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Agomelatine

London New Drugs Group

APC/DTC Briefing Document June 2009

AGOMELATINE Summary

Contents Summary Background Safety Efficacy studies Short term studies Short term studies with active controls Long term/ prevention of relapse Absence of discontinuation symptoms Sexual dysfunction Sleep disorders Rating scales and Sleep assessments Cost per 100,000 population References Appendices

1 5 6 7 9 12 13 14 15 17 19 20 21 24

Produced for the London New Drugs Group by: Alexandra Denby, Regional MI Manager Medicines Information Service Northwick Park Hospital Middlesex HA1 3UJ Tel: 020 8869 3551 [email protected] Further copies of this document are available from URL: www.nelm.nhs.uk

The drug and the review • Agomelatine is a new antidepressant with selective agonist actions at melatonin receptors and selective antagonist action at serotonin 5HT-2C receptors. It does not affect the uptake of serotonin, noradrenaline or dopamine. • Agomelatine was launched in the UK in June 2009. • This review evaluates the evidence supporting agomelatine use in adults with major depressive episodes and seeks to define agomelatine’s potential place in therapy. Background • NICE Guidance (2004 and draft update 2009) recommends an SSRI antidepressant (e.g. generic fluoxetine or citalopram) first-line for patients with moderate to severe depression. • Following first-line treatment failure the evidence for sequencing antidepressants is inconclusive, choice should therefore be based on the needs of the patient, the profile of the drug and financial considerations. • New NICE Guidelines on the treatment of depression in adults are anticipated in September 2009. Literature searched • We searched: Medline (agomelatine.af [Limit to: Humans and English Language]); Embase (agomelatine.af [Limit to: Human and English Language] and [DEPRESSION/dt [Drug Therapy] or *MAJOR DEPRESSION/dt [Drug Therapy]]); and IDIS ("AGOMELATINE 28160472"). • This was supplemented with information from the EMEA website (Public Assessment Report), NICE guidance, and contact with the manufacturer Servier Laboratories. • The study programme was extensive: • 1 short-term placebo-controlled dose ranging study (8 weeks) • 2 short-term placebo-controlled studies (6 weeks with optional extension for a further 46 weeks) • 3 short –term placebo-controlled studies with paroxetine or fluoxetine active controls (6 weeks and optional extension to 6 months) • 2 long-term relapse prevention studies. • 1 study vs. venlafaxine (6 weeks with optional extension to 6 months), primary endpoint sleep, secondary endpoint efficacy • 1 study vs. venlafaxine (12 weeks with optional extension to 6 months), primary endpoint sexual function, secondary endpoint efficacy

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Agomelatine

• 1 study vs. sertraline (6 weeks with extension to 6 months), primary endpoint actigraphy, secondary endpoint efficacy

• 1 open study in patients with major depressive disorder (6 weeks) looking at the effect on sleep EEG

• 1 study vs. fluoxetine in patients with severe depression (8 weeks with optional extension to 6 months)

• 1 study on sexual disturbance vs. paroxetine. Efficacy studies • Antidepressant efficacy is generally determined from 6–8 week RCTs comparing response against placebo or active comparators, or 6–10 month RCTs comparing relapse rate against placebo; depression symptoms are evaluated using rating scales. • All analyses were carried out in the intention-to-treat populations: i.e. analysis was performed according to the assigned treatment group regardless of protocol deviations and participant compliance or withdrawal. Short-term placebo-controlled • A dose-ranging study (n=711) identified agomelatine 25mg daily as the target dose when compared with agomelatine 1mg and 5mg daily • In two 6 week placebo controlled RCTs patients with a HAMD score ≥ 22 [moderate to severe depression] were randomised to either agomelatine (25mg initial for 2 weeks increased to 50mg in non-responders) or placebo; primary endpoint was mean final HAMD score. • In the first study, 212 patients received agomelatine (n=106) or placebo (n=105). For the ITT population the between group difference for the mean final HAMD scores was 2.30 (S.E. 1.02), p=0.026. • 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 was 3.44 (S.E. 0.92), p<0.001 • 3 unpublished placebo-controlled studies in which paroxetine or fluoxetine were used as active controls 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. • All 3 studies enrolled patients with moderate to severe depression [HAMD ≥ 22] and followed similar methodologies: initial run-in followed by randomisation to agomelatine, placebo, or active control for 6 weeks with subsequent 18 week extensions. • The option to increase the agomelatine dose from 25mg to 50mg was not included in these studies. • The primary endpoint of difference in HAMD was compared between active control and placebo, and between agomelatine and placebo. For the first trial, a statistically significant difference (p=0.008) was seen between active control and placebo at 6 weeks for reduction in HAMD score versus placebo, but not for agomelatine and placebo; Neither the second nor third trial showed statistically significant differences between agomelatine or the active control and placebo for any comparison at either 6 or 24 weeks, meaning that 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 reason why agomelatine may have failed to differentiate from placebo in the first study. The second and third studies were associated with high placebo response rates. Active comparator studies • 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 increased after 2 weeks for non-improved patients]. The primary endpoint of the study was the efficacy on rest-activity circadian rhythms. For the secondary endpoint of an improvement in HAMD score, the difference in scores after 6 weeks was 1.68, in favour of agomelatine (p=0.031). • There were two studies in patients with moderate to severe depression in which agomelatine was compared with venlafaxine.

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•

In the 12 week study patients were randomised to agomelatine 50mg (n=137) or venlafaxine 150mg (n=140). The primary endpoint of the study was deterioration in sexual function and demonstrated statistically significant differences in favour of agomelatine versus venlafaxine. For the secondary endpoint of the final MADRS score, agomelatine was shown to be at least as effective as venlafaxine (10.1 vs. 9.8). • In the 6 week study patients were randomised to either agomelatine (n=165) or venlafaxine (n=167). The primary endpoint was the effects on sleep variables and demonstrated statistically significant differences in favour of agomelatine versus venlafaxine; final HAMD score was the secondary endpoint. The final HAMD scores were similar between the groups, indicating similar efficacy for agomelatine and venlafaxine (9.9 vs. 11.0). • A 8 week study randomised 500 outpatients with HAMD score ≥25 and CGI severity of illness score ≥4 (severely depressed) to agomelatine 25-50mg (n=247) or fluoxetine 20-40mg (n=257) [for agomelatine the initial lower dose was increased at 2 weeks in non-improved patients, for fluoxetine the initial lower dose was increased at 4 weeks]. The primary endpoint was improvement in HAMD score from baseline, the difference in scores at week 8 was 1.49, 95% CI=[0.20;2.77] (p=0.024) in favour of agomelatine. Long-term relapse-prevention • Relapse is classified as the appearance of the symptoms of the index episode soon after medication is stopped, whilst recurrence is the appearance of symptoms in a new episode. Relapse indicates that the treatment duration was too short. • A study reported in the EPAR had an 8-week open label phase (n=610) during which response to agomelatine was determined, followed by a 26-week double-blind randomised phase (n=367; agomelatine 25mg, n=187; placebo, n=180). • At the end of the 26 week double-blind phase, a significant effect was not demonstrated for the primary endpoint of relapse (agomelatine 25.9% vs. placebo 23.5%). The placebo relapse rate in this trial was unexpectedly low (approximately half that seen in other studies of similar design). This may be reflective of some methodological aspects e.g. the broad range of the severity of depression of patients at inclusion. • 169 severely depressed patients (n=89 agomelatine, n=80 placebo) (HAMD >25 and CGI-S ≥5) continued in an 18 week extension; at the end of this extension there was a statistically significant difference in favour of agomelatine (21.3% vs. 31.3%) p=0.046. • A second (published) study, that included a high proportion of patients with moderate to severe depression reflecting the types of patient generally seen by psychiatrists, had an 8-10 week openlabel dose determination phase (n=492) followed by a 24 week double-blind phase (n=390) • For the primary endpoint of relapse, results at 24 weeks were significantly lower (p=0.0001) for agomelatine (21.7%) than for placebo (46.6%); agomelatine reduced relapse risk by 54% (HR 0.458; 95% CI 0.305–0.60). • 190 patients (n=106 agomelatine, n=84 placebo) continued in double-blind 20 week extension. A statistically significant difference in the time to relapse was detected: at 10 months twice as many patients treated with placebo relapsed (49.9%) compared to those treated with agomelatine (23.9%) (p<0.0001). • The three short term studies with active controls all had 18 week extensions. In one study the relapse rates were lower with agomelatine (14.3%) and fluoxetine (17.8%) than with placebo (33.3%), p=0.017 and p=0.045 respectively. In the other 2 studies there were no differences seen between agomelatine or active control and placebo which means no discernable results could be drawn. Safety • Agomelatine does not cause weight gain, has a low risk of sexual dysfunction, low incidence of gastro-intestinal reactions, absence of discontinuation symptoms, no sedation or daytime drowsiness and an overall incidence rate of adverse events that is similar to placebo. • Emergent elevations of liver transaminase enzymes more than 3x upper limit of normal (3x ULN) occur rarely (approx. 1% of patients). Overall incidences of elevations >3xULN in all patients (i.e. regardless of their transaminase values at baseline) were 1.1% with agomelatine 25mg and 0.72% with placebo (p=not significant). The 0.4% absolute difference with placebo compares to a

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0.7% absolute difference seen with duloxetine/placebo.

• Agomelatine should not be prescribed in patients with cirrhosis or active liver disease. • Check liver function tests (LFTs) on initiation; then at around 6, 12 and 24 weeks; and thereafter • •

when clinically indicated (if transaminases are elevated repeat LFTs within 48 hours; if transaminases are >3x ULN, discontinue agomelatine). Agomelatine should be used with caution in any patient who drinks substantial quantities of alcohol or is treated with other medicines associated with a risk of hepatic injury. Agomelatine should not be prescribed in patients taking potent CYP1A2 inhibitors, such as fluvoxamine and ciprofloxacin, as this may result in increased serum levels of agomelatine. Moderate CYP1A2 inhibitors, such as propranolol, should be used concomitantly with caution.

Critical evaluation of the evidence base Use of depression rating scales • HAMD and MADRS measure similar quantifiable elements of depression; CGI measures clinician rated global improvement and is thus less sensitive • Rating scales may not capture functional impairment appropriately despite this being an important determinant of depression severity • NICE suggest that clinical efficacy is demonstrated by a weighted mean between-group difference of at least three points or a standardised mean difference of at least 0.5 in HAMD rating score • EMEA guidance states that acceptable scales for use as the primary endpoint in trials of new antidepressants to determine symptomatic improvement include the Hamilton Depression rating scale of Depression (HAMD) or the Montgomery Asberg Depression Rating Scale (MADRS). The HAMD scale (17-item scale as recommended) was used for the majority of the agomelatine trials; others used the MADRS. The placebo effect in depression studies • Use of a placebo in an antidepressant trial does not necessarily mean that the patient is untreated. Patients will have regular visits to their doctor, supportive help and interest in their welfare. In some trials they will be able to contact the therapist when they need to. Patients in the placebo arm will receive everything apart from the active drug, and this can constitute a treatment in itself. It has been estimated that 30% of patients assigned to placebo will respond within six weeks. • Despite this, SSRIs and serotonin/noradrenaline reuptake inhibitor (SNRI) antidepressants remain superior to placebo in treating depression regardless of its severity. • Study population selection (and enrolment of severely depressed patients) is particularly important for external validity of antidepressant trials. Particular considerations for agomelatine • In the two short-term placebo-controlled studies, statistically significant improvement in symptoms of depression was seen with agomelatine compared with placebo. • When compared with other antidepressants, agomelatine was more efficacious than sertraline and fluoxetine, and as effective as venlafaxine in treating the symptoms of depression. • Agomelatine demonstrated significant efficacy in only one of the two placebo-controlled relapseprevention studies. In the first study the relapse rate in the placebo arm was unexpectedly low and may reflect some of the methodological aspects, such as the broad range of the severity of depression of patients included in the study. A more severely depressed cohort was enrolled in the second trial, which demonstrated benefit (80% of enrolled patients in the second study vs. 46% in the first study).

• Overall, the data demonstrate a potential role for agomelatine in treating adults with major depressive disorder. The efficacy studies suggest comparable efficacy to currently licensed antidepressants.

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Potential benefits over existing therapy • As with any new antidepressant, agomelatine’s place in therapy is not yet clear. Agomelatine may be useful in the case of failure of another antidepressant, either because of lack of efficacy or due to poor tolerability (e.g. unacceptable side effects). It has demonstrated superior efficacy to Sertraline in one study, fluoxetine in another study and demonstrated benefits over venlafaxine in two other studies. • Abrupt withdrawal of agomelatine (after 12 weeks of therapy) has not been shown to be associated with discontinuation symptoms, which can be problematic with other antidepressants. This means that no dose tapering is necessary on treatment discontinuation. • There is suggestion that sexual dysfunction caused by agomelatine is less than that caused by venlafaxine The pooled analysis of studies using the Arizona Sexual Experience Scale (ASEX) showed that agomelatine was not associated with sexual dysfunction. In healthy volunteers agomelatine preserved sexual function in comparison with paroxetine. • Agomelatine had neutral effect on body weight, heart rate and blood pressure in clinical studies. • Sleep studies have shown that agomelatine increases sleep efficiency and slow-wave sleep and has significantly better effects on subjective sleep variables than venlafaxine. • Agomelatine has a good tolerability profile compared with other classes of antidepressants. Potential disadvantages over existing therapy • There is a lack of long term active comparator controlled studies. As such defining a place in therapy in comparison with the other better established alternatives is not possible. For a new antidepressant agomelatine has robust data for both short and long term treatment effectiveness, which will need to be validated in real life clinical practice. Health economics • No health economic studies of agomelatine have been published. Budget impact model: per 100,000 population • The budget impact model is based on the use of agomelatine as second-line or later treatment. The incidence of this is estimated at 0.40%, affecting 400 patients per 100,000. • If agomelatine takes 10% of patients from each second-line treatment, 40 patients would be treated with it, at a cost of £38.53 per 28 days. • Over the first year, taking into account a reduction in prescribing costs of the other second line treatments and the need for liver function tests, the net increase in prescribing costs is estimated to be £5,892 (1.45% increase in spend). This would rise to an increase of £9,285 (2.29% increase in spend) in the second year and £11,607 (2.87% increase in spend) in the third year, as more patients are prescribed agomelatine.

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Background Agomelatine was launched in the UK in June 2009 for the treatment of major depressive episodes in adults.1 The recommended dose is 25mg, taken at bedtime, which can be increased to 50mg after two weeks if there is no improvement in symptoms. Treatment should continue for at least six months to ensure that the patient is free of symptoms. No dose tapering is required on treatment discontinuation.2 Current NICE guidance (Dec 2004)3 and the draft 2009 Guidance4 both recommend that an SSRI should be used first line in patients with moderate to severe depression, as they are as effective as tricyclic antidepressants and less likely to be discontinued due to side effects. Generic versions, such as fluoxetine, paroxetine, sertraline and citalopram, would be reasonable choices. Following first line treatment failure (lack of response, withdrawal due to adverse effects) the evidence for treatment sequencing is weak. Choice should therefore be based on the profile of the drug, needs of the patient and financial considerations. NICE Guidelines on the treatment of depression in adults are anticipated in September 2009. Pharmacology Agomelatine is a synthetic analogue of the hormone melatonin, and strongly binds to and stimulates the activity of melatonin MT1 and MT2 receptors, normalising disturbed circadian rhythms and disrupted sleep-wake cycles.5 (Melatonin regulates circadian rhythms, including sleep-wake cycles.) Disturbances in circadian rhythms have been implemented in the development of mood disorders.5 Agomelatine is also a serotonin-receptor antagonist and binds to and inhibits the activity of serotonin 5HT2C receptors.5 This antagonism is associated with antidepressant and anti-anxiety activity, and increases slow-wave sleep. Agomelatine does not affect the uptake of serotonin, noradrenaline or dopamine. The inhibition of 5HT2C receptors increases noradrenaline and dopamine in the frontal cortex and may contribute to agomelatine’s antidepressant activity.5 Agomelatine has no effect on monoamine uptake and no affinity for a, b adrenergic, histaminergic, cholinergic, dopaminergic and benzodiazepine receptors.2

No difference between dosing, effectiveness or safety of agomelatine between older and younger adults has been reported from trials.5 There are no data on the use of agomelatine in children. No specific data have been reported on the safety of it during pregnancy, though animal studies have reported no risks.5 Agomelatine should be used cautiously in patients with liver impairment, but its lack of toxicity and broad safety margin suggest lower doses could be used with appropriate clinical monitoring.5 Special populations Agomelatine is not recommended for use in children and adolescents below 18 years of age and should be used with caution in the elderly (≥65 years of age) due to lack of clinical efficacy data. There is limited clinical data on the use of agomelatine in patents with moderate or severe renal impairment; it should be used with caution in such patient.2 Agomelatine should not be used in patients with hepatic impairment (i.e. cirrhosis or active liver disease).2 There is no clinical data on the effect of agomelatine on pregnancy. Animal studies do not indicate direct or indirect harmful effects to the foetus. Caution should be exercised when prescribing to pregnant women.2 Safety Agomelatine does not cause weight gain, has a low risk of sexual dysfunction, low incidence of gastro-intestinal reactions, absence of discontinuation symptoms and an overall incidence rate of adverse events that is similar to placebo.6 In clinical trials, over 3900 patients have received agomelatine. The incidence of emergent elevations of liver transaminase enzymes more than 3x upper limit of normal (3xULN) was 0.8% in patients treated with agomelatine and with normal baseline levels and 0.3% those treated with placebo. In patients treated with agomelatine 50mg, the incidence was 1.3%.6 The incidences in all patients (i.e. regardless of their transaminase values at baseline) were 1.04% (agomelatine 25mg), 1.39% (agomelatine 50mg) and 0.72% (placebo) the differences from placebo are not statistically significant.6 Liver function tests (LFTs) should be performed at the start of treatment then periodically around 6, 12 and 24 weeks and thereafter when clinically indicated.2 If serum transaminases rise, the LFTs

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should be repeated within 48 hours. Therapy should be discontinued if the increase exceeds 3xULN and liver function tests should be performed regularly until they return to normal.2 If any patient develops symptoms which suggest hepatic dysfunction, LFTs should be carried out and the decision to continue therapy should be a clinical one, based on laboratory evaluations. If jaundice develops, treatment must be stopped. Agomelatine should be used with caution in patients who consume a large quantity of alcohol or who are treated with other drugs that may cause hepatic damage.2 Agomelatine is metabolised mainly by cytochrome P450 1A2 (CYP1A2) (90%) and by CYP2C9 (10%). Treatment with agomelatine is contraindicated in patients who are also taking potent CYP1A2 inhibitors, such as fluvoxamine and ciprofloxacin as they can increase the serum levels of agomelatine. Use of moderate CYP1A2 inhibitors, such as oestrogens and propranolol with agomelatine should be with caution until more experience has been gained.2 Agomelatine does not induce CYP450 isoenzymes and will not modify exposure to medicinal products metabolised by CYP450.2 The placebo response Over the years there has been an increase in the percentage of patients responding in the placebo arms of published studies of major depression.3 There have been no studies comparing placebo with no treatment in depression, so these patients represent several different kinds of treatment effect, such as patients who may have had their depression scores inflated to ensure study entry, patients who were accurately rated but show an early spontaneous remission and true responders to placebo.3 The difference in improvements in depressive symptoms between the drug and the placebo is thought to be greater with increasing degrees of severity of depression. This is often difficult to demonstrate as data is quoted for entire groups, rather than individual patients and the distribution of the depression rating scores can overlap, thereby diluting the effect.3 Use of a placebo in an antidepressant trial does not necessarily mean that the patient is untreated.4 Patients will have regular visits to their doctor, supportive help and interest in their welfare. In some trials they will be able to contact the therapist when they need to. Patients in the placebo arm will receive everything apart from the active drug, and this can constitute a treatment in itself. It has been estimated that 30% of

patients assigned to placebo will respond within six weeks.4 The problem for the evaluation of antidepressants is that the study population is likely to determine the magnitude of the treatment benefit. A poorly selected study population will make a drug look bad; a well selected study population will make a drug look better. Since treatment of real patients is not subject to the perverse incentives of drug trials, it is often assumed that trials that recruit a more severe study population corresponds better to everyday practice than trials that do not. The existence of poorly conducted trials showing minimal benefits cannot be ignored, however, and has been used to case doubt on the efficacy of antidepressants as a class. Efficacy studies A number of studies have been carried out assessing the efficacy and safety of agomelatine. These are described in detail in this review, and their design and main results are summarised in Appendix 1. All patients enrolled had moderate to severe depression. The study programme was extensive:

• 1 short-term placebo-controlled dose ranging • •

• • •

• • • •

study (8 weeks)7 2 short-term placebo-controlled studies (6 weeks with optional extension for a further 46 weeks)8;9 3 short –term placebo-controlled studies with paroxetine or fluoxetine active controls (6 weeks and optional extension to 6 months)6 2 long-term relapse prevention studies6;10;11 1 study vs. venlafaxine (6 weeks with optional extension to 6 months), primary endpoint sleep, secondary endpoint efficacy12 1 study vs. venlafaxine (12 weeks with optional extension to 6 months), primary endpoint sexual function, secondary endpoint efficacy13 1 study vs. sertraline (6 weeks with extension to 6 months), primary endpoint actigraphy, secondary endpoint efficacy14;15 1 open study in patients with major depressive disorder (6 weeks) looking at the effect on sleep EEG16 1 study vs. fluoxetine in patients with severe depression (8 weeks with optional extension to 6 months) (conference abstract only) 1 study on sexual disturbance vs. paroxetine18

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Guidance from the EMEA19 for the clinical investigation of medicinal products for the treatment of depression states that acceptable scales for use as the primary endpoint to determine symptomatic improvement include the Hamilton Depression rating scale of Depression (HAMD, 17-item scale) or the Montgomery Asberg Depression Rating Scale. NICE recommend that where a weighted mean difference is calculated, a between-group (drug/placebo) difference of at least three points (two for treatment-resistant depression) is considered clinically significant for the HAMD.3 The EMEA also state that the disorder should be classified according to an internationally acknowledged classification system, preferably the DSM-IV: the clinical trials enrolled patients who did have depressive disorder according to the DSM-IV criteria.

sponder rates. The agomelatine/placebo difference in HAMD score was not always greater than 3 points (ref 8 and the active control studies), the difference considered to be clinically significant by NICE. The agomelatine/sertraline HAMD score difference was greater than 1.5 points, which is considered clinically significant. The dose ranging study and the three short term studies with active controls did not have the option to increase the agomelatine dose to 50mg, which will results in an underestimate of the efficacy of agomelatine as ~23.5% of patients with require a 50mg dose. Longer term studies will show whether these effects are sustained over a suitable treatment period of 4-6 months.

Short term studies NICE Guidance recommends that when treating a patient with moderate-severe depression, the antidepressant dose should be titrated to the recognised therapeutic dose and the efficacy of this dose assessed over 4-6 weeks.20 If this is effective, treatment should be continued for a further 4-6 months, or longer in patients with recurrent depression, at the full treatment dose.3;20 If the dose is not effective, it should be increased in line with the schedule recommended in the Summary of Product Characteristics. If there has been a partial response after a month, a decision to switch to another antidepressant can be postponed until 6 weeks of therapy. A poorly tolerated antidepressant should be switched to another one.3 The following trials were long enough to assess the initial efficacy of the treatment, but too short to make any conclusions about whether agomelatine is effective in maintaining remission. Randomised, double-blind comparisons versus placebo are needed to permit adequate evaluation of efficacy and for distinguishing disease manifestations from adverse reactions.19 The use of a placebo is controversial and precautions to minimise the impact of the study should be taken: generally a duration of 6 weeks should be sufficient and a longer duration should be justified. Three-arm trials including both a placebo and active control are recommended. Nine short term studies have been conducted. What these short term studies show is that after six weeks of treatment agomelatine has a favourable effect on the symptoms of depression, as seen by reductions in HAMD scores and high reTHIS IS AN NHS DOCUMENT NOT TO BE USED FOR COMMERCIAL AND MARKETING PURPOSES. PRODUCED TO INFORM LOCAL DECISION-MAKING USING THE BEST AVAILABLE EVIDENCE AT THE TIME OF PUBLICATION.

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6-week randomised, doubleblind study in adults with HAMD score ≥22.8

Agomelatine 1mg, 5mg, 25mg or placebo. Paroxetine 20mg used to validate study results.

Doseranging 8week study in 711 patients with a mean HAMD score of 27.4 (entry criteria of HAMD score ≥22).7

Agomelatine 25-50mg daily (n=106) or placebo (n=105). Agomelatine dose increased to 50mg after 2 weeks in nonimproved patients

Treatment

Study design

Short term studies

HAMD final score (ITT population) Secondary efficacy variables: response to treatment (≥50% reduction in HAMD score), time to first response, CGI-Severity and CGIImprovement scores.

Response, defined as a 50% or more improvement in the HAMD score from baseline.

Primary endpoint

•

•

•

•

population): 14.1, agomelatine, 16.5 vs. placebo; difference 2.4, p=0.026. Group whose dose was increased at wk 2: 17.5, agomelatine vs. 20.4 placebo; difference 2.9, p=0.045. severe depression: 14.4, agomelatine vs. 17.3, placebo; difference 2.9, p=0.024). Response rates: 49.1%, agomelatine vs. 34.3%, placebo, p=0.03. Remission rates: 20.8%, agomelatine vs. 13.3%, placebo.

• HAMD scores: • at endpoint (overall ITT

agomelatine 25mg (83/135); 46.3% placebo (p=0.036); 56.3% paroxetine (not significantly better than placebo). • Remission rates (HAMD <7): 30.4%, agomelatine 25mg and 25.7%, paroxetine groups (p<0.01 and p<0.05 vs. placebo), placebo (15.4%).

• Response rates: 61.5%

Results

increased in 36 patients in the agomelatine group and 38 in the placebo group. Seven out of the 12 in the placebo group who discontinued did so because of lack of efficacy, compared to two out of the seven in the agomelatine group who discontinued. • The difference in HAMD scores in the overall population is below that defined by NICE as clinically significant. Results are detailed further in Appendix 1. • Dizziness, nasopharyngitis and influenza were more common in the agomelatine group, whilst headache, nausea, fatigue, dry mouth and diarrhoea were more common in the placebo group.

• The mean baseline HAMD score was 26. The dose was

gests it is a good choice for achieving remission, as short-term studies do not often show significance differences. Based on the lower total HAMD-D score and higher percentages of patients responding and in remission, this study shows that 25mg is the target dose for agomelatine. • No significant difference between agomelatine and placebo was seen for any adverse event. Headache, anxiety, abdominal pain and diarrhoea were the most common side effects with agomelatine. No clinically relevant changes were seen in vital signs, weight, ECG and biological parameters. The two deaths that occurred during the study were not related to treatment.

• The higher response rate seen with agomelatine sug-

number of patients had severe depression.

• Mean HAMD score at baseline indicates that a sufficient

Comments

Agomelatine Page 9

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Agomelatine 25-50mg (n=118) or placebo (n=120). Agomelatine dose increased to 50mg after 2 weeks in nonimproved patients .

Agomelatine 25-50mg (n=247) or fluoxetine 20-40mg (n=257).

Agomelatine 25-50mg (n=154) or sertraline 50-100mg (n=159). Doses were increased after 2 weeks in nonimproved patients .

6-week randomised, double-blind study in adults with HAMD score ≥22.9

Doubleblind, randomised, 8 week study in patients with HAMD score ≥25 & CGI severity illness score ≥4.17

6 week randomised, double-blind study in adults with HAMD score ≥22.14;15 Secondary endpoint: change in HAMD score from baseline of ≥50 in ITT population

Efficacy on rest-activity cycle.

Change in HAMD score from baseline.

Primary endpoint

Treatment

Study design

•

•

•

•

agomelatine vs. 12.1, sertraline; difference 1.68, p=0.031. Responder rates: 70% agomelatine vs. 61.5% sertraline, p=0.119. Between-group difference for CGI-S: 0.28, p=0.043. Between-group difference for CGI-I: 0.29, p=0.023. Both CGI differences in favour of agomelatine.

• HAMD final scores: 10.3,

agomelatine vs. 12.7, fluoxetine. • Change in HAMD score: 17.3, agomelatine, -16.0, fluoxetine. • Between-group difference: 1.46, p=0.024 in favour of agomelatine.

• HAMD final scores: 11.1,

•

•

agomelatine vs. 18.1 placebo; difference 3.5, p=<0.001. Response rates: 54.3%, agomelatine vs. 35.3%, placebo, p=0.003. Decreases in CGI-I and CGI-S scores indicate improvements in symptoms of depression, with differences between the two groups in favour of agomelatine.

• HAMD final score: 14.6,

Results

after six weeks of treatment.

•

mouth, headache, diarrhoea and fatigue. More patients discontinued sertraline (11.3%) than agomelatine (2.6%). See Sleep Disorders section for primary endpoint data.

• Most commonly reported adverse events were dry

• This has only been published as a conference poster. • Superiority of agomelatine over sertraline was shown

fore cannot be fully evaluated: information comes from the World Psychiatric Association conference, April 2009. • Doses were increased after 2 weeks (agomelatine) or 4 weeks (fluoxetine) in non-improved patients. • Patients enrolled in this trial had severe depression.

• This study has not yet been fully published and there-

•

•

18/35 patients discontinuing were in the placebo group; the most common reason was lack of efficacy. At week two, 28 (25.2%) of patients taking agomelatine and 55 (48.6%) of patients taking placebo had a dose increase. Symptoms of depression improved in all patients. Greater sleep improvements were seen with agomelatine, which would be expected from the pharmacological action of the drug. With agomelatine treatment, early-night and mid-night insomnia were significantly improved and there was a trend towards an improvement in early-hours insomnia. 3.4% of patients treated with agomelatine discontinued due to adverse events compared with 5.8% on placebo. ~42% of all patients reported AEs, with the majority mild to moderate in severity. Serious adverse events occurred in six patients, four in the agomelatine group, but none were considered to be related to study treatment. Agomelatine was not found to be associated with sexual side effects such as impotence, ejaculation difficulties or decreased libido

• The mean baseline HAMD total score was 27.3±2.8.

Comments

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Patients could continue with an 18-week extension.6

Changes in HAMD-17 score and CGI-

Secondary endpoint:

Leeds Sleep Evaluation Questionnaire ‘getting to sleep score’

Secondary endpoint: antidepressant efficacy and tolerability

Change in sexual function.

Primary endpoint

11.2±7.0, agomelatine vs. 11.2±6.9, venlafaxine.

• HAMD final scores:

tients:

• • Severely depressed pa-

6.6, agomelatine vs. 11.0 ± 7.4 venlafaxine. Between-group difference of 1.1. • Response rates: 76.4% agomelatine vs. 70.6% venlafaxine. • CGI global improvement final scores: 1.6±0.7, agomelatine vs. 1.6±0.8, venlafaxine.

• HAMD final scores: 9.9 ±

agomelatine vs. 9.8 venlafaxine. • Responder rates: 82.5% agomelatine vs. 79.9% venlafaxine. • Remitter rates: 73% agomelatine vs. 66.9% venlafaxine.

• MADRS final score: 10.1,

Results

depression, in both the overall population and the severely depressed patients. • The time course of improvements in the HAMD score was similar for each treatment group and there was no significant difference between the groups at any study visit. After an additional 18 weeks more patients taking agomelatine (71.6%) compared with those taking venlafaxine (66.7%) were still in remission. Bias from the initial focus on subjective sleep parameters in favour of agomelatine cannot be ruled out. 6 • Nausea, dizziness and vomiting were more common with venlafaxine than with agomelatine (22.6% vs. 6.0%; 9.5% vs. 1.8% and 4.8% vs. 1.2% respectively). Serotonin syndrome occurred in 3% of patients on venlafaxine. More patients withdrew due to adverse events in the venlafaxine group (13.2%) vs. the agomelatine group (4.2%). • See Sleep Disorders section for primary endpoint data.

• Agomelatine was as effective as venlafaxine in treating

ments in the treatment of depression, as shown by the reduction in MADRS score and CGI-S and CGI-I score changes from baseline. Similar percentages of patients were responders and remitters in both groups. • 38.1% of patients on venlafaxine had adverse events vs. 20.4% on agomelatine. Nausea, headache and upper respiratory tract infections were the more common in both groups. More patients discontinued venlafaxine (8.6%, mainly because of gastrointestinal or central nervous system side effects) than agomelatine (2.2%). • See Sexual dysfunction section for primary endpoint data.

• There was no significant difference between the treat-

Comments

Hamilton Depression Rating Scale (HAMD) score ≥22 = DSM-IV criteria for major depressive disorder (moderate or severe) Response to treatment = ≥50% reduction in HAMD score. Intention-to-treat population: ITT

Randomised, double-blind 6 week study comparing the effects of agomelatine and venlafaxine on subject sleep variables. Patients had HAMD score ≥20.12

Agomelatine 50mg (n=137) or venlafaxine 150mg (n=140).

Doubleblind, randomised 12 week study comparing the sexual side effects of agomelatine and venlafaxine in adults with moderate depression (MADRS ≥20).13

Agomelatine 25mg (n=165) or venlafaxine 75mg (n=167). Doses were increased after 2 weeks in nonimproved patients

Treatment

Study design

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Agomelatine 25mg (n=133) or fluoxetine 20mg (n=137) or placebo (n=149)

Agomelatine 25mg (n=142) or paroxetine 20mg (n=138) or placebo (n=137).

Agomelatine 25mg (n=150) or 50mg (n=151) or fluoxetine 20mg (n=148) or placebo (n=158).

Randomised, double-blind 6 week study in adults with HAMD score ≥22.6

Randomised, double-blind 6 week study in adults with HAMD score ≥22.6

Randomised, double-blind 6 week study in adults with HAMD score ≥22.6

Secondary variables included CGI, Hamilton Anxiety Rating Scale, Leeds Sleep Evaluation Questionnaire.

HAMD score

Primary endpoint

relapse and loss of first response when comparing agomelatine or paroxetine with placebo. • HAMD final score: 12.0±8.2 agomelatine vs. 13.4±8.4 placebo (p=NS). • HAMD final in fluoxetine group was 0.53 lower than in the placebo group (p=NS).

• After 18 week extension: • No statistically significant differences in the rates of

fluoxetine, (p=0.017 agomelatine vs. placebo; p=0.045 fluoxetine vs. placebo). • HAMD final score: 13.0±8.0 agomelatine vs. 13.8±8.0 placebo (p=NS). • HAMD final score in paroxetine group 12.2±8.1. p= NS vs. placebo. • Response to treatment and time to remission.

• Relapses: 14.3% agomelatine, 33.3% placebo, 17.8%

ine.

• After 18 week extension: • HAMD: 10.0, agomelatine, 10.7 placebo, 8.4 fluoxet-

8.6 placebo (not statistically significantly different, NS). • HAMD final score in fluoxetine group was 2.59 points lower than in the placebo group (p=0.008). • Responders: 53% agomelatine vs. 47% placebo (p=NS); 58% fluoxetine vs. 47% placebo (p=NS).

• HAMD final score: 14.5±8.2 agomelatine vs. 15.9±

Results

• Agomelatine was not more

efficacious than placebo after six and 18 weeks of treatment. • Paroxetine (active control) was also not significantly better than placebo at either time point. • No discernable results can be drawn from the study

• Agomelatine was not more

agomelatine 25mg was not significantly better than placebo in treating depression but fluoxetine was significantly better than placebo. • At the end of the 18 week extension the rate of relapse was significantly lower with agomelatine (and fluoxetine) than with placebo.

• After six weeks of treatment,

Comments

compared to placebo. No direct comparisons between agomelatine and fluoxetine or paroxetine were performed. Data from these studies comes from the EMEA CHMP Public Assessment Report.6

efficacious than placebo after six and 18 weeks of treatment. • Fluoxetine was also not significantly better than pla• After 18 week extension: cebo at either time point. • No statistically significant differences in the rates of • No discernable results can relapse and loss of first response when comparing be drawn from the study agomelatine or fluoxetine with placebo. • The option to increase the agomelatine dose from 25mg to 50mg was not included in these studies so some patients may not have been adequately treated. A meta-analysis of agomelatine trials shows that 23.5% of patients require a 50mg dose, which is a reason why agomelatine failed to differentiate from placebo. • About 50-60% of placebo-controlled efficacy studies fail to show a superior efficacy of the antidepressant used to validate the study population. One reason for this is the inclusion of patients with insufficient severity, making it difficult to demonstrate a statistically significant treatment effect compared to placebo.

Treatment

Study design

In the following studies, fluoxetine and paroxetine were used as the active controls to validate the studies. The main aim of the studies was to confirm the efficacy of the target dose of agomelatine

Short term studies with active controls

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June 2009 vs. 49.9%, placebo, p<0.0001. In the more severely depressed patients, this risk was reduced by 58.6% (p<0.0001).

• • After a further 20 weeks24 • Relapse: 23.9%, agomelatine

latine vs. 46.6%, placebo, p<0.0001. • Risk of relapse reduced by 54% (hazard ratio 0.458, 95% CI 0.305 to 0.60). • Depressive relapse: 20.6%, agomelatine vs. 41.4%, placebo. • Cumulative relapses: 22.7%, agomelatine vs. 50.4%, placebo, p<0.0001.

• At 24 weeks: • Relapse rates: 21.7%, agome-

analysis (pts with more severe depression,46% of the total trial population): 21.3%, agomelatine vs. 31.3% placebo. The difference became statistically significant at week 52 (p=0.046).

• • Relapse rates in a post-hoc

latine vs. 23.5%, placebo, p = not significant.

• Relapse rates: 25.9%, agome-

Results

groups were similar. The patients were on average 43.3 years old, with ~3.6 prior depressive episodes, and over 70% were female. The mean HAMD17 total score at the beginning of the openlabel period was 27 and the mean GCI-S score was 4.9; by the start of the double-blind phase these had fallen to 6 and 1.8 respectively, indicating that 8-10 weeks of agomelatine open-label treatment had improved depressive symptoms. • 390 patients of the 492 originally enrolled entered the 24-week double-blind phase. • Three patients discontinued due to lack of efficacy, all in the agomelatine group. Adverse events were the reason for discontinuation in 4 patients on agomelatine compared with one taking placebo. The most commonly reported adverse events were headache (10.3% in the agomelatine group and 7.5% in the placebo group), nasopharyngitis (6% vs. 9.8%) and back pain (6.1% vs. 3.4%).

• Baseline characteristics of the two treatment

No statistically significant difference in HAMD total scores between the two groups was seen. • Similar results in both groups for the secondary endpoints, measuring severity of illness and improvements in the condition, were seen. • The relapse rate in the placebo arm was unexpectedly low and may reflect some of the methodological aspects, such as the broad range of the severity of depression of patients included in the study.

• No relapse-preventing effect was demonstrated.

Comments

is the appearance of symptoms in a new episode.17 Relapse indicates that the treatment duration was too short. One failed to demonstrate a difference in the time to relapse.23 An additional relapse prevention study was finalised after the negative CHMP opinion in 2006.

Hamilton Depression Rating Scale (HAMD) score ≥22 = DSM-IV criteria for major depressive disorder (moderate or severe). There is one fundamental difference between the two trials. In the second trial, a larger proportion of patients had severe depression (80% vs. 46%). The results of the second trial were accepted by the CHMP as a demonstration of maintenance of efficacy, probably because of this larger pool of severely depressed patients.6

190 pts (agomelatine 106 and placebo 84) continued with a further 20 weeks of treatment.

Relapse, defined as HAMD ≥16 or any withdrawal for lack of efficacy or suicide/ suicide attempt (ITT population)

8 week open label followed by a 26 weeks double-blind, randomised phase.6

8-10 week open label study followed by a 24 week double-blind, randomised, phase. Adults enrolled if they had HAMD ≥22 and CGIS ≥4.10;11

HAMD total score W0 to W8, time to relapse after week 8 defined as HAMD ≥16 or suicide/suicide attempt (ITT population)

Agomelatine 25mg for 8 weeks then, in patients with HAMD ≤10, agomelatine 25mg (n=187) or placebo (n=180) for 26 weeks.

Agomelatine 25-50mg for 8-10 weeks then, in patients with HAMD ≤10, agomelatine 25mg (n=141), 50mg (n=24) or placebo (n=174) for 24 weeks.

Primary endpoint

Treatment

Study design

There are two relapse prevention studies, undertaken to demonstrate the efficacy of agomelatine in the prevention of relapse after an initial response. Relapse is classified as the appearance of the symptoms of the index episode soon after medication is stopped, whilst recurrence

Long term/prevention of relapse studies

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June 2009 Agomelatine: 88 rerandomised, 27 to placebo. Paroxetine: 104 rerandomised, 43 to placebo.

Agomelatine 25mg (n=167) or paroxetine 20mg (n=168). Paroxetine was used to validate the study design.

Treatment

Total number of emergent DESS symptoms in first and second 7day periods of the discontinuatio n period.

Primary endpoint

•

• No statistically significant difference in the number of emergent discontinuation symptoms was seen between patients discontinuing agomelatine and those continuing with agomelatine. After the first 7-day discontinuation period, a statistically significant difference in the number of emergent discontinuation symptoms was seen between patients discontinuing paroxetine (7.3±7.1) and those continuing with paroxetine (3.5±4.1), p<0.001. No statistically significant difference was seen after the second period.

Results

•

•

•

•

Patients had a MADRS score of 18-27, which indicates moderate to severe depression. Abrupt discontinuation of agomelatine did not cause any discontinuation symptoms. It should be noted that after 12 weeks of treatment it is recommended that the paroxetine dose is reduced over a number of weeks, or even months and not stopped abruptly, in order to avoid discontinuation symptoms.19;27 These results support the fact that abrupt withdrawal of paroxetine is associated with a significant increase in discontinuation symptoms. The main symptoms reported more frequently in patients discontinuing paroxetine were insomnia, dreaming, muscle aches, dizziness, runny nose, chills, nausea and diarrhoea (p<0.05). The study was not designed to investigate the persistence of the discontinuation symptoms beyond 2 weeks. Discontinuation symptoms would be expected to appear during the first week and decline during the second week.

Comments

Symptoms include nausea, vomiting, headaches, loss of appetite, agitation, sweating, worsening of symptoms and weakness. These usually occur within the first few days of discontinuing treatment and are generally mild to moderate, but in some patients may be severe.26

DESS: Discontinuation Emergent Signs and Symptoms check list, a clinician rated instrument which covers 43 signs and symptoms associated with discontinuation or interruption of antidepressant treatment. The limitation to the DESS is that some symptoms could occur even if no discontinuation has taken place.

Double-blind 12 week study in patients with moderate depression to assess the effects of abrupt discontinuation of agomelatine. Pts with sustained remission rerandomised to either placebo (to assess discontinuation symptoms) or active (to act as control) for a further 2 weeks (‘discontinuation period’).28

Study design

All antidepressants have the potential to cause withdrawal symptoms. The Maudsley Prescribing Guidelines recommend that when one has been taken for 6 weeks or longer, it should not be stopped abruptly unless a serious adverse event has occured.18

Absence of discontinuation symptoms

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Agomelatine 50mg (n=137) or venlafaxine 150mg (n=140).

Double-blind, randomised 12 weeks study comparing the sexual side effects of agomelatine and venlafaxine in adults with moderate depression (MADRS ≥20).13

Percentage of patients in the SAR group reporting a deterioration of at least one point from baseline in the Sex FX scale.

Primary endpoint Percentage of SAR population with: • Deterioration in total scores: 7.3% agomelatine vs. 15.7% venlafaxine. • Reduced sex drive/desire: 3.6% agomelatine vs. 19.4% venlafaxine, p=0.007. • Deterioration in orgasm in women: 4.3% agomelatine vs. 21.2% venlafaxine, p<0.0001. • Trend towards more favourable scores with agomelatine with other domain and total scores.

Results

sults were analysed separately for men and women (but note the small number of men in the trial). Treatment-emergent sexual dysfunction was significantly less prevalent among sexuallyactive patients who received agomelatine compared with venlafaxine. The main differences were in reduced desire and orgasm, which reflects the pharmacological differences between the two treatments. Venlafaxine inhibits noradrenaline, dopamine and serotonin, whilst agomelatine is a melatonin agonist and also increases noradrenaline and dopamine. It should be noted that, as for other antidepressant trials, no sexually related adverse events were recorded, but instead they were reported via indirect questioning. 38.1% of patients on venlafaxine had adverse events vs. 20.4% on agomelatine. Nausea, headache and upper respiratory tract infections were the more common in both groups. More patients discontinued venlafaxine (8.6%, mainly because of gastrointestinal or central nervous system side effects) than agomelatine (2.2%). Seen Short Term studies section for data on depression.

• The differences were maintained when the re-

Comments

therapy. The effects of dopamine and noradrenaline on sexual functioning could explain the diminished feelings of desire and arousal experienced by patients with depression. Dopamine influences desire and motivates sexual behaviour, whilst noradrenaline stimulates arousal. Serotonin systems have a negative effect on arousal.27

Secondary endpoint: changes in depression.

Percentage of SA-FS population • with deterioration in: • Desire: 6% agomelatine vs. 16.4% venlafaxine. • Orgasm: 9.1% agomelatine vs. 18.5% venlafaxine • Total Sex FX score: 8.2% agomelatine vs. 15.2% venla• faxine. • P<0.0001 for all. Assessments used: Sex FX scale to assess sexual function (the first 11 out of the 13 item scale address three domains: desire, arousal and orgasm, whilst the last two items provide a measure of global satisfaction). MADRS, CGI-S and CGI-I scales to assess depression. SAR: sexually active remitters group: agomelatine n=60 (14 male), venlafaxine n=51 (18 male). Patients in this group had a decrease at week 10 of 50% or more in sexual activity from baseline and a f inal MADRS score of ≤12. SA-FS : sexually active full set – all subjects sexually active at baseline; agomelatine n=103, venlafaxine n=90.

Treatment

Study design

Sexual dysfunction is a side effect that has been attributed to antidepressant use, and can be problematic, especially leading to problems with long-term treatment compliance.29 About one third of patients (36%) find antidepressant-induced sexual dysfunction to be an unacceptable side effect, constituting grounds for discontinuation of

Sexual dysfunction

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Agomelatine 25mg or 50mg, paroxetine 20mg or placebo (n=23 in each group).

Phase 1 randomised, double-blind, placebocontrolled, 4group parallel-design 8week study in healthy male volunteers (18-30 years) to compare the effects of agomelatine and paroxetine on sexual function.18 Secondary endpoints included moderate or severe sexual dysfunction and erectile function.

Sexual dysfunction assessed by PRSEXDQSALSEX.

Primary endpoint Sexual Acceptability Set (n=87): • A SD according to PRSEXDQ-SALSEX at each visit from week 2 to 8: 22.7% agomelatine 25mg; 4.8% agomelatine 50mg; 85.7% paroxetine, p<0.0001 for each comparison. (8.7% placebo) • Adjusted risk of SD vs paroxetine: 74% reduction with agomelatine 25mg (RR = 0.26, 95% CI 0.12, 0.58) and 94% reduction with agomelatine 50mg (RR=0.06%, 95% CI 0.01, 0.38). • Moderate or severe SD: 1 volunteer (4.5%) agomelatine 25mg, 1 volunteer (4.8%) agomelatine 50mg and 13 volunteers (61.9%) paroxetine, p<0.001, for each comparison. No volunteer in the placebo group affected. • Adjusted risk of moderate or severe SD: 93% reduction with agomelatine 25mg (RR=0.07, 95% CI 0.01, 0.51, p<0.0001), 92% reduction with agomelatine 50mg (RR=0.08, 95% CI 0.01, 0.54, p=0.0001). • Sustained SD: 22.7% agomelatine 25mg, 4.8% agomelatine 50mg, 81.0% paroxetine and 4.3% placebo. • PRSEXDQ-SALSEX score: 0.9±0.2, agomelatine 25mg, 0.2±0.9 agomelatine 50mg, 5.2±3.6 paroxetine, p<0.0001 for both comparisons. (0.5±1.2, placebo). • PRSEXDQ-SALSEX individual items: for all items the results were statistically significantly in favour of both agomelatine doses compared with paroxetine, except for ‘decreased libido’ agomelatine 25mg.

Results

•

•

•

•

•

•

•

This was a phase 2 study in healthy volunteers, not patients with major depressive episodes. The risk of sexual dysfunction was significantly lower with agomelatine use than with paroxetine use. The difference was seen as early as week 2. The risk of sustained sexual dysfunction was significantly higher with paroxetine than with agomelatine. The greatest difference in favour of agomelatine in PRSEXDQ-SALSEX scores was for delayed orgasm/ ejaculation: 9.1% and 4.8% for agomelatine 25mg and 50mg vs. 81% paroxetine (p<0.0001). Erectile function decreased in the paroxetine but not the agomelatine groups. The most common side effect with agomelatine was somnolence, occurring in twice as many patients in each agomelatine group than in the paroxetine group. Although the study was not designed to directly compare agomelatine with placebo, the results suggest that sexual dysfunction caused by agomelatine was comparable to that caused by placebo.

Comments

PRSEXDQ-SALSEX: Psychotrophic-related sexual dysfunction questionnaire. 7 items on sexual function. Sexual dysfunction (SD) was defined as at least one impairment in one of the following four items: decreased libido, delayed orgasm/ejaculation, anorgasmia/no ejaculation (score of ≥1 for each of these three) and erectile dysfunction (score of ≥2). Score 0 = no sexual dysfunction, 15 = maximum sexual dysfunction. For each item 0=nil or never, 3 = severe or always. Sexual Acceptability Set: all volunteers having a sexual dysfunction assessment after at least 2 weeks and compliant to the treatment.

Treatment

Study design

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Agomelatine 2550mg (n=154) or sertraline 50-100mg (n=159).

Agomelatine 25mg (n=15) for 42 days.

Open-label study in adults to assess the effects of agomelatine on sleep. Patients with sleep apnoea, shift workers and postmenopausal women were excluded. Patients scored at least 20 on the HAMD scale.16

Randomised 6 week study assessing the rest-activity circadian rhythm using wrist actigraphy in patients with a HAMD score ≥22.14;15

Treatment

Study design

Secondary endpoint: change in HAMD score. (see Short term studies)

Relative amplitude (RA) of rest/ activity cycle, sleep latency, sleep efficiency.

Sleep cycle analysed by polysomnography, on six nights.

Primary endpoint

•

•

Sleep latency (how quickly to fall asleep), changes from baseline: 22.5 to 18.9 minutes, agomelatine (p<0.0001), vs. 23.48 to 27.75 minutes, sertraline. Sleep efficiency (total sleep time: total sleep period): 78.85% agomelatine (p<0.0001) vs. 76.70% sertraline.

•

•

•

•

In animal models agomelatine has been shown to resynchronise altered circadian rhythms. Relative amplitude is based on average activity level during the 10 most active and 5 least active hours of a 24 hour period. The mean RA was stable between days 0-7 in the agomelatine group and decreased in the sertraline group. The mean RA increased in the sertraline group from day 7, and from day 14 there was no significant difference between the groups. Sleep efficiency increased at each assessment point with agomelatine, yet with sertraline it alternated between decreasing and increasing: a longer study may show no difference between the two treatments. Improvements in both measurements were seen as early as after one week of treatment with agomelatine. Most commonly reported adverse events were dry mouth, headache, diarrhoea and fatigue. More patients discontinued sertraline (11.3%) than agomelatine (2.6%).

Data comes from a conference abstract.

•

•

• •

•

•

•

At baseline 11 patients reported difficulties in becoming wide awake in the morning often or very often, and 13 patients complained of daytime sleepiness often or very often. By day 42 these problems were reported in two patients. This small study shows that agomelatine can increase sleep efficiency and slow-wave sleep, as shown by the lengthening of stage 3-4 sleep and does not suppress REM sleep, which can be poor in patients with depression, stage 1 or 2 sleep and time to sleep onset. Dosedependent suppression of REM sleep has been seen with tricyclic antidepressants, SSRIs and venlafaxine. It has been thought that the increase in the delta power ratio, seen with e.g. sertraline and amitriptyline, could be due to their REM suppression effect, leading to a delay in the first REM sleep, but this is not the case for agomelatine. The authors of this study state that agomelatine improves the deficiency of the homeostatic system of sleep regulation, by improving slow wave sleep and activity. Further controlled studies investigating sleep and daytime alertness would be warranted.

•

• Total sleep time increased from 363±60 minutes at baseline to 392±95 minutes at day 42 (not statistically significant). Time to both sleep onset and REM onset improved significantly by day 7. No significant changes from baseline in stage 1 or 2 sleep, any aspect of the REM sleep, the time of sleep onset and the delta power ratio (indicating improvement in NREM) by day 42. Trend towards an improvement in REM latency (uncorrected value) by day 42. Statistically significant improvements were seen at day 42 in the intra-sleep awakening time, decreasing from 48±31 minutes to 29±27 minutes; the sleep efficiency (total sleep time: total sleep period ratio), increasing from 88% to 93% and stages 3-4 slowwave sleep increasing from 15.9% of the total sleep period to 19.4%, a mean increase of 14 minutes. SWS started to improve as early as day 7.

Comments

This whole cycle is non-rapid eye movement (NREM) sleep, making up 75-85% of a normal nights sleep. Each cycle is followed by a discrete episode of REM sleep, during which time EEG activity quickens and rapid horizontal eye movements are detected by the electro-oculogram (EOG). There are usually four or five REM periods across a normal nights sleep, separated by 90-minute intervals.29 Patients with depression can suffer from poor sleep efficiency, decreased slow-wave sleep (SWS), reduced REM latency and increased REM activity.29

Results

One of the major complaints of patients suffering with depression is poor sleep.16 Sleep neurophysiology can be studied using all-night electroencephalograms (EEG). Healthy sleep is divided into four stages: stage 1 is the transition from drowsiness to light sleep, shown by a slowing of EEG activity; sleep spindles and K-complex waves appear during the onset of the deeper sleep of stage 2 and stages 3 and 4 (deepest sleep) are defined by desynchronised slow (delta) waves.29

Sleep disorders

Agomelatine Page 17

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London New Drugs Group APC/DTC Briefing

June 2009 •

•

•

•

•

•

• HAMD score: 9.9 ± 6.6, agomelatine vs. 11.0 ± 7.4 venlafaxine. Response rates: 76.4% agomelatine vs. 70.6% venlafaxine. LSEQ getting to sleep score: 70.5±16.8, agomelatine vs. 64.1±18.2, p=0.001 for the between group difference of 6.36mm. No significant difference between the groups in whether the patients felt more or less drowsy. LSEQ quality of sleep, sleep awakening and integrity of behaviour scores: betweengroup differences were statistically significant in favour of agomelatine. HAMD insomnia score (max 6 from 3 items): decreased by similar amount in both groups. Difference in final score statistically significant and due to difference in favour of agomelatine for early and middle insomnia. Sleep diary: improved sleep latency and reduced number of awakenings, in both treatment groups.

Results

•

•

•

•

•

•

•

The comparison between agomelatine and venlafaxine on their effects on sleep was performed only if no significant difference between the two drugs with respect to the final HAMD scores was seen. Full results are in Appendix 2. No comment was made by the investigators on the changes from week 1 to the last visit for within-group scores. Similar improvements were seen for quality of sleep score, sleep awakening scores improved to a slightly better extent with agomelatine and integrity of behaviour scores (assessing whether patients feel more alert and less clumsy after waking up) improved by a greater extent with venlafaxine. The differences in the HAMD insomnia scores were very small and may not be reproduced in a larger study. Interpretation of the sleep diary data is difficult because many omissions occurred and the rating by the patient can be contaminated by cognitive distortion seen in patients with depression. Nocturnal awakenings do not consider the ‘micro-awakenings’ that occur frequently in the night in depressed patients that are responsible for a poor quality of sleep. Both agomelatine and venlafaxine improved depression, sleep, daytime alertness and well-being after six weeks of treatment in this patient group. ‘Getting to sleep’ scores were higher with agomelatine but the improvements were seen to the same extent with venlafaxine. The venlafaxine dose was not titrated above 150mg/day, so it is possible that some patients were not adequately treated. The authors state that any such efficacy benefit might be at the expense of poorer tolerability: three times as many patients withdrew because of venlafaxine side effects (n=22 vs. 7). Increasing the venlafaxine dose could have increased the drop-out rate and biased the results. Longer term studies are needed to determine whether the effects of agomelatine on sleep are sustained. After an additional 18 weeks, remission rates were higher with agomelatine (71.6%) compared with venlafaxine (66.7%). Bias from the initial focus on subjective sleep parameters in favour of agomelatine cannot be ruled out.6

Comments

LSEQ: Leeds Sleep Evaluation Questionnaire, assessed using a visual analogue scale. These are very subjective and are best for comparing changes within individuals, rather than between individuals. Clinical relevance is a 10mm or greater change from baseline. Note all patients start with a baseline rating of 50 on the LSEQ scale – from this start point improvement or worsening of symptoms is determined.

HAMD-17 and CGI

Sleep diary

Pittsburgh Sleep Quality Index questionnaire

LSEQ – ‘getting to sleep’ score. Visual analogue scale for daytime sleepiness (ITT population)

The Primary Endpoints were:

Patients could continue with an 18week extension.6

Doses were increased at 2 weeks in non-improved patients Doses were increased in 23 and 17 patients respectively.

Patients were treated with : Agomelatine 25mg (n=165) or venlafaxine 75mg (n=167).

Randomised, double-blind 6 week study compared the effects of agomelatine and venlafaxine on subject sleep variables. Patients had HAMD score ≥20.12

Study design and primary endpoints

Agomelatine Page 18

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Agomelatine

Figure 1: Rating scales Hamilton Rating Scale for Depression (HAMD)21 • Rates severity of depression. • Items: Depressed mood; Feelings of guilt; Suicide; Insomnia: Early, Middle and Late; Work and Activities; Retardation, psychomotor; Agitation; Anxiety (psychological); Anxiety (somatic), Somatic symptoms (gastrointestinal); Somatic symptoms (general); Genital symptoms; Hypochondriasis; Loss of weight; Insight; Diurnal variation, Depersonalisation and derealisation; Paranoid symptoms; Obsessional and compulsive symptoms. • Scale: 0 (absent) to 4 (most severe symptoms). Maximum score: 66. A score of >18 indicates moderate to severe depression.22 Clinical Global Impression (CGI)23 • Three-item scale to assess treatment response. • Severity of illness, at the time of assessment: 7 point scale, 1 = normal, 7 = extremely ill • Global Improvement – the clinician rates how the patients illness has improved or worsened relative to a baseline state: 7 point scale: 1 = very much improved, 7 = very much worse Efficacy Index: 4 point scale: none to outweighs therapeutic effect Montgomery-Asberg Depression Rating Scale (MADRS)24 • Rates severity of depression. Provides an instrument sensitive to minor changes. • Items include: Apparent sadness; Reported sadness; Inner tension; Reduced sleep; Suicidal thoughts. • Scale: 0 (absent) to 6 (most severe symptoms). • Maximum score: 60. Suggested cut-off points: 0-6 (absence of symptoms), 7-19 (mild depression), 20-34 (moderate depression), 35-60 (severe depression). Figure 2: Sleep assessments12 Leeds Sleep Evaluation Questionnaire • Quantifies subjective assessments of the effects of drugs on sleep and early morning behaviour. • 10 items grouped into 4 scores, each item quantified by a 100mm visual analogue scale (VAS). A high score indicates improvement. • 4 scores evaluate: ease of getting to sleep (3 VAS items), perceived quality of sleep (2 VAS items), ease of awakening (2 VAS items) and integrity of behaviour after awakening (3 VAS items). • There is no baseline evaluation as the LSEQ assesses the changes during treatment relative to those before treatment. Visual analogue scale • For daytime sleepiness and feeling well, completed at each visit. Pittsburgh Sleep Quality Index questionnaire • Completed at inclusion to check the comparability of the treatment groups regarding their status. Sleep diary • Completed every morning to the week 3 visit recording: times of light off, wake-up and getting up, sleep onset latency and number of nocturnal awakenings. HAMD-17 and CGI-I • For assessing the efficacy of study medication on depression. Responders showed a decrease of ≥50% in HAMD score relative to baseline.

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Page 20

Agomelatine Cost per 100,000 population31

As already stated, NICE recommends an SSRI as first line treatment for moderate to severe depression. The budget impact model has been based on agomelatine use in second-line or later treatment for depression, with agomelatine taking a 10% share of the current patients who fall into this category. Below is a breakdown of the cost per 100,000 population if agomelatine is used as a second-line or later treatment for depression, for year 1. Population: 100,000

Year 1

Incidence of specified second-line or later treatment (all treatments)

0.40%, n=397

Average number of days on therapy

179

Number of packs

1,918

Second-line or later patients are prescribed: Venlafaxine

24.6%, n=98

Zispin®

18.6%, n=74

Mirtazapine

29.2%, n=116

Escitalopram

19.5%, n=77

Duloxetine

8.1%, n=32

If agomelatine takes 10% of each second line treatment

N = 10 + 7 + 12 + 8 + 3 = 40

Agomelatine price

£38.53 per 28 days treatment

Average daily dose

30.9mg

Agomelatine patients in year 1

40 (based on 10% market share)

Agomelatine prescriptions in year 1

192

Cost of agomelatine prescribing

£9,124

Cost of agomelatine prescribing including liver function tests

£9,464

For years 2 and 3, the number of patients treated with agomelatine is expected to rise. Year 1

Year 2

Year 3

Patients starting agomelatine

40

50 (+25%)

62 (+25%)

Patients taking agomelatine during period

40

69

86

Total cost of prescribing without Agomelatine

£381,644

£381,644

£381,644

Plus cost of agomelatine

£9,124

£14,379

£17,973

Less reduction in prescribing of other agents

£3,572

£5,629

£7,036

Total cost of prescribing with Agomelatine

£387,196

£390,394

£392,581

Net increase in prescribing costs

£5,552

£8,750

£10,937

Net increase in prescribing costs including liver function tests

£5,892

£9,285

£11,607

Percentage increase in spend

1.45%

2.29%

2.87%

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Agomelatine

Current costs of antidepressant drugs: Drug*

Dose

Cost (Drug Tariff April 2009)32

Agomelatine

25mg, increased to 50mg daily

To be confirmed, anticipated at £30 per 28 days treatment.

Amitriptyline‡

75mg, increased to 150-200mg daily

28x25mg: £0.94 28x50mg: £1.13

Citalopram‡

20mg, increased to 60mg daily

28x20mg: £1.26 28x40mg: £1.44

Duloxetine†

60mg daily

28x60mg: £27.72 (Cymbalta)

Escitalopram‡

10mg, increased to 20mg daily

28x10mg: £14.91 (Cipralex) 28x20mg: £25.20 (Cipralex)

Fluoxetine‡

20mg, increased to 60mg daily

30x20mg: £1.02 30x60mg: £55.73

Fluvoxamine‡

50-100mg, increased to 300mg daily

60x50mg: £6.17 30x100mg: £8.22

Paroxetine‡

20mg, increased to 50mg daily

28x20mg: £2.84 28x30mg: £6.21

Sertraline‡

50mg, increased to 100mg daily

28x50mg: £1.36 28x100mg: £1.67

75mg daily increased to 150mg daily, to max 375mg daily.

56x37.5mg tabs: £21.07 (Efexor) 56x75mg tabs: £35.12 (Efexor) 28x75mg MR caps: £22.50 (Efexor XL) 28x150mg MR caps: £37.51 (Efexor XL)

Venlafaxine†

*generic unless otherwise stated ‡ selective serotonin re-uptake inhibitor (SSRI) † serotonin and noradrenaline re-uptake inhibitor, SNRI Reference List (1) Anon. Servier's Valdoxan receives EU approval for depression. Scrip 2009; No. 3534:20. (2)

Summary of Product Characteristics. Valdoxan 25mg film coated tablets. Servier Laboratories Limited

(3) Clinical Guideline 23.Depression (amended 27/04/2007). NICE Accessed via: http:// www.nice.org.uk/Guidance/CG23#documents, on 16/12/08. (4)

Depression: the treatment and management of depression in adults. NICE Guidance. Draft for consultation, February 2009. NICE Accessed via http://www.nice.org.uk/nicemedia/pdf/ DepressionUpdateNICEGuidelineDraft.pdf on 31/03/09.

(5) Howland R. Agomelatine. A novel atypical antidepressant. J Psych Nurse 2007; 45(12):13-17. (6)

CHMP Assessment report for Valdoxan. Committee for Medicinal Products for Human Use (CHMP) Accessed via: http://www.emea.europa.eu/humandocs/PDFs/EPAR/valdoxan/H-915en6.pdf on 18/03/09.

(7)

Loo H, Hale A, D'haenen H. Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT2c antagonist, in the treatment of major depressive disorder: a placebocontrolled dose range study. Int Clin Psychopharmacol 2002; 17(5):239-247.

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Agomelatine

(8)

Kennedy SH, Emsley R. Placebo-controlled trial of agomelatine in the treatment of major depressive disorder. Eur Neuropsychopharmacol 2006; 16(2):93-100.

(9) Olie JP, Kasper S. Efficacy of agomelatine, a MT1/MT2 receptor agonist with 5-HT2c antagonistic properties in major depressive disorder. International Journal of Neuropsychopharmacology 2007; 10(5):661-673. (10) Goodwin G, Rouillon F, Emsley R Long-term efficacy of agomelatine, a novel antidepressant, in the prevention of relapse in out-patients with major depressive disorder. Poster presentation. European College of Neuropsychopharmacology, 21st ECNP Congress. Barcelona, Spain. 30 August - 3 September: 2008 (11)

Goodwin GM, Rouillon F, Emsley R Long-term treatment with agomelatine: prevention of relapse in patients with major depressive disorder over 10 months. Poster presentation. European College of Neuropsychopharmacology. 21st ECNP Congress. Barcelona, Spain. 30 August - 3 September: 2008

(12) Lemoine P, Guilleminault C, Alvarez E. Improvement in subjective sleep in major depressive disorder with a novel antidepressant, agomelatine: randomized, double-blind comparison with venlafaxine. J Clin Psychiatry 2007; 68:1723-1732. (13)

Kennedy SH, Rizvi S, Fulton K et al. A double-blind comparison of sexual functioning, antidepressant efficacy and tolerability between agomelatine and venlafaxine XR. J Clin Psychopharmacol 2008; 28:329-333.

(14) Kasper S, Laigle L, Bayle F Superior antidepressant efficacy of agomelatine vs sertraline: a randomized, double-blind study. Poster presentation. 21st ECNP Congress, Barcelona, Spain. 30 August - 3 September.: 2008 (15)

Kasper S, Wulff K, Laigle L et al. Effect of agomelatine on rest-activity cycle in patients with major depressive disorder compared to sertraline. 21st ECNP Congress, Barcelona, Spain. 30 August - 3 September.: 2008

(16) Quera Salva M-A, Vanier B, Laredo J et al. Major depressive disorder, sleep EEG and agomelatine: an open-label study. International Journal of Neuropsychopharmacology 2007; 10 (5):691-696. (17) Data on file: 045 study Agomelatine vs. fluoxetine: Difference in HAM-D17 change from baseline to week 8. Reference: 09MKA0147.. Presented at the World Psychiatric Assocation Conference, Florence, Italy. April 2009. Servier Laboratories Limited (18) Montejo AL, Preito N, Terleira A et al. Better sexual acceptability of agomelatine (25 and 50mg) compared with paroxetine (20mg) in healthy male volunteers. An 8-week, placebocontrolled study using the PRSEXDQ-SALSEX scale. J Psychopharmacol (Oxf) 2008; 00(00):110. (19)

Note for Guidance on Clinical Investigation of Medicinal Products in the Treatment of Depression Committee for Medicinal Products for Human Use (CHMP) Accessed via http:// www.emea.europa.eu/pdfs/human/ewp/051897en.pdf on 23/04/09. Ref: CPMP/EWP/518/97 Rev. 1.

(20) Taylor D, Paton C, Kerwin L. Depression & Anxiety. In: The Maudsley Prescribing Guidelines, 9th edition. London: Informa Healthcare., 2007: 177-270 (21)

Hamilton Depression Rating Scale (HDRS) Date accessed: 19/11/08 Accessed via: http:// healthnet.umassmed.edu/mhealth/HAMD.pdf

(22)

Kirsch I, Deacon BJ, Huedo-Medina TB et al. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Medicine 2008; 5 (2):260-268.

(23) Clinical Global Impression (CGI). AstraZeneca Accessed on 19/11/08. Accessed via: http:// www.seroquel.info/assessment-tools/CGI?itemId=826546#. (24)

McDowell I. Measuring Health: A guide to rating scales and questionnaires, Third edition. Oxford.: Oxford University Press., 2006: 382-384

(25)

Committee for Medicinal Products for Human Use. Summary of Positive Opinion: Valdoxan. EMEA Accessed via www.emea.europa.eu, on 19/12/08. Doc ref: EMEA/CHMP/575411/2008.

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Agomelatine

(26)

Goodwin GM, Rouillon F, Emsley R European College of Neuropsychopharmacology. 21st ECNP Congress. Barcelona, Spain. 30 August - 3 September: 2008

(27)

Summary of Product Characteristics. Seroxat 10mg, 20mg, 30mg tablets, 20mg/10ml oral suspension. GlaxoSmithKline UK Accessed via http://emc.medicines.org.uk on 12/12/08. Date of revision of the text: 26/3/08.

(28)

Montgomery SA, Kennedy SH, Burrows GD et al. Absence of discontinuation symptoms with agomelatine and occurrence of discontinuation symptoms with paroxetine: a randomized, double-blind, placebo-controlled discontinuation study. Int Clin Psychopharmacol 2004; 19 (5):271-280.

(29)

Clayton AH, Montejo AL. Major depressive disorder, antidepressants, and sexual dysfunction. J Clin Psychiatry 2006; 67(S6):33-37.

(30) Thase ME. Depression, sleep and antidepressants. J Clin Psychiatry 1998; 59(4):55-65. (31) Major Depressive Disorder Budget Impact Model: Agomelatine. June 2009. Servier Laboratories Limited (32)

Department of Health., Welsh Assembly Government. National Health Service England and Wales. Drug Tariff. April. 2009

(33)

Goodwin GM, Rouillon F, Emsley R European College of Neuropsychopharmacology. 21st ECNP Congress. Barcelona, Spain. 30 August - 3 September: 2008

The LNDG would like to thank Guy Goodwin, Professor of Psychiatry, Waneford Hospital, Oxford; Karen Harvey, Senior Lead Pharmacist, Mental Health, Charing Cross Hospital; Trudi Hilton, Chief Pharmacist, West London Mental Health Trust; Svetlana Jokic, Senior Mental Health Pharmacist, Imperial College Healthcare, and David Taylor, Professor of Psychopharmacology, Kings College, for their comments on the initial draft of the review. Servier Laboratories has commented on the final review.

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Agomelatine

Appendix 1. Agomelatine: results from the clinical studies: Treatments

Agomelatine 1, 5, 25mg or placebo Paroxetine 20mg (active control) for 8 weeks. (n=711) Loo et al7

Agomelatine 2550mg (n=106) or placebo (n=105) for 6 weeks Kennedy et al8

Agomelatine 2550mg (n=118) or placebo (n=120) for 6 weeks Olie et al9

Agomelatine 2550mg (n=247) or fluoxetine 2040mg (n=257). Data on file.17 Agomelatine 2550mg (n=154) or sertraline 50100mg (n=159) for 6 weeks Kasper et al14;15

Endpoints

Response: 50% improvement in HAMD from baseline Remission: HAMD<7

Primary: HAMD final score (ITT). Secondary: Response: 50% improvement in HAMD from baseline; CGI-S and CGI-I.

Primary: HAMD final score (ITT). Secondary: Response: 50% improvement in HAMD from baseline, CGI-S and CGI-I.

Primary: change in HAMD score from baseline. Response: 50% improvement in HAMD from baseline Sleep latency, sleep efficiency.

Agomelatine

Placebo / active control/ comparator

Agomelatine 25mg

Placebo

Paroxetine

Response

61.5% (25mg), p=0.036 vs. placebo

46.3%

56.3%, not statistically different from placebo.

Remission

30.4% (25mg), p<0.01 vs. placebo

15.4% %

25.7%, p<0.05 vs. placebo

Final HAMD scores

12.77

15.34

13.09

Drug-placebo difference in HAMD scores

2.57

-

2.25

Response

49.1%, p=0.03

34.3%

Response, severely depressed

48.7%, p≤0.024

30.7%

Remission

20.8%

13.3%

Remission, severely depressed

21.1%

12.0%

HAMD final score – all patients

14.1 ± 7.7

16.5 ±7.4

Drug-placebo difference

2.4, p=0.026

-

HAMD final score – severely depressed patients

14.4 ± 7.9

17.3 ± 7.2

Drug-placebo difference

2.9

-

CGI-S, final score

3.2±1.3

3.6±1.3

Results

Drug-placebo difference

0.44, p=0.017

CGI-I, final score

2.4±1.1

Drug-placebo difference

0.25, p=0.098

Response

54.3%, p=0.003

35.3%

Response, severely depressed

49.4%, p=0.0476

34.1%

HAMD final score – all patients

13.9 ± 7.8

17 ± 7.9

Drug-placebo difference

3.1, p=0.002

-

HAMD final score – severely depressed

14.6 ± 7.4

18.1 ± 8.4

Drug-placebo difference – severely depressed

3.6, p=0.002

CGI-I, final score

2.2±1.2

Drug-placebo difference

0.45, p=0.006

CGI-S final score

3.1±1.4

3.6±1.4

Drug-placebo difference

0.50, p=0.006

-

HAMD final score

11.1±7.3

12.7±8.5

Change from baseline

-17.3±7.3

-16.0±8.4

Difference in change from baseline Response after 2 weeks

2.7±1.1

2.7±1.2

1.49, p=0.024 20%, p=0.027

10.9% 61.5%

HAMD final score

70%, p: not significant 10.3, p=0.031

Sleep latency, change

From 22.5 to 18.9

From 23.48 to 27.75mins

Response after 6 weeks

12.1

mins THIS IS AN NHS DOCUMENT NOT TO BE USED FOR COMMERCIAL AND MARKETING PURPOSES. efficiency 78.85% 75.70%. PRODUCED TO INFORM LOCAL DECISION-MAKINGSleep USING THE BEST AVAILABLE EVIDENCE AT THE TIME OF PUBLICATION

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Agomelatine

Treatments

Endpoints

Agomelatine 25mg (n=167) or paroxetine 20mg (n=168) for 12 weeks Montgomery et al28

Number of discontinuation symptoms, DESS.

Agomelatine 25mg for 8 weeks then agomelatine (n=187) or placebo (n=180) for 26 weeks. EPAR6

HAMD total score, time to relapse.

Agomelatine 2550mg (n=165) or placebo (n=174) for 24 weeks plus 20 weeks. Goodwin et al10l33

Relapse: HAMD ≥16

Agomelatine 50mg (n=137) or venlafaxine 75-150mg (n=140) for 12 weeks Kennedy et al13

Agomelatine 25mg or 50mg, paroxetine 20mg or placebo (n=23/ group).Montejo18

Agomelatine 25mg (n=15) for 6 weeks Quera Salva et al16

Agomelatine 2550mg (n=165) or venlafaxine 75150mg (n=167) for 6 weeks Lemoine et al12

Percentage of patients with 50% or more decrease in sexual activity from baseline (SAR group) with ≥1 point reduction in Sex FX scale. Full set = all subjects sexually active at baseline.

Results

Agomelatine

Placebo / comparator

After 7 days, discontinuing vs. continuing

3.0±4.2 vs. 4.4±5.7

7.3±7.1 vs. 3.5±4.1, p≤0.001

After 14 days, discontinuing vs. continuing

2.0±2.3 vs. 3.0±3.3

3.0±3.9 vs. 2.8±3.5

Relapse rates

25.9%, p=NS

23.5%

Relapse rates in pts with more severe depression

21.3%, p=0.046 at week 52

31.3%

Relapse over 6 months

21.7%, p<0.0001

46.6%

Relapse over 10 months

23.9%, p<0.0001

49.9%

MADRS final score

10.1 ±4.6

9.8 ± 7.9

Between group difference

0.03

≥1 reduction in Sex FX scale (SAR)

7.3%

15.7%

Reduced sex drive (SAR)

3.6%, p=0.007

19.4%

4.3%, p<0.0001

21.2%

6%, p<0.0001

16.4%

9.1%, p<0.001

18.5%

Reduced Sex FX scores (full set)

8.2%, p<0.0001

15.2%

Moderate or severe SD

4.5% (25mg) 4.8% (50mg)

61.9% (paroxetine) 0% (placebo)

Sustained SD

22.7% (25mg) 4.8% (50mg)

81.0% (paroxetine) 4.3% (placebo)

Total sleep time change

From 363 to 393 mins

Intra-sleep awakening time change

From 48 to 29 mins

Sleep efficiency change

From 88% to 93%

Stage 3-4 slow wave sleep change

From 15.9% to 19.4%

Final HAMD score

9.9 ± 6.6

11.0 ± 7.4

Getting to sleep score

70.5±16.9, p=0.001

64.1±18.2

Quality of sleep score

72.5±21.4, p=0.021

66.9±22.3

Sleep awakening score

66.9±20.5, p=0.04

62.0±21.8

66.2±20.1, p=0.024

61.0±20.9

1.4±1.6, p=0.044

1.8±1.7

76.4%

70.6%

Deterioration in orgasm (SAR) Reduction in desire (full set) Reduction in orgasm (full set)

Sexual dysfunction.

Variables relating to the sleep-wake cycle, measured by polysomnography

Primary: ‘getting to sleep score’ in LSEQ. Secondary: LSEQ subscores, HAMD

Integrity of behaviour score HAMD insomnia item score Responders

CGI: Clinical Global Impression, Severity or Improvement DESS: Discontinuation Emergent Signs and Symptoms HAMD: Hamilton rating scale for Depression LSEQ: Leeds Sleep Evaluation Questionnaire, measured on visual analogue scale MADRS: Montgomery-Asberg Depression Rating Scale SAR: Sexually active remitters, agomelatine n= 60, venlafaxine n=51 THIS IS AN NHS DOCUMENT NOT TO BE USED FOR COMMERCIAL AND MARKETING PURPOSES. PRODUCED TO INFORM LOCAL DECISION-MAKING USING THE BEST AVAILABLE EVIDENCE AT THE TIME OF PUBLICATION.

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Agomelatine

Appendix 2: Results of the improvements in subjective sleep study, agomelatine vs. venlafaxine.12

Agomelatine LSEQ ‘Getting to sleep’ score (mm)

Venlafaxine

Estimated between group difference (agomelatine - venlafaxine Mean 95% CI P value

Week 1

Not stated

Not stated

5.40

Not stated

0.007

Week 2

Not stated

Not stated

4.92

Not stated

0.017

Week 3

Not stated

Not stated

4.86

Not stated

0.009

Week 6

Not stated

Not stated

5.57

Not stated

0.006

Last

70.5±16.8

64.1±18.2

6.36

Not stated

0.001

Getting to sleep, last visit scores, mm, ITT and severely depressed populations Easier / Harder: ITT

78.7±19.8

73.3±20.3

5.40 (2.34)

Severely depressed

77.9±19.6

69.4±22.7

8.47

Quicker / Slower: ITT

77.9±17.4

72.3±20.3

5.58 (2.35)

Severely depressed

75.5±21.8

68.2±23.0

7.25

Felt more / less drowsy: ITT

60.2±25.7

54.3±24.5

5.91 (3.14)

Severely depressed

60.0±27.6

54.8±24.5

0.79 to 10.00

0.022 0.004

0.94 to 10.21

0.019 0.020

-0.28 to 12.09

0.061 Not significant

LSEQ quality of sleep score (mm) Week 1

61.2±19.6

55.7±19.8

5.51 (2.26)

1.06 to 9.96

0.015

Week 2

62.2±20.1

61.3±21.4

0.89 (2.39)

-3.82 to 5.60

0.71

Week 3

67.0±20.7

64.9±18.3

2.19 (2.31)

-2.25 to 6.73

0.343

Week6

76.3±21.4

71.4±19.8

4.85 (2.37)

0.19 to 9.51

0.041

Last

72.5±21.4

66.9±22.3

5.63 (2.43)

0.85 to 10.41

0.021

Within group change

11.3

11.2

LSEQ sleep awakening score (mm) Week 1

57.4±18.9

53.8±18.2

3.69 (2.13)

-0.50 to 7.88

0.084

Week 2

61.1±18.0

55.5±18.1

5.57 (2.09)

1.45 to 9.69

0.008

Week 3

63.1±20.5

57.5±19.5

5.54 (2.36)

0.89 to 10.19

0.02

Week6

69.4±19.4

64.3±21.4

5.13 (2.54)

0.12 to 10.14

0.045

Last

66.9±20.5

62.0±21.8

4.86 (2.35)

0.23 to 9.49

0.040

Within group change

9.5

8.2

LSEQ intergrity of behaviour score (mm) Week 1

58.6±17.8

48.4±18.5

10.25 (2.05)

6.21 to 14.29

<0.0001

Week 2

57.8±18.4

55.2±19.2

2.60 (2.15)

-1.63 to 6.83

0.227

Week 3

61.0±19.2

59.5±18.5

1.49 (3.61)

-2.87 to 5.85

0.501

Week6

68.8±18.1

65.2±18.9

3.61 (2.30)

-0.93 to 8.15

0.118

Last

66.2±20.1

61.0±20.9

5.16 (2.28)

0.68 to 9.65

0.024

Within group change

7.6

12.6

0.044

HAMD insomnia items score Baseline

4.6±1.2

4.6±1.4

Last visit

1.4±1.6

1.8±1.7

0.37

0.01 to 0.72

Early insomnia (max score 2)

Not stated

Not stated

0.18

Not stated

<0.05

Middle insomnia (max score 2)

Not stated

Not stated

0.17

Not stated

<0.05

Early awakening (max score 2)

Not stated

Not stated

0.02

-0.13 to 0.16

Not stated

HAMD total score, last value

9.9±6.6

11.0±7.4

Responders

76.4%

70.6%

Change from baseline excluding sleep items

21.3±3.0 to 8.5±5.6

21.4±2.9 to 9.2±6.3

CGI-I week 1

3.2±0.8

3.6±0.9

0.39

0.20 to 0.58

<0.0001

CGI-I week 6

1.6±0.7

1.6±0.8

0.32

0.06 to 0.58

0.016

Depression scores (all patients) Not significant -15.35 to 3.73

THIS IS AN NHS DOCUMENT NOT TO BE USED FOR COMMERCIAL AND MARKETING PURPOSES. PRODUCED TO INFORM LOCAL DECISION-MAKING USING THE BEST AVAILABLE EVIDENCE AT THE TIME OF PUBLICATION.

June 2009

London New Drugs Group APC/DTC Briefing