Agomelatine (Valdoxan) for generalised anxiety disorder – first or second line

April 2011

This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes.

The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research

April 2011

Agomelatine (Valdoxan) for generalised anxiety disorder – first or second line

Target group • Generalised anxiety disorder (GAD) – first or second line.

Background GAD is defined as excessive worry and tension about everyday events and problems, on most days, for at least 6 months, to the point where the person experiences distress or has marked difficulty in performing everyday tasks1. GAD is characterised by increased motor tension, autonomic hyperactivity and increased vigilance and scanning, but not by panic attacks6. Symptom severity is measured on continuous rating scales; frequently used scales include the Hamilton Anxiety Scale (HAM-A), the Clinical Global Impressions Scale (CGI) and Spielberger State-Trait Anxiety inventory (STAI)1. GAD commonly co-exists both with other anxiety disorders and with depressive disorders, as well as various physical health disorders. ‘Pure’ GAD in the absence of another anxiety or depressive disorder is less typical than co-morbid GAD2.

Technology description Agomelatine (Valdoxan, Thymanax, AG0178) is an oral melatonin agonist and 5-HT2C antagonist. It has a strong affinity for the melatonin binding site in the pars tuberalis of the hypothalamus and inhibits local forksolin-stimulated cAMP production. By acting on the suprachiasmatic nucleus of the hypothalamus, it is able to resynchronise disrupted circadian rhythms. In a phase III trial agomelatine was administered orally at 25-50mg once daily3.

Agomelatine is currently licensed in the EU for the treatment of major depression. Some of the common recognised adverse effects of agomelatine include: headache, dizziness, somnolence, insomnia, migraine, hyperhydrosis, back pain, fatigue and anxiety4. Agomelatine is also in phase III trials for depressive disorders (in older people and for the prevention of relapse), and is in phase II trials for anxiety disorders.

Innovation and/or advantages If licensed, agomelatine may offer another treatment option for patients with GAD, with potentially improved tolerability, including a low propensity to cause weight gain and sexual dysfunction.

Developer Servier Laboratories Ltd.

Availability, launch or marketing dates, and licensing plans In phase III trials.

NHS or Government priority area This topic is relevant to the National Service Framework for Mental Health (1999).

Relevant guidance • NICE technology appraisal. Quetiapine for the treatment of generalised anxiety disorder. Suspended June 20105.

2 April 2011

• NICE clinical guideline. Management of anxiety (panic disorder, with or without agoraphobia, and generalised anxiety disorder) in adults in primary, secondary and community care. Partial update. 20112. • NICE clinical guideline. Management of anxiety (panic disorder, with or without agoraphobia, and generalised anxiety disorder) in adults in primary, secondary and community care. 20076.

Clinical need and burden of disease The Adult Psychiatric Morbidity in England Survey (1999) estimated that the proportion of people in England with GAD was 4.4%, this figure has varied little across the three survey years 1993, 1997 and 20077,2. A further observational study in the UK estimated that 4.7% of people had GAD in 2000, 4.6% in men and 4.8% in women1. Prevalence rates are generally between 1.5 and 2.5 times higher in women than men1,2. GAD has a lifetime prevalence of approximately 5%8. Epidemiological studies have found GAD to be less common in older age groups, above the age of 55 years, and in younger adults below the age of 35 years1. The average age at onset is thought to be around 30 years of age7.

In England, there were 817 finished consultant episodes and 720 hospital admissions due to GAD in 2009-2010 (ICD 10: F41.1)9. GAD is more commonly seen in primary care occurring in about 5% of attendees2, though evidence suggests that GAD is still significantly under-detected and under-treated in the UK2. GAD is typically a chronic and disabling condition with few patients having remission after 12 months and less than half of patients diagnosed having full remission after 5 years1. Evaluation of prognosis is complicated by frequent co-morbidity with other anxiety disorders and depression, which worsen the long-term outcome and accompanying burden of disability2.

Existing comparators and treatments The aim of treatment for GAD is to relieve symptoms, restore function and prevent relapse2. Current treatment options include1,2a: • Psychological therapies: o Cognitive behavioural therapy (CBT) including exposure, relaxation and cognitive restructuring. o Counselling. • Pharmacological therapies: o Benzodiazepines and buspirone are used for the immediate management of GAD, if necessary and for short-term use only. o Antidepressants commonly used for longer-term management of GAD include: imipramine, paroxetine, sertraline, escitalopram, venlafaxine and opipramol. o Antipsychotic drugs may be used to reduce anxiety in GAD, but have serious adverse effects. o Pregabalin and the antihistamine hydroxyzine have also been used to reduce anxiety.

Efficacy and safety

Trial Adults; agomelatine vs placebo; phase ISRCTN38094599; agomelatine vs III. placebo; phase III. Sponsor Servier Laboratories Ltd. Servier Laboratories Ltd. a Expert opinion. 3 April 2011

Status Complete and published in abstract. Complete. Source of Abstract10, publication11. Trial registry12. information Location Finland and South Africa. EU and Canada. Design Randomised, placebo-controlled. Open-label, then randomised, placebo-controlled. Participants n=121; adults; GAD (DSM-IV b); without n=370 (planned); adults; GAD (DSM- and schedule depression. IV); without depression. Randomised to agomelatine 25-50mg Randomised to agomelatine 25-50mg daily or placebo for 12 weeks. Trial daily or placebo for 26 weeks followed flexible dose design, doses following 16 weeks of open-label raised if participants insufficiently agomelatine at 25mg daily. improved according to HAM-A total score and CGI score. Follow-up 12 week treatment period. 42 week treatment period. Primary HAM-A total score, CGI. Time to relapse. outcomes Secondary HAM-A somatic and psychic subscales, HAM-A. outcomes CGI scales, Leeds Sleep Evaluation questionnaire, Sheenan Disability Scale (SDS). Key results In agomelatine vs placebo respectively: Not yet reported. HAM-A (SD) total score decreased from 29±(4.4) to 12.4±(8.9) vs 28.6±3.8 to 15.4 ± (9.5) (p=0.04). Rate of response at last value 66.7% vs 46.6% (p=0.026) and remission at endpoint was 41.3% vs 22.4% (p=0.027). HAM-A somatic and anxiety subscale scores improved for agomelatine group. Statistically significant vs placebo for somatic symptoms, (p=0.015). Mean CGI severity of illness between 2 groups decreased from 4.9 (0.7) to 2.7 (0.4) vs 9.7 (0.6) to 3.2 (1.4), p= 0.0049. Improvement in sleep symptoms on Leeds Sleep Evaluation Questionnaire more marked in agomelatine group vs placebo items including: getting off to sleep 30.3 ± 17.5 vs 42.3 mm ± 15.2 at last value, p<0.001), quality of sleep 31.2 ± 21.3 vs 43.1mm ± 18.9, (p= 0.002), and sleep awakening 34.8 (20.4) vs 49.1mm (16.7),( p<0.0001). Mean scores on SDS at week 12 lower for each subscale in agomelatine group vs placebo, reaching statistical significance for family subscale (p=0.035). Mean level of each item on DSM-IV symptom severity scale numerically lower in agomelatine group vs placebo.

b Diagnostic and Statistical Manual of Mental Disorders. 4 April 2011

Adverse effects No difference in proportion of patients Not yet reported. (AEs) reporting treatment related AEs between agomelatine (38.1%) and placebo group (34.5%) or agomelatine 25mg (36.1%) and 50mg group (38.5%). Most common AEs more frequently reported in agomelatine group were dizziness (8.0% vs 3.4%) and nausea (4.8% vs 1.7%). Most AEs rated mild or moderate.

Trial ISRCTN03554974; agomelatine, escalitopram or placebo; phase III. Sponsor Servier Laboratories Ltd. Status Ongoing. Source of Trial registry13. information Location EU. Design Randomised, active-controlled. Participants n=390 (planned); adults; GAD (DSM-IV); without depression. and schedule Randomised to agomelatine 25 or 50mg daily, escitalopram 10 or 20mg daily or placebo. Follow-up 12 week treatment period. Primary HAM-A total score. outcomes Secondary HAM-A, CGI severity and CGI improvement, self rating depression scale, Leeds outcomes Sleep Evaluation questionnaire. Expected Anticipated trial completion Q3 2011. reporting date

Estimated cost and cost impact The cost of agomelatine (Valadoxan) has not yet been determined for this indication. However, agomelatine for the treatment of major depression costs £30.00 for a 28 tab pack of 25mg tablets14.

Claimed or potential impact – speculative Patients Reduced mortality or increased  Reduction in associated morbidity Quicker, earlier or more accurate length of survival or Improved quality of life for diagnosis or identification of patients and/or carers disease Other: None identified

Services Increased use Service organisation Staff requirements

Decreased use Other:  None identified

Costs Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative coming for treatment investment needed  New costs: new treatment option. Savings:  Other: uncertain unit cost compared to other pharmacological therapies.

5 April 2011

Other issues  Clinical uncertainty or other research question identified: the optimum None identified length of treatment has not been established.

References

1 Gale C and Millichamp J. Clinical Evidence – Generalised anxiety disorder. http://clinicalevidence.bmj.com/ceweb/conditions/meh/1002/1002-get.pdf Accessed 28 February 2011. 2 National Institute for Health and Clinical Excellence. Management of anxiety (panic disorder, with or without agrophobia, and generalised anxiety disorder) in adults in primary, secondary and community care. Partial update. Clinical Guideline CG113. London: NICE; February 2011. 3 Stein DJ, Ahokas A and Fabiano A. Agomelatine in generalized anxiety disorder: a randomized, placebo- controlled study. European Neuropsychopharmacology 2007; 17 (S4): 509-510. 4 Electronic Medicines Compendium (eMC). Summary of product characterics – Valdoxan http://www.medicines.org.uk/EMC/medicine/21830/SPC/Valdoxan/#UNDESIRABLE_EFFECTS Accessed 28 February 2011. 5 National Institute for Health and Clinical Excellence. Quetiapine for the treatment of generalised anxiety disorder. Technology appraisal. Suspended June 2010. 6 National Institute for Health and Clinical Excellence. Management of anxiety (panic disorder, with or without agrophobia, and generalised anxiety disorder) in adults in primary, secondary and community care. Clinical Guideline CG22. London: NICE; April 2007. 7 Office for National Statistics. Adult Psychiatric Morbidty Survery, 2007 http://www.ic.nhs.uk/pubs/psychiatricmorbidity07 Accessed 7 March 2011. 8 Anxiety UK. Generalised anxiety disorder or chronic worrying – a brief guide. http://www.anxietyuk.org.uk/about-anxiety/anxiety-disorders/generalised-anxiety-disorder-gad/ Accessed 3 March 2011. 9 NHS. Hospital episode statistics. NHS England 2009-10. HES data 2001 www.hesonline.nhs.uk 10 Stein DJ, Ahokas AA and Fabiano A. Agomelatine in generalized anxiety disorder: a randomized, placebo- controlled study. European Neuropsychopharmacology 2007;17 (S4): 509-510. 11 Stein DJ, Ahokas AA and de Bodinat C. Efficacy of agomelatine in generalized anxiety disorder a randomized, double-blind, placebo-controlled study. Journal of Clinical Psychopharmacology 2008; 28: 561-566. 12 WHO Internal Clinical Trials Registry. Long-term efficacy and safety of agomelatine in non-depressed out- patients with generalised anxiety disorder. A 26-week randomised double-blind placebo-controlled parallel group study following an open label period of 16 weeks with agomelatin. http://apps.who.int/trialsearch/Default.aspx Accessed 3 March 2011. 13 WHO International Clinical Trials Registry. Efficacy and safety of agomelatine (25mg/day with potential blinded adjustment to 50mg/day) for 26 weeks in non-depressed out-patients with generalised anxiety disorder. http://apps.who.int/trialsearch/Default.aspx Accessed 3 March 2011. 14MIMS-Valdoxan.http://www.mims.co.uk/Drugs/central-nervous-system/depression-other-affective- disorders/valdoxan/?DCMP=ILC-SEARCH Accessed 1 April 2011.

The National Institute for Health Research National Horizon Scanning Centre Research Programme is funded by the Department of Health. The views expressed in this publication are not necessarily those of the NHS, the NIHR or the Department of Health

The National Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, 90 Vincent Drive, Edgbaston, Birmingham, B15 2SP, England Tel: +44 (0)121 414 7831 Fax +44 (0)121 414 2269 www.haps.bham.ac.uk/publichealth/horizon

6