AFFINITY trial A ssessment o F F luoxet IN e I n s T roke recover Y

1. AFFINITY trialAssessment oFFluoxetINe In sTroke recoverY Co- principal investigators: Hackett M, Hankey GJ. Steering committee: Almeida O, Anderson CS, Beer C, Billot L, Dennis MS, Flicker L, Ford A, Jan S, Mead G

2. The burden of disability due to stroke • 4th leading cause of global disease burden • 16 million 1st-ever events • 51 million disability-adjusted life years • 5.7 million deaths • 50% of stroke survivors have long-term residual disability. • How can we improve recovery & reduce disability after stroke?

3. Fluoxetine Animal studies suggest fluoxetine is effective ?directly improves motor function ? indirectly improves motivation and attention FLAME trial (Lancet Neurology, 2011;10:123-130) • Fluoxetine on Motor Rehabilitation after ischaemic stroke • RCT: 118 with acute ischaemic stroke & unilateral motor weakness • Intervention: 20 mg fluoxetine daily, 3 months vs. placebo

4. FLAME trial: Modified Rankin score at 90 daysmRS 0-2: 26.3% fluoxetine vs 8.9% placeboOR = 3.8, 95% CI 1.2 to 10.7

5. FLAME trial: Fugl Meyer Motor scores Adjusted mean Fugl-Meyer motor scale (FMMS) total scores at days 0, 30, and 90 Error bars represent 95% CI

7. Rationale for a new trial FLAME results promising, however: • ? Internal validity (Random error) • only 57 pts assigned fluoexetine vs 56 placebo • Wide 95% CI of estimates (Independency OR = 3.8, 95% CI 1.2 to 10.7) • ? External validity (generalisability) We need to know: • Does fluoxetine really work? • Are the results generalisable to an Australian population? • Do the benefits persist after treatment has ceased?

8. Assessment oFFluoxetine IN sTroke recoverY (AFFINITY) trial

9. Primary aim 1 ◦ To determine if taking fluoxetine, 20 mg, once daily, for 6 months, started 2-15 days post acute stroke improves participants’ neurological outcome (functional ability).

10. Secondary aims 2◦ To determine if fluoxetine… • Improves at 6 months • survival, • mood (PHQ-9), • cognitive function (TICSm), • HRQoL (SF-12), • Reduces at 6 months • fatigue (SF-36 vitality domain) • Is safe • Reduces the cost of health and social care • Has persisting effects at 12 months on: • functional ability, survival, mood, cognitive function, HRQoL, and fatigue

11. Inclusion criteria • Male or female • ≥ 18 years of age • Clinical diagnosis of stroke; onset 2-15 days ago • Imaging consistent with ICH or ischaemic stroke • Neurological deficits at randomisation which are severe enough to warrant Rx (pt or carer perspective)

12. Exclusion criteria • History of: • Epileptic seizures • Bipolar disorders • Drug overdose • Attempted suicide • Allergy to fluoxetine • Current or recent (<5/52) Rx with MAOI or pimozide • Current or recent (<1/12) depression requiring Rx with SSRI • Current Rx with other antidepressants unless agree to discontinue on randomisation • Unlikely to be contactable or available for follow-up over 12 months • Unlikely to survive 12 months (e.g. life-threatening illness) • SAH (except if 2◦ to ICH) • Pregnant or breast feeding, female of child bearing age not on adequate contraception • Hepatic impairment (ALT < 120 U/L) • Renal impairment (Creatinine > 220 micromol/l) • Hyponatraemia (Sodium < 130mmol/L)

13. Trial recruitment and assessments: from the patients’ perspective Approached by member of clinical team Receive patient information leaflet and verbal explanation They have time to consider whether they wish to take part They, or their next of kin give consent if wish to join the trial They provide information which is entered into the trial database

14. Randomisation Web-based, central randomisation service Rx allocation ratio 1:1 Stratified randomisation: Presence of a motor deficit Presence of aphasia (i.e. allocates each patients to the Rx that leads to the least difference between the two groups with respect to these features)

15. Intervention • Fluoxetine 20 mg/day or Placebo one/day • Oral • Double-blind • 6 months

16. Outcome measures • Primary: modified Rankin score at 6 months • Secondary • Adherence to medication • New clinical diagnosis of depression • Survival • Depression (PHQ 9; 9 questions) • Cognition (TICSm; 13 questions) • Fatigue (Vitality score of SF-36; 4 questions) • Resource use (3 questions) Optional • Overall health status: Stroke impact score (59 items, 8 domains) • Health-related quality of life (SF 12; 12 questions)

17. Adverse effectsBMJ 2011; 343: d4551; d4660 • Stroke or TIA (HR 1.15; 95% CI: 1.05 to 1.26) • Myocardial infarction • Epileptic seizures (HR 1.80; 1.32 to 2.43) • Falls (HR 1.27; 1.20 to 1.35) • Fractures (HR 1.26; 1.15 to 1.37) • Hyponatraemia (HR 1.44; 1.19 to 1.75 • Attempted suicide/self harm (HR 1.27; 0.97 to 1.66) • Upper GI bleeding (HR 1.22; 1.07 to 1.40)

18. Adverse effects of newer antidepressants and suggested management.BMJ 2012; 344: d8300. Adverse effect Comment Management • Dizziness < 10% Check BP standing and lying; symptoms may improve over time; Decrease dose or change treatment. Ensure adequate fluid intake • Sedation Not common May be desirable; May improve over time. Change time of dosing and treatment • Dry mouth Probably dose related Tolerance may develop; change treatment; Sugarless gum or saliva substitutes • Sexual dysfunction Common Reduce dose, wait for improvement, switch to a different antidepressant, or consider sildenafil • Insomnia Common Try to distinguish from insomnia caused by depression Change time of dosing (earlier or later may help), improve sleep hygiene, try a different antidepressant, or short course of benzodiazepine, zopiclone, or low dose trazadone • Suicidal thoughts Age < 30 Review often (within a week of starting Rx and until no longer needed). No evidence that asking about suicide increases likelihood of self- harm. Prescribe small amounts of medication. • Anxiety Often when starting Rx Consider using a benzodiazepine for no longer than two weeks • Hyponatraemia A problem in the elderly Check sodium before and after starting treatment Consider changing to mirtazapine if it becomes problematic • Serotonin syndrome Confusion/agitation, Stop the antidepressant Autonomic instability,and Hydration, Rx of hyperthermia, and benzodiazepines Neuromuscular hyperactivity Consider cyproheptadine or chlorpromazine in severe cases • Discontinuation syndrome Decrease dose over four weeks. Warn the patient

19. Sample size calculations • Expect % of independent participants (mRS 0-2) in intervention group to: • increase by 7.5% absolute percentage points (from 50% to 57.5%) • increase by 15 relative percentage points, • odds ratio of 1.35 • (cf. FLAME: OR = 3.8, 95%: CI 1.2 to 10.7)

20. 1,580 patients Informed consent and trial specific screen and baseline assessment Central randomisation 2 to 15 days post-stroke Intervention group (n=790) Control group (n=790) 1 month on-intervention assessment 3 month on-intervention assessment and dispensing End of 6-month intervention assessment 6-month off-intervention (12 month) assessment Trial design:Flow of participants and assessments

21. Collaborators (UK FOCUS)Prof Martin Dennis Prof Gillian Mead • Larger, similar trial • FOCUS pilot phase • Funded by The Stroke Association • Protocol funded by NIHR Stroke Research Network • FOCUS main phase • Funding application to NIHR HTA • Planned prospective meta-analysis

22. AFFINITY/FOCUS joint analyses FOCUS aims to recruit 3000 If we complete both FOCUS and AFFINITY and enrol 4500 patients we could reliably detect a 4.4% absolute increase in mRS 0-2.

23. We welcome interested collaborators

24. Back up

25. Management of depression Options Give fluoxetine 20mg od (but potentially ‘dilute’ treatment effect) Tricyclic antidepressant Mirtazipine: favoured by Allan House, literature suggests interactions are uncommon and not serious