E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Major depressive disorder with an incomplete response to monoaminergic antidepressants and with biomarker profile indicative of inflammation |
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E.1.1.1 | Medical condition in easily understood language |
People with: - major depressive disorder whose condition has not improved with the current antidepressant medications. - increased levels of inflammation. |
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E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025453 |
E.1.2 | Term | Major depressive disorder NOS |
E.1.2 | System Organ Class | 100000004873 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The principal research objective is to evaluate whether a new anti-inflammatory drug, called JNJ-54175446, is effective in treating depressive symptoms in patients with major depressive disorder. This drug works by blocking a receptor called P2X7 which is known to cause brain inflammation in response to stress. We predict that blocking P2X7 will be beneficial for depressed patients who have not responded completely to standard anti-depressant drugs and who have blood test results at screening which indicate high levels of P2X7 activity.
Effectiveness will be measured using a standard clinical depression scale, called MADRS, after 8 weeks of treatment, and we will test the hypothesis that there is significantly greater improvement of depression in the patients treated with JNJ-54175446 compared to the patients treated with placebo.
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the trial include: 1. To evaluate if any anti-depressant effects of JNJ-54175446 are correlated with baseline levels of various immune biomarkers. 2. To evaluate if any anti-depressant effects of JNJ-54175446 are correlated with baseline cognitive functions, fatigue and brain structure and function. 3. To evaluate whether there is any anti-depressant effect after 2 weeks of treatment. 4. To evaluate whether JNJ-54175446 is safe and tolerable in patients, and determine how the body processes the drug by measuring the amount of drug in the participants' blood at various time points.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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.
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E.4 | Principal 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: - 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. 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is change from baseline in total score on the Montgomery-Åsberg Depression Rating Scale (MADRS) at week 8 (Visit 4). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary endpoint will be assessed at around 8 weeks (days 56 +/- 3) from the start of treatment. |
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E.5.2 | Secondary end point(s) |
The secondary endpoints include: 1. change in scores of clinical symptom scales 2. change in scores of participant-reported questionnaires 3. change in scores of various cognitive tasks. 4. participant activity and sleep patterns during the trial. 5. salivary cortisol levels 6. Heart rate variability 7. Brain structure and functional changes 8. Changes in peripheral immunophenotypes |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Clinical symptom scales: participants assessed at clinic visits at baseline, week 2, 5 and 8. 2. Participant-reported questionnaires: weekly from baseline to week 8 3. Cognitive tasks: participants assessed at clinic visits at baseline, week 2, 5 and 8. 4. Participant activity and sleep patterns during the trial: throughout the trial starting from 7 days before treatment to the end of treatment (week 8). 5. salivary cortisol levels: within 7 days before treatment and before the end of treatment. 6. Heart rate variability: participants assessed at clinic visits at baseline, week 2, 5 and 8. 7. Brain structure and functional changes: at baseline and at week 8 8. Peripheral immunophenotypes: samples taken for analysis of this secondary endpoint at screening, baseline and week 8. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 9 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 9 |