A randomised, placebo-controlled clinical trial with the α2/3/5 subunit selective GABAA positive allosteric modulator PF-06372865 in patients with chronic low back pain.

Abstract

The effect of PF-06372865, a subtype-selective positive allosteric modulator of the γ-aminobutyric acid type A (GABAA) receptor, on chronic low back pain was investigated in a randomised, placebo- and active-controlled phase 2 clinical trial. The parallel treatment group trial consisted of a 1-week single-blind placebo run in the phase, followed by 4-week double-blind treatment. Patients were randomised to receive either PF-06372865, naproxen, or placebo twice a day for 4 weeks. The primary end point was the numerical rating score of low back pain intensity after 4 weeks of active treatment. Secondary end points included the Roland Morris Disability Questionnaire and the Hopkins Verbal Learning Test-Revised. The trial had predefined decision rules based on the probability that PF-06372865 was better than placebo. The study was stopped at the interim analysis for futility. At this time, a total of 222 patients were randomised and the mean PF-06372865 4-week response on the low back pain intensity was 0.16 units higher (worse) than placebo (90% confidence interval -0.28 to 0.60). There were small, statistically significant reductions in the delayed recall test score with PF-06372865, as measured by Hopkins Verbal Learning Test-Revised. The effects of naproxen were in line with expectations. PF-06372865 was well tolerated. The most common treatment-related adverse events in the PF-06372865 arm were somnolence (5 mild and 4 moderate), dizziness (2 mild and 3 moderate), and nausea (2 mild). Although the reason for the lack of analgesic effect is not completely clear, it may be a result of not achieving sufficient receptor occupancy to drive efficacy.

• Authors: Rachel Gurrell, Pinky Dua, Gang Feng, Maria Sudworth, Mark Whitlock, David S Reynolds, Richard P Butt
• Journal: Pain (Pain) Vol. 159 Issue 9 Pg. 1742-1751 (Sep 2018) ISSN: 1872-6623 [Electronic] United States
• PMID: 29787472 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• GABA Modulators
• Receptors, GABA-A
• Naproxen

Topics

• Adolescent
• Adult
• Aged
• Anti-Inflammatory Agents, Non-Steroidal (therapeutic use)
• Chronic Pain (drug therapy)
• Double-Blind Method
• Female
• GABA Modulators (therapeutic use)
• Humans
• Low Back Pain (drug therapy)
• Male
• Middle Aged
• Naproxen (therapeutic use)
• Pain Measurement
• Receptors, GABA-A
• Treatment Outcome
• Young Adult