Antidepressant Trial with P2X7 Antagonist JNJ-54175446
According to the World Health Organization (http://www.who.int), more than 300 million people suffer from depression globally, equivalent to a lifetime prevalence of 7 to 12% for men and 20 to 25% for women. MDD is the leading cause of disability worldwide and a major contributor to the overall global burden of disease. Psychological and social stress is a major causal risk for the development of MDD, and increased stress is also often an effect of depressive illness. Although effective treatments for depression are available, approximately a third of patients do not adequately respond to first-line antidepressant treatment with monoaminergic drugs, like serotonin or noradrenaline reuptake inhibitors, or psychotherapy. Given the high prevalence and socio-economic costs of depression, it is an important priority to discover new treatment options for the large number of patients whose symptoms do not respond adequately to existing drugs, including those with so-called treatment-resistant depression.
There is significant unmet clinical need for novel antidepressant treatments, indicated by the large proportion (approximately one third) of patients with MDD who do not experience satisfactory resolution of depressive symptoms following treatment with existing antidepressant drugs at adequate dose and duration. In this study the antidepressant efficacy of a novel anti-inflammatory CNS-penetrant P2X7 receptor antagonist, JNJ-54175446 will be assessed. This study is performed in a public-private partnership and as a continuation of the Wellcome Trust-funded Neuroimmunology of Mood Disorders and Alzheimer's Disease (NIMA) consortium (https://www.neuroimmunology.org.uk/). In preparation for this study, a biomarker study (BIODEP) was performed.
This will be a multi-centre, double-blind, randomised, placebo-controlled, parallel-group trial of JNJ-54175446 50 mg/day administered orally for 8 weeks to male and female participants (aged 18-60 years) with a DSM-5 diagnosis of MDD, a suboptimal response to monoaminergic antidepressant drugs, and a biomarker profile predictive of activated P2X7 signalling. In this study at least five UK centres are planned to be included in this trial, however, we may increase the number of recruitment centres if required to obtain complete data on the required number of participants. At least 120 participants are required to complete this trial. This will require approximately 142 participants to be enrolled (assuming an attrition rate of 15%). The total number of patients recruited may change in line with the actual attrition rate.
Main inclusion criteria
Each potential participant must satisfy all the following criteria to be included in the trial.
- Provided written informed consent.
- Aged 18 to 60 years of age, inclusive at screening.
- BMI between 18.0 and 36.0 kg/m2 inclusive.
- Must meet the DSM-5 diagnostic criteria for current MDD, without psychotic features (past or current), as confirmed by the MINI.
- Must have an PHQ-9 total score at screening ≥10.
- Note: a participant who does not fulfil this criterion cannot be re-screened until at least 6 months after the date of first screening.
- Is currently being treated with one antidepressant drug from one of three classes of monoaminergic antidepressant drugs: selective serotonin reuptake inhibitors [SSRI], serotonin and norepinephrine reuptake inhibitors [SNRI], or tricyclic antidepressant [TCA] drugs.
- Monoaminergic antidepressant treatment must have been prescribed at an adequate dose, and for at least 6 weeks. In addition, patients may receive stable augmentation therapy with mirtazapine, low-dose quetiapine (≤150 mg/day), or low-dose amitriptyline (<50 mg/day).
- Must be medically stable based on clinical laboratory tests, medical history, vital signs, and 12-lead ECG performed at screening and baseline (for clinical laboratory tests only screening results will be considered). If the results of the serum chemistry panel, haematology, or urinalysis are outside the normal reference ranges for this population, retesting of any abnormal lab value(s) that may lead to exclusion will be allowed once during the screening phase at a separate clinic visit. Blood pressure will be the average of 2 measurements.
- The person may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant or to be appropriate and reasonable for the population under study. This determination must be recorded in the participant's source documents and initialled by the investigator.
- A retest of an abnormal ECG value will be allowed once as a repeat batch of 3 ECGs in the screening phase. Please note that QTcF should be ≤ 470msec in female and ≤ 450msec in male patients, and PR-interval of ≤240msec.
- Men who are sexually active with a woman of childbearing potential and have not had a vasectomy must agree to use a barrier method of birth control e.g., either condom or partner with occlusive cap (diaphragm or cervical/vault caps) for the duration of the trial plus 3 months after receiving the last dose of IMP, and their female partners should also use an additional method of birth control (which may include a hormonal method, an intrauterine device [IUD] or an intrauterine system [IUS]) for at least the same duration.
- All men must not donate sperm during the study and for 3 months after receiving the last dose of trial drug.
- Women must be either:
- Not of childbearing potential defined as:
- Postmenopausal: >55 years of age with amenorrhea for at least 12 months OR any age with amenorrhea for at least 6 months and a serum follicle stimulating hormone (FSH) level >40.0 IU/L).
- permanently sterilised (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy); or
- incapable of pregnancy
- Of childbearing potential and practising highly effective methods of birth control (i.e. one that results in a less than 1% per year failure rate when used consistently and correctly). This may include:
- Established and ongoing use of oral, patch, injected or implanted hormonal methods of contraception in combination with barrier methods.
- Placement of an IUD or IUS in combination with barrier methods.
- Male partner sterilization (the vasectomized partner should be the sole partner for that participant).
- True abstinence (when this is in line with the preferred and usual lifestyle of the participant).
- Not of childbearing potential defined as:
Accepted barrier methods as indicated above include:
- occlusive cap (diaphragm or cervical/vault caps)
Note that a barrier method on its own is not sufficient.
Women must agree to continue using these methods of contraception throughout the study and for at least 3 months after receiving the last dose of trial drug.
Note: If a woman of childbearing potential who is not heterosexually active becomes active after the start of the study, she must begin a highly effective method of birth control, as described above.
- A woman of childbearing potential must have a negative serum pregnancy test at screening.
- A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction from the start of dosing and for at least 3 months after receiving the last dose of trial drug.
Main exclusion criteria
Any potential participant who meets any of the following criteria will be excluded from participating in the study.
- Has a primary DSM-5 diagnosis of posttraumatic stress disorder.
- Note: People with comorbid GAD, social anxiety disorder, obsessive-compulsive behaviour or panic disorder are not excluded.
- Has failed to respond to more than 3 antidepressant treatments despite an adequate dose and duration, in the last 24 months.
- 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.
- Venous blood concentration of C-reactive protein, measured by high sensitivity assay (hs-CRP) less than 1 mg/L.
- Has a current or recent history of clinically significant suicidality within the past 6 months. People with a prior suicide attempt of any sort, or prior serious suicidal ideation/plan >6 months ago, should be carefully screened for current suicidal ideation and only be included at the discretion of the investigator.
- 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. However, people who have completed treatment for (alcohol) addiction more than 6 months prior to first dose administration, may be included at the discretion of the investigator if the risk of relapse is considered minimal and no significant abnormalities are shown in clinical laboratory or other pre-dose safety assessments.
- Has positive test result(s) for alcohol or drugs of abuse (including methadone, opiates, cocaine, cannabinoids, amphetamine/methamphetamine and ecstasy) at screening and/or admission to the site at each visit.
- If the participant has a positive alcohol or drug screen at screening, the test may be repeated once during the screening phase, based on the investigator's discretion. This determination, and the reason for permitting a repeat test, must be recorded in the participant's source documents and initialled by the investigator. A positive, repeat alcohol or drug screen is exclusionary.
- 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)
- Has used:
- Monoamine oxidase inhibitors (MAOIs) within 12 weeks before screening
- Other antidepressant drugs not belonging to the allowed classes of SSRI, SNRI, or TCA (see Appendix 2), such as St. John Wort, bupropion or mianserin, within 6 weeks of screening.
- Is currently treated with antipsychotic drugs (D2-antagonists; except for low-dose quetiapine), lithium, other mood stabilizers or opiates.
- Has implanted or embedded metal objects, or fragments in the head or body that would present a risk during the MRI scanning procedure, or inability to tolerate the confines of an MRI scanner (such as claustrophobia).
- Use of any over-the-counter medication, herbal medication, vitamins, or mineral supplements within 14 days or 5 half-lives prior to trial drug administration (not including paracetamol, acetaminophen and ibuprofen). However, the use of over-the-counter medication that is considered not to have any impact on the study results may be allowed after agreement between the investigator and the Chief Investigator.
- Use of prescription medications that are prohibited in the trial
- Hypersensitivity to JNJ-54175446, placebo or any of the excipients
- Has current signs/symptoms of one or more of the below:
- liver insufficiency defined as
- AST or ALT >2.0 x ULN, or Total bilirubin >20μmol/L (participants with Gilbert’s Syndrome are however eligible if their unconjugated bilirubin does not exceed 68μmol/L and is accompanied with normal ALT and AST)
- Unconjugated bilirubin >68umol/L for participant’s with Gilbert Syndrome
- renal impairment defined as eGFR (as per MDRD equation) to be less than
- <60ml/min/1.73m2 or
- Between 60 and <90 ml/min/1.73m2 with the presence of protein or blood in urine
- (controlled or uncontrolled) diabetes mellitus (type I and II)
- hypothyroidism or hyperthyroidism
- Note: normal thyroid-stimulating hormone [TSH] is required at screening; people with thyroid disease who are on stable treatment with normal TSH may participate but people with thyroid supplementation for antidepressant purposes are not allowed in the study
- significant and uncontrolled cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, inflammatory (e.g., rheumatoid arthritis, inflammatory bowel disease, Crohn’s disease) or metabolic disturbances.
- Note: Conditions that are controlled with stable medication that has not been changed within 3 months prior to randomisation are not excluded.
- liver insufficiency defined as
- Plans to start or stop non-medication interventions during the period of the trial, or has started psychotherapy for less than 3 months. Non-medication interventions include psychotherapy, acupuncture, electrical or magnetic stimulation (TMS, VNS, ECT).
- Pregnant or breast feeding woman.
- Patients who plan to conceive a child while enrolled in this study or within 3 months after the last dose of IMP.
- Has a history of malignancy within 5 years before screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the investigator is considered cured with minimal risk of recurrence).
- Has received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 60 days prior to screening, or has participated in 2 or more interventional clinical studies in the previous 1 year, or is currently enrolled in any drug or non-medication interventional study.
- 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.
- Is unable to read and understand the consent forms and patient-reported outcomes, complete trial-related procedures, and/or communicate with the trial staff.
- Has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the person (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
Funders and sponsors
Prof Edward T. Bullmore
Clinical Trial Coordinator: Elizabeth Chong
Telephone: 01223 254919 | Email: email@example.com