Methods

4.2.1

SANAD

SANAD [180] had two arms, A and B. In the case of arm A, the recruited patients were those for whom clinicians considered carbamazepine the first line standard treatment, 89% of whom were classified with a focal epilepsy. Patients were randomly allocated to treatment with carbamazepine, gabapentin, lamotrigine, oxcarbazepine or topiramate. Overall results indicated that lamotrigine was a potential first line treatment as it was significantly superior to carbamazepine for the outcome time to treatment failure (lamotrigine vs. carbamazepine: HR 0.78 95% CI (0.63 to 0.97)), but similar to carbamazepine for time to 12 month remission. Gabapentin and topiramate were identified as poor first line treatments, gabapentin due to lack of efficacy and topiramate due to both lack of efficacy and poor tolerability.

The methods for the SANAD study have been published elsewhere [180]. In summary, patients were eligible for inclusion in the study if, in the previous year, they had a history of at least two clinically definite unprovoked epileptic seizures, they were at least five years old, and if the recruiting clinician deemed carbamazepine as opposed to valproate, to be the optimal standard treatment option in the case of arm A and valproate rather than carbamazepine to be the optimal in the case of arm B. Patients generally had newly diagnosed and untreated epilepsy, but could also be recruited if they were taking a monotherapy drug that was not being investigated in SANAD (e.g. phenytoin) with a change in drug indicated, or if they had previously been treated with an antiepileptic drug,

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had had a seizure remission, but had a recurrence of seizures following antiepileptic drug withdrawal.

Exclusion criteria included treatment contraindication, a history of progressive neurological disease or a history of only acute symptomatic seizures such as febrile seizures. Patients were recruited to the trial between December 1st 1999 and August 31st 2004 and were

followed-up, if possible, until between May 1st 2005 and August 31st 2005 although some

follow-up data were obtained up to January 13th 2006. Following enrolment by the

recruiting physician and obtainment of informed consent, patients were allocated randomly to treatment. Between December 1st 1999 and June 1st 2001 patients were allocated in a ratio of 1:1:1:1 to carbamazepine, gabapentin, lamotrigine, and topiramate in arm A, and 1:1:1 to valproate, lamotrigine and topiramate in arm B.

From 1st June 2001 to 31st August 2004 an oxcarbazepine group was added to arm A of the

trial and patients were randomly allocated in a ratio of 1:1:1:1:1 to carbamazepine, gabapentin, lamotrigine, oxcarbazepine or topiramate. Randomisation was by a central telephone service via the minimisation method which was balanced across centre, gender and treatment history. While the drug allocation was randomised, the dose and preparation was based on the clinicians’ usual practice aided by guidelines in the trial protocol.

Baseline clinical information and demographic data such as neurological history, EEG, brain imaging results, seizure classification and epilepsy type were obtained for all randomised patients. Where there was uncertainty between focal onset and generalised onset seizures, patients were recorded as having unclassified convulsive, or other unclassified, seizures. Follow-up occurred at three, six and 12 months and successive yearly intervals from randomisation with additional visits as clinically indicated. At each visit the

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occurrence of seizures, adverse events, hospital admissions and antiepileptic drug treatment were recorded.

There were two primary outcomes - time to treatment failure from randomisation and time to 12 month remission from randomisation. Treatment failure can be split into two main categories; inadequate seizure control for which the randomised drug might be withdrawn or a second treatment added, or due to unacceptable adverse events. Patients were categorised into these two main failure reasons as in the original SANAD analyses [180, 181]. Patients categorised as failing due to inadequate seizure control included those citing inadequate seizure control as the only reason for treatment failure, those with both inadequate seizure control and unacceptable side effects, and those who died where the cause of death was related to epilepsy. Patients were categorised as failing due to adverse events if they recorded unacceptable adverse events, withdrew treatment following a period of remission of less than 12 months where adverse events likely influenced the decision to withdraw treatment, and those withdrawing treatment due to pregnancy or planned pregnancy due to concerns about teratogenic effects. Time to 12 month remission was defined as time from randomisation to 365 days of seizure freedom.

4.2.2

Prognostic Modelling

Analyses were undertaken using R version 2.9.2 [182] and SAS version 9 [183].

The aim of the prognostic modelling was to identify two sets of factors – one set that predict time to 12 month remission, and one set that predict time to treatment failure. Clinical consensus and knowledge from previous prognostic studies in epilepsy [119, 120] led to the following list of potential prognostic factors: gender, febrile seizure history, first degree relative with epilepsy, CT/MR scan result, treatment history, age, time from first seizure to randomisation, neurological insult (e.g. hemiparesis), total number of seizures ever before randomisation, EEG result, seizure type and epilepsy type. For the CT/MR

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results, scans were classified as normal, abnormal and not done. Patients were classified as having neurological insult if they had learning disabilities or neurological deficit. EEGs were classified as normal, not done, non-specific abnormality and epileptiform abnormality (focal or generalised spikes or spike and slow wave activity).

Seizure types were classified according to the International League Against Epilepsy seizure classification [76]. Epilepsy type was first classified as focal, generalised or unclassified. In arm A, patients with a focal epilepsy were further classified as temporal lobe, frontal lobe, parietal lobe, occipital lobe, benign focal epilepsy, or focal epilepsy not localised. For the regression modelling, due to small numbers of participants, occipital lobe, parietal lobe and benign focal epilepsy were combined in a group referred to as other.

Modelling methods used are as outlined in detail in Chapter 3 but in summary variables associated with a higher chance of treatment failure and a higher chance of achieving 12 month remission were determined after adjusting for multiple variables using Cox proportional hazards modelling methods. As oxcarbazepine was only included in the

randomisation after June 1st 2001 all analyses were stratified by randomisation period to

account for the reduced patient numbers for this drug.

Variables were centred to diminish multicollinearity [158] and tested via the likelihood ratio test [167]. Best-fitting, parsimonious, multivariable models were produced with backwards elimination with AIC – selection starts with the full model and eliminates predictors one at a time, at each step considering whether the criterion will be improved, smaller AIC, by adding back in a variable removed at a previous step [178]. From the multivariable model the probability of the event was calculated for combinations of risk factors. The proportional hazards assumption was investigated using Schoenfeld residual plots [173] and incorporation of time-dependent covariate effects while the internal

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validity was assessed by the concordance statistic which evaluates the discriminatory power and the predictive accuracy of nonlinear statistical models [184].

Assessment of the different reasons for treatment withdrawal requires a competing risks analysis which considers the probability of one of several different events occurring. Cumulative incidence analyses were undertaken to assess the probability of one of the two treatment failure events occurring (inadequate seizure control and unacceptable adverse events), with covariates tested by Gray’s method [174].

Continuous variables were investigated using log, fractional polynomial and fractional polynomial with spike transformations [144, 145, 185, 186]. The results for the continuous variables are presented as post-hoc defined categorical variables with categories chosen according to knot positions for a spline model fit to the data [143] as described in Chapter 3. In the final model the variables were retained as continuous and presented as categorical variables on for ease of interpretation by non-statisticians.

The variable for time from first seizure to randomisation includes extreme values. A sensitivity analysis was performed which examined time to treatment failure and time to 12 month remission in two scenarios. First, time from first seizure to randomisation was included unchanged, and second the variable was reduced by excluding patients with extreme values (1% at either end of the range). Patients with a seizure 18 days or less before randomisation and with a seizure over 41 years before randomisation were consequently examined to determine their impact on the analysis.

An alternative scenario would involve regarding the extreme values as missing data and re- estimating them via imputation. However, recommended practice is to remove the 1% extreme values as this smoothly draws in the extreme tails [187]. Following this sensitivity analysis the 1% extreme values were removed therefore people with a time from first

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seizure to randomisation in the first or last one percent of the variable were removed from the dataset – this applied to 34 patients (labelled ‘extremes’ in Figure 4).