SANAD

Marson, Anthony G et al. “The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial.” Lancet (London, England) vol. 369,9566 (2007): 1016-26. doi:10.1016/S0140-6736(07)60461-9

The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial

Clinical Question

The SANAD study aimed to compare the longer-term effects of these drugs in patients with generalised onset seizures or seizures that are difficult to classify.

What are the relative efficacies and longer-term effects of valproate, lamotrigine, and topiramate for patients with generalized onset seizures or seizures that are difficult to classify?

Guidelines

THe 2013 ILAE guidelines now consider SANAD I findings for treatment of patients with generalized-onset seizures. Valproate is now considered firstline therapy for patients with generalized-onset or unclassifiable epilepsy.

Design

• Multicenter, unblinded, randomized, controlled trial
• N=716
  • Valproate (n=238)
  • Lamotrigine (n=239)
  • Topiramate (n=239)
• Setting: Hospital-based outpatient clinics in the UK
• Enrollment: Jan 1999 to Aug 2004; follow-up data up to Jan 13, 2006.

Population

Inclusion Criteria

Patients were referred following these two criterias:

if they

• (1) had a history of 2 or more clinically definite and unprovoked epileptic seizures in the preceding year and
• (2) the recruiting physician regarded valproate as a more appropriate standard

of treatment than carbamazepine.

Exclusion Criteria

Patients were excluded if

• 1) the clinician or patient felt that treatment was contraindicated,
• 2) all their seizures had been acute symptomatic seizures (including febrile seizures),
• 3) were aged 4 years or younger
• 4) had a history of progressive neurological disease."

Interventions

Participating patients in arm B were randomly allocated in a 1:1:1 ratio to valproate, lamotrigine, or topiramate. To randomise a patient, the clinician telephoned a central randomisation service, and provided patient identifying information and the clinical factors used for stratification of randomisation, which were centre, sex, and treatment history (newly diagnosed and untreated, treated with ineffective monotherapy, relapse after remission of epilepsy). After the groups were randomized to receive a treatment, clinicians were alllowed to make subsequent changes in dose or preparation, so that everyday practice could be accurately mirrored.

Outcomes

Primary Outcomes

Hazard Ratios - As compared to Valproate

Endpoint

Time to treatment failure

Lamotrigine: HR 1.25 (95% CI 0.94-1.68). Topiramate: HR 1.57 (95% CI 1.19-2.08)

Time to treatment failure for idiopathic generalized epilepsy

Lamotrigine: HR 1.55 (95% CI 1.07-2.24). Topiramate: HR 1.89 (95% CI 1.32-2.70)

For inadequate seizure control

Lamotrigine: HR 1.55 (95% CI 1.07-2.24). Topiramate HR 1.45 (95% CI 0.92-2.27)

For 1-year remission (intention-to-treat analysis, per protocol)

Lamotrigine HR 1.25 (95% CI 0.94-1.68). Topiramate: HR 0.77 (95% CI 0.61-0.97)

Criticisms

- The recruitment was below the desired level, which could have allowed for a greater level of bias. This was likely due to reluctance by cliniciais to randomise women of child-bearing age, as there were concerns with valproate and fetal malformation risk. As such, 60% of patients randomised to valproate were men.

- Patients could switch from one medication to another, but, despite that, when analysing clinical, quality of life, and health economic outcomes, patients were analysed in the treatment groups to which they had been initially allocated (intention-to-treat analysis).

-Patients in this study had a variety of different types of epilepsy, therefore, it is difficult to know how each seizure type would have responded individually.

Funding

The SANAD study was funded by the Funded by the Health Technology Assessment UK Programme. Also, 20% of resources came from companies with products assessed.