Antidepressant trial of a novel P2X7 receptor blocker JNJ-54175446
| ISRCTN | ISRCTN44411633 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN44411633 |
| EudraCT/CTIS number | 2018-001884-21 |
| Secondary identifying numbers | 39882 |
- Submission date
- 25/02/2019
- Registration date
- 26/03/2019
- Last edited
- 21/08/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Stopped
- Condition category
- Mental and Behavioural Disorders
Plain English Summary
Background and study aims
Depression affects over 300 million people globally and is one of the main causes of severe disability. Symptoms of depression often persist despite adequate antidepressant drug therapy, possibly because currently available antidepressant drugs have a similar mechanism of action. It is therefore important to identify new treatments that work in a different way. There is evidence to suggest that some patients with depression have increased levels of inflammation in the body. Animal studies support the link between increased inflammation and the development of a range of depressive symptoms. Hence, it is suggested that anti-inflammatory mechanisms may offer a new approach to treating depression. The aim of this study is to test whether a new anti-inflammatory drug has the potential to treat patients suffering from depression who have not responded to their current medications. This will be carried out using a series of questionnaires and clinical assessments. The researchers also wish to find out how the drug affects the body by measuring the levels of biomarkers in the blood and saliva. A biomarker is a biological molecule in the body tissues, blood or other bodily fluids that can be measured and can be used to indicate whether a process is as expected or not. The researchers will also take images of the brain to assess the effects of the drug on the brain structure and function.
Who can participate?
Patients aged between 18 and 60 who are currently experiencing symptoms of depression and are being treated with an antidepressant medication
What does the study involve?
Participants are randomly allocated to take either the new drug or a placebo (dummy) drug (one capsule a day) for about 8 weeks alongside their current antidepressant medication. Participants make 6 clinic visits to the research centre over about 14 weeks, and are also contacted by phone four times including a pre-screening phone call. Participants have to fast overnight before two of the visits. Over the duration of the trial, participants provide blood and urine samples for various tests, and undergo ECG and MRI scans (2 MRI scans). Participants also have to complete some activities at home including continuous wear of an wrist activity monitor, complete a daily sleep diary and provide saliva samples.
What are the possible benefits and risks of participating?
Participants may experience some improvements in their symptoms of depression. They will be compensated for reasonable travel expenses. They will receive up to £500 for their time and effort in the trial. The exact amount will depend on the number of visits completed. The drug has been tested on more than 300 people already and has been shown to be very safe. Mild side-effects that were seen include headache, fatigue and nausea. Participants will not receive any more trial drug after the trial, even if their symptoms improved during the trial.
Where is the study run from?
Cambridge Clinical Trials Unit (UK)
When is the study starting and how long is it expected to run for?
June 2018 to June 2022
Who is funding the study?
Janssen Pharmaceuticals and the Wellcome Trust (UK)
Who is the main contact?
Elizabeth Chong
Elizabeth.chong@addenbrookes.nhs.uk
Contact information
Public
Cambridge Clinical Trials Unit
Coton House Level 6, Box 401
Addenbrooke’s Hospital
Hills Road
Cambridge
CB2 0QQ
United Kingdom
| Phone | +44 (0)1223 254919 |
|---|---|
| Elizabeth.chong@nhs.net |
Scientific
University of Cambridge
Department of Psychiatry
Herchel Smith Building for Brain & Mind Sciences
Cambridge Biomedical Campus
Cambridge
CB2 0SZ
United Kingdom
 ORCID ID |
0000-0002-8955-8283 |
|---|---|
| Phone | +44 (0)1223 336583 |
| etb23@cam.ac.uk |
Public
Cambridge Clinical Trials Unit
Cambridge University Hospitals NHS Foundation Trust
Addenbrooke's Hospital
Coton House Level 6, Flat 61
Hills Road
Cambridge
CB2 0QQ
United Kingdom
| Phone | +44 (0)1223 254919 |
|---|---|
| rachel.lee@addenbrookes.nhs.uk |
Study information
| Study design | Randomised; Interventional; Design type: Treatment, Drug |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| Scientific 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 |
| Study acronym | ATP |
| Study hypothesis | The primary hypothesis of this study is that adjunctive treatment with JNJ-54175446 50mg qd, compared to placebo, will cause a significant reduction in depressive symptom severity measured (MADRS total score) after 8 weeks of treatment. The secondary hypotheses are: 1. Adjunctive antidepressant treatment response to JNJ-54175446, ie. Improved symptoms, fatigue and cognitive scores, will be greatest in MDD patients with peripheral biomarker evidence for P2X7-mediated inflammation. 2. Adjunctive antidepressant treatment response to JNJ-54175446 will be associated with changes in structure and function of brain reward circuit components, e.g., ventral striatum and medial prefrontal cortex, which have previously been implicated in mood disorders and the brain’s response to peripheral inflammation. 3. Anti-inflammatory effects on depressive symptom scores could be measurable within 2 weeks after start of treatment, based on clinical data suggestive of a rapid mood-lifting effect of anti-TNF antibodies in the treatment of patients with rheumatoid arthritis and “comorbid” depressive symptoms. 4. That JNJ-54175446 50mg qd will be safe and well-tolerated based on the following considerations: (i) the prior clinical safety database on JNJ-54175446, has demonstrated good safety and tolerability for similar dosing regimens in healthy volunteers and MDD patients; and (ii) the low affinity of the P2X7 receptor for ATP means that it is only activated by abnormally high levels of ATP, under stress conditions, and has no known functional role at lower, more physiological, levels of ATP. |
| Ethics approval(s) | Approved 04/06/2019, East of England – Cambridge Central REC (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS; +44 (0)207 104 8108; nrescommittee.eastofengland-cambridgecentral@nhs.net), ref: 19/EE/0035 |
| Condition | Major depressive disorder |
| Intervention | Participants will be randomised 1:1 to either active drug or placebo. This will be carried out using a web-based randomisation system. Eligible participants will be randomly allocated to receive either 50 mg/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 MRI brain scans at different visits throughout the trial. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | JNJ-54175446 |
| Primary outcome measure | Depression symptoms measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline and week 8 (Visit 4) |
| Secondary outcome measures | 1. Depressive symptom severity measured using: 1.1. Clinician-reported scales MINI and HDRS17 at screening and baseline and MADRS at weeks 2 and 5 1.2. Participant-reported questionnaires SHAPS, QIDS-SR16, GAD-7, Chalder Fatigue Questionnaire, Perceived Stress Scale, Beck’s Depression Inventory and Childhood Trauma Questionnaire at baseline and over time at every visit until week 8 2. Suicidality assessed using the Columbia Suicidal Severity Rating Scale assessed at every clinic visit (screening, baseline visit 1, visit 2, visit 3, visit 4 and follow up visit 5) 3. Cognitive function assessed using computerised cognitive tasks designed to test for emotion-independent functions, emotion-dependent functions and sustained attention at baseline and over time at every visit until week 8 4. Stress assessed by cortisol levels in the saliva before baseline and before the last dose 5. Fatigue and activity measured using an activity monitor at baseline and over time until week 8 6. Functions of the autonomic nervous system measured by variability in heart rate at baseline and week 8 7. Brain structure and function assessed by functional MRI scan at baseline and week 8 8. Peripheral immunophenotypes measured by various biomarker assays looking at proportions of immune cells, level of cytokine release, CRP protein (marker of inflammation) levels, and gene expression at baseline and week 8 |
| Overall study start date | 01/06/2018 |
| Overall study end date | 01/06/2022 |
| Reason abandoned (if study stopped) | IMP supplier withdrew support |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 142; UK Sample Size: 142 |
| Total final enrolment | 15 |
| Participant inclusion criteria | For a detailed description of inclusion criteria please refer to protocol section 10.1 1. Provided written informed consent 2. Between the age of 18 to 60 years inclusive 3. Meets the DSM-5 diagnostic criteria for MDD (International Classification of Diseases (ICD)-code F32.x and F33.x), without psychotic features, as confirmed by the M.I.N.I 7.0 (Mini International Neuropsychiatric Interview 7.0) 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 |
| Participant exclusion criteria | For a detailed description of exclusion criteria please refer to protocol section 10.2 1. Has a primary DSM-5 diagnosis of posttraumatic stress disorder 2. Has failed more than 3 treatments despite an adequate dose and duration, in the last 24 months 3. Loss of function allele at one or both of two SNPs on the P2RX7 gene: rs3751143 (1487 A> C) and rs1653624 (1703 T> A) 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: 8.1. Monoamine oxidase inhibitors (MAOIs) within 12 weeks before screening 8.2. 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 breastfeeding 13. Is a man who 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 |
| Recruitment start date | 09/09/2019 |
| Recruitment end date | 10/06/2022 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
- Wales
Study participating centres
Cambridge Road
Fulbourn
Cambridge
CB21 5EF
United Kingdom
Cambridge
CB2 0QQ
United Kingdom
Headington
Oxford
OX3 7JX
United Kingdom
1345 Govan Road
Glasgow
G51 4TF
United Kingdom
Cutcombe Road
London
SE5 9RT
United Kingdom
Cardiff
CF24 4HQ
United Kingdom
Cardiff
CF14 4XW
United Kingdom
Sponsor information
Hospital/treatment centre
Elizabeth House
Fulbourn Hospital
Fulbourn
Cambridge
CB21 5EF
England
United Kingdom
| Website | http://www.cpft.nhs.uk/ |
|---|---|
"ROR" |
https://ror.org/040ch0e11 |
University/education
Research Office
School of Clinical Medicine
Addenbrooke's Hospital
Box 111
Hills Road
Cambridge
CB2 0SP
England
United Kingdom
| Phone | +44 (0)1223 333543 |
|---|---|
| croenquiries@admin.cam.ac.uk |
Funders
Funder type
Industry
No information available
Private sector organisation / International organizations
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/06/2023 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Stored in repository |
| Publication and dissemination plan | Upon trial completion and submission of the end of trial approximately 1 year after the overall trial end date, a results summary will also be posted to publicly available clinical trial registers and on the NIMA Consortium website. The results of this trial may be published or presented at scientific meetings. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study will be stored in a publically available repository. Name of repository: APOLLO (https://www.repository.cam.ac.uk/) Type of data shared: All of the individual participant data collected during the trial, after deidentification. Data will become available indefinitely after the final trial report has been submitted and following key publications. Data will be available to anyone who wishes to access the data for any purpose. Participants will be informed that de-identified trial data will become open data after the trial, and will be asked to provide their written consent. Data will be available via the Apollo website, the specific weblink is not yet known. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
21/08/2023: The following changes have been made:
1. The study has been prematurely terminated.
2. The overall study end date has been changed from 01/06/2024 to 01/06/2022 and the plain English summary updated accordingly.
20/06/2022: The recruitment end date was changed from 31/12/2023 to 10/06/2022, the total final enrolment was added.
25/04/2022: A study contact has been added.
22/04/2022: Recruitment to this study is no longer paused.
21/04/2022: The following changes have been made:
1. The recruitment end date has been changed from 01/06/2021 to 31/12/2023.
2. The overall trial end date has been changed from 01/06/2022 to 01/06/2024 and the plain English summary has been updated to reflect this change.
3. The phase has been changed from Not Applicable to Phase II.
17/04/2020: Due to current public health guidance, recruitment for this study has been paused.
04/09/2019: The following changes were made to the trial record:
1. The ethics approval was added.
2. The recruitment start date was changed from 01/06/2019 to 09/09/2019.
03/04/2019: The condition has been changed from "Specialty: Mental Health, Primary sub-specialty: Depression; Health Category: Inflammatory and immune system, Mental health; Disease/Condition: Mood [affective] disorders" to "Major depressive disorder" following a request from the NIHR.
26/03/2019: Trial's existence confirmed by the NIHR.
