Page 2AgomelatineJune 2009London New Drugs Group APC/DTC
Briefing
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1 study vs. sertraline (6 weeks with extension to 6 months), primary endpoint actigraphy,secondary endpoint efficacy
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1 open study in patients with major depressive disorder (6 weeks) looking at the effect onsleep EEG
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1 study vs. fluoxetine in patients with severe depression (8 weeks with optional extension to6 months)
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1 study on sexual disturbance vs. paroxetine.
Efficacy studies
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Antidepressant efficacy is generally determined from 6–8 week RCTs comparing responseagainst placebo or active comparators, or 6–10 month RCTs comparing relapse rate against pla-cebo; depression symptoms are evaluated using rating scales.
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All analyses were carried out in the intention-to-treat populations: i.e. analysis was performedaccording to the assigned treatment group regardless of protocol deviations and participantcompliance or withdrawal.
Short-term placebo-controlled
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A dose-ranging study (n=711) identified agomelatine 25mg daily as the target dose when com-pared with agomelatine 1mg and 5mg daily
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In two 6 week placebo controlled RCTs patients with a HAMD score
≥
22 [moderate to severedepression] were randomised to either agomelatine (25mg initial for 2 weeks increased to50mg in non-responders) or placebo; primary endpoint was mean final HAMD score.
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In the first study, 212 patients received agomelatine (n=106) or placebo (n=105). Forthe ITT population the between group difference for the mean final HAMD scores was2.30 (S.E. 1.02), p=0.026.
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In the second study, 238 patients received agomelatine (n=118) or placebo (n=120).For the ITT population the between group difference for the mean final HAMD scores was3.44 (S.E. 0.92), p<0.001
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3 unpublished placebo-controlled studies in which paroxetine or fluoxetine were used as activecontrols to validate the study design are reported in the EMEA public assessment report (EPAR).The efficacy of agomelatine was not directly compared to that of the active controls.
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All 3 studies enrolled patients with moderate to severe depression [HAMD
≥
22] and fol-lowed similar methodologies: initial run-in followed by randomisation to agomelatine,placebo, or active control for 6 weeks with subsequent 18 week extensions.
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The option to increase the agomelatine dose from 25mg to 50mg was not included inthese studies.
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The primary endpoint of difference in HAMD was compared between active control andplacebo, and between agomelatine and placebo. For the first trial, a statistically signifi-cant difference (
p
=0.008) was seen between active control and placebo at 6 weeks forreduction in HAMD score versus placebo, but not for agomelatine and placebo; Neitherthe second nor third trial showed statistically significant differences between agomelatineor the active control and placebo for any comparison at either 6 or 24 weeks, meaningthat no discernable results could be drawn from these studies. A meta-analysis of agomelatine trials shows that 23.5% of patients require a 50mg dose, which is a reasonwhy agomelatine may have failed to differentiate from placebo in the first study. Thesecond and third studies were associated with high placebo response rates.
Active comparator studies
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A 6 week study randomised 313 patients with a HAMD score
≥
22 to agomelatine 25–50mg(n=154) or sertraline 50–100mg (n=159) [for each drug the lower initial dose was increasedafter 2 weeks for non-improved patients]. The primary endpoint of the study was the efficacyon rest-activity circadian rhythms. For the secondary endpoint of an improvement in HAMDscore, the difference in scores after 6 weeks was 1.68, in favour of agomelatine (p=0.031).
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There were two studies in patients with moderate to severe depression in which agomelatinewas compared with venlafaxine.
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