A double-blind, randomized, placebo-controlled, active reference study of Lu AA21004 in patients with major depressive disorder

Abstract

The efficacy, safety, and tolerability of Lu AA21004 vs. placebo using venlafaxine XR as active reference in patients with DSM-IV-TR major depressive disorder (MDD) were evaluated. Lu AA21004 is a novel antidepressant that is a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1A receptor agonist, 5-HT1B receptor partial agonist and inhibitor of the 5-HT transporter in recombinant cell lines. In this 6-wk, multi-site study, 429 patients were randomly assigned (1:1:1:1) to 5 or 10 mg Lu AA21004, placebo or 225 mg venlafaxine XR. All patients had a baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥ 30. The primary efficacy analysis was based on the MADRS total score adjusting for multiplicity using a hierarchical testing procedure starting with the highest dose vs. placebo. Lu AA21004 was statistically significantly superior to placebo (n=105) in mean change from baseline in MADRS total score at week 6 (p<0.0001, last observation carried forward), with a mean treatment difference vs. placebo of 5.9 (5 mg, n=108), and 5.7 (10 mg, n=100) points. Venlafaxine XR (n=112) was also significantly superior to placebo at week 6 (p<0.0001). In total, 30 patients withdrew due to adverse events (AEs)--placebo: four (4%); 5 mg Lu AA21004: three (3%); 10 mg Lu AA21004: seven (7%); and venlafaxine: 16 (14%). The most common AEs were nausea, headache, hyperhidrosis, and dry mouth. No clinically relevant changes over time were seen in the clinical laboratory results, vital signs, weight, or ECG parameters. In this study, treatment with 5 mg and 10 mg Lu AA21004 for 6 wk was efficacious and well tolerated in patients with MDD.

Trial registration: ClinicalTrials.gov NCT00839423.

Fig. 1

Flow chart of patient disposition. AE, Adverse events, ITT, intention to treat; LoE, lack of efficacy; MADRS, Montgomery–Åsberg Depression Rating Scale; PBO, placebo; Ven 225, venlafaxine XR 225 mg.

Fig. 2

Mean change from baseline in Montgomery–Åsberg Depression Rating Scale (MADRS) total scores (ANCOVA, FAS, OC, over time) and LOCF (week 6). * p<0.05, ** p<0.01, *** p<0.001 vs. placebo. FAS, Full-analysis set; LOCF, last observation carried forward; OC, observed cases.

Fig. 3

Mean change from baseline in Hamilton Rating Scale for Anxiety (HAMA) total scores (ANCOVA, FAS, OC, over time) and LOCF (week 6). * p<0.05, ** p<0.01, *** p<0.001 vs. placebo. FAS, Full-analysis set; LOCF, last observation carried forward; OC, observed cases. Some patients were excluded due to the use of a non-validated scale in France.