Low-Dose Active-Control Trials in Psychedelic and CNS Drug Development

This week, Compass Pathways plc (Nasdaq: CMPS) announced the successful achievement of the primary endpoint in the ongoing Phase 3 COMP005 trial, the first of two Phase 3 trials evaluating COMP360, a synthetic, proprietary formulation of psilocybin, for treatment-resistant depression (TRD). Psilocybin is a psychedelic drug. The field of psychedelic drug development is experiencing a renaissance, driven by growing interest in their potential to treat mental health disorders including major depression disorder, Post-Traumatic Stress Disorder (PTSD), and advancements in research methodologies. It is interesting to see that the phase 3 study conducted by Compass Pathways plc utilized the clinical trial design with low dose or sub-perceptual dose of the active drug as the control group (versus the traditional placebo as the control group). 

Challenges in Clinical Trial Design for Psychedelic Drug Development

According to FDA guidance "Psychedelic Drugs:Considerations forClinical Investigations", the followings are key challenges for psychedelic drug clincial trials. 

• Functional Unblinding and Expectancy Bias: Psychedelic drugs cause intense perceptual disturbances and alterations in consciousness, making it difficult to maintain blinding in studies. Subjects receiving the active drug often experience "functional unblinding." Additionally, high expectations from participants receiving the active drug, or disappointment (nocebo effect) in those receiving a placebo, can influence outcomes.

• Control Conditions: Using a traditional placebo can be problematic for assessing efficacy due to functional unblinding and the potential for a nocebo effect. While inactive controls help contextualize safety, alternatives like subperceptual doses or other psychoactive drugs are being considered, but they also present their own challenges.

• Contribution of Psychotherapy: Many psychedelic drug development programs incorporate psychological support or psychotherapy. This adds a variable that complicates the assessment of the drug's effectiveness and presents challenges for future product labeling. The specific contribution of the psychotherapy component to any observed efficacy is not yet characterized and has the potential to increase expectancy and performance biases.

• Dose-Response Relationship: The dose-response relationship for most psychedelic drugs is not well understood for both efficacy and safety.

• Durability of Treatment Effect and Repeat Dosing: While current programs explore single or intermittent dosing, many conditions being studied are chronic. Characterizing the durability of response, recommended interdose intervals, and the safety and efficacy of repeat dosing are significant challenges.

• Safety Monitoring During Sessions: Subjects remain in a vulnerable state for up to 12 hours after receiving active treatment. This necessitates specific safety monitoring measures, including observation by two monitors, with a lead monitor who is a healthcare provider with graduate-level training and clinical experience in psychotherapy and is licensed to practice independently.

• Abuse Potential Assessment: Psychedelic drugs act on the central nervous system and produce psychoactive effects, requiring evaluation for abuse potential. This includes monitoring abuse-related adverse events, even if they are hypothesized to be associated with a therapeutic response.

Reagan-Udall Foundation for the FDA organized a workshop "Advancing Psychedelic Clinical Study Design Design", the challenges in psychedelic clinical trial design were extensively discussed:

• Blinding & Expectancy: It's difficult to blind studies due to the profound psychoactive effects, leading to "functional unblinding" where participants and therapists often know who received the active drug. High expectations from media coverage can also inflate outcomes 
• Control Conditions: Traditional placebos can be problematic, leading to unblinding and nocebo effects. Active comparators are an option, but finding one with similar subjective effects without being therapeutic is challenging. Sub-perceptual doses are also being explored, but they might still have psychoactive effects.
• Role of Psychotherapy/Facilitation: The therapeutic intervention (preparation, in-session monitoring, integration) significantly influences outcomes, and its contribution needs to be distinguished from the drug's effect 
• Dose-Response Relationship: Understanding the dose-response relationship for safety and efficacy is crucial, and dose-response trials are considered valuable 
• Durability of Treatment Effect: A major question is how long the effects last and the need for redosing, especially for chronic conditions

One of the approaches to address the blinding issue or functional unblinding issue is to use the low dose (or sub-perceptual dose, sub-optimal dose) of the active drug (in this example, the psychedelic drug psilocybin).  

Low-dose active control is used beyond the psychedelic drug clinical trials. It is also used in other CNS drug clinical trials. Some of the trials with low-dose active control lead to the drug approval by the FDA. Here are examples of Low-Dose Active-Control Trials in CNS Drug Approvals

• Lamotrigine XR (Lamictal XR) – Indication: Conversion to monotherapy for partial-onset seizures in patients ≥13 years. Trial: Study LAM30055 (multicenter conversion-to-monotherapy). Sponsor: GlaxoSmithKline. FDA Approval: April 2011. Reason for design: In epilepsy monotherapy trials, giving a true placebo is unethical. The FDA accepted a “pseudoplacebo” control (historical data from low‐dose valproate) to demonstrate lamotrigine’s efficacy This low-dose VPA arm served as an inferior active control so that a full placebo arm could be avoided while still assessing drug effect.

• Oxcarbazepine (Trileptal) – Indication: Monotherapy for partial-onset seizures. Trial: Two Phase 3 trials comparing high-dose Trileptal (2400 mg/day) to a subtherapeutic Trileptal dose (300 mg/day). Sponsor: Novartis. FDA Approval: mid-2000s (first-line monotherapy around 2005). Reason: Again, placebo was deemed unethical in active seizure patients. The control arm received only 300 mg (a suboptimal dose) of oxcarbazepine. This “low-dose active” control (essentially a pseudo-placebo) allowed demonstration of efficacy (fewer seizures/dropouts in the high-dose arm) without exposing patients to no treatment.

• Pregabalin (Lyrica) – Indication: Monotherapy for partial-onset seizures. Trial: Randomized conversion-to-monotherapy trial of pregabalin 600 mg/day vs pregabalin 150 mg/daypmc.ncbi.nlm.nih.gov (high-dose vs low-dose active control). Sponsor: Pfizer. FDA Approval: ~2017 (supplement to extend indication). Reason: As with other AEDs, full placebo was not used. The trial randomized patients to a high dose or a low “pseudo-placebo” dose (150 mg) of pregabalin. Using a subtherapeutic active dose allowed assessment of efficacy (few patients worsened on 600 mg) while avoiding a true placebo arm. Regulatory briefing notes explain that monotherapy trials in epilepsy often use a “pseudo-placebo” (suboptimal dose of drug) for exactly this ethical reason.

Rationale for Low-Dose Active Controls

These examples share a common rationale: in serious conditions like major depression disorder, PTSD, and epilepsy, withholding effective therapy (i.e. using true placebo) is ethically problematic. Using true placebo results in the functional unblinding. Regulatory authorities have allowed a “low-dose active” or “pseudo-placebo” comparator to ensure trial blinding and assay sensitivity while not denying therapy In practice, patients in the control group receive a sub-therapeutic dose of an anticonvulsant (e.g. low-dose valproate or pregabalin) instead of no drug. This strategy maintains the appearance of treatment, minimizes risk of uncontrolled seizures, and still permits demonstration of dose–response or superiority of the higher dose. As noted in FDA/clinical guidance and literature, this design avoids exposing patients to a completely inert treatment in life‐threatening disorders. In all cases above, the low-dose arm (active control) was chosen for ethical reasons (protecting patients) and to meet regulatory requirements for demonstrating efficacy without a true placebo.