Interventieonderzoek (trials en cohort)
Study reference Study characteristics Patient characteristics Intervention (I) Comparison / control (C) Follow-up Outcome measures and effect size Comments

Trinka et al., 2013

Type of study:

Unblinded RCT

Setting:

Multicenter study (269 centres) between February 2005 and October 2007 

Country:

23 European countries and Australia

Source of funding: UCB Pharma

Inclusion criteria:

-aged ≥16 yr

- two or more unprovoked seizures in the previous 2 yrs with at least one during the previous 6 months

 

Exclusion criteria:

- Have been treated with LE, VPA or CBZ before or treated for epilepsy with any other AED in the last 6 months.

- Acute seizure treatment for >2 wks duration or within 1 week before screening

N= 1698

à 1092 with focal seizures

à 487 with primary generalised seizures

VPA stratum (n=696):

LEV:

N: 349 à 109 focal and 235 generalised

Mean age ± SD:

35.9 ± 17.8

Sex: 56.2% M / 43.8% F

VPA-ER:

N: 347 à 101 focal and 242 generalised

Mean age ± SD:

38.2 ± 17.9

Sex: 58.2% M / 41.8% F

CBZ stratum (n=992):

LEV:

N: 492 à 434 focal and 62 generalised

Mean age ± SD:

44 ± 17

Sex: 55.9% M / 44.1% F

CBZ-CR:

N: 500 à 448 focal and 48 generalised

Mean age ± SD:

42.7 ± 17.5

Sex: 54.8% M / 45.2% F

Groups comparable at baseline?

Yes

At screening, the clinician decided whether VPA or CBZ would be the standard first-line treatment. Central randomisation was done to LEV or the best recommended treatment.

Intervention was LEV starting dose 500 mg/day administered twice daily as equal doses and up-titrated over 2 weeks to 1000 mg/day. If a seizure occured the dose could be up-titrated to a maximum of 3000 mg/day.

Control was VPA-ER starting dose 500 mg/day or CBZ-CR 200 mg/day administered twice daily as equal doses and up-titrated over 2 weeks to 1000 respictively 600 mg/day. If a seizure occured doses could be up-titrated to a maximum of respectively 2000 or 1600 mg/day.

Endpoint of follow-up: 1 yr

For how many participants were no complete outcome data available?

422/1698 (25%)

VPA stratum:

LEV: 76/349

VPA-ER: 76/347

CBZ stratum:

LEV:126/ 492

CBZ-CR: 144/ 500

Reasons for incomplete outcome data described?

yes

Main reasons: adverse event, lack of efficacy, lost to follow-up, withdrawal of consent, other reason

Significant differences between groups?

Probably not

Seizure freedom rate at 12 months:

 

For patients with generalised seizures:

LEV vs VPA-ER:

LEV: 61.1 (95% CI 53.9 – 67.5)

VPA-ER: 68.3 (95% CI 61.5 – 74.1)

 

LEV vs CBZ-CR:

Not reported

 

For patients with focal seizures:

 

LEV vs VPA-ER:

Not reported

 

LEV vs CBZ-CR:

LEV: 48.1 (95% CI 42.9 – 53.1)

CBZ-CR: 56.2 (95% CI 51.0 – 61.0)

 

Adverse events:

≥1 treatment-emergent adverse event:

LEV: 587/835 (70,3%)

VPA-ER: 212/342 (62%)

CBZ-CR: 162/499 (72,5%)

 

Severe adverse events:

LEV: 130/835 (15.6%)

VPA-ER: 22/342 (6.4%)

CBZ-CR: 70/499 (14%)

 

Top 5 adverse events:

LEV:

Headache (19.3%), fatigue (14.4%), dizziness (8.1%), somnolence (8.1%) and weight increased (5.6%)

VPA-ER: weight increased (19%), headache (17%), fatigue (11.4%), tremor (9.4%) and diarrhoea (5.6%)

CBZ-CR: headache (22.4%), fatigue (19%), dizziness (10.4%), nausea (7.8%) and somnolence (7%)

Funded by UCB Pharma

Giri et al., 2016

Type of study: Prospective RCT

Setting: Department of Pharmacology in collaboration with Department of Medicine at Teerthanker Mahaveer Medical College & Research Centre (TMMC&RC), Moradabad, Uttar Pradesh, during the period from April 2014 to March 2015

Country: India

Source of funding: Not mentioned. There are no financial or other competing interests

Inclusion criteria: (a) Age 18 years or above, (b) Newly diagnosed idiopathic generalized tonic-clonic seizures, (c) Patient had experienced clearly observable minimum of two or more generalized tonic-clonic seizures in the preceding one year, (d) Normal general and neurological findings on clinical examination, (e) Normal features in computed tomography (CT Scan) / magnetic resonance imaging (MRI) of brain, (f) Normal intelligence

Exclusion criteria: (a) Secondary generalized tonic–clonic seizures; (b) Progressive neurological disorder; (c) A psychiatric disorder requiring medication; (d) Clinically significant chronic hepatic, renal and cardiac conditions; (e) Any disease that could interfere with drug absorption, distribution, metabolism, or excretion; (f) Long term co-medication with other drugs; (g) Suspected poor compliance; (h) Pregnant or lactating women; (i) Had been treated with investigational antiepileptic drugs in previous one year.

N= 60

VPA-grpup: N=30

LTG-grpup: N=30

Sex

VPA: 66,7%M / 33,3% F

LTG: 56,7%M / 43,3% F

Groups comparable at baseline? Yes

Valproic acid was initiated at 10 mg/kg/day in two to three divided doses. Dose was increased by 5 mg/kg/day every 3 days until seizures were controlled, intolerable side effects occurred, or a maximum dose of 30 mg/kg/day had been reached. 

Lamotrigine was initiated at 0.5 mg/kg/day in two divided doses for 2 weeks, followed by 1.0 mg/kg/day for additional two weeks. Thereafter, dose was increased by 1 mg/kg/day until seizures were controlled, intolerable adverse effects occurred, or a maximum dose of 12 mg/kg/day had been reached.

Endpoint of follow-up: 12 months

For how many participants were no complete outcome data available?

Reasons for incomplete outcome data described?

Treatment-emergent adverse events

Main reasons:

Significant differences between groups?

Effectiveness:Effectiveness was assessed by reduction from baseline in the percentage of patients remaining seizure-free and by reduction from baseline in the mean number of seizures per month, after 12 months follow-up.

After 12 months follow-up, 76.67% patients taking valproic acid and 56.67% patients taking lamotrigine were seizure-free.

(a) Excellent control: seizure–free. (b) Good control: >/ = 50% reduction in seizure frequency from baseline. (c) Poor control: <50% reduction in seizure frequency from baseline.

Adverse effects:Adverse effects were analyzed by Naranjo Adverse Drug Reaction Probabilty Scale.

Common adverse effects recorded were nausea, dyspepsia, headache and skin rash.