PF-04995274 and Emotional Processing in Treatment Resistant Depression (RESTART)

Study Description

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Brief Summary:

This study will test whether seven days adjunctive administration of a serotonin receptor subtype 4 (5HT4) agonist called PF-04995274 has positive effects on emotional processing and neural activity in medicated, treatment-resistant depressed patients compared to placebo.

Condition or disease	Intervention/treatment	Phase
Depression, Unipolar; Treatment Resistant Depression	Drug: PF-04995274; Drug: Placebo Oral Tablet	Phase 1

Detailed Description:

This study uses a double-blind, placebo-controlled, randomised between-groups design to test if adjunctive administration of a serotonin receptor subtype 4 (5HT4) agonist called PF-04995274 has positive effects on emotional processing and neural activity in medicated treatment-resistant depressed patients. Participants are patients who fulfill criteria for current episode of Major Depressive Disorder (MDD) and have shown lack of response to antidepressant treatment, and they will be randomised to receive 7 days treatment with either PF-04995274 (15 mg daily) or a matched placebo. Participants will come for a Screening Visit, a First Dose Visit, and a Research Visit (including measures of emotional processing and non-emotion cognition).

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	50 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Intervention Model Description:	Participants will be randomly allocated to one of two groups (PF-04995264 or placebo) and receive their allocated study medication for 7 days.
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Basic Science
Official Title:	The Effects of PF-04995274 on Emotional Processing in Treatment-resistant, Medicated, Depressed Patients
Actual Study Start Date :	May 31, 2018
Estimated Primary Completion Date :	April 30, 2020
Estimated Study Completion Date :	April 30, 2020

Arms and Interventions

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Arm	Intervention/treatment
Experimental: PF-04995274; PF-04995274, three x 5mg tablet (15mg total), once daily for 7-9 days	Drug: PF-04995274; PF-04995274 tablets
Placebo Comparator: Placebo; 3 placebo tablets, once daily for 7-9 days	Drug: Placebo Oral Tablet; Placebo tablet, identical appearance to experimental tablet

Outcome Measures

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Primary Outcome Measures :

1. Facial Expression Recognition Task (FERT) [ Time Frame: Completed on Day 7 ]
   Facial expressions of basic emotions (happiness, fear, anger, disgust, sadness, surprise) are displayed on the screen and participants are asked to correctly classify them. Each emotion is presented at different intensity levels. Responses are made via a button-press and accuracy and reaction time are recorded.

Secondary Outcome Measures :

1. Emotional Memory Task [ Time Frame: Completed on Day 7 ]
   Recall and recognition of affective words displayed earlier in the testing session is tested
2. Auditory Verbal Learning Task (AVLT) [ Time Frame: Completed on Day 7 ]
   Accuracy of recall on the auditory verbal learning task
3. Probabilistic Instrumental Learning Task (PILT) [ Time Frame: Completed on Day 7 ]
   Participants have to learn which shapes are associated with wins and losses and sensitivity to reward is assessed.

Eligibility Criteria

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Ages Eligible for Study:	16 Years to 65 Years (Child, Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Male or female;
• Aged 18-65 years;
• Willing and able to give informed consent for participation in the study;
• Sufficiently fluent English to understand and complete the tasks;
• Registered with a GP and consents to GP being informed of participation in study;
• Participants need to meet a number of concurrent clinical criteria:
• Current criteria for Major Depressive Disorder [as determined by the Structured Clinical interview for DSM-V (SCID)];
• Failure within the current depressive episode to respond clinically to at least one course of antidepressant therapy, each given at a therapeutic dose for at least four weeks [as determined by use of the MGH Antidepressant Treatment Response Questionnaire (ATRQ)];
• Currently taking an antidepressant, which must be either a Selective Serotonin Reuptake Inhibitor (SSRI) - with the exception of fluoxetine, paroxetine or fluvoxamine - or a Serotonin-norepinephrine reuptake inhibitor (SNRI) ; Participants currently taking excluded medications can be switched to sertraline or citalopram;
• Participants engaging in sex with a risk of pregnancy must agree to use a highly effective method of contraception from Screening Visit until 30 days after receiving study medication treatment, and male participants must not donate sperm.

Exclusion Criteria:

• History of or current DSM-V bipolar disorder, schizophrenia or eating disorders. Participants who fulfil current criteria for other comorbid disorders may still be entered into the study, if, in the opinion of the Investigator, the psychiatric diagnosis will not compromise safety or affect data quality;
• First-degree relative with a diagnosis of Bipolar Disorder type 1;
• Participants currently taking strong cytochrome P450 (CYPs) enzymes inhibitors, such as fluoxetine, paroxetine or fluvoxamine (in order to avoid drug-drug interactions);
• Participants currently taking psychotropic medications which in the opinion of the investigator may interfere with the safety of the participant or the scientific integrity of the study;
• Participants who have previously failed a combination/augmentation therapy (i.e., therapy with the combination of two or more pharmacological agents) for the treatment of depression, which in the opinion of the Investigator may reduce the likelihood of responding;
• Electroconvulsive therapy for the treatment of the current episode of depression;
• Participants undergoing any form of face-to-face structured psychological treatment during the study;
• Clinically significant abnormal values for liver function tests, clinical chemistry, urine drug screen, blood pressure measurement and ECG. A participant with a clinical abnormality or parameters outside the reference range for the population being studied may be included only if the Investigator considers that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures;
• History of stimulant abuse (lifetime; e.g. amphetamine, cocaine), or of alcohol abuse within one year or of alcohol dependence within the lifetime;
• History of, or current medical conditions which in the opinion of the investigator may interfere with the safety of the participant or the scientific integrity of the study, including epilepsy/seizures, brain injury, severe hepatic or renal disease, severe gastro-intestinal problems, Central Nervous System (CNS) tumors, severe neurological problems (like Parkinson's Disease; blackouts requiring hospitalisation);
• Clinically significant risk of suicide;
• Current pregnancy (as determined by urine pregnancy test taken during Screening and First Dose Visits), breastfeeding or planning a pregnancy during the course of the study;
• Participant not willing to use a suitable method of contraception for 30 days after receiving study medication treatment;
• Participants with Body Mass Index (BMI - kg/m2) outside the 18 - 36 range at the Screening Visit;
• Night-shift working or recent travel involving significant change of timezones;
• Excessive caffeine consumption, i.e., consumption higher than 8 cups of standard caffeinated drinks (tea, instant coffee) or higher than 6 cups of stronger coffee or other drinks containing methylxanthines such as coca cola or Red Bull per day;
• Participation in a psychological or medical study involving the use of medication within the last 3 months;
• Previous participation in a study using the same, or similar, emotional processing tasks;
• Smoker > 10 cigarettes per day or similar levels of tobacco consumption in other forms.
• Participant received prescribed medication within 28 days prior to First Dose Visit (apart from their prescribed antidepressant and the contraceptive pill). Participants who have taken prescription medication may still be entered into the study, if, in the opinion of the Investigator, the medication received will not interfere with the study procedures or compromise safety;
• Participant received non-prescription medication, including supplements such as vitamins and herbal supplements within 48 hours prior to First Dose Visit (apart from paracetamol). Participants who have taken non-prescription medication may still be entered into the study, if, in the opinion of the Investigator, the medication received will not interfere with the study procedures or compromise safety;
• Participant with a known hypersensitivity to PF-04995274 or any other serotonergic agents;
• Participant with planned medical treatment within the study period that might interfere with the study procedures;
• Participant who is unlikely to comply with the clinical study protocol or is unsuitable for any other reason, in the opinion of the Investigator.

Contacts and Locations

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Contacts

Contact: Amy Gillespie	01865 618324	amy.gillespie@psych.ox.ac.uk
Contact: Wendy Howard	01865 618286	wendy.howard@psych.ox.ac.uk

Locations

United Kingdom
University of Oxford	Recruiting
Oxford, Oxfordshire, United Kingdom, OX3 7JX
Contact: Amy Gillespie amy.gillespie@psych.ox.ac.uk
Principal Investigator: Catherine Harmer, PhD
Sub-Investigator: Philip Cowen, MD

Sponsors and Collaborators

University of Oxford

Investigators

Principal Investigator:	Catherine Harmer	University of Oxford

More Information

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Responsible Party:	University of Oxford
ClinicalTrials.gov Identifier:	NCT03515733 History of Changes
Other Study ID Numbers:	PF04995274 Study 2 RESTART
First Posted:	May 4, 2018
Last Update Posted:	July 4, 2018
Last Verified:	May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

Studies a U.S. FDA-regulated Drug Product:		No
Studies a U.S. FDA-regulated Device Product:		No

Additional relevant MeSH terms:

Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant	Behavioral Symptoms; Mood Disorders; Mental Disorders