An 8-Week, Randomized, Phase 2, Double-Blind, Sequential Parallel-Group Comparison Study of Two Dose Levels of the GABAA Positive Allosteric Modulator PF-06372865 Compared With Placebo as an Adjunctive Treatment in Outpatients With Inadequate Response to Standard of Care for Generalized Anxiety Disorder.

Abstract

BACKGROUND:

Generalized anxiety disorder (GAD) is a common psychiatric disorder, but many patients experience only partial relief of symptoms with existing therapies. Benzodiazepines are effective in many cases but are limited by a number of significant adverse effects. PF-06372865 is a subtype-selective gamma-aminobutyric acid A (GABAA)-positive allosteric modulator lacking in functional activity at alpha 1-containing receptors that are believed to mediate many of these adverse effects.

METHODS:

PF-06372865 was evaluated as an adjunct to current GAD treatment in a double-blind, placebo-controlled, sequential parallel comparison study in patients with GAD who showed an incomplete response to current standard-of-care pharmacotherapy. A total of 90 subjects (of the planned 384) were randomized into the study before the decision to terminate the study. Two doses of PF-06372865 (2.5 mg twice daily and 7.5 mg twice daily) were compared with placebo.

RESULTS:

Neither dose of PF-06372865 differentiated from placebo on week 4 Hamilton Anxiety Inventory total (primary end point) or on the Sheehan Disability Scale total score (secondary end point). Adverse events including dizziness, headache, and somnolence were observed, and the 7.5 mg dose demonstrated some impairment on the Digit Symbol Substitution test and the Epworth Sleepiness Scale relative to placebo and the 2.5 mg dose.

CONCLUSIONS:

Factors contributing to the negative results include the limited sample size and failure to explore a broader range of doses.

• Authors: Arthur Simen, Mark Whitlock, Ruolun Qiu, Jeff Miceli, Laura Zumpano, Michaele Du Metz, Pinky Dua, Brendon Binneman
• Journal: Journal of clinical psychopharmacology (J Clin Psychopharmacol) 2019 Jan/Feb Vol. 39 Issue 1 Pg. 20-27 ISSN: 1533-712X [Electronic] United States
• PMID: 30531477 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial)

Chemical References

• Anti-Anxiety Agents
• Imidazoles
• PF-06372865
• Pyridazines

Topics

• Adolescent
• Adult
• Anti-Anxiety Agents (adverse effects, blood, therapeutic use)
• Anxiety Disorders (drug therapy)
• Double-Blind Method
• Drug Therapy, Combination
• Female
• Humans
• Imidazoles (adverse effects, blood, therapeutic use)
• Male
• Middle Aged
• Outpatients
• Pyridazines (adverse effects, blood, therapeutic use)
• Standard of Care
• Treatment Outcome
• Withholding Treatment
• Young Adult