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

The Effects of PF-04995274 on Emotional Processing in Treatment-resistant, Medicated, Depressed Patients

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 non-emotional cognition in medicated, treatment-resistant depressed patients compared to placebo.

Study Overview

• Status: Completed
• Conditions: Treatment Resistant Depression; Depression, Unipolar
• Intervention / Treatment: Drug: PF-04995274; Drug: Placebo Oral Tablet

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 Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OX3 7JX
      • University of Oxford

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 65 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Facial Expression Recognition Task (FERT)	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.	Completed on Day 7
Auditory Verbal Learning Task (AVLT)	Accuracy of recall on the auditory verbal learning task	Completed on Day 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Emotional Memory Task	Recall and recognition of affective words displayed earlier in the testing session is tested	Completed on Day 7
Probabilistic Instrumental Learning Task (PILT)	Participants have to learn which shapes are associated with wins and losses and sensitivity to reward is assessed.	Completed on Day 7

Collaborators and Investigators

• Sponsor: University of Oxford

Publications and helpful links

General Publications

• Murphy SE, de Cates AN, Gillespie AL, Godlewska BR, Scaife JC, Wright LC, Cowen PJ, Harmer CJ. Translating the promise of 5HT4 receptor agonists for the treatment of depression. Psychol Med. 2021 May;51(7):1111-1120. doi: 10.1017/S0033291720000604. Epub 2020 Apr 3.

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 31, 2018
• Primary Completion (ACTUAL): July 26, 2022
• Study Completion (ACTUAL): July 26, 2022

Study Registration Dates

• First Submitted: April 23, 2018
• First Submitted That Met QC Criteria: April 23, 2018
• First Posted (ACTUAL): May 4, 2018

Study Record Updates

• Last Update Posted (ACTUAL): November 4, 2022
• Last Update Submitted That Met QC Criteria: November 1, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant
• Other Study ID Numbers: PF04995274 Study 2 RESTART

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No