Background
Methods
Patients and procedures
Statistical Modelling
Results
Seizure characteristics
Arm A – focal epilepsy
Variable | Hazard Ratio (95% CI) | Negative binomial: rate of seizures | |||
---|---|---|---|---|---|
PWP-TT: Rate of recurrent seizures | Cox: First seizure | Cox: 12-month remission | |||
Treatment | Carbamazepine | 1.00 | 1.00 | 1.00 | 1.00 |
Gabapentin | 0.97 (0.89, 1.07) | 1.34 (1.13, 1.59) | 0.76 (0.63, 0.91) | 1.45 (1.06, 1.99) | |
Lamotrigine | 0.98 (0.89, 1.08) | 1.23 (1.04, 1.45) | 0.91 (0.76, 1.09) | 0.91 (0.67, 1.25) | |
Oxcarbazepine | 0.91 (0.82, 1.02) | 1.03 (0.84, 1.26) | 1.03 (0.83, 1.28) | 0.67 (0.46, 0.98) | |
Topiramate | 1.06 (0.97, 1.17) | 1.06 (0.90, 1.26) | 0.84 (0.70, 1.01) | 1.25 (0.91, 1.72) | |
Intercept | N/A | N/A | N/A | −2.68 (−2.89, − 2.45) |
Variable | Hazard Ratio (95% CI) | Negative Binomial: Rate of seizures | |||
---|---|---|---|---|---|
PWP-CP: Rate of recurrent seizures | Cox PH: First seizure | Cox PH: 12-month remission | |||
Gender | Female Male | 1.00 0.94 (0.89, 1.00) | 1.00 0.84 (0.75,0.94) | 1.00 1.22 (1.07, 1.38) | 1.00 0.72 (0.59, 0.89) |
Febrile Seizure History | Absent Present | 1.00 1.06 (0.93, 1.20) | N/A | N/A | N/A |
First degree relative with epilepsy | Absent Present | 1.00 0.88 (0.80, 0.97) | N/A | N/A | N/A |
Treatment History | Treatment naïve Seizures after remission Taking non-SANAD AEDs | 1.00 0.92 (0.70, 1.22) 1.04 (0.96, 1.11) | 1.00 1.02 (0.70, 1.47) 1.59 (1.37, 1.85) | 1.00 0.87 (0.58, 1.30) 0.52 (0.43, 0.63) | 1.00 0.99 (0.52,2.15) 1.86 (1.14, 2.51) |
Neurological Insult | Absent Present | 1.00 1.07 (0.98, 1.17) | 1.00 1.20 (1.01, 1.42) | 1.00 0.78 (0.63, 0.97) | N/A |
EEG Result | Normal Epileptiform abnormality Non-specific abnormality Not clinically indicated | 1.00 1.01 (0.94, 1.09) 1.01 (0.93, 1.11) 0.95 (0.85, 1.07) | N/A | N/A | 1.00 1.24 (0.86, 1.82) 0.69 (0.51, 0.94) 0.95 (0.73, 1.23) |
CT or MRI Result | Normal Abnormal Not clinically indicated | 1.00 1.10 (1.02, 1.18) 0.93 (0.85, 1.02) | N/A | 1.00 0.89 (0.77, 1.04) 1.16 (0.97, 1.38) | N/A |
Focal site of onset | Temporal Not localised Frontal Other Unclassified | 1.00 0.98 (0.91, 1.05) 0.84 (0.73, 0.96) 0.83 (0.71, 0.96) 0.50 (0.29, 0.86) | N/A | 1.00 0.93 (0.80, 1.07) 1.18 (0.91, 1.54) 1.26 (0.97, 1.65) 1.33 (1.07, 1.65) | N/A |
Age at randomisation (years) | ≤10 11–24 25–36 37–49 50–70 ≥71 | N/A | 1.00 0.99 (0.99, 1.00) 0.99 (0.98, 0.99) 0.98 (0.97, 0.99) 0.97 (0.96, 0.99) 0.97 (0.95, 0.99) | 1.00 1.01 (1.00, 1.01) 1.01 (1.00, 1.02) 1.02 (1.01, 1.03) 1.03 (1.01, 1.04) 1.03 (1.01, 1.05) | 1.00 0.91 (0.86, 0.96) 0.81 (0.71, 0.92) 0.71 (059, 0.87) 0.61 (0.45, 0.82) 0.51 (0.34, 0.76) |
Annual rate seizures prior to randomisation | ≤1 1–4 4–10 10–25 25–175 ≥175 | 1.00 0.98 (0.96, 0.99) 0.96 (0.94, 0.99) 0.95 (0.92, 0.98) 0.93 (0.88, 0.97) 0.89 (0.83, 0.96) | 1.00 1.15 (1.12, 1.18) 1.26 (1.21, 1.32) 1.37 (1.30, 1.45) 1.61 (1.48, 1.75) 2.06 (1.82, 2.34) | 1.00 0.86 (0.83, 0.90) 0.75 (0.69, 0.81) 0.60 (0.52, 0.69) 0.52 (0.43, 0.63) 0.45 (0.36, 0.56) | N/A |
Seizure type | Simple or complex partial Simple or complex partial with generalised tonic-clonic Uncertain | 1.00 1.09 (1.02, 1.17) 1.91 (1.15, 3.17) | 1.00 0.93 (0.81, 1.05) 0.67 (0.54, 0.84) | N/A | 1.00 0.75 (0.59, 0.95) 1.19 (0.26, 15.42) |
Treatment | Carbamazepine Gabapentin Lamotrigine Oxcarbazepine Topiramate | 1.00 0.97 (0.88, 1.06) 0.98 (0.89, 1.08) 0.92 (0.82, 1.02) 1.06 (0.97, 1.17) | 1.00 1.42 (1.20, 1.68) 1.26 (1.07, 1.50) 1.11 (0.90, 1.36) 1.08 (0.91, 1.28) | 1.00 0.73 (0.60, 0.87) 0.89 (0.74, 1.06) 0.98 (0.79, 1.22) 0.82 (0.68, 0.99) | 1.00 1.41 (1.03, 1.93) 1.02 (0.74, 1.39) 0.80 (0.56, 1.17) 1.13 (0.83, 1.53) |
Intercept | N/A | N/A | N/A | −2.17 (−2.62, −1.71) |
Arm B – generalised epilepsy
Variable | Hazard Ratio (95% CI) | Negative binomial: Rate of seizures | |||
---|---|---|---|---|---|
PWP-TT: Rate of recurrent seizures | Cox: First seizure | Cox: 12-month remission | |||
Treatment | Valproate | 1.00 | 1.00 | 1.00 | 1.00 |
Lamotrigine | 1.12 (0.99, 1.26) | 1.40 (1.12, 1.76) | 0.75 (0.60, 0.93) | 1.86 (1.15, 2.99) | |
Topiramate | 1.13 (1.00, 1.29) | 1.21 (0.97, 1.52) | 0.87 (0.70, 1.08) | 1.66 (1.03, 2.67) | |
Intercept | N/A | N/A | N/A | −2.42 (− 2.74, − 2.07) |
Variable | Hazard Ratio (95% CI) | Negative binomial: Rate of seizures | |||
---|---|---|---|---|---|
PWP-CP: Rate of recurrent seizures | Cox PH: First seizure | Cox PH: 12-month remission | |||
Gender | Female Male | 1.00 1.09 (0.99, 1.20) | 1.00 0.79 (0.65,0.96) | N/A | N/A |
Febrile Seizure History | Absent Present | 1.00 0.72 (0.63, 0.82) | N/A | N/A | 1.00 0.43 (0.22, 0.91) |
First degree relative with epilepsy | Absent Present | 1.00 1.11 (0.96, 1.28) | 1.00 1.28 (1.01, 1.61) | 1.00 0.71 (0.56, 0.91) | 1.00 2.04 (1.30, 3.31) |
Treatment History | Treatment naïve Seizures after remission Taking non-SANAD AEDs | 1.00 0.74 (0.59, 0.92) 1.18 (0.99, 1.41) | N/A | 1.00 0.85 (0.52, 1.41) 0.79 (0.49, 1.00) | 1.00 0.77 (0.30, 2.36) 3.40 (1.75, 7.30) |
Neurological Insult | Absent Present | 1.00 1.38 (1.23, 1.55) | 1.00 1.27 (0.95, 1.70) | 1.00 0.64 (0.47, 0.87) | 1.00 2.84 (1.56, 5.53) |
EEG Result | Normal Epileptiform abnormality Non-specific abnormality Not clinically indicated | 1.00 1.02 (0.90, 1.15) 0.83 (0.67, 1.03) 0.78 (0.61, 0.99) | N/A | N/A | N/A |
Treatment | Valproate Lamotrigine Topiramate | 1.00 1.17 (1.05, 1.31) 1.16 (1.02, 1.31) | 1.00 1.53 (1.22, 1.93) 1.23 (0.98, 1.55) | 1.00 0.79 (0.64, 0.99) 0.92 (0.74, 1.14) | 1.00 1.02 (0.65, 1.61) 1.51 (0.96, 2.38) |
Age at randomisation (years) | ≤7 8–13 14–19 20–27 28–50 > 50 | 1.00 0.97 (0.95, 0.99) 0.95 (0.90, 0.99) 0.93 (0.87, 0.99) 0.90 (0.82, 0.98) 0.87 (0.78, 0.97) | 1.00 0.93 (0.89, 0.97) 0.87 (0.80, 0.95) 0.83 (0.74, 0.93) 0.77 (0.66, 0.91) 0.72 (0.59, 0.89) | N/A | 1.00 0.82 (0.77, 0.88) 0.62 (0.53, 0.72) 0.44 (0.34, 0.57) 0.21 (0.12, 0.35) 0.07 (0.02, 0.16) |
Annual rate of tonic-clonic seizures prior to randomisation | ≤1 1–2 2–6 > 6 | N/A | 1.00 1.02 (0.99, 1.06) 1.05 (0.98, 1.11) 1.09 (0.97, 1.21) | N/A | N/A |
Seizure type | Generalised tonic-clonic Absence Myoclonic or absence with tonic-clonic Unclassified tonic-clonic Other seizures | 1.00 0.85 (0.72, 1.01) 1.05 (0.90, 1.23) 1.05 (0.90, 1.23) 0.87 (0.74, 1.03) | 1.00 3.34 (1.98, 5.63) 2.18 (1.67, 2.84) 1.16 (0.88, 1.53) 2.63 (1.70, 4.08) | 1.00 0.62 (0.47, 0.81) 0.56 (0.43, 0.72) 0.83 (0.65, 1.05) 0.58 (0.39, 0.86) | 1.00 1.52 (6.70, 21.16) 6.34 (3.82, 10.61) 1.42 (0.88, 2.32) 4.77 (2.22, 11.42) |
Intercept | N/A | N/A | N/A | −3.03 (−3.77, −2.77) |
Sensitivity analyses – PWP-TT model
Arm A – focal epilepsy
Hazard Ratio (95% CI) | ||||||
---|---|---|---|---|---|---|
Variable | On randomised drug only | Recurrent tonic-clonic recurrent seizures only | On randomised drug only & recurrent tonic-clonic seizures only | Recurrent tonic-clonic & complex partial seizures only | On randomised drug only & recurrent tonic-clonic & complex partial seizures only | |
Treatment | Carbamazepine | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 |
Gabapentin | 1.19 (1.05, 1.36) | 1.01 (0.87, 1.17) | 1.02 (0.85, 1.23) | 1.01 (0.87, 1.17) | 1.02 (0.85, 1.23) | |
Lamotrigine | 0.94 (0.83, 1.07) | 0.97 (0.84, 1.13) | 0.83 (0.69, 0.99) | 0.97 (0.84, 1.13) | 0.83 (0.69, 0.99) | |
Oxcarbazepine | 0.83 (0.71, 0.97) | 0.87 (0.71, 1.05) | 0.75 (0.59, 0.96) | 0.87 (0.71, 1.05) | 0.75 (0.59, 0.96) | |
Topiramate | 1.18 (1.03, 1.34) | 1.02 (0.87, 1.19) | 0.99 (0.83, 1.19) | 1.02 (0.87, 1.19) | 0.99 (0.83, 1.19) |
Variable | Hazard Ratio (95% CI) | |||||
---|---|---|---|---|---|---|
On randomised drug only | Recurrent tonic-clonic seizures only | On randomised drug only & recurrent tonic-clonic seizures only | Recurrent tonic-clonic & complex partial seizures only | On randomised drug only & recurrent tonic-clonic & complex partial seizures only | ||
Gender | Female Male | N/A | 1.00 0.88 (0.85, 0.91) | 1.00 0.84 (0.80, 0.88) | 1.00 0.88 (0.85, 0.91) | 1.00 0.84 (0.80, 0.88) |
Febrile Seizure History | Absent Present | N/A | N/A | 1.00 1.11 (0.99, 1.25) | N/A | 1.00 1.11 (0.99, 1.25) |
First degree relative with epilepsy | Absent Present | N/A | 1.00 0.88 (0.84, 0.93) | 1.00 0.93 (0.86, 1.00) | 1.00 0.88 (0.84, 0.93) | 1.00 0.93 (0.86, 1.00) |
Treatment History | Treat. naïve Seizures Not SANAD AED | 1.00 0.94 (0.85, 1.03) 1.05 (1.01, 1.09) | 1.00 0.77 (0.70, 0.86) 1.01 (0.98, 1.05) | 1.00 1.30 (1.11, 1.52) 1.02 (0.96, 1.08) | 1.00 0.77 (0.70, 0.86) 1.01 (0.98, 1.05) | 1.00 1.30 (1.11, 1.52) 1.02 (0.96, 1.08) |
Neurological Insult | Absent Present | N/A | N/A | N/A | N/A | N/A |
EEG Result | Normal Epi. abnorm. N/S abnorm. Not indicated | 1.00 0.80 (0.76, 0.84) 0.88 (0.84, 0.92) 1.04 (1.01, 1.08) | 1.00 0.94 (0.88, 1.00) 0.93 (0.88, 0.98) 0.97 (0.93, 1.02) | 1.00 0.93 (0.83, 1.03) 0.90 (0.84, 0.97) 1.09 (1.02, 1.16) | 1.00 0.94 (0.88, 1.00) 0.93 (0.88, 0.98) 0.97 (0.93, 1.02) | 1.00 0.93 (0.83, 1.03) 0.90 (0.84, 0.97) 1.09 (1.02, 1.16) |
CT or MRI Result | Normal Abnormal Not indicated | 1.00 1.05 (1.01, 1.08) 0.95 (0.91, 0.99) | 1.00 1.17 (1.12, 1.22) 1.10 (1.04, 1.16) | 1.00 1.03 (0.98, 1.10) 1.16 (1.08, 1.25) | 1.00 1.17 (1.12, 1.22) 1.10 (1.04, 1.16) | 1.00 1.03 (0.98, 1.10) 1.16 (1.08, 1.25) |
Focal site of onset | Temporal Not localised Frontal Other Unclassified | 1.00 1.06 (1.03, 1.10) 1.29 (1.22, 1.37) 0.84 (0.79, 0.90) 0.43 (0.30, 0.60) | 1.00 1.05 (1.01, 1.09) 0.93 (0.86, 1.00) 1.01 (0.93, 1.09) 0.39 (0.30, 0.50) | 1.00 0.98 (0.93, 1.04) 0.85 (0.76, 0.96) 0.94 (0.84, 1.05) 0.44 (0.29, 0.67) | 1.00 1.05 (1.01, 1.09) 0.93 (0.86, 1.00) 1.01 (0.30, 0.50) 0.39 (0.93, 1.02) | 1.00 0.98 (0.93, 1.04) 0.85 (0.76, 0.96) 0.94 (0.84, 1.05) 0.44 (0.29, 0.67) |
Age at randomisation (years) | ≤10 11–24 25–36 37–49 50–70 ≥71 | 1.00 1.01 (1.00, 1.01) 1.01 (1.00, 1.02) 1.02 (1.00, 1.03) 1.02 (1.00, 1.05) 1.03 (1.00, 1.06) | N/A | N/A | N/A | N/A |
Annual rate seizures prior to randomisation | 1 1–4 4–10 10–25 25–175 ≥175 | 1.00 1.01 (1.00, 1.01) 1.01 (1.00, 1.02) 1.02 (1.00, 1.03) 1.03 (1.00, 1.05) 1.04 (1.01, 1.07) | N/A | 1.00 1.04 (1.02, 1.05) 1.06 (1.04, 1.08) 1.08 (1.05, 1.11) 1.13 (1.08, 1.17) 1.17 (1.11, 1.23) | N/A | 1.00 1.04 (1.02, 1.05) 1.06 (1.04, 1.08) 1.08 (1.05, 1.11) 1.13 (1.08, 1.17) 1.17 (1.11, 1.23) |
Seizure type | S/C partial S/C + gen. TC Uncertain | 1.00 0.96 (0.94, 0.99) 2.05 (1.47, 2.87) | 1.00 0.84 (0.80, 0.88) 2.03 (1.57, 2.62) | 1.00 1.05 (0.98, 1.13) 2.06 (1.36, 3.13) | 1.00 0.84 (0.80, 0.88) 2.03 (1.57, 2.62) | 1.00 1.05 (0.98, 1.13) 2.06 (1.36, 3.13) |
Treatment | Carbamazepine Gabapentin Lamotrigine Oxcarbazepine Topiramate | 1.00 1.20 (1.15, 1.25) 0.94 (0.90, 0.97) 0.84 (0.79, 0.89) 1.15 (1.11, 1.20) | 1.00 0.98 (0.93, 1.03) 0.95 (0.90, 1.01) 0.85 (0.80, 0.91) 0.97 (0.80, 0.88) | 1.00 1.05 (0.97, 1.14) 0.86 (0.80, 0.93) 0.75 (0.68, 0.83) 1.01 (0.93, 1.09) | 1.00 0.98 (0.93, 1.03) 0.95 (0.90, 1.01) 0.85 (0.80, 0.91) 0.97 (0.92, 1.03) | 1.00 1.05 (0.97, 1.14) 0.86 (0.80, 0.93) 0.75 (0.68, 0.83) 1.01 (0.93, 1.09) |
Arm B – generalised epilepsy
Variable | Hazard Ratio (95% CI) | |||
---|---|---|---|---|
On randomised drug only | Recurrent tonic-clonic seizures only | On randomised drug only & recurrent tonic-clonic seizures only | ||
Treatment | Valproate | 1.00 | 1.00 | 1.00 |
Lamotrigine | 1.18 (1.01, 1.38) | 1.26 (1.06, 1.51) | 1.54 (1.23, 1.93) | |
Topiramate | 1.58 (1.33, 1.88) | 1.24 (1.03, 1.49) | 2.08 (1.64, 2.63) |
Variable | Hazard Ratio (95% CI) | |||
---|---|---|---|---|
On randomised drug only | Recurrent tonic-clonic seizures only | On randomised drug only & recurrent tonic-clonic seizures only | ||
Gender | Female Male | 1.00 1.29 (1.22, 1.36) | 1.00 1.29 (1.19, 1.39) | 1.00 1.28 (1.14, 1.44) |
Febrile Seizure History | Absent Present | N/A | 1.00 0.82 (0.71, 0.95) | 1.00 1.33 (1.09, 1.63) |
First degree relative with epilepsy | Absent Present | 1.00 1.21 (1.14, 1.30) | N/A | 1.00 1.55 (1.37, 1.75) |
Treatment History | Treat. naïve Seizures Not SANAD AED | 1.00 0.81 (0.68, 0.97) 1.45 (1.31, 1.61) | 1.00 0.68 (0.53, 0.87) 1.08 (0.97, 1.21) | 1.00 1.09 (0.79, 1.50) 1.46 (1.24, 1.72) |
Neurological Insult | Absent Present | N/A | 1.00 1.17 (1.04, 1.31) | 1.00 0.79 (0.66, 0.93) |
EEG Result | Normal Epi. abnorm. N/S abnorm. Not indicated | 1.00 0.77 (0.64, 0.93) 0.75 (0.65, 0.85) 1.19 (1.11, 1.29) | 1.00 0.74 (0.63, 0.87) 0.61 (0.53, 0.70) 0.83 (0.76, 0.91) | 1.00 1.01 (0.75, 1.35) 0.65 (0.54, 0.80) 1.08 (0.95, 1.23) |
Age at randomisation (years) | ≤7 8–13 14–19 20–27 28–50 > 50 | 1.00 0.94 (0.93, 0.95) 0.89 (0.87, 0.91) 0.85 (0.82, 0.88) 0.80 (0.76, 0.84) 0.75 (0.71, 0.80) | 1.00 0.96 (0.94, 0.97) 0.92 (0.88, 0.95) 0.89 (0.84, 0.93) 0.85 (0.79, 0.91) 0.81 (0.74, 0.89) | 1.00 0.98 (0.95, 1.00) 0.96 (0.91, 1.01) 0.94 (0.88, 1.01) 0.92 (0.84, 1.01) 0.90 (0.80, 1.02) |
Annual rate seizures prior to randomisation | 1 1–2 2–6 > 6 | N/A | 1.00 0.99 (0.98, 1.00) 0.98 (0.96, 1.00) 0.96 (0.92, 0.99) | N/A |
Seizure type | Gen. TC Absence Myo./Abs + TC Unclass. TC Other | 1.00 1.14 (1.04, 1.26) 1.12 (1.03, 1.22) 1.00 (0.91, 1.11) 0.96 (0.85, 1.07) | 1.00 1.04 (0.84, 1.30) 1.43 (1.30, 1.57) 1.11 (1.00, 1.23) 1.45 (1.24, 1.70) | 1.00 0.88 (0.69, 1.12) 1.51 (1.32, 1.73) 1.02 (0.88, 1.18) 1.56 (1.25, 1.95) |
Treatment | Valproate Lamotrigine Topiramate | 1.00 1.26 (1.18, 1.34) 1.61 (1.50, 1.73) | 1.00 1.24 (1.14, 1.36) 1.29 (1.18, 1.42) | 1.00 1.57 (1.38, 1.79) 2.16 (1.88, 2.47) |