OSU6162 as add-on in SSRI/SNRI-resistant Depression

Study Overview
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Brief Summary
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This is a randomised, placebo-controlled, parallel-group trial comparing OSU6162 at flexible dosage with placebo as add-on to treatment with an SSRI/SNRI in patients with depression that have not responded to treatment with an SSRI/SNRI per se for at least 6 weeks. The study will last for 6 weeks, after which those not having responded will leave the trial and those having responded will be offered to continue treatment without unblinding for another 4 weeks. While assessment of the efficacy and safety of OSU6162 is the main objective of this study, possible differences between the two treatment groups with respect to a number of biomarkers in serum will also be explored. Multicenter trial: Multiple sites four Gothenburg, Lund, Stockholm and Uppsala.

Detailed Description
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The treatment period will be 6 weeks during which all patients will make 7 study visits and be in contact with study nurse or physician by phone at 4 occasions. The first visit is a screening visit followed by a baseline visit for inclusion and start of treatment with OSU6162 or placebo. Those responding to treatment will be offered to participate in the extension phase of the study for an additional 4 weeks during which the patients will make 3 study visits and take 3 telephone interviews. Before inclusion in the study, all patients will be informed both verbally and in writing about its purpose, its procedures, and possible risks associated with participation. Before any study-specific procedures take place, written informed consent will be obtained. Multicenter trial. Multiple sites 4: Sahlgrenska University Hospital Gothenburg, Skåne University Hospital Psychiatry Lund, Karolinska Institutet Clinical Neuroscience Stockholm and Uppsala University Hospital Department of neuroscience Uppsala. For participation in the extension phase, four factors must be fulfilled: 1. The patient must regard himself/herself as clearly improved and be willing to continue. 2. The investigator must assess the patient as clearly improved. 3. The patient must display at least 50% reduction on HDRS6 as compared to baseline. 4. The patient must have signed a new informed consent. While assessment of the efficacy and safety of OSU6162 is the main objective of this study, possible differences between the two treatment groups with respect to a number of biomarkers in serum will also be explored. The primary evaluation of efficacy will be undertaken at the endpoint of the 6-week trial. All analyses will however be repeated also at the endpoint of the 4-week extension phase for subjects participating in this part of the study. Data will be analysed using mixed models for repeated measurement which means that the model includes data from all depression ratings from baseline to endpoint; this method, which is usually recommended to be used in depression trials by the authorities, is considered to handle data loss due to patients leaving a study prematurely in a better way than imputation methods such as the last observation carried forward (LOCF) technique.

Official Title
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OSU6162 as add-on in SSRI/SNRI-resistant Depression (ODEN): a Double-blind, Placebo-controlled Evaluation of Efficacy and Safety

Conditions
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Depression, Depressive Disorder, Treatment-Resistant, Depressive Disorder, Depressive Episode, Recurrent Depressive Disorder, Recurrent Depression

Intervention / Treatment
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* Drug: OSU6162
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria In order to be included in the study, subjects must meet the following criteria: Signed informed consent. Age: 25-65 on the day of screening. Meeting DSM-5 criteria for major depressive disorder as confirmed by the Mini International Neuropsychiatric Interview (MINI). A symptom-free period preceding the current episode within the past two years confirmed at interview. Not significantly improved, as judged by both doctor and patient, after having been treated with one of the following SSRIs/SNRIs: citalopram, escitalopram, paroxetine, sertraline, fluoxetine, duloxetine, or venlafaxine for at least 6 weeks. Displaying a sum score of MADRS ≥22. In women of childbearing potential (WOCBP): negative result of a pregnancy test and a method of contraception with a failure rate of less than 1 %. Contraception must be used during the treatment and follow-up period. Acceptable forms of contraception are: Use of combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation oral intravaginal transdermal progestogen-only hormonal contraception associated with inhibition of ovulation: oral injectable implantable Placement of intrauterine device (IUD) or intrauterine hormone releasing system (IUS) Bilateral tubal occlusion or ligation Vasectomised partner (with appropriate post-vasectomy documentation of the absence of sperm in the ejaculate and provided that male partner is the sole sexual partner of the WOCBP trial participant). Sexual abstinence. Male patients must agree to use condoms during the study and for 2 weeks after the end of the study/last dose of IMP, unless their partner is using a highly efficient method of contraception, as described above. Exclusion criteria Subjects must not be included in the study if any of the following criteria are met: Meeting MINI criteria at interview for suicidality, manic episode, hypomanic episode, bipolar I, bipolar II, bipolar unspecified, bipolar I with psychotic symptoms, panic disorder (current), agoraphobia, posttraumatic stress disorder, alcohol dependency, alcohol abuse, substance dependency (non-alcoholic), substance abuse (non-alcoholic), psychotic disorders, mood disorders with psychotic features, anorexia nervosa, bulimia nervosa, anorexia nervosa binge eating / purging type, or antisocial personality disorder. Meeting MINI criteria at interview for generalised anxiety disorder, obsessive compulsive disorder or social anxiety (social phobia), unless the present symptoms can predominantly be attributed to a diagnosis of major depressive disorder. A history of substance/alcohol abuse within 2 years prior to screening. A previous diagnosis of a personality disorder, autism spectrum disorder, attention-deficit/hyperactivity disorder, or intellectual disability. Any other previously diagnosed or suspected CNS disorder that according to the investigator renders the patient unsuitable for participation in the trial. Any factor that according to the investigator renders it unlikely that the patient will comply with the instructions regarding treatment, visits etc. Any somatic illness that according to the investigator renders the patient unsuitable for participation in the trial. Any signs or symptoms of somatic illness resulting from assessment of vital signs, physical examination, clinical laboratory tests, and 12-lead ECG that according to the investigator renders the patient unsuitable for participation for safety reasons, including a QTc-time on ECG exceeding 450 ms in men and 460 ms in women. Any change in dosage of said SSRI/SNRI within 4 weeks prior to screening or at any time during the course of the trial. Treatment with any other psychoactive drug than said SSRI/SNRI with the exception of using mirtazapine up to 15 mg for sleep, occasional use of benzodiazepines and benzodiazepine-like anxiolytics or hypnotics and occasional use of antihistaminergic sedatives (without anti-dopaminergic effects) within 4 weeks prior to screening and at any time during the course of the trial. Patients who are receiving concomitant therapy with potent cytochrome P450 enzyme inhibitors (e.g., bupropion, fluvoxamin, ketoconazole, itraconazole, telithromycin, clarithromycin, protease inhibitors, quinidine, and terbinafine). Ongoing treatment with drugs with a narrow therapeutic window where either lower or higher serum levels are potentially harmful (including but not limited to warfarin along with other anticoagulants, digoxin along with other antiarrythmics, anticonvulsants prescribed for treatment of epilepsy, cyclosporine, immunosuppressants, and lithium). Current treatment with any prescribed or OTC drug that according to the investigator renders the subject unsuitable for participation in the trial. Previous intake of OSU6162. Current participation in another clinical trial. Nursing women.

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double-blind
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: OSU6162<br>White, circular, coated tablets. Flexible dosage: the starting dose will be 15 mg TID and the maximal dose 45 mg TID. | Drug: OSU6162<br>* OSU6162<br>* Other names: PNU-96391;|
| Placebo Comparator: Placebo<br>Coated tablets, flexible dosage, TID | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bech 6-item subscale of the Hamilton Depression Rating Scale (HDRS) | Change from baseline with respect to the total score of the investigator-rated Bech 6-item subscale of the Hamilton Depression Rating Scale (HDRS) at endpoint. Lower scores mean a better outcome. | Endpoint at 42 days treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hamilton Depression Rating Scale (HDRS) | Number of participants displaying clinical response defined as ≥50% reduction in the total score of the investigator-rated Bech 6-item subscale of the HDRS. Number of participants displaying clinical remission defined as a sum rating of ≤4 in the total score of the investigator-rated Bech 6-item subscale of the HDRS. Change from baseline with respect to investigator-rated item 1 (depressed mood) of the HDRS. Change from baseline with respect to the total score of the investigator-rated HDRS. Lower scores mean a better outcome. | Endpoint at 42 days treatment | 
| Investigator-rated Montgomery Åsberg Depression Rating Scale (MADRS) | Change from baseline with respect to the total score. Lower scores mean a better outcome. | Endpoint at 42 days treatment | 
| investigator-rated Clinical Global Impression - Severity scale (CGI-S) | Change from baseline with respect to the total score. Lower scores mean a better outcome. | Endpoint at 42 days treatment | 
| Clinical Global Impression - Change scale (CGI-C) | Investigator rating. Lower scores mean a better outcome. | Endpoint at 42 days treatment | 
| Patient-rated Fatigue Severity Scale (FSS) | Change from baseline with respect to the total score. Lower scores mean a better outcome. | Endpoint at 42 days treatment | 
| Patient-rated MADRS-S (self) | Change from baseline with respect to the total score. Lower scores mean a better outcome. | Endpoint at 42 days treatment | 
| Patient-rated Snaith-Hamilton Pleasure Scale (SHAPS) | Change from baseline with respect to the total score. Lower scores mean a better outcome. | Endpoint at 42 days treatment | 
| Global Rating of Change Scale (GRC) | Patient rating. Lower scores mean a better outcome. | Endpoint at 42 days treatment | 
| Bech 6-item subscale of the HDRS | Change from baseline with respect to the total score of the investigator-rated Bech 6-item subscale of the HDRS at endpoint in patients displaying a sum rating of ≥36 at the Fatigue Severity Scale at baseline. Lower scores mean a better outcome. | Endpoint at 42 days treatment | 
| Patient Global Rating of Change Scale (GRC) | Patient rating of the Global Rating of Change Scale (GRC) at endpoint in patients displaying a sum rating of ≥36 at the Fatigue Severity Scale at baseline. Lower scores mean a better outcome. | Endpoint at 42 days treatment | 
| Possible markers of depression | Change from baseline to endpoint with respect to serum levels of a number of possible markers of depression: C-reactive protein (CRP), tumor necrosis factor alpha (TNFα), brain-derived neurotrophic factor (BDNF) and interleukin-6 (IL-6). | Endpoint at 42 days treatment | 
| AE/SAE | Number of participants with individual AEs and individual SAEs throughout the trial. | Through study completion | 
| Serum levels of medications | Serum levels of OSU6162 at endpoint and of the prescribed SSRI/SNRI at screening and endpoint. | Endpoint at 42 days treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antidepressant, drug therapy, combination, Dopamine Drugs, Dopamine, Selective Serotonin Reuptake Inhibitor, SNRI, SSRI, Serotonin and Norepinephrine Reuptake Inhibitors