Evaluation of Ademetionine Intramuscular Injection as an Adjunctive Therapy to Antidepressants in Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Study
- Trial ID
- 2024-513022-29-00
- Protocol
- MYL-1603N-3002
- Sponsor
- Mylan Inc.
Trial statistics
Objectives
The primary objective of this study is to demonstrate that **Samyr** intramuscular (IM) is superior to placebo IM as an enhancer adjunctive to antidepressant therapy in patients with **Major Depression Disorders**. The primary endpoint is the change from baseline in the Montgomery Asberg Depression Rating Scale (MADRS) score after 7 days of treatment. This is clinically relevant as it aims to provide evidence for the efficacy of Samyr as an adjunctive treatment, potentially offering a new therapeutic option for patients who have not experienced sufficient symptom improvement with standard antidepressant treatments.
Secondary objectives include evaluating the change from baseline at scheduled visits in the following measures:
- MADRS
- HRDS-6 (Per-Bech)
- Clinical Global Impression (CGI) and Patient Global Impression (PGI)
Participants
The clinical trial involves participants diagnosed with **Major Depression Disorders**. The study population includes both male and female subjects aged between 18 to 65 years. Participants are required to have a primary diagnosis of Major Depression Disorder for at least 12 weeks, as per the DSM-5 criteria. They must be on a prescribed SSRI or SNRI antidepressant treatment at an approved and stable dose for at least four weeks prior to screening, with a partial response to the treatment in the last eight weeks. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants are expected to comply with the study protocol, including visits, assessments, and scales. Key lifestyle considerations such as diet, physical activity, or habits are not specified. The selection criteria ensure that participants have a Montgomery-Asberg Depression Rating Scale (MADRS) score of at least 22 at screening and a score of 19 or higher at randomization, with less than a 15% reduction at baseline post run-in treatment.
Plans and Procedures
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** administered intramuscularly compared to a placebo in patients with **Major Depression Disorders**. The trial aims to demonstrate that Samyr is superior to placebo as an enhancer adjunctive to antidepressant therapy. The primary endpoint is the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) score after 7 days of treatment. The trial is expected to conclude by June 2025, with recruitment having commenced in January 2019.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, diagnosis, and current antidepressant treatment. Eligible participants will be randomly assigned to receive either Samyr or placebo. The study includes multiple follow-up visits to monitor changes in MADRS scores and other secondary endpoints, such as changes in HRDS-6, CGI, and PGI scores. The end-of-study visit will evaluate the overall treatment efficacy and safety.
The expected length of participant involvement is approximately 2 weeks, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include non-compliance with the study protocol, adverse events, or withdrawal of consent. Participants are required to provide written informed consent and demonstrate a partial response to their current antidepressant treatment, as defined by less than 50% symptom reduction. The study is conducted under strict adherence to ethical guidelines and regulatory requirements.
Treatment
The clinical trial involves the administration of **SAMYR** 400 mg/5 ml, a **solution for injection** containing the active substance **ademetionine**. This experimental medication is provided in the form of a powder and solvent for injectable solution, intended for **intramuscular use**. The maximum daily dose of ademetionine is 800 mg, with a total maximum dose of 10,800 mg over the treatment period. The treatment duration is limited to a maximum of 2 weeks. Ademetionine, also known as S-adenosylmethionine or S-adenosyl-L-methionine, is a chemical compound used in this study to evaluate its efficacy as an enhancer adjunctive to antidepressant therapy in patients with Major Depression Disorder. The administration schedule and participant compliance are monitored throughout the trial to ensure adherence to the dosing regimen.
The study also includes a **placebo** group, which receives a saline solution as a comparator treatment. The placebo is designed to mimic the experimental treatment in appearance and administration route, ensuring the study remains double-blind. The placebo is administered intramuscularly, similar to the experimental medication, to maintain consistency in the treatment protocol. The use of a placebo allows for the assessment of the true efficacy and safety of SAMYR as an adjunctive treatment by providing a baseline for comparison. Participant compliance with the placebo administration is similarly monitored to maintain the integrity of the trial results.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) score after 7 days of treatment. This endpoint will be evaluated at visit 13. The MADRS is a widely used and validated scale for assessing the severity of depressive episodes in patients with Major Depressive Disorder (MDD). Secondary endpoints include the MADRS change from baseline at scheduled visits, the change in the HRDS-6 (Per-Bech) score, and changes in the Clinical Global Impression (CGI) and Patient Global Impression (PGI) scores from baseline at scheduled visits. These assessments will provide a comprehensive evaluation of the antidepressant efficacy of **ademetionine** as an adjunctive treatment compared to placebo. The trial is designed as a randomized, double-blind, placebo-controlled, parallel-group, multi-center study, ensuring robust and reliable data collection and analysis.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Written and signed informed consent needs to be provided by participant before starting any protocol-specific procedures.
- Male and female participant 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), criteria.
- Participant is on prescribed SSRI (citalopram / escitalopram / sertraline / paroxetine) or SNRI (venlafaxine / duloxetine) antidepressant treatment, at approved and stable dose (based on local SmPC), for at least 4 weeks prior to screening.
- Partial-response to the prescribed antidepressant during the last 8 weeks prior to screening. Partial response is defined as less than 50% symptom reduction based on the investigator judgment and the treatment history.
- Participant who have a Montgomery-Asberg Depression Rating Scale (MADRS) score as assessed by the site investigator of at least 22 at screening and with less than 15% reduction at baseline, post run in treatment. Additionally, participant must have a MADRS score of ≥19 at randomization.
Exclusion Criteria
- 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.
- Participant 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).
- Treatment with Monoamine Oxidase (MAO)-inhibitors including selegiline and moclobemide, during the 4 weeks prior to screening.
- Treatment with linezolid or pimozide.
- Treatment with at least one prohibited medication as detailed in appendix 1 (prohibit drug medication prior and during the study).
- Cardiac disorder which in the Investigator’s opinion would place the participant at an unacceptable risk from trial participation.
- Known QT interval prolongation or congenital long QT syndrome.
- Treatment with products that are known to prolong the QT interval.
- Hepatic values that in the Investigator’s opinion would place the participant at an unacceptable risk as a result of trial participation.
- Decrease in the baseline MADRS score by ≥ 15% vs screening visit.
- 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.
- Female participant who are pregnant or plan to be pregnant or breast-feeding.
- Female participant 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.
- 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.
- History of bipolar disorders, Schizophrenia and other psychotic disorders.
- Substance abuse or dependence.
- 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, OR - “Yes” to Questions 4 or 5 on the Since Last Visit version of the Suicidal Ideation section at the Baseline Visit - “Yes” to any question on the Suicidal Behavior section at the Baseline Visit.
- Use of more than 4 acceptable antidepressant treatments since the diagnosis of depression or treatment with ECT or ketamine during the current episode or lifetime treatment with Vagus Nerve Stimulation (VNS) during the last 5 years.
- Previous treatment with Samyr which was not effective or resulted in an AE, or already treatment with Samyr during the current episode.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 17 Jan 2019 | 468 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Samyr placebosaline solution | Placebo | N/A | — | — | — | N/A |
SAMYR 400 mg/5ml polvere e solvente per soluzione iniettabile | Test | POLVERE E SOLVENTE PER SOLUZIONE INIETTABILE | INTRAMUSCULAR USE | 800 | 2 | PRD4744261 |
Sodio Cloruro Fresenius Kabi Italia 0,9%, solvente per uso parenterale | Placebo | SOLVENTE PER USO PARENTERALE | INTRAMUSCULAR USE | 10 | 18 | PRD2503743 |