Evaluation of Ademetionine Efficacy and Safety as Adjunctive Therapy in Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to demonstrate that **Samyr®** (ademetionine) is superior to a placebo tablet in patients with Major Depressive Disorder (MDD) who have an inadequate response to antidepressants. This is assessed by the Hamilton Depression Rating Scale (HDRS-17) score after six weeks of treatment, with a baseline score of 15-20 and up to a 10% reduction. The clinical relevance of this objective lies in potentially providing an effective adjunctive treatment option for patients with MDD who do not adequately respond to standard antidepressant therapies.

Secondary objectives include: - Evaluating the general improvement on the Patient Global Impression (PGI) scale and the Clinical Global Impression (CGI) scale following six weeks of treatment. - Assessing the safety and tolerability of Samyr® tablets. These objectives aim to provide a comprehensive understanding of the treatment's impact on patient-reported outcomes and its safety profile.

The clinical trial focuses on individuals diagnosed with **Major Depression Disorder** (MDD) who have shown an inadequate response to antidepressants. The study population includes both male and female participants aged between 18 to 65 years. Participants are required to have a primary diagnosis of MDD for at least 12 weeks, confirmed by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), and the Mini International Neuropsychiatric Interview (MINI). They must be on a stable dose of prescribed SSRI or SNRI antidepressant treatment for at least four weeks prior to screening, with an inadequate response defined as less than 50% symptom reduction. The Hamilton Depression Rating Scale (HDRS-17) score for participants should be between 15-20 at screening, with no more than a 10% reduction at baseline. The trial includes a vulnerable population, and participants must provide written and signed informed consent. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled, parallel-group, multi-center study** to evaluate the anti-depressive efficacy and safety of Samyr® tablets compared to placebo tablets in patients with **Major Depression Disorder** (MDD) exhibiting mild to moderate symptoms. The trial will involve participants who have an inadequate response to their current antidepressant treatment, as determined by a Hamilton Depression Rating Scale (HDRS-17) score between 15-20. The primary objective is to demonstrate the superiority of Samyr® over placebo when used alongside adjunctive antidepressant therapy over a six-week treatment period, with the primary endpoint being the change in HDRS-17 score from baseline to the end of the study.

The trial will commence with a screening visit to confirm eligibility based on inclusion criteria, such as age range (18-65 years), diagnosis of MDD according to DSM-5, and current antidepressant treatment stability. Participants will be randomized to receive either Samyr® or placebo, both administered orally in the form of gastro-resistant tablets. The study will span approximately six weeks, with participants attending a series of scheduled visits to monitor progress and assess treatment efficacy and safety. These visits will include baseline assessments, interim evaluations, and a final end-of-study visit at week six, where the primary and secondary endpoints will be measured.

Participant involvement is expected to last for the entire six-week duration of the trial, barring any conditions that may necessitate early termination, such as adverse events or withdrawal of consent. The trial's design ensures that neither the participants nor the investigators are aware of the treatment assignments, maintaining the integrity of the double-blind methodology. The study aims to provide robust data on the efficacy of Samyr® as an adjunctive treatment for MDD, contributing valuable insights into its potential role in managing this psychiatric disorder.

The clinical trial involves the administration of **SAMYR 400 mg** gastro-resistant tablets, which contain the active substance **ademetionine**. Ademetionine, also known as S-adenosylmethionine or S-adenosyl-L-methionine, is a chemical compound used in the treatment of major depressive disorder. The pharmaceutical form of SAMYR is a gastro-resistant tablet, designed to prevent the release of the active substance until it reaches the intestine, thereby enhancing its absorption and efficacy. The medication is administered orally, with a maximum daily dose of 1600 mg and a total maximum dose of 58800 mg over the course of the treatment. The treatment period is set for a maximum of six weeks. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

The study also includes a **placebo** group, which receives a tablet identical in appearance to the SAMYR tablet but without the active substance. The placebo is formulated with the same excipients as the SAMYR tablet to maintain blinding in the study. The placebo is administered in the same manner as the active treatment, ensuring that any observed effects can be attributed to the active substance rather than the act of taking a tablet. The use of a placebo control is essential in this double-blind, randomized, placebo-controlled trial to objectively assess the efficacy and safety of SAMYR in patients with major depressive disorder.

Efficacy in this clinical trial will be assessed by evaluating the change in the **Hamilton Depression Rating Scale-17 (HDRS-17)** score from baseline to visit 9, which corresponds to week 6 of treatment. The primary endpoint focuses on this change in HDRS-17 score, which is a widely recognized tool for measuring the severity of depression symptoms. The trial aims to demonstrate the superiority of Samyr® tablets over placebo tablets when used alongside adjunctive antidepressant therapy in patients with Major Depressive Disorder (MDD) who have shown an inadequate response to their current antidepressant treatment.

Secondary endpoints include the change from baseline in the Patient Global Impression (PGI) and Clinical Global Impression (CGI) scales after 6 weeks of treatment. These scales provide additional insights into the patient's overall impression of their condition and the clinician's assessment of the patient's illness severity and improvement. The assessments will be conducted at specified timepoints, with the primary focus on the results at the end of the 6-week treatment period. The trial is designed as a randomized, double-blind, placebo-controlled, parallel-group, multi-center study, ensuring rigorous evaluation of the efficacy parameters.