OSU6162 as add-on in SSRI/SNRI-resistant Depression (ODEN)

• ClinicalTrials.gov Identifier: NCT05641623
• Recruitment Status: Recruiting
• First Posted: December 7, 2022
• Last Update Posted: December 7, 2022
• Sponsor: Göteborg University
• Collaborator: Arvid Carlsson Research AB
• Information provided by (Responsible Party): Göteborg University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Depression; Depressive Disorder, Treatment-Resistant; Depressive Disorder; Depressive Episode; Recurrent Depressive Disorder; Recurrent Depression	Drug: OSU6162; Drug: Placebo	Phase 2

Detailed Description:

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.

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 72 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Double-blind
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Monitor
• Primary Purpose: Treatment
• Official Title: OSU6162 as add-on in SSRI/SNRI-resistant Depression (ODEN): a Double-blind, Placebo-controlled Evaluation of Efficacy and Safety
• Actual Study Start Date: April 21, 2022
• Estimated Primary Completion Date: May 31, 2026
• Estimated Study Completion Date: August 31, 2026

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: OSU6162; White, circular, coated tablets. Flexible dosage: the starting dose will be 15 mg TID and the maximal dose 45 mg TID.	Drug: OSU6162; OSU6162; Other Names: OSU-6162; PNU-96391
Placebo Comparator: Placebo; Coated tablets, flexible dosage, TID	Drug: Placebo; Placebo

Outcome Measures

Primary Outcome Measures :

1. Bech 6-item subscale of the Hamilton Depression Rating Scale (HDRS) [ Time Frame: Endpoint at 42 days treatment ]

   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.

Secondary Outcome Measures :

1. Hamilton Depression Rating Scale (HDRS) [ Time Frame: Endpoint at 42 days treatment ]

   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.

2. Investigator-rated Montgomery Åsberg Depression Rating Scale (MADRS) [ Time Frame: Endpoint at 42 days treatment ]
   Change from baseline with respect to the total score. Lower scores mean a better outcome.
3. investigator-rated Clinical Global Impression - Severity scale (CGI-S) [ Time Frame: Endpoint at 42 days treatment ]
   Change from baseline with respect to the total score. Lower scores mean a better outcome.
4. Clinical Global Impression - Change scale (CGI-C) [ Time Frame: Endpoint at 42 days treatment ]
   Investigator rating. Lower scores mean a better outcome.
5. Patient-rated Fatigue Severity Scale (FSS) [ Time Frame: Endpoint at 42 days treatment ]
   Change from baseline with respect to the total score. Lower scores mean a better outcome.
6. Patient-rated MADRS-S (self) [ Time Frame: Endpoint at 42 days treatment ]
   Change from baseline with respect to the total score. Lower scores mean a better outcome.
7. Patient-rated Snaith-Hamilton Pleasure Scale (SHAPS) [ Time Frame: Endpoint at 42 days treatment ]
   Change from baseline with respect to the total score. Lower scores mean a better outcome.
8. Global Rating of Change Scale (GRC) [ Time Frame: Endpoint at 42 days treatment ]
   Patient rating. Lower scores mean a better outcome.
9. Bech 6-item subscale of the HDRS [ Time Frame: Endpoint at 42 days treatment ]

   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.

10. Patient Global Rating of Change Scale (GRC) [ Time Frame: Endpoint at 42 days treatment ]

    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.

11. Possible markers of depression [ Time Frame: Endpoint at 42 days treatment ]
    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).
12. AE/SAE [ Time Frame: Through study completion ]
    Number of participants with individual AEs and individual SAEs throughout the trial.
13. Serum levels of medications [ Time Frame: Endpoint at 42 days treatment ]
    Serum levels of OSU6162 at endpoint and of the prescribed SSRI/SNRI at screening and endpoint.

Eligibility Criteria

• Ages Eligible for Study: 25 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Signed informed consent.
2. Age: 25-65 on the day of screening.
3. Meeting DSM-5 criteria for major depressive disorder as confirmed by the Mini International Neuropsychiatric Interview (MINI).
4. A symptom-free period preceding the current episode within the past year confirmed at interview.
5. 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.
6. Displaying a sum score of MADRS ≥22.

7. 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:

   1. Use of combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation

      • oral
      • intravaginal
      • transdermal

   2. progestogen-only hormonal contraception associated with inhibition of ovulation:

      • oral
      • injectable
      • implantable
   3. Placement of intrauterine device (IUD) or intrauterine hormone releasing system (IUS)
   4. Bilateral tubal occlusion or ligation
   5. 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).
8. 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:

1. Meeting MINI criteria at interview for suicidality, manic episode, hypomanic episode, bipolar I, bipolar II, bipolar unspecified, bipolar I with psychotic symptoms, panic disorder, agoraphobia, social anxiety (social phobia), obsessive compulsive disorder, 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, generalised anxiety disorder, or antisocial personality disorder.
2. A history of substance/alcohol abuse within 2 years prior to screening.
3. A previous diagnosis of a personality disorder, autism spectrum disorder, attention-deficit/hyperactivity disorder, or intellectual disability.
4. Any other previously diagnosed or suspected CNS disorder that according to the investigator renders the patient unsuitable for participation in the trial.
5. Any factor that according to the investigator renders it unlikely that the patient will comply with the instructions regarding treatment, visits etc.
6. Any somatic illness that according to the investigator renders the patient unsuitable for participation in the trial.
7. 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.
8. Any change in dosage of said SSRI/SNRI within 4 weeks prior to screening or at any time during the course of the trial.
9. Treatment with any other psychoactive drug than said SSRI/SNRI with the exception of 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.
10. Patients who are receiving concomitant therapy with potent cytochrome P450 enzyme inhibitors (e.g., bupropion, fluvoxamin, ketoconazol, itraconazole, telitromycin, clarithromycin, protease inhibitors, quinidine, and terbinafine).
11. 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).
12. Current treatment with any prescribed or OTC drug that according to the investigator renders the subject unsuitable for participation in the trial.
13. Previous intake of OSU6162.
14. Current participation in another clinical trial.
15. Nursing women.

Contacts and Locations

Contacts

Contact: Elias Eriksson, Professor; +46 709 555055; elias.eriksson@neuro.gu.se

Contact: Jakob Näslund, MD, PhD; +46 702 947960; jakob.naslund@vgregion.se

Locations

Sweden

Sahlgrenska Universitetssjukhuset; Recruiting

Göteborg, Västra Götaland, Sweden

Contact: Jakob Näslund, MD, PhD +46702947960 jakob.naslund@pharm.gu.se

Contact: Christin Englund, MD +46313421000 christin.englund@vgregion.se

Sponsors and Collaborators

Göteborg University

Arvid Carlsson Research AB

Investigators

• Study Director: Elias Eriksson, Professor; Göteborg University

More Information

• Responsible Party: Göteborg University
• ClinicalTrials.gov Identifier: NCT05641623
• Other Study ID Numbers: EudraCT number: 2020-005860-69; 2020-005860-69 ( EudraCT Number )
• First Posted: December 7, 2022
• Last Update Posted: December 7, 2022
• Last Verified: December 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Göteborg University:

Antidepressant; drug therapy, combination; Dopamine Drugs; Dopamine; Selective Serotonin Reuptake Inhibitor; SNRI; SSRI; Serotonin and Norepinephrine Reuptake Inhibitors

Additional relevant MeSH terms:

Disease; Recurrence; Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant; Pathologic Processes; Disease Attributes; Behavioral Symptoms; Mood Disorders; Mental Disorders; 3-(3-(methylsulfonyl)phenyl)-1-propylpiperidine; Dopamine D2 Receptor Antagonists; Dopamine Antagonists; Dopamine Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs