Seaport Therapeutics Investigates Clinical Trial Design and Placebo Response in Major Depressive Disorder Studies
Seaport Therapeutics (“Seaport” or “the Company”), a clinical-stage biopharmaceutical company focused on advancing innovative neuropsychiatric medicines, has presented a new meta-analysis examining the impact of clinical trial design factors on placebo response magnitude in major depressive disorder (MDD) studies. This research was showcased in a poster presentation at the International Society for CNS Clinical Trials and Methodology (ISCTM) Conference, held from February 19–21, 2025, in Washington, D.C.
The Challenge of Placebo Response in CNS Trials
Clinical trials in central nervous system (CNS) disorders, including MDD, pose unique challenges, one of the most significant being high placebo response rates. A strong placebo effect can obscure the true efficacy of investigational treatments, making it difficult for pharmaceutical companies and researchers to achieve meaningful results. Seaport Therapeutics aims to address this issue by analyzing past studies and identifying factors that contribute to increased placebo response rates.
“CNS clinical trials present unique challenges, including high placebo responses. Analyzing past studies in a systematic way can help propel the entire field forward,” said Tony Loebel, M.D., Chief Medical Officer and President of Clinical Development at Seaport Therapeutics. “At Seaport, as we progress our pipeline of investigational antidepressants and anxiolytics, we believe our experience in the field, combined with our focus on clinically validated mechanisms, positions us to run better-designed and more informed trials that minimize placebo effects. Through sharing analyses such as these, we hope to contribute to broader knowledge in the field.”
The Importance of Addressing Placebo Effects
The presence of a strong placebo response in MDD trials is a well-documented issue, with research suggesting that approximately 50–70% of such trials fail to meet their primary endpoint. Randomized, placebo-controlled trials often show high placebo responses on clinical endpoints, complicating the assessment of investigational drug efficacy. These failures not only hinder drug development but also delay the introduction of potentially beneficial treatments to patients in need.
Given the impact of placebo responses, understanding the factors that contribute to their magnitude is essential for improving trial design. The goal of Seaport’s meta-analysis was to identify which design elements have the most significant influence on placebo effects and to provide insights that can be leveraged to optimize future MDD trials.
Key Findings from the Meta-Analysis
Seaport’s meta-analysis reviewed data from 27 industry-sponsored Phase 2–4, placebo-controlled MDD trials conducted over the past decade. Each of these studies adhered to strict inclusion criteria, including the use of the Hamilton Depression Rating Scale (HAM-D) or the Montgomery–Åsberg Depression Rating Scale (MADRS) as primary endpoints.
Key findings from the research include:
- Frequency and Number of Clinician-Administered Assessments (CAAs) Impact Placebo Response:
- The analysis revealed a strong correlation between an increased number and frequency of clinician-administered assessments and higher placebo response rates. This relationship persisted even when accounting for other factors such as trial site numbers, patient in-clinic visits, and treatment type.
- Trial Duration and Number of Sites Did Not Show a Significant Effect:
- Contrary to previous assumptions, neither the length of the study nor the number of trial sites had a meaningful association with placebo response. These findings suggest that simply extending the duration of a trial or expanding its geographic reach may not be effective strategies for reducing placebo effects.
- Baseline Depression Severity and Placebo Response:
- Higher baseline depression severity, as measured by HAM-D scores, appeared to have a modest association with greater placebo-related improvements. However, the impact of baseline severity was observed in a limited subset of studies, indicating that additional research is needed to confirm this relationship.
These findings offer important insights for the design of future MDD trials, highlighting the need to carefully consider the role of clinician-administered assessments in trial protocols.
Implications for Future MDD Trials
Understanding how trial design elements influence placebo responses can guide the development of more effective study protocols. Based on the findings of Seaport’s meta-analysis, researchers and trial sponsors may consider:
- Optimizing the Use of CAAs:
- Since an increased number and frequency of clinician-administered assessments were linked to higher placebo responses, trial designers may need to rethink the necessity and timing of these assessments to mitigate their impact.
- Refining Patient Selection Criteria:
- The observation that higher baseline depression severity may contribute to placebo response suggests that more stringent inclusion criteria or stratification based on severity levels could be beneficial.
- Exploring Alternative Study Designs:
- Given that neither trial duration nor number of sites significantly impacted placebo response, researchers may need to explore novel study methodologies, such as adaptive trial designs or placebo run-in phases, to better manage this effect.
Seaport’s Commitment to Innovation in Neuropsychiatry
Seaport Therapeutics is dedicated to addressing unmet needs in neuropsychiatric medicine. The company is actively advancing a pipeline of investigational antidepressants and anxiolytics based on clinically validated mechanisms. By leveraging insights from analyses like this meta-study, Seaport aims to design more efficient and effective clinical trials that can accelerate the development of new treatments for MDD and related disorders.
The presentation at ISCTM 2025 underscores Seaport’s commitment to collaboration and knowledge-sharing in the field of CNS drug development. Through ongoing research and strategic trial optimization, the company hopes to contribute to industry-wide advancements in understanding and mitigating placebo effects in MDD trials.
