A research study to compare the antidepressant ability and safety of Samyr® tablets versus placebo tablets as an adjunct to additional antidepressant treatment in patients with major depressive disorder (MDD)

Prior treatment

• Treatment with Monoamine Oxidase (MAO)-inhibitors including selegiline and moclobemide, during the 4 weeks prior to screening.
• Treatment with linezolid or pimozide during the 4 weeks prior to screening; these must not be taken during study.
• Treatment with prohibited medication prior to screening as detailed in Appendix 1.
• Receipt of another investigational drug within 45 days prior to screening, or if the screening visit is within 5 half-lives of another investigational drug received (whichever is longer) or scheduled to receive another investigational drug during the current study period.
• Any elective surgery requiring hospitalization planned during the study period.
• Any lifetime history of bipolar disorders or psychotic disorders (other than MDD with psychotic features in a prior but not the current episode) as per the MINI.
• History of drug abuse and/or marijuana use and/or alcohol dependence during the 3 years prior to screening.
• Previous treatment with Samyr which was not effective or resulted in an AE, or already treated with Samyr for the current episode.

Other illness

• History or presence of a medical condition or disease that in the Investigator’s opinion would place the participant at an unacceptable risk as a result of trial participation.
• Hypersensitivity to the active substance or to any of the excipients of Samyr or placebo (lactose).
• Cardiac disorder which in the Investigator’s opinion would place the participant at an unacceptable risk from trial participation.

Lab values

• Known QT interval prolongation or congenital long QT syndrome.
• Currently treatment with products that are known to prolong the QT interval.
• Any clinically significant abnormality in electrocardiogram (ECG) or safety laboratory tests that in the Investigator’s opinion would place the participant at an unacceptable risk as a result of trial participation.

Other

• Participants with known genetic defects which affect the methionine cycle and/or cause homocystinuria and/or hyperhomocysteinaemia (e.g. cystathionine beta-synthase deficiency, defects of vitamin B12 metabolism).
• Hepatic values that in the Investigator’s opinion would place the participant at an unacceptable risk as a result of trial participation.
• Female participants who are pregnant or breast-feeding or are planning to become pregnant during the study.
• Female participants of childbearing potential who are not able/willing to use oral contraception or acceptable methods of contraception as outlined in this protocol (Protocol Section 4.3), from the time of screening and for the duration of the study, through study completion.
• The participant is, in the investigator’s opinion, at significant current risk of harming himself/herself, or provides the following answers on the C-SSRS at screening: - “Yes” to Question 4 or 5 on the Lifetime version Suicidal Ideation section and the ideation was within the last 3 months at Screening Visit, OR - “Yes” to question on the Lifetime version Suicidal Behavior section (other than preparatory behavior) and the ideation was within the last 3 months at Screening Visit.
• Use of more than any 4 acceptable antidepressant treatments since the diagnosis of depression.

• Written and signed informed consent needs to be provided by participants before starting any protocol-specific procedures.
• Male and female participants between the ages of 18 to 65 years, both ages inclusive.
• Participant who is able and willing to comply with the requirements of the study protocol including the visits scheme, assessments and scales.
• Primary diagnosis of MDD of at least 12 weeks duration, according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and as confirmed by version 7.0 of the Mini International Neuropsychiatric Interview (MINI).
• Participant is on prescribed SSRI (citalopram / escitalopram / sertraline / paroxetine / fluoxetine) or SNRI (venlafaxine / desvenlafaxine / duloxetine) antidepressant treatment, at approved and stable dose, for at least 4 weeks prior to screening that is insufficient/ineffective.
• The participant is deemed to have inadequate response (less than 50% symptom reduction) to their current antidepressant based on the investigator judgment and the treatment history.
• Participants who have a HDRS-17 score between 15-20 at screening. The baseline score must remain ≤20 and should not have >10% reduction between screening and baseline (randomization visit).