Clinical trials in status epilepticus

AED X1 - Miami April 28th 2011

Simon Shorvon

UCL Institute of Neurology,

University College London

Tonic clonic status epilepticus (SE)

- Definitions

- Outcome - death/cerebral damage

- Current treatment – staged therapy (I3)

Evidence base

- Stage 1 – sufficient

- Stages 2 & 3 – wholly insufficient

Issues for designing clinical trials

- Outcome measures

- Power/numbers

- Randomisation, blinding, consent

- Other studies – neuroprotection

Definition of SE and purpose of therapy

• Status epilepticus is defined as a seizure which has

persisted for 30 minutes or more (or recurring seizures

without recovery of consciousness for 30 mins of more)

• Urgent drug treatment is vital to prevent cerebral

damage (thus intravenous therapy at least by the

time the patient is admitted to hospital)

• Purpose of therapy is to stop seizures – because:

i. SE has a significant mortality rate

ii. SE results in cerebral damage resulting in:

- ongoing epilepsy

- cognitive disturbance

- focal neurological deficit

Cerebral damage caused by SE

• Risk of cerebral damage strongly related to duration

- 30 to 60 mins of onset of SE

• Excitotoxicity is main cause of damage

Mortality of SE

• Mortality rate of TCSE

- 27% VA study 1998

- 22% Richmond study (de Lorenzo et al 1996)

- 19% Minnesota study (Hesdorffer et al 1998)

- 33% Bologna study (Vignatelli et al 2005)

- 7.6 % EPISTAR (Coeyteux et al 2000)

- 9.3% Hessen (Knake et al 2001)

- 19% Rochester (Logroscino et al 2002)

• Factors influencing mortality and morbidity include:

- Underlying aetiology

- Duration of SE

- Age and other factors including EEG,

GCS on arrival, treatment

(Neligan and Shorvon. Epilepsy Research 2011 93: 1-10)

Staged protocols for the treatment of SE

Conventional therapy in convulsive SE is staged – balancing risk

of disease .v. risk of treatment

Stage 1: Premonitory / early SE (Usual treatment = benzodiazepine;

out-of-hospital IM/Nasal; in-hospital IV)

Stage 2: Established SE(Usual treatment = IV AEDs - PTH or PB or Val)

Stage 3: Refractory SE (Usual treatment = general anaesthesia)

Super-refractory SE

Out of hospital therapy - RCT comparing buccal midazolam and rectal diazepam in acute seizures

RCT in a residential school setting

79 children with continuous seizures of >5mins

Midazolam given at dose of 10mg in 2ml on buccal mucosa .v. Diazepam given at dose of 10mg via rectal tubule

Seizure control: Midazolam 30/40 (75%)

Diazepam 23/39 (53%)

(Scott; Lancet 1999 353: 623)

10

20

15

5

0Buccal midazolam Rectal diazepam

Treatment

Time from drug administration to end of seizure (min)_____________________________________________

RCT: buccal midazolam .v. rectal diazepam in children

Multicentre RCT - buccal midazolam .v. rectal diazepam

0.5mg/kg (approx). 219 episodes.

Acute seizures and SE presenting to A&E (mean 30-47 mins of

seizures before trial; 31% had had prior initial therapy)

Conclusion – buccal midazolam is more effective than rectal

diazepam

(McIntyre et al. Lancet 2005: 366: 205-9)

OUTCOME MDZ DZP

(n=109) (n=110)

Seizure control (within 10 mins) 56% 27%

Time to seizure control (median) 8 mins 15 mins

Respiratory depression 5% 6%

Required additional therapy 33% 57%

RCT of IV lorazepam, diazepam and placebo

From : Alldredge et al

NEJM 2001 345: 631

• In out-of—hospital treatment: Study from San Francisco; 205 adult

patients randomised to lorazepam 2mg, diazepam 5mg or placebo’

Lorazepam is, onthe basis, of thisstudy now considered the treatment of choice for IV therapy in earlySE

Stage 1: Early SE - benzodiazepines

Lorazepam 4 mg (IV bolus; rate not critical), can be repeated

after 10 mins if no response

Diazepam 10-20mgs (IV bolus; not more than 5mg/min; can be repeated after 10 mins if not response)

In-hospital IV therapy in early SE

- Lorazepam vs diazepam – 3 RCTs (n=289)- Lorazepam vs placebo – 1 RCT (n=137)- Lorazepam vs diazepam/phenytoin – 1 RCT (n=192)- Lorazepam vs phenobarbital – 1 RCT (n=188)- Lorazepam vs phenytoin – 1 RCT (n=198)- Midazolam vs lorazepam – 1 RCT (n=27)- Midazolam vs diazepam – 1 RCT (n=40)- Diazepam vs placebo – 1 RCT (n=139)

Conclusions (10 RCTs):

1. DZP and LZP are better than placebo 2. LZP is better than phenytoin3. LZP may be better than DZP (2 out of 3 measures)

Stage 2: established SE – traditional therapy - DPH/PB

RCTs in established SE:

- Diazepam/phenytoin vs phenobarbital - 2 RCTs (n=222)

- Phenytoin vs phenobarbital - 1 RCT (n= 186)

- Diazepam/phenytoin vs phenytoin - 1 RCT (n= 196)

Conclusions (4 RCTs):

- no significant differences

- trend to favour DZP/PHT over PB

- trend to favour PB over PHT

Stage 2: established SE – other IV antiepileptic drugs

• In Europe – widespread use of VPA, LEV, LCM

• Two RCTs of VPA (compared to DPH)

- Underpowered, unblinded, statistical flaws

- Variable endpoints and designs

• No RCTs of levetiracetam or lacosamide

• Retrospective and some prospective case series

- PHT - 703 patients -efficacy 44-88%

- VPA - 499 patients - efficacy 63-95%

- LEV - 489 patients - efficacy 40-100%

- LCM - <60 patients - efficacy 30-100% ( figurse includes case reports and small series;

significant publication bias )

Stage 2: Refractory SE - general anaesthesia

• Current guidelines suggest use of general anaesthesia

- Most common recommendations are for: thiopental

(pentobarbital), midazolam or propofol

- Others include: ketamine, inhalational anaesthetics

• One so-called ‘meta-analysis’ although actually simply a

collection of all cases, but data not reproducible

• Anaesthesia will control seizures in all cases (by definition)

so outcome measured in recurrence on withdrawal or

rebound, or short-term mortality:

- Thiopental/pentobarbital - mortality 20-55%

- Midazolam - mortality 17-69%

- Propofol - mortality 26-88%

(from 6 representative series)

Issues in the design of SE trials

• Design

- must be a RCT

• Randomization

- cluster/individual

• Need for double blinding ?

- By definition the patient is unconscious

- Side-effects, administration, precautions will vary

• Issues of consent

- By definition, patients with lack capacity for consent

- Delay of even minutes can adversely affect outcome

- Randomisation and consent can be initiated in some

countries (eg UK: Clin Trial Reg 2006, amend 2,

Statutory instrument 2984)

- Informed consent in retrospect from pt or proxy and

if declined pt removed from study and data deleted

Issues in the design of SE trials – outcome measures

• Stage 2: established SE

- Seizure control at 2 hours

- 30 day outcome

- Time to seizure control

- EEG control

- Others – time on ITU, need for ventilation,

side-effects, health economic etc

• Stage 3: refractory SE

- Seizure control on anaesthetic withdrawal

- 30 day outcome/mortality

- Failed anaesthesia

- Health economic etc

• Stratification by age, aetiology etc ?.

Issues in the design of SE trials – numbers / power

• Stage 2: established SE

- Data on efficacy is poor which compromises power

calculation

- CHMP in UK wish for superiority design but will

accept lower significance values

- Power calculations: e.g. comparison of therapy

with PTH: assume PTH efficacy 55%, minimum

superiority of 10%, 5% drop out, 80% power, 2-

tailed significance level of 5%

number needed is 550 per arm

- Major centres treat 10-50 cases per year (mean 20)

- Studies must be multicentre and probably

multinational

Evidence base for therapy of refractory SE

Therapy No of patients in published studies

RCT

Thiopental/propofol/midsazolam

193 nil

Ketamine <5 nil

Inhalational anaesthetics <10 nil

Hypothermia <10 nil

AED strategy nil nil

Magnesium <5 nil

Steroids/immunotherapy <10 nil

Emergency surgery <10 nil

ECT, ketogenic diet, Stim, CSF <10 nil

Trials for SE – neuroprotection

Neuroprotection

- Early studies focus on GluR blockadegenerally not successful – ‘ the horse has bolted’

More recent studies have other targets/approaches:- Rapamycin- Anti-inflammatory drugs- Immunosuppression- Leucocyte adhesion molecules- Hypothermia- Free radicals - Mitochondria- Antiepileptics

Experimental evidence, weak clinical evidence

Trials for SE – Summary

Studies are needed urgently in Stage 2 and Stage 3

SE (stage 1 SE, evidence is now sufficient)

Currently mortality and morbidity is high and advice on therapy is individual and subjective.

Current evidence base is wholly insufficient

There are formidable problems in study design relating to outcome measures, numbers, randomisation, blinding, consent

Studies are unlikely to emanate from industry

Multicentre studies needed; databases

Regulatory authorities have set the bar to high –resulting in largely off-label prescribing.