FDA Closes Inspection of Site for Phase 3 TRANQUILITY II Trial of BXCL501 in Alzheimer Agitation

Vimal Mehta, PhD

According to a recent announcement, the FDA has closed its inspection of a single site in the phase 3 TRANQUILITY II trial (NCT05271552) under 21 C.F.R. 20.64(d)(3) and issued the Establishment Inspection Report, designating the site with a status of “Voluntary Action Indicated.”¹

TRANQUILITY is a double-blind, placebo-controlled trial assessing the therapeutic potential of BXCL501 (BioXcel Therapeutics), an investigational proprietary, orally dissolving film formulation of dexmedetomidine, as a potential treatment for Alzheimer disease (AD) agitation. For context, in October 2023, BioXcel conducted an independent audit after the drugmaker disclosed that a principal investigator involved in the study was under investigation in a regulatory filing. According to the SEC filing, the same investigator was being accused of fabricating an email correspondence related to the reported timing of a serious adverse event (AE) as required in the study protocol.

At the time, the company reported that the principal investigator enrolled around 40% of the trial participants and was investigating protocol adherence and data integrity at the site. Analysts noted that the company’s shares declined due to multiple factors, including "lost confidence in management," concerns over the "quality of the data package," uncertainty about FDA acceptance of the package, the timing of a supplemental new drug application submission, and the potential timing of any related revenue, if it materialized.

"We believe this report and the closing of the investigation, together with the positive findings from the independent audit we announced in October 2023, further reaffirm the data integrity from the single site and the body of clinical evidence we intend to include in a potential sNDA submission," Vimal Mehta, PhD, chief executive officer at BioXcel, said in a statement.¹ "We have already received FDA feedback on the protocol for our TRANQUILITY In-Care Phase 3 trial and look forward to advancing this program with our lead neuroscience asset BXCL501."

The designation “Voluntary Action Indicated” showed that the agency identified minor issues or deviations from regulations that do not warrant immediate action. In essence, the issues observed do not pose a significant risk to public health or violate critical regulatory requirements. In addition, the FDA does not plan to take further action, such as issuing a warning letter or initiating law enforcement, as long as the facility resolves the concerns adequately and in a timely manner.

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TRANQUILITY included 149 patients with mild to moderate dementia who were from assisted living facilities and residential care settings who needed minimal assistance with daily living activities. Each patient was randomly assigned to self-administered 40 mcg or 60 mcg of BXCL501 or placebo for agitation episodes over a 12-week treatment period. Topline data announced in September 2023 showed that the agent was well tolerated and met its primary end point, demonstrating a statistically significant reduction in Positive and Negative Syndrome Scale-Excitatory Component (PEC) total score.

In the study, patients on 60 mcg dose of BXCL501 showed a 7.5-point reduction in PEC total score at 2 hours compared with reductions of 5.4 for those on placebo (P = .0112). The same dosage also met its first key secondary end point of reducing agitation symptoms at 1 hour during the first episode of agitation (P = .0185); however, it did not meet the other key secondary end point of change from baseline in PEC score at 30 minutes. In addition, the 60 mcg dose group demonstrated a reduction in PEC total score from predose versus placebo at 1 hour (P = .011) and 2 hours (P = .0044) for all episodes of agitation (n = 443).

Over the 12-week study, 294 episodes occurred after the first treatment across all dose groups, with no instances of syncope or falls attributed to trial therapy. All falls, except one with placebo, occurred outside the 24-hour treatment window, including 5 falls in the 40 mcg group, 7 in the 60 mcg group, and 5 in the placebo group. Most safety events within 24 hours of dosing were mild or moderate, and subsequent dosing did not lead to a significant increase in adverse effects. No treatment-related serious adverse events were reported during the study.

REFERENCES
1. BioXcel Therapeutics Announces FDA Closed its Inspection of Site for Phase 3 TRANQUILITY II Trial for Acute Treatment of Agitation Associated with Alzheimer’s Dementia. News release. BioXcel Therapeutics. March 3, 2025. Accessed March 6, 2025. https://www.globenewswire.com/news-release/2025/03/03/3035455/0/en/BioXcel-Therapeutics-Announces-FDA-Closed-its-Inspection-of-Site-for-Phase-3-TRANQUILITY-II-Trial-for-Acute-Treatment-of-Agitation-Associated-with-Alzheimer-s-Dementia.html
2. Dennis M. BioXcel's shares crater on data integrity doubts for Alzheimer's agitation drug. News Release. First Word Pharma. Published June 9, 2023. Accessed March 6, 2025. https://firstwordpharma.com/story/5756276?aid=5756276
3. BioXcel Therapeutics Announces Positive Topline Results From TRANQUILITY II Phase 3 Trial of BXCL501 for Acute Treatment of Alzheimer’s Disease-Related Agitation. News Release. BioXcel Therapeutics. Published June 29, 2023. Accessed March 6, 2025. https://ir.bioxceltherapeutics.com/news-releases/news-release-details/bioxcel-therapeutics-announces-positive-topline-results