Efficacy and Safety Evaluation of Intranasal BPL-003 in Treatment-Resistant Depression: A Quadruple-Masked, Dose-Finding Study with Open-Label Extension

The primary objective of this study is to determine the **efficacy** of BPL-003, administered intranasally with psychological support, in participants with **Treatment-Resistant Depression (TRD)**. This is clinically relevant as TRD represents a significant challenge in psychiatric treatment, with patients often not responding to standard therapeutic interventions. The study aims to assess whether BPL-003 can provide a viable treatment option for this difficult-to-treat population.

Secondary objectives include:

• Determining the efficacy, including early onset, of BPL-003 given with psychological support to participants with TRD.
• Assessing the safety of various dosages of BPL-003 administered with psychological support to participants with TRD.
• Evaluating the pharmacokinetics of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and its metabolites, including bufotenine, in participants with TRD after nasal administration of BPL-003.
• Determining the effects on depression and disability of different dosages of BPL-003 given with psychological support to participants with TRD.
• Evaluating the efficacy of BPL-003 in an open-label extension phase, given with psychological support to participants with TRD.
• Assessing the pharmacokinetics of 5-MeO-DMT and its metabolites in an open-label extension phase after nasal administration of BPL-003.
• Determining the effects of BPL-003 on depression and disability in an open-label extension phase, given with psychological support to participants with TRD.

The clinical trial involves a total of **85 participants** diagnosed with **Treatment-Resistant Depression (TRD)**. The study population includes both male and female subjects, aged between 18 to 75 years, who have been diagnosed with at least moderate major depressive disorder, either as a single or recurrent episode, as per DSM-5 criteria. Participants were selected based on their failure to respond to an adequate dose and duration of at least two pharmacological treatments in the current episode. The trial includes individuals who are willing to abstain from recreational drugs and alcohol for specified periods and are able to comply with all study requirements. Participants must have a Hamilton Depression Rating Scale score of 19 or higher at screening and baseline. The trial population is characterized by a willingness to discontinue current antidepressant medications, following local treatment guidelines to avoid withdrawal symptoms. The study does not exclude individuals based on intermittent use of cannabinoids prior to screening, provided they do not meet the criteria for substance use disorder. The trial includes a vulnerable population, ensuring informed consent and communication with participants' general practitioners and consultants as appropriate.

The clinical trial is designed to evaluate the **efficacy** and safety of intranasal BPL-003 in patients with **treatment-resistant depression** (TRD). This study is a randomized, quadruple-masked, dose-finding trial with an open-label extension phase. The trial is expected to commence on November 15, 2023, and conclude by March 7, 2025. Participants will be involved in the study for a duration that includes multiple visits, starting with a screening visit to assess eligibility based on inclusion criteria such as age, diagnosis of TRD, and willingness to comply with study requirements. The trial will include follow-up visits to monitor the primary endpoint, which is the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS), and secondary endpoints such as treatment-emergent adverse events and changes in various clinical parameters.

Study visits are structured to ensure comprehensive data collection and participant safety. The initial screening visit will confirm eligibility, including a diagnosis of moderate major depressive disorder and failure to respond to at least two pharmacological treatments. Participants will then undergo baseline assessments before randomization. Follow-up visits will occur at specified intervals to evaluate the primary and secondary endpoints, including changes in depression severity and safety assessments. The end-of-study visit will finalize data collection and assess the overall impact of the treatment.

Participant involvement is expected to last throughout the trial duration, with specific conditions outlined for early termination, such as non-compliance with study protocols or the occurrence of significant adverse events. The trial's design ensures that all participants receive psychological support alongside the investigational product, with the open-label extension phase focusing on long-term safety. The study's methodology, including its randomized and masked nature, aims to provide robust data on the therapeutic potential of BPL-003 for individuals with TRD.

The clinical trial involves the administration of **BPL-003**, a chemical compound developed by Beckley Psytech Ltd. The active substance in BPL-003 is **5-Methoxy-N,N-dimethyltryptamine benzoate**, also known by its synonyms BPL-003 benzoate and 5-MeO-DMT benzoate. The pharmaceutical form of BPL-003 is not specified in the available data. The trial aims to evaluate the efficacy and safety of intranasal administration of BPL-003 in patients with treatment-resistant depression. The dosage, frequency, and specific administration details are not disclosed in the provided information.

In addition to the experimental treatment, the study includes psychological support as a non-experimental component to assist participants with treatment-resistant depression. The psychological support is intended to complement the administration of BPL-003, although specific details regarding the nature and frequency of this support are not provided. The trial is designed as a quadruple-masked, dose-finding study with an open-label extension to further assess the safety of BPL-003 in the target population.

The efficacy of the investigational product BPL-003 in patients with **Treatment Resistant Depression** (TRD) will be assessed using several primary and secondary endpoints. The primary endpoint for the CORE study is the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) scores. This scale is a widely used, validated tool for assessing the severity of depressive episodes. The secondary endpoints include additional changes in MADRS scores, the percentage of responders (defined as a 50% reduction in MADRS total score), and the percentage of participants in remission (defined as a MADRS total score ≤ 10). Other secondary endpoints involve changes in the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16), Quality of Life in Depression Scale (QLDS), and Sheehan Disability Scale (SDS) scores, as well as changes in Clinical Global Impression-Severity (CGI-S) scores.

For the Open Label Extension (OLE) phase, efficacy will be further evaluated by monitoring changes in MADRS scores compared to both OLE and CORE baselines. The percentage of responders and participants in remission will also be assessed. Plasma levels of 5-MeO-DMT and its metabolites, including bufotenine, will be measured following nasal administration of BPL-003. The incidence of suicidal ideation or behavior will be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS). These assessments will be conducted at specified timepoints throughout the study to ensure comprehensive evaluation of the treatment's efficacy.