug: Placebo<br>* double-blind oral intake of single doses of the aforementioned drug or placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in a delay discounting task. | This validated computer-based decision-making test will be filled in by each participant at three time points during the study: 1-3 weeks before, 5 hours after, and approx. 1 week after a single oral intake of 1 out of 3 possible doses of PF-06412562, or matching placebo. | 1-3 weeks before (= baseline), 5 hours after, and approx. 1 week after drug intake. | 
| Change from baseline in a risk discounting task. | This validated computer-based decision-making test will be filled in by each participant at three time points during the study: 1-3 weeks before, 5 hours after, and approx. 1 week after a single oral intake of 1 out of 3 possible doses of PF-06412562, or matching placebo. It will be carried out after the test for outcome 1. | 1-3 weeks before (= baseline), 5 hours after, and approx. 1 week after drug intake. | 
| Effect of PF-06412562 on an effort discounting task (compared to placebo). | This validated computer-based decision-making test will be completed by each participant 5 hours after a single oral intake of 1 out of 3 possible doses of PF-06412562, or matching placebo and after having completed the tests for outcome 1 and 2. | 5 hours after drug intake. | 
| Effect of PF-06412562 on the Pavlovian to instrumental transfer task (compared to placebo). | This validated computer-based decision-making task tests Pavlovian acquisition and transfer. It will be carried out by each participant immediately after the test in outcome 3. | 5 hours after drug intake. | 
| Effect of PF-06412562 on an exploration / exploitation task (compared to placebo). | This validated computer-based decision-making task tests different aspects of value-based decision making. It will be carried out by each participant immediately after the test in outcome 4. | 5 hours after drug intake. | 
| Effect of PF-06412562 on a probabilistic reversal learning task (compared to placebo). | This validated computer-based decision-making task tests different aspects of value-based decision making. It will be carried out by each participant immediately after the test in outcome 5. | 5 hours after drug intake. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events (safety and tolerability of PF-06412562) | continuous assessment of adverse events by non-leading questions, repeated safety laboratory tests, repeated ECGs, repeated control of vital parameters. | throughout the study and up to 1 week after study drug intake. |