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Antidepressant Trial With P2X7 Antagonist JNJ-54175446 (ATP)

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ClinicalTrials.gov Identifier: NCT04116606
Recruitment Status : Recruiting
First Posted : October 4, 2019
Last Update Posted : October 4, 2019
Sponsor:
Collaborator:
Janssen Pharmaceuticals
Information provided by (Responsible Party):
CCTU-Core, Cambridgeshire and Peterborough NHS Foundation Trust

Brief Summary:

Depression is one of the most important causes of disability in the world today, with major personal, social and economic costs. Although some moderately effective drug treatments are already available, about a third of patients with major depressive disorder (MDD) remain depressed despite current treatment.

There is growing evidence that inflammation - the response of the body's immune system to physical and social stresses - can cause depressive symptoms in some patients. It is therefore predicted that anti-inflammatory drugs could have anti-depressant effects and the research team aims to test this using a new drug, JNJ-54175446, which blocks the activity of a receptor called P2X7. P2X7 is present on many immune cells and plays a key role in the release of inflammatory molecules during stress, which may be linked to stress-related depression.

The research team will recruit approximately up to 142 participants with MDD to this clinical trial. Patients will have moderate-severe depressive symptoms despite ongoing treatment with a conventional anti-depressant drug, and they will have blood test results at screening that indicate they are likely to have active P2X7 signalling in the brain. Eligible participants will be randomly allocated to receive either 50mg/day JNJ-54175446 or placebo for 8 weeks. Participants will be assessed at weeks 2, 5 and 8 using a standard clinical depression scale and the scores compared between those treated with placebo and those treated with JNJ-54175446. To understand more about the effects of JNJ-54175446 on the immune system and the brain, patients will also complete additional blood tests, questionnaires and magnetic resonance imaging (MRI) brain scans at different visits throughout the trial. The trial will be carried out across 5 centres in the UK.


Condition or disease Intervention/treatment Phase
Depressive Disorder, Major Inflammation Drug: Active JNJ-54175446 Drug: Placebo Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 142 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomised, Placebo-controlled, Double-blind Trial of the Antidepressant Efficacy of a Novel CNS-penetrant P2X7 Receptor Antagonist, JNJ-54175446, in People With Major Depressive Disorder, an Incomplete Response to Monoaminergic Antidepressant Drugs, and a Biomarker Profile Predictive of Active P2X7 Signalling
Actual Study Start Date : September 12, 2019
Estimated Primary Completion Date : May 31, 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antidepressants

Arm Intervention/treatment
Active Comparator: Active JNJ-54175446
JNJ-54175446 is an unlicensed drug currently being developed by Janssen Pharmaceuticals. The drug is presented in oral capsules, each capsule containing 50 mg of JNJ-54175446. Participants will be asked to self-administer one capsule daily for 8 weeks.
Drug: Active JNJ-54175446
JNJ-54175446 is a novel, potent, selective, and brain-penetrant antagonist of the adenosine triphosphate (ATP)-gated P2X7 channel.

Placebo Comparator: Matching placebo Drug: Placebo
Matching placebo containing the same excipients




Primary Outcome Measures :
  1. Change from baseline in total score on the MADRS scale at week 8 [ Time Frame: At baseline and at 8 weeks of treatment ]

    The Montgomery Asberg Depression Rating Scale (MADRS), a researcher-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The test consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.

    (Visit 4)



Secondary Outcome Measures :
  1. Change from baseline in total score on the MADRS scale [ Time Frame: At baseline, 2 and 5 weeks of treatment ]
    The Montgomery Asberg Depression Rating Scale (MADRS), a researcher-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The test consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition.

  2. Change in scores on Perceived Stress Scale [ Time Frame: At baseline, 2, 5 and 8 weeks of treatment ]
    Perceived Stress Scale is a questionnaire measure of recent or current social stress. This scale ranges from 0 to 40; scores ranging from 0-13 would be considered low stress; scores ranging from 14-26 would be considered moderate stress; scores ranging from 27-40 would be considered high perceived stress.

  3. Change in scores on SHAPS [ Time Frame: At baseline, 2, 5 and 8 weeks of treatment ]
    Snaith-Hamilton Pleasure Scale. SHAPS is an instrument developed for the assessment of hedonic capacity and consists of 14-items. Four major domains are covered in the scale, namely interest/pastimes, social interaction, sensory experience, and food/drink. The score range is 0-14. The higher the score the lower the ability to experience pleasure of the patient.

  4. Change in scores on CFQ [ Time Frame: At baseline, 2, 5 and 8 weeks of treatment ]
    Chalder Fatigue Questionnaire (CFQ). The Fatigue Scale, sometimes referred to as the Chalder Fatigue Questionnaire, is a self-administered questionnaire for measuring the extent and severity of fatigue within both clinical and non-clinical, epidemiological populations. The respondent's global score can range from 0 to 33. The global score also spans two dimensions—physical fatigue (measured by items 1-7) and psychological fatigue (measured by items 8-11).

  5. Change in scores on QIDS-SR16 [ Time Frame: At baseline, 2, 5 and 8 weeks of treatment ]
    Quick Inventory of Depressive Symptomatology (QIDS-SR16). The QIDS-SR16 is designed to assess the severity of depressive symptoms and is sensitive to change due to with medications, psychotherapy, or other treatments. Participants will provide responses to each item of this instrument with a 4-point Likert scale, with scores ranging from 0-3 for each item. The total score ranges from 0 to 27. Using a scale of severity of depression of none, mild, moderate, severe, and very severe, corresponding QIDS-SR16 total scores are none 1 to 5, mild 6 to 10, moderate 11 to 15, severe 16 to 20 and very severe 21 to 27.

  6. Change in scores on GAD-7 [ Time Frame: At baseline, 2, 5 and 8 weeks of treatment ]
    Generalized Anxiety Disorder 7 (GAD-7). GAD-7 is a self-reported questionnaire for screening and severity measuring of GAD. GAD-7 has seven items, which measure severity of various signs of GAD according to reported response categories with assigned points. Assessment is indicated by the total score, which made up by adding together the scores for all 7 items. The score ranges from 0 to 21. Using a scale of severity of anxiety of none, mild, moderate and severe, corresponding to GAD-7 total scores are none 0 to 4, mild 5 to 9, moderate 10 to 14 and severe 15 to 21.

  7. Change in score on participant self-reported depression scale [ Time Frame: At baseline and at 8 weeks of treatment ]
    Participants will be asked to self-assess their depression using the Beck Depression Inventory scale (BDI). BDI is a 21-question multiple-choice self-report inventory, widely used for assessment of depression, including in the NIMA BIODEP study, with a score range of 0-63. Each of the 21 items is rated by the participant on a 4 point scale.

  8. Change in scores in the cognitive function test ReVeRe-D [ Time Frame: At baseline, 2, 5 and 8 weeks of treatment ]
    Revere-D is an application developed by Johnson and Johnson, and consists of a battery of eight validated cognitive tasks that assesses cognitive functions, such as memory and learning, that do not involve cognitive processing of emotionally salient stimuli.

  9. Change in scores in Continuous performance test [ Time Frame: At baseline, 2, 5 and 8 weeks of treatment ]
    The continuous performance test is a computerised test of sustained attention which provides a measure of cognitive fatigue.

  10. Change in scores in Emotional Test battery [ Time Frame: At baseline and 2 weeks of treatment ]
    The emotional test battery will consist of 3 validated computerised tasks which are used to assess cognitive functions that involve processing emotionally salient stimuli, such as human faces expressing emotional states.

  11. Change in Salivary cortisol levels as a measure of biological stress [ Time Frame: Samples collected within 7 days prior to Baseline visit and within 7 days prior to visit 4 ]
    Participants will be asked to provide saliva samples before treatment commencement and during the last week of treatment in order for the cortisol levels to be analysed.

  12. Change in Brain structure and function [ Time Frame: Baseline and at 8 weeks fo treatment ]
    Brain structure and function will be assessed using fMRI/MRI

  13. Change in heart rate variability [ Time Frame: Baseline and at 8 weeks fo treatment ]
    Heart rate variability will be measured for 15 minutes during rest and whilst completing one of the cognitive tasks.

  14. Measurement of peripheral blood peripheral cytokine and chemokine levels [ Time Frame: Baseline and at 8 weeks fo treatment ]
    Blood samples will be collected for the analysis of cytokine and chemokine levels with a multiplex immunoassay using the MSD Multi-spot assay system with the Cytokine Panel 1, Proinflammatory panel 1 and Chemokine panel 1 kits providing concentration of all analytes of the panel in pg/ml.

  15. Measurement of peripheral blood immunophenotypes [ Time Frame: Baseline and at 8 weeks fo treatment ]
    The immune cellular content of the blood samples will be analysed with mass cytometry using the commercial kit Maxpar® Direct™ Immune Profiling Assay.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

The key eligibility criteria are listed below, to obtain the full list please contact the trial team.

Inclusion Criteria:

  1. Provided written informed consent
  2. Between the age of 18 to 60 years inclusive
  3. Meets the Diagnostic and statistical manual - 5 (DSM-5) diagnostic criteria for MDD without psychotic features (past or present), as confirmed by the M.I.N.I v7.0.
  4. Has Hamilton Depression Rating Scale (HDRS) score of ≥17.
  5. BMI between 18 and 36 kg/m2 inclusive.
  6. Currently being treated with one antidepressant monoaminergic drug (e.g. SSRI, SNRI, TCA) at an adequate dose, and for at least 6 weeks and for a maximum of 24 months.
  7. Must be medically stable based on clinical laboratory tests, medical history, vital signs, and 12-lead ECG performed.
  8. Agree to practice highly effective method of birth control as stated in the protocol.
  9. A woman of childbearing potential must have a negative serum pregnancy test at screening.
  10. Agree not to donate eggs or sperm from start of dosing and for at least 3 months after receiving the last dose of study drug.

Exclusion Criteria:

  1. Has a primary DSM-5 diagnosis of posttraumatic stress disorder.
  2. Has failed to respond to more than 3 antidepressant treatments despite an adequate dose and duration, in the last 24 months.
  3. Presence of two copies of the loss-of-function C allele at rs3751143, and/or has one copy of the loss-of-function A allele at rs1653624 in the P2RX7 gene.
  4. Has a current or recent history of clinically significant suicidality.
  5. Has a history of moderate or severe substance or alcohol use disorder according to DSM-5 criteria, except nicotine or caffeine, within 12 months before screening.
  6. Has positive test result(s) for alcohol or drugs of abuse (including methadone, opiates, cocaine, cannabinoids, amphetamine/methamphetamine and ecstasy).
  7. Has a current diagnosis of a psychotic disorder (e.g. schizophrenia, bipolar disorder), an eating disorder (e.g. anorexia, bulimia), or learning disability or a personality disorder that is considered by the investigator to interfere with the ability of the subject to adhere to the protocol (e.g. narcissistic personality, borderline personality disorder)
  8. Has used:

    • Monoamine oxidase inhibitors (MAOIs) within 12 weeks before screening
    • Within 6 weeks prior to enrolment use of other antidepressant drugs not belonging to the allowed classes of SSRI, SNRI, or TCA.
  9. Is currently treated with antipsychotic drugs (D2-antagonists; except for low-dose quetiapine), lithium, other mood stabilizers or opiates.
  10. Unable to complete MRI scans.
  11. Has current signs/symptoms of liver or renal insufficiency, diabetes mellitus (type I and II), hypothyroidism or hyperthyroidism without stable treatment, or other significant and uncontrolled medical conditions.
  12. Is a woman who is pregnant or breast feeding.
  13. Plans to conceive a child while enrolled in this study or within 3 months after the last dose of IMP.
  14. Has a history of malignancy within 5 years before screening.
  15. Has received an investigational drug/vaccines, used an invasive investigational medical device within 60 days before the planned first dose of IMP, or has participated in 2 or more interventional clinical studies in the previous 1 year, or is currently enrolled in any drug or non-drug interventional study.
  16. Venous blood concentration of C-reactive protein, measured by high sensitivity assay (hs-CRP) less than 1 mg/L.
  17. Has had major surgery, (i.e. requiring general anaesthesia) within 12 weeks before screening, or will not have fully recovered from surgery, or has surgery planned during the time they are expected to participate in the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04116606


Contacts
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Contact: Elizabeth Chong 01223 254919 elizabeth.chong@nhs.net
Contact: CCTU Core 01223 596474 cctuc@addenbrookes.nhs.uk

Locations
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United Kingdom
Addenbroooke's Hospital Recruiting
Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
Contact: Ciara O'Donnell    01223 465221    atp@medschl.cam.ac.uk   
Principal Investigator: David Christmas         
Cardiff University Brain Research Imaging Centre Not yet recruiting
Cardiff, United Kingdom, CF24 4HQ
Contact: Caroline Young       ATPTrial@cardiff.ac.uk   
Principal Investigator: Neil Harrison         
Queen Elizabeth University Hospital Not yet recruiting
Glasgow, United Kingdom, G3 8SW
Contact: Murray Sutherland    0141 232 7600      
Principal Investigator: Nagore Penades         
The Maurice Wohl Clinical Neuroscience Institute Not yet recruiting
London, United Kingdom, SE5 9RT
Contact: Courtney Worrell    0207 8485440    atpstudy@kcl.ac.uk   
Principal Investigator: Maria Antonietta         
Warneford Hospital Not yet recruiting
Oxford, United Kingdom, OX3 7JX
Contact: Alanna Sheldon-Battle    01865 902135    oxfordhealth.crf@nhs.net   
Principal Investigator: Phil Cowen         
Sponsors and Collaborators
CCTU-Core
Janssen Pharmaceuticals
Investigators
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Principal Investigator: Edward Bullmore Cambridgeshire and Peterborough NHS Foundation Trust

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Responsible Party: CCTU-Core, Chief Investigator, Cambridgeshire and Peterborough NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT04116606     History of Changes
Other Study ID Numbers: CCTU0251
2018-001884-21 ( EudraCT Number )
First Posted: October 4, 2019    Key Record Dates
Last Update Posted: October 4, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: All publications resulting from this study will be made available Open Access. There are plans for anonymised datasets from the trial to become 'open data' and be stored in an online database so that it is publicly available. This page will be updated with information about research outputs as soon as they become available.
Time Frame: After declaration of end of trial to authorities and submission of end of trial report.
Access Criteria: Data will be made available free of charge to anyone interested in the research.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by CCTU-Core, Cambridgeshire and Peterborough NHS Foundation Trust:
P2X7
Major Depressive Disorder
Additional relevant MeSH terms:
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Inflammation
Depressive Disorder
Depression
Depressive Disorder, Major
Pathologic Processes
Mood Disorders
Mental Disorders
Behavioral Symptoms
Antidepressive Agents
Psychotropic Drugs