AFFINITY trialAssessment oF FluoxetINe 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

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?

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

FLAME trial: Modified Rankin score at 90 daysmRS 0-2: 26.3% fluoxetine vs 8.9% placebo

OR = 3.8, 95% CI 1.2 to 10.7

FLAME trial: Fugl Meyer Motor scoresAdjusted mean Fugl-Meyer motor scale (FMMS) total scores at days 0, 30, and 90

Error bars represent 95% CI

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?

Assessment oF Fluoxetine IN sTroke recoverY (AFFINITY) trial

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).

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

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)

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)

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

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)

Intervention

• Fluoxetine 20 mg/day or Placebo one/day– Oral– Double-blind– 6 months

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)

Adverse effects BMJ 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)

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 benzodiazepinesNeuromuscular hyperactivity Consider cyproheptadine or chlorpromazine in severe cases

• Discontinuation syndrome Decrease dose over four weeks. Warn the patient

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)

Expected distributions of mRS scores at 6 months (end of fluoxetine)

mRS score 0 1 2 3 4 5 6Control group 0.10 0.20 0.20 0.15 0.10 0.10 0.15

Intervention group 0.13 0.24 0.21 0.14 0.09 0.08 0.12

Trial design:Flow of participants and assessments

3 month on-intervention assessment and dispensing

1,580 patients

Central randomisation 2 to 15 days post-stroke

Intervention group (n=790) Control group (n=790)

Informed consent and trial specific screen and baseline assessment

End of 6-month intervention assessment

1 month on-intervention assessment

6-month off-intervention (12 month) assessment

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

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.

We welcome interested collaborators

Back up

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