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
试验速览
- 阶段
- 2 期
- 发起方
- 入组人数
- 142
- 试验地点
- 5
- 主要终点
- Change from baseline in total score on the MADRS scale at week 8
研究概览
简要总结
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.
详细描述
This trial will be a multi-centre, phase II, randomised, double blinded, placebo-controlled, parallel group trial.
The research team estimates that the majority of the participants will be recruited through the trial website, posters and research databases. In order to better assess the suitability of the interested participants, interested participants are required to answer pre-screening questions.
Only those who might be suitable to take part will be invited to a screening visit to continue with the rest of the trial screening procedures. The trial will consist of 3 phases - a screening phase, treatment phase of 8 weeks and follow up phase. This includes a total of 6 clinic visits and will be spread over about 15 weeks. Each clinic visit will last between 1.5 hours to 5 hours. Participants will have to be fasted overnight (10 hrs) prior to baseline visit 1 and visit 4 for biomarker blood samples. At these visits, breakfast will be provided after sample collection.
The list below outlines the study schedule and key assessments applicable to a participant who passes the pre-screening questions:
Screening phase clinic visit Participants who are interested in taking part will be invited to attend a screening visit in the clinic which lasts about 4 hours. At this visit the trial team will discuss the trial further and answer any queries the participants may have. If the participants agree, they will then provide informed consent prior to any screening tests and procedures being undertaken. An alcohol breath test and urine drug screen will be carried out. Urine samples will be taken for urinalysis.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Provided written informed consent
- •Between the age of 18 to 60 years inclusive
- •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.
- •Has PHQ-9 score of ≥
- •BMI between 18.0 and 36.0 kg/m2 inclusive.
- •Currently being treated with one antidepressant monoaminergic drug (e.g. SSRI, SNRI, TCA) at an adequate dose, and for at least 6 weeks.
- •Must be medically stable based on clinical laboratory tests, medical history, vital signs, and 12-lead ECG performed.
- •Agree to practice highly effective method of birth control as stated in the protocol.
- •A woman of childbearing potential must have a negative serum pregnancy test at screening.
- •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.
排除标准
- •Has a primary DSM-5 diagnosis of posttraumatic stress disorder.
- •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.
- •Has a current or recent history of clinically significant suicidality.
- •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.
- •Has positive test result(s) for alcohol or drugs of abuse (including methadone, opiates, cocaine, cannabinoids, amphetamine/methamphetamine and ecstasy).
- •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)
- •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.
- •Is currently treated with antipsychotic drugs (D2-antagonists; except for low-dose quetiapine), lithium, other mood stabilizers or opiates.
- •Unable to complete MRI scans.
- •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.
- •Is a woman who is pregnant or breast feeding.
- •Plans 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.
- •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.
- •Venous blood concentration of C-reactive protein, measured by high sensitivity assay (hs-CRP) less than 1 mg/L.
- •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.
研究组 & 干预措施
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.
干预措施: Active JNJ-54175446 (Drug)
Matching placebo
干预措施: Placebo (Drug)
结局指标
主要结局
Change from baseline in total score on the MADRS scale at week 8
时间窗: 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)
次要结局
- Change in scores on CFQ(At baseline, 2, 5 and 8 weeks of treatment)
- Change in scores in Continuous performance test(At baseline, 2, 5 and 8 weeks of treatment)
- Change from baseline in total score on the MADRS scale(At baseline, 2 and 5 weeks of treatment)
- Change in scores on QIDS-SR16(At baseline, 2, 5 and 8 weeks of treatment)
- Change in scores on GAD-7(At baseline, 2, 5 and 8 weeks of treatment)
- Change in scores in the cognitive function test ReVeRe-D(At baseline, 2, 5 and 8 weeks of treatment)
- Change in scores in Emotional Test battery(At baseline and 2 weeks of treatment)
- Change in Brain structure and function(Baseline and at 8 weeks fo treatment)
- Change in heart rate variability(Baseline and at 8 weeks fo treatment)
- Change in scores on Perceived Stress Scale(At baseline, 2, 5 and 8 weeks of treatment)
- Change in scores on SHAPS(At baseline, 2, 5 and 8 weeks of treatment)
- Change in score on participant self-reported depression scale(At baseline and at 8 weeks of treatment)
研究者
CCTU-Core
Chief Investigator
Cambridgeshire and Peterborough NHS Foundation Trust