Evaluation of Accelerated Intermittent Theta-Burst Stimulation with D-Cycloserine Augmentation in Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this clinical trial is to assess the **efficacy** of adding a daily oral dose of 100 mg D-cycloserine for patients with **Major Depressive Disorder (MDD)** compared to placebo. This evaluation will occur over a nine weekday treatment course of accelerated intermittent theta-burst stimulation (aiTBS). The primary outcome measure is the difference between groups in changes in depressive symptoms, specifically in a population aged over 18 years with a current depressive episode, as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score greater than 19.

The secondary objectives are to evaluate the efficacy of the same treatment regimen on other associated psychiatric symptoms, overall function, health perception, cognitive function as measured by THINC-it, and neurophysiological brain functioning. The latter will be assessed using resting state Electroencephalography (EEG) and frontal functional near-infrared spectroscopy (fNIRS).

The clinical trial focuses on evaluating the efficacy of adding a daily oral dose of 100 mg D-cycloserine for **Major Depressive Disorder (MDD)** compared to placebo. The study population includes adults aged 18 years and older who are currently experiencing a depressive episode, as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score greater than 19. Both male and female participants are included, with specific considerations for female subjects of fertile age to use adequate contraception. Participants are required to meet the ICD-10 criteria for a diagnosis of major depressive disorder and must have sustained moderate to severe depression symptoms at screening, defined by a MADRS total score of 20 or higher. The trial population is selected based on their ability to read, speak, and understand Swedish, and their willingness to adhere to study requirements, including attending all study visits and completing evaluations. Participants must have experienced a failure to achieve clinical response with at least one adequate trial of a first-line antidepressant medication or psychotherapy. The sponsor has not provided information regarding the total number of participants. The trial includes both male and female subjects and considers vulnerable populations. Participants must have had unchanged antidepressant medications for four weeks prior to enrollment and should not intend to change medications during the first 28 days of the study.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy of adding a daily oral dose of 100 mg **D-cycloserine** for the treatment of **major depressive disorder** (MDD). The trial will span a period of nine weekdays, during which participants will receive either the active treatment or a placebo. The primary objective is to assess the difference in changes in depressive symptoms between the treatment and placebo groups, as measured by the Montgomery-Asberg Depression Rating Scale (MADRS). The trial is set to commence on October 1, 2025, with an estimated completion date of December 31, 2028.

Participants will be involved in the study for a maximum of 180 days, with the treatment phase lasting nine weekdays. The study will include several key visits: an initial screening visit to confirm eligibility, followed by treatment visits, and multiple follow-up visits. The inclusion visit will ensure that participants meet the criteria, such as being over 18 years old, having a current depressive episode, and a MADRS score of 20 or higher. Follow-up visits will occur on days 5, 12, 28, 42, and 180 to monitor changes in depressive symptoms and other health parameters. The end-of-study visit will take place on day 180, marking the conclusion of participant involvement.

Participants may be withdrawn from the study if they fail to adhere to the study protocol, experience significant adverse effects, or if there is a need to initiate new antidepressant treatments. The primary endpoint is the between-group difference in the change of the MADRS total score from baseline to day 28. Secondary endpoints include changes in depressive symptoms at various time points, response and remission rates, and survival time to new antidepressant treatment initiation. The study will also assess changes in cognitive functioning, anxiety symptoms, and general health perception.

The clinical trial involves the administration of **CYCLOSERINE**, a hard capsule formulation, as the experimental medication. Each capsule contains 100 mg of the active substance cycloserine, which is of chemical origin. The medication is administered orally, with a maximum daily dose of 100 mg and a total maximum dose of 900 mg over the course of the treatment. The treatment period is set for nine weekdays. The cycloserine capsules have been re-capsuled from an original 250 mg to 100 mg to meet the study's dosing requirements. The cycloserine used in this trial is provided by NEON HEALTHCARE LIMITED and ANTIBIOTICE SA, with marketing authorization numbers PL 45043/0109 and 129/2007/01, respectively.

The trial also includes a **placebo** control, which is a size 1, opaque, orange hard gelatine capsule. The placebo is identical in appearance and similar in weight to the investigational medicinal product (IMP) to ensure blinding. These capsules are filled with microcrystalline cellulose and are administered orally at the same frequency and duration as the cycloserine capsules. The placebo is used to assess the efficacy of cycloserine in comparison to a non-active treatment, maintaining the double-blind nature of the study.

The efficacy of the clinical trial will be assessed by evaluating the impact of adding a daily oral dose of 100 mg **D-cycloserine** for the treatment of major depressive disorder (MDD) compared to a placebo. The primary endpoint for efficacy assessment is the between-group difference in the change of the Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline to Day 28, as evaluated by a blinded rater through video consultation. This assessment will be documented on an item level in the electronic Case Report Form (eCRF).

Secondary endpoints include changes in observer-rated depressive symptoms using MADRS on treatment days 12 and 180, and the Clinical Global Impression (CGI) at days 12, 28, and 180. Additional secondary endpoints involve response and remission rates at all time points using both observer-rated MADRS and self-rated depressive symptoms via the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR). Other measures include survival time to initiation of new antidepressant treatment, hospitalization, or death during the study period, and changes in self-rated depressive symptoms, suicidal ideation, anxiety symptoms, functioning, and general health perception at specified time points. Cognitive functioning, pre-attentive stimuli detection, frontal oxygenation, and resting EEG measures will also be evaluated as part of the secondary endpoints.