Cognitive and Neural Effects of ARA290 (CONEARA)

The Effects of ARA290 on the Cognitive and Neural Processing of Emotions in Healthy Volunteers

Studies on the hormone Erythropoietin (EPO) have indicated that EPO may have antidepressant properties. However, EPO may cause serious side-effects with repeated administration (thrombosis), which limits its usefulness as an antidepressant. ARA290 is a peptide that does not have the effects of EPO on blood cells but may still have its effect on brain function. In an attempt to replicate previous findings with (a single dose of) EPO in healthy volunteers, we study the effects of ARA290 on the cognitive and neural processing of emotions in healthy volunteers. We hypothesize that a single dose of ARA290 will lead to a positive shift in information processing compared to placebo, 7 days post-administration.

Study Overview

• Status: Completed
• Conditions: Depression
• Intervention / Treatment: Drug: Placebo; Drug: ARA290

Detailed Description

SUMMARY Rationale: Studies on the cognitive and neuronal effects of a single administration of Erythropoietin (EPO) in healthy volunteers and in depressed patients have suggested that EPO may have antidepressant effects. Due to its haematopoietic effects, EPO may cause serious side-effects with repeated administration, which limits its usefulness as an antidepressant. ARA290 is a peptide that does not have the haematopoietic effects of EPO but may still have its neurotrophic effects.

Objective: To study the effects of ARA290 on the cognitive and neural processing of emotions in healthy volunteers 7 days post-administration.

Study design: Randomized double-blind placebo-controlled experiment. Study population: Male and female healthy volunteers, n= 36; 18-35 yr old. Intervention: One group receives a single dose of 2 mg ARA290, the other group receives placebo.

Main study parameters/endpoints:

1. Behavioral study: Performance on an Emotional Test battery (ETB) which has been shown sensitive to antidepressant administration in healthy volunteers. The ETB includes a measure of facial expression recognition, emotional memory and attentional vigilance.
2. Neuroimaging study: Neural processing of emotions, in particular amygdala, hippocampal and VMPFC response to viewing facial stimuli expressing negative versus positive emotions.

Nature and extent of the burden and risks and benefits associated with participation:

Risks: No adverse events have been associated with the administration of a single dose of 70 -2000 μg ARA290 among 36 individuals, with the exception of one individual (with an undisclosed significant prior history of fainting) who fainted shortly after the intravenous dose administration of 700 μg ARA290 and recovered without medical intervention. Fourteen individuals have participated in a multiple dosing study with no serious adverse effects. Single doses of ARA290 in patients with renal impairment did not raise a safety signal.

Burden: Minimal. Emotional information processing test battery, burden comparable with playing computer games. fMRI measurement.

Benefits: Probably none. Possibly transient and small improvement of mood state. Financial compensation for participating.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Leiden, Netherlands
    • Leiden University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Dutch-speaking
• Age 18-35
• Right-handedness
• BMI 18 to 33 kg/m2

Exclusion Criteria:

• Major physical illness, such as diabetes, thyroid disease, epilepsy, stroke, multiple sclerosis, pituitary disease, or any other serious medical condition.
• Any current or past psychiatric disorder, including subclinical claustrophobia if severe enough to cause anxiety during scanning.
• Using medication likely to interfere with the study, including OTC (over the counter) medication (e.g., St John's Wort) and benzodiazepines.
• Pregnancy or breastfeeding
• Use of any nicotine products or soft drugs (hash, marihuana) in the three months prior to the study
• Any hard drug use (including XTC) (lifetime)
• Alcohol use of more than 14 units per week or more than 4 units on any day during the week prior to the study or during the study period.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: ARA290; 11-amino acid, linear peptide ARA290; intravenous injection with 2 mg ARA290 (single dosage).	Drug: ARA290
PLACEBO_COMPARATOR: Placebo; saline (NaCl 0.9%)	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
performance on information processing test battery, particularly emotion recognition	Performance on an Emotional Test battery (ETB) which has been shown sensitive to antidepressant administration in healthy volunteers. The ETB includes a measure of facial expression recognition, emotional memory and attentional vigilance.	1 week

Secondary Outcome Measures

Outcome Measure	Time Frame
• Performance on a task of working memory	1 week

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neural response to angry faces	Neural processing of emotions, in particular amygdala, hippocampal and ventromedial prefrontal cortex (VMPFC) response to viewing facial stimuli expressing a negative or positive emotion.	1 week

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Investigators: Principal Investigator: Willem Van der Does, PhD, Leiden University

Publications and helpful links

General Publications

• Brines M, Cerami A. Erythropoietin-mediated tissue protection: reducing collateral damage from the primary injury response. J Intern Med. 2008 Nov;264(5):405-32. doi: 10.1111/j.1365-2796.2008.02024.x.
• Miskowiak KW, Vinberg M, Harmer CJ, Ehrenreich H, Kessing LV. Erythropoietin: a candidate treatment for mood symptoms and memory dysfunction in depression. Psychopharmacology (Berl). 2012 Feb;219(3):687-98. doi: 10.1007/s00213-011-2511-1. Epub 2011 Sep 23.
• Cerit H, Veer IM, Dahan A, Niesters M, Harmer CJ, Miskowiak KW, Rombouts SA, Van der Does W. Testing the antidepressant properties of the peptide ARA290 in a human neuropsychological model of drug action. Eur Neuropsychopharmacol. 2015 Dec;25(12):2289-99. doi: 10.1016/j.euroneuro.2015.09.005. Epub 2015 Sep 18.

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (ACTUAL): February 1, 2013
• Study Completion (ACTUAL): February 1, 2014

Study Registration Dates

• First Submitted: February 23, 2014
• First Submitted That Met QC Criteria: February 23, 2014
• First Posted (ESTIMATE): February 25, 2014

Study Record Updates

• Last Update Posted (ESTIMATE): February 25, 2014
• Last Update Submitted That Met QC Criteria: February 23, 2014
• Last Verified: February 1, 2014

More Information

Terms related to this study

• Keywords: depression; cognition; information processing; emotion perception
• Additional Relevant MeSH Terms: Behavioral Symptoms; Depression
• Other Study ID Numbers: 2010-024364-18