Trial

Outcomes reported

Summary of results

Callaghan 1985

1. Seizure control:

excellent (seizure‐free)
good (> 50% reduction)
poor (< 50% reduction)

2. Side effects

1. PHT (n = 58); CBZ (n = 59)

PHT: 39 (67%); CBZ: 22 (37%)
PHT: 7 (12%); CBZ: 22 (37%)
PHT: 12 (21%); CBZ: 15 (25%)

PHT: 6 (10%); CBZ: 5 (8%)

Cereghino 1974

1. Behaviour measured with rating scale modified from the Ward Behaviour Rating Scale

2. Seizure control

3. Side effects

4. Withdrawals

1. Behavioural scores were similar on both drugs

2. No difference between CBZ and PHT in terms of seizure control

3. Gastrointestinal and “impaired function” side effects were more common on CBZ than PHT in the first few study days. Side effects of both drugs were minimal in later stages of the study

4. PHT: 21 withdrawals out of 45 participants (47%); CBZ: 27 withdrawals out of 45 participants (60%)

Czapinski 1997

1. Proportion achieving 24‐month remission at 3 years

2. Proportion excluded after randomisation due to adverse effects or no efficacy

1. PHT: 59%; CBZ: 62%

2. PHT: 23%; CBZ: 30%

Forsythe 1991

1. Cognitive assessments

2. Withdrawals from randomised drug

1. No significant differences between the two treatment groups on any cognitive tests
2. PHT: 6 withdrawals out of 20 participants (30%); CBZ: 9 withdrawals out of 23 participants (39%)

Miura 1993

1. Proportion of all randomised participants with seizure recurrence (by seizure type)

2. Proportion of participants with optimum plasma levels with seizure recurrence (by seizure type)

PHT (n = 51); CBZ (n = 66)

1. PHT (partial): 10/31 (32%); PHT (generalised): 7/20 (35%);
CBZ (partial): 21/53 (40%); CBZ (generalised): 2/13 (15%)

2. PHT (partial): 4/17 (24%); PHT (generalised): 1/8 (13%);
CBZ (partial): 4/17 (24%); CBZ (generalised): 0/7 (0%)

Pulliainen 1994

1. Cognitive assessments (visual motor speed, co‐ordination, attention and concentration, verbal and visuospatial learning, visual and recognition memory, reasoning, mood, handedness)

2. Harmful side effects

1. Compared to CBZ, participants on PHT became slower (motor speed of the hand) and their visual memory decreased. There was an equal decrease in negative mood (helplessness, irritability, depression) on PHT and CBZ

2. Three participants taking PHT complained of tiredness, and 1 participant taking CBZ complained of facial skin problems, another tiredness and memory problems

Ramsay 1983

1. Side effects (major and minor)

2. Treatment failure/seizure control

3. Laboratory results

1. Incidence of:

• major side effects (among analysed participants): PHT 8/35 participants (23%); CBZ 8/35 participants (23%)

• minor side effects: cognitive impairment and sedation twice as likely on CBZ as PHT

• other minor side effects similar between groups

2. Treatment failures among analysed participants:
PHT 4/35 (11%); CBZ: 5/35 (14%)

Seizure control (among analysed participants with no major side effects): PHT: 23/27 participants (86%); CBZ: 22/27 participants (82%)

3. Significantly lower mean LDH level at 24 weeks in CBZ participants than PHT participants (P < 0.01). Other laboratory results similar across treatment groups

Ravi Sudhir 1995

1. Cognitive measures (verbal, performance, memory, visuomotor, perceptomotor organisation, visual organisation, dysfunction)

1. No significant differences between any tests of cognitive function taken before treatment and after 10 ‐ 12 weeks for both treatment groups

Trial

Number randomised

Time to withdrawal of

allocated treatment

Time to 12‐month

remission

Time to 6‐month remission

Time to first seizure

PHT

CBZ

Total

PHT

CBZ

Total

PHT

CBZ

Total

PHT

CBZ

Total

PHT

CBZ

Total

De Silva 1996¹

54

54

108

53

53

106

54

54

108

54

54

108

54

54

108

Heller 1995²

63

61

124

61

60

121

63

61

124

63

61

124

63

61

124

Mattson 1985³

165

155

320

165

154

319

165

154

319

165

154

319

162

151

313

Forsythe 1991⁴

20

23

43

20

23

43

Information not available

Information not

available

Information not available

Ogunrin 2005⁵

18

19

37

Information not available

Information not available

Information not

available

18

19

37

Total

320

312

632

299

290

589

282

269

551

282

269

551

297

285

582

Reason for early termination

Classification

De Silva 1996²

Forsythe 1991

Heller 1995^2,3

Mattson 1985

Total¹

CBZ

n = 53

PHT

n = 53

CBZ

n = 23

PHT

n = 20

CBZ

n = 60

PHT

n = 63

CBZ

n = 154

PHT

n = 165

CBZ

n = 290

PHT

n = 299

Adverse events

Event

3

2

4

1

8

1

11

8

26

12

Seizure recurrence

Event

12

10

2

1

5

8

3

6

22

25

Both seizure recurrence and adverse events

Event

6

5

0

0

4

2

31

33

31

40

Non‐compliance/participant choice

Event

0

0

3

4

0

0

11

26

14

30

Participant went into remission

Censored

18

24

0

0

6

14

0

0

24

38

Lost to follow‐up

Censored

0

0

0

0

0

0

26

19

26

19

Death⁴

Censored

0

0

0

0

0

0

4

5

4

5

Other⁵

Censored

0

0

0

0

0

0

16

11

16

11

Completed the study (did not withdraw)

Censored

14

12

14

14

37

38

53

57

118

121

 Analysis

Time to withdrawal

Time to six‐month

remission

Time to 12‐month

remission*

Time to first seizure

Original analysis

P: 1.18 (0.87, 1.60)

G: 0.42 (0.18, 0.96)

O: 1.04 (0.78, 1.39)

P: 1.02 (0.79, 1.33)

G: 1.30 (0.89, 1.92)

O: 1.11 (0.89, 1.37)

P: 0.94 (0.71, 1.25)

G: 1.17 (0.53, 2.57)

O: 1.01 (0.78, 1.31)

P: 0.86 (0.68, 1.08)

G: 0.84 (0.57, 1.24)

O: 0.85 (0.70, 1.04)

Test for interaction

Chi² = 5.18; df = 1

P = 0.02; I² = 80.7%

Chi² = 1.03; df = 1

P = 0.31; I² = 3.4%

Chi² = 0.25; df = 1

P = 0.62; I² = 0%

Chi² = 0.01; df = 1

P = 0.93; I² = 0%

Generalised and age at onset > 30

(classified as uncertain epilepsy type)

P: 1.18 (0.87, 1.60)

G: 0.51 (0.21, 1.24)

U: 0.19 (0.02, 2.14)

O: 1.05 (0.79, 1.40)

P: 1.02 (0.79, 1.33)

G: 1.69 (1.07, 2.27)

U: 0.84 (0.35, 1.98)

O: 1.13 (0.91, 1.41)

P: 0.94 (0.71, 1.25)

G: 1.44 (0.90, 2.31)

U: 0.52 (0.20, 1.34)

O: 1.01 (0.80, 1.28)

P: 0.86 (0.68, 1.08)

G: 0.91 (0.57, 1.46)

U: 0.97 (0.43, 2.18)

O: 0.88 (0.72, 1.07)

Test for interaction

 Chi² = 4.99; df = 2

P = 0.08; I² = 59.9%

Chi² = 4.01; df = 2

P = 0.13; I² = 50.2%

 Chi² = 4.32; df = 2

P = 0.12; I² = 53.7%

 Chi² = 0.12; df = 2

P = 0.94; I² = 0%

Generalised and age at onset > 30

(reclassified as partial epilepsy)

P: 1.11 (0.82, 1.50)

G: 0.51 (0.21, 1.24)

O: 1.02 (0.77, 1.36)

P: 1.02 (0.80, 1.31)

G: 1.69 (1.07, 2.27)

O: 1.15 (0.92, 1.42)

P: 0.91 (0.69, 1.19)

G: 1.44 (0.90, 2.31)

O: 1.02 (0.81, 1.29)

P: 0.86 (0.69, 1.08)

G: 0.91 (0.57, 1.46)

O: 0.87 (0.71, 1.07)

Test for interaction

Chi² = 2.65; df = 1

P = 0.10; I² = 62.3%

Chi² = 3.63; df = 1

P = 0.06; I² = 72.5%

Chi² = 2.79; df = 1

P = 0.09; I² = 64.2%

Chi² = 0.04; df = 1

P = 0.83; I² = 0%

Trial

Adverse event data¹

Summary of reported results

Carbamazepine (CBZ)

Phenytoin (PHT)

Callaghan 1985²

All adverse events according to drug (note: no participants withdrew due to adverse events)

CBZ (n = 59):

drowsiness (n = 2), rash (n = 3)

PHT (n = 58):

gum hypertrophy (n = 2), rash (n = 2), ataxia (n = 2)

Cereghino 1974^2,3

Most frequently observed side effects

Gastrointestinal side effects and “impaired function” (general malaise). Frequency not clearly stated

Gastrointestinal side effects and “impaired function” (general malaise). Frequency not clearly stated

Czapinski 1997⁴

“Exclusions” due to adverse events or no efficacy”

Proportion “excluded”:

CBZ: 30% (out of 30 randomised to CBZ)

Proportion “excluded”:

PHT: 23.3% (out of 30 randomised to PHT)

De Silva 1996

“Unacceptable” adverse events

leading to drug withdrawal⁵

CBZ (n = 54):

drowsiness (n = 1), blood dyscrasia (n = 1)

PHT (n = 54):

drowsiness (n = 2), skin rash (n = 1), blood dyscrasia (n = 1), hirsutism (n = 1)

Forsythe 1991

Withdrawal due to adverse events (no other adverse event data reported)

4 participants out of 23 randomised to CBZ withdrew for the following reasons (some withdrew for more than adverse event):

slowing of mental function, headache, anorexia, nausea, abdominal pain, fatigue and drowsiness²

1 participant out of 20 randomised to PHT withdrew from the study due to depression and anorexia

Heller 1995

“Unacceptable” adverse events

leading to drug withdrawal⁵

CBZ (n = 61):

drowsiness (n = 3), rash (n = 2), headache (n = 1), depression (n = 1)

PHT (n = 63):

myalgia (n = 1), irritability (n = 1)

Mattson 1985²

Narrative report of ‘Adverse effects’ and ‘Serious side effects’

CBZ (n = 155):

motor disturbance (ataxia, incoordination, nystagmus, tremor: 33%);

dysmorphic and idiosyncratic side effects (gum hypertrophy, hirsutism, acne and rash: 14%);

gastrointestinal problems (27%);

decreased libido or impotence (13%);

No serious side effects

PHT (n = 165);

motor disturbance (ataxia, incoordination, nystagmus, tremor: 28%);

dysmorphic and idiosyncratic side effects (gum hypertrophy, hirsutism, acne and rash: 22 %);

gastrointestinal problems (24%);

decreased libido or impotence (11%)

1 serious side effect – 1 participant has confirmed lymphoma, rash improved rapidly following discontinuation of PHT

Miura 1993

No adverse events reported

N/A

N/A

Ogunrin 2005²

Participant reported symptomatic complaints (provided as IPD)

CBZ (n = 19):

memory impairment (n = 9)

psychomotor retardation (n = 1)

inattention (n = 1)

transient rash (n = 1)

CBZ‐induced cough (n = 1)

PHT (n = 18):

memory impairment (n = 7)

psychomotor retardation (n = 1)

inattention (n = 2)

transient rash (n = 1)

Pulliainen 1994

Participant‐reported adverse events

1 participant on CBZ complained of facial skin problems;

1 participant on CBZ complained of tiredness and memory problems

3 participants on PHT complained of tiredness

Ramsay 1983²

Major and minor side effects

CBZ (n = 35):

Major side effects:

rash (n = 1), pruritus (n = 1), impotence (n = 2), dizziness (n = 1), headaches (n = 1), impaired cognition (n = 1), elevated liver enzymes (n = 1)

Mild side effects:

nausea (33%), headaches (24%), cognitive impairment (33%), nystagmus (52%), sedation (33%), fine tremor (20%)

PHT (n = 35):

Major side effects:

rash (n = 4), exfoliative dermatitis (n = 1), impotence (n = 1), dizziness (n = 1), nausea/vomiting (n = 1)

Mild side effects:

nausea (38%), gingival hyperplasia (12%), headaches (32%), cognitive impairment (15%), nystagmus (40%), sedation (15%), fine tremor (28%)

Ravi Sudhir 1995

No adverse events reported

N/A

N/A