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Tiagabine add-on for drug-resistant partial epilepsy

  1. Jennifer Pulman1,*,
  2. Jane L Hutton2,
  3. Anthony G Marson1

Editorial Group: Cochrane Epilepsy Group

Published Online: 5 FEB 2014

DOI: 10.1002/14651858.CD001908.pub3


How to Cite

Pulman J, Hutton JL, Marson AG. Tiagabine add-on for drug-resistant partial epilepsy. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD001908. DOI: 10.1002/14651858.CD001908.pub3.

Author Information

  1. 1

    Institute of Translational Medicine, University of Liverpool, Department of Molecular and Clinical Pharmacology, Liverpool, Merseyside, UK

  2. 2

    University of Warwick, Department of Statistics, Coventry, UK

*Jennifer Pulman, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Clinical Sciences Centre for Research and Education, Lower Lane, Fazakerley, Liverpool, Merseyside, L9 7LJ, UK. jennifer.pulman@liv.ac.uk.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 5 FEB 2014

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Characteristics of included studies [ordered by study ID]

MethodsRandomised, double-blind, placebo-controlled, cross-over study, based on a response-dependent design. Two treatment arms: one TGB, one PCB. Participants randomly assigned to one of two sequences. TGB started during screening phase at 12 mg/d QID. Seven-week double-blind treatment period during which participants continued on TGB or crossed over to PCB arm


ParticipantsMulti-centre study (five centres: two in UK, two in The Netherlands and one in Denmark)
44 participants with drug-resistant partial epilepsy were randomly assigned (30 male), aged 18 to 53 years
Participants already taking one to three background AEDs
Median baseline seizure frequency = 2.7/wk.


InterventionsGroup one: PCB

Group two: TGB (optimal dose 64 mg/d)
Mean daily dose for all randomly assigned participants was 46 mg during the double-blind phase


Outcomes
  1. 50% responder rates
  2. Median percentage reduction in four-weekly seizure rate
  3. Adverse events


NotesFrom the 44 people randomly assigned to the double-blind phase, seven were excluded from the intent-to-treat analysis. All participants were evaluated for adverse events


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskParticipants randomly assigned in a 1:1 ratio at each centre to one of two sequences. No further details on how the sequences were generated

Allocation concealment (selection bias)Low riskSequentially allocated sealed packages used

Blinding (performance bias and detection bias)
All outcomes
Low riskUsed identical packaging and medication

Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition rates reported and intention-to-treat analysis employed

Selective reporting (reporting bias)Low riskAll outcomes reported in methods section were reported in text; however, no protocol is available for comparison of outcomes


MethodsOpen-label, head-to-head controlled, parallel study. Two treatment arms: one TGB, one TPM. Participants were randomly assigned using non-random component Duration of screening period: eight weeks, followed by a titration phase of three months and a maintenance period of three months


ParticipantsNo information regarding study sites or countries

41 participants with drug-resistant partial epilepsy randomly assigned. Baseline data reported for only 30 participants who completed the whole study

Participants already taking one to three background AEDs


InterventionsGroup one: TGB at least 20 mg/d; mean 32 mg/d

Group two: TPM at least 200 mg/d; mean 335 mg/d


Outcomes
  1. 50% responder rates
  2. Cognitive effects
  3. Quality of life


NotesNon-accurate baseline data reported. Four participants excluded from ITT analysis for seizure reduction outcome


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNon-randomisation component employed in the sequence generation process. Sequence generated by odd versus even number of week in which participant was seen

Allocation concealment (selection bias)High riskNo concealment used

Blinding (performance bias and detection bias)
All outcomes
High riskStudy was open-label

Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition rates reported and intention-to-treat analysis employed

Selective reporting (reporting bias)Unclear riskAll outcomes reported in methods section were reported in text; however, no protocol was available for comparison of outcomes. Participant characteristics reported for only 30 participants who completed the whole study of the 41 randomly assigned


MethodsRandomised, double-blind, placebo-controlled, two-treatment parallel-group study. Two treatment arms: one PCB, one TGB. Participants randomly assigned using computer-generated sequence. Treatment period: 22 weeks (six-week run in period, 12-week fixed-dose period, four-week termination period)


ParticipantsMulti-centre study (11 centres in Europe—one each in Denmark and Sweden, two in Finland and seven in UK
154 participants with drug-resistant partial epilepsy were randomly assigned (90 male), aged 17 to 71 years
77 were randomly assigned to placebo and 77 to 30 mg/d tiagabine
Participants already taking one to three background AEDs
Median four-weekly baseline seizure frequency: placebo = 10.5, tiagabine = 12.2
Cognitive and quality of life effects were assessed on a subset of 43 individuals


InterventionsGroup one: PCB

Group two: TGB 30 mg/d TDS


Outcomes
  1. 50% responder rates
  2. Treatment withdrawal
  3. Adverse effects
  4. Cognitive effects
  5. Quality of life


NotesNo participants were excluded from analysis. 29 people withdrew from the study: 21 receiving tiagabine and eight receiving placebo


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskUsed a computer-generated allocation sequence

Allocation concealment (selection bias)Low riskUsed sequentially allocated sealed packages

Blinding (performance bias and detection bias)
All outcomes
Low riskUsed identical packaging and medication

Incomplete outcome data (attrition bias)
All outcomes
Low riskAttriition rates reported and intention-to-treat analysis employed

Selective reporting (reporting bias)Low riskAll outcomes reported in methods section were reported in text; however, no protocol available for comparison of outcomes


MethodsRandomised, double-blind, placebo-controlled, cross-over study based on a response-dependent design. Two treatment arms: one PCB, one TGB. Participants randomly assigned using 1:1 ratio. Treatment period: 23 weeks (three-week run-in period, seven-week assessment period, three-week cross-over period, seven-week assessment period, three-week termination period)


ParticipantsMulti-centre study (five centres in UK and Denmark)
94 participants with drug-resistant partial epilepsy were randomly assigned (61% male), aged 19 to 71 years
25 participants were randomly assigned to placebo-tiagabine sequence and 21 to tiagabine-placebo
Participants already taking one to three AEDs
Median complex partial seizure rate per four weeks = six
Cognitive effects were reported for a subset of 22 individuals


InterventionsGroup one: PCB

Group two: TGB 52 mg/d QID

Mean daily dose was 33.4 mg (range 12 to 52 mg)


Outcomes
  1. 50% responder rates
  2. Median percentage reduction in four-weekly seizure rate
  3. Adverse events
  4. Cognitive effects


NotesFrom the 46 people randomly assigned to the double-blind phase, seven failed to complete the study. Of these, only four were excluded from the intent-to-treat analysis. All participants were evaluated for adverse events. The characteristics of people ineligible for the double-blind phase were similar to those of people qualifying, with regard to epilepsy history, seizure frequency and concurrent treatment


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk1:1 ratio employed at each centre. No further details of sequence generation

Allocation concealment (selection bias)Low riskUsed sequentially allocated sealed packages

Blinding (performance bias and detection bias)
All outcomes
Low riskUsed identical packaging and medication

Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition rates reported and intention-to-treat analysis employed

Selective reporting (reporting bias)Low riskAll outcomes reported in methods section were reported in text; however, no protocol was available for comparison of outcomes


MethodsRandomised, double-blind, placebo-controlled, parallel-group study. Three treatment arms: one PLC, two TGB. Participants randomly assigned using ratio 1:1:1 in blocks of six
Treatment periods = 12 weeks


ParticipantsMulti-centre US study (26 centres)
318 participants (178 male) aged 12 to 71 years with drug-resistant partial epilepsy were randomly assigned
107 to PCB, 106 to TGB 16 mg BID, 105 to TGB 8 mg QID
Valproate allowed in combination with an enzyme-inducing drug but not as monotherapy
Median baseline four-weekly complex partial seizures; frequency during baseline was as follows: PCB = 8.4; TGB 16 mg BID = 8.4; TGB 8 mg QID = 7.9


InterventionsAdd-on placebo, TGB 16 mg BID or TGB 8 mg QID


Outcomes
  1. 50% responder rates
  2. Treatment withdrawal
  3. Adverse effects


NotesFrom the 318 people randomly assigned to the double-blind phase, four were excluded from the intention-to-treat analyses. All 318 people were evaluated for adverse events.
47 people withdrew from the study: 10 receiving PLC; 16 receiving TGB 16 mg BID; 21 receiving TGB 8 mg QID


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskUsed ratio of 1:1:1 in blocks of six per study centre

Allocation concealment (selection bias)Low riskUsed sequentially allocated sealed packages

Blinding (performance bias and detection bias)
All outcomes
Low riskUsed identical packaging and medication

Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition rates reported and intention-to-treat analysis employed

Selective reporting (reporting bias)Low riskAll outcomes reported in methods section were reported in text; however no protocol was available for comparison of outcomes


MethodsRandomised, double-blind, placebo-controlled, parallel-group study. Four treatment arms: one PCB, three TGB. Participants randomly assigned using ratio of 3:2:3:2. Treatment period: 20 weeks (four-week titration phase, 12-week fixed-dose treatment period, four-week tapering period)


ParticipantsMulti-centre US study (21 centres)
297 participants with drug-resistant partial epilepsy were randomly assigned (172 male), aged 12 to 77 years
Participants already taking one to three AEDs, valproate allowed in combination with an enzyme-inducing drug but not as monotherapy
Median four-weekly baseline complex partial seizure frequency was: PCB = 7.4; TGB 16 mg = 8.5; TGB 32 mg = 9.6; TGB 56 mg = 9.1
Cognitive effects were reported for a subset of 162 individuals


InterventionsGroup one: PCB

Group two: TGB 16 mg/d QID

Group three: TGB 32 mg/d QID

Group 4: TGB 56 mg/d QID


Outcomes
  1. 50% responder rates
  2. Treatment withdrawal
  3. Adverse effects
  4. Cognitive effects
  5. Quality of life


NotesFrom the 297 people randomly assigned to the double-blind phase, five were excluded from the intention-to-treat analyses because no double-blind assessments were done or their centres lacked participants in all treatment groups. All 297 people were evaluated for adverse events
54 people withdrew from the study: 13 receiving PCB; six receiving 16 mg TGB; 18 receiving 32 mg TGB and 17 receiving 56 mg TGB


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRatio of 3:2:3:2 was used, no further details of sequence generation reported in text

Allocation concealment (selection bias)Low riskUsed sequentially allocated sealed packages

Blinding (performance bias and detection bias)
All outcomes
Low riskUsed identical packaging and medication

Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition rates reported and intention-to-treat analysis employed

Selective reporting (reporting bias)Low riskAll outcomes reported in methods section were reported in text; however no protocol was available for comparison of outcomes

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Arroyo 2005This is a non-placebo controlled study

Bauer 1995This is an open add-on study of tiagabine in treatment of people with resistant partial and/or secondarily generalised seizures. In this study, the results reported were part of an ongoing multi-national, multi-centre trial. It is not randomised

Gustavson 1997This is an open-label, single-dose study that was designed to examine the pharmacokinetics of tiagabine in children with epilepsy. It is not randomised

Uldall 1995This is a single-blind study of safety, tolerability and preliminary efficacy of tiagabine as adjunctive treatment of children with epilepsy. It is not randomised

 
Comparison 1. Tiagabine versus placebo control—50% or greater reduction in seizure frequency

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Intention-to-treat analysis3769Risk Ratio (M-H, Fixed, 95% CI)3.16 [1.97, 5.07]

 2 Worst-case scenario3769Risk Ratio (M-H, Fixed, 95% CI)2.70 [1.75, 4.19]

 3 Best-case scenario3769Risk Ratio (M-H, Fixed, 95% CI)3.32 [2.08, 5.32]

 
Comparison 2. Treatment withdrawal

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Treatment withdrawal3769Risk Ratio (M-H, Fixed, 95% CI)1.81 [1.25, 2.62]

 
Comparison 3. Adverse effects

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Ataxia1297Risk Ratio (M-H, Fixed, 99% CI)1.24 [0.34, 4.55]

 2 Dizziness3769Risk Ratio (M-H, Fixed, 99% CI)1.69 [1.13, 2.51]

 3 Fatigue3769Risk Ratio (M-H, Fixed, 99% CI)1.38 [0.89, 2.14]

 4 Nausea3769Risk Ratio (M-H, Fixed, 99% CI)1.24 [0.69, 2.22]

 5 Somnolence3769Risk Ratio (M-H, Fixed, 99% CI)1.18 [0.76, 1.83]

 6 Headache1154Risk Ratio (M-H, Fixed, 99% CI)1.15 [0.48, 2.79]

 7 Infection1154Risk Ratio (M-H, Fixed, 99% CI)1.0 [0.36, 2.76]

 8 Nervousness1318Risk Ratio (M-H, Fixed, 99% CI)10.65 [0.78, 146.08]

 9 Tremor1297Risk Ratio (M-H, Fixed, 99% CI)4.56 [1.00, 20.94]

 
Comparison 4. Tiagabine versus topiramate

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 50% or greater reduction in seizure frequency (ITT)141Risk Ratio (M-H, Fixed, 95% CI)0.54 [0.19, 1.58]

 2 Treatment withdrawal (ITT)141Risk Ratio (M-H, Fixed, 95% CI)1.43 [0.74, 2.74]

 
Summary of findings for the main comparison. Tiagabine versus placebo control—50% or greater reduction in seizure frequency for drug-resistant partial epilepsy

Tiagabine versus placebo control50% or greater reduction in seizure frequency for drug-resistant partial epilepsy

Patient or population: patients with drug-resistant partial epilepsy
Settings: hospital outpatient setting
Intervention: tiagabine versus placebo control—50% or greater reduction in seizure frequency

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlTiagabine versus placebo control—50% or greater reduction in seizure frequency

Intention-to-treat analysisStudy populationRR 3.16
(1.97 to 5.07)
769
(three studies)
⊕⊕⊕⊕
high
All three trials found significant improvement in the tiagabine add-on group compared with the placebo group

69 per 1000218 per 1000
(136 to 350)

Moderate

65 per 1000205 per 1000
(128 to 330)

Worst-case scenarioStudy populationRR 2.7
(1.75 to 4.19)
769
(three studies)
⊕⊕⊕⊕
high
When participants with missing data were treated as non-responders, tiagabine add-on was still significantly more effective in reducing seizures than placebo

80 per 1000216 per 1000
(140 to 335)

Moderate

65 per 1000176 per 1000
(114 to 272)

Best-case scenarioStudy populationRR 3.32
(2.08 to 5.32)
769
(three studies)
⊕⊕⊕⊕
high
The overall effect was increased slightly when participants with missing data were treated as responders to tiagabine

69 per 1000229 per 1000
(144 to 368)

Moderate

65 per 1000216 per 1000
(135 to 346)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 
Table 1. Percentage of 50% responders (95% CI), intention-to-treat regression analysis

TrialPlacebo, proportion16 mg/d30 to 32 mg/d56 mg/d

Uthman 1998 actual4.48.219.318.1

Kalviainen 1998 actual6.514.3

Uthman 1998 and Kalviainen 1998 fitted6.3 (4.1 to 9.4)6.3 (4.1 to 9.4)19.7 (15.2 to 25.0)19.7 (15.2 to 25.0)

Sachdeo 1997 actual10.228.6

Sachdeo 1997 fitted9.8 (6.4 to 14.9)28.7 (23.3 to 34.9)

 
Table 2. Percentage of 50% responders (95% CI), best-case regression analysis

TrialPlacebo16 mg/day30 to 32 mg/day56 mg/day

Uthman 1998 actual4.48.221.631.6

Kalviainen 1998 actual6.514.3

Uthman 1998 and Kalviainen 1998 fitted6.2 (4.9 to 9.3)6.2 (4.9 to 9.3)21.5 (16.9 to 27.1)21.5 (16.9 to 27.1)

Sachdeo 1997 actual9.329.4

Sachdeo 1997 fitted9.2 (5.9 to 14.0)29.5 (24.0 to 35.6)

 
Table 3. Percentage of 50% responders (95% CI), worst-case regression analysis

TrialPlacebo16 mg/d30 to 32 mg/d56 mg/d

Uthman 1998 actual5.58.219.328.1

Kalviainen 1998 actual6.514.3

Uthman 1998 and Kalviainen 1998 fitted7.0 (4.7 to 10.2)7.0 (4.7 to 10.2)19.4 (15.0 to 24.7)19.4 (15.0 to 24.7)

Sachdeo 1997 actual12.128.6

Sachdeo 1997 fitted11.3 (7.5 to 16.6)29.0 (23.6 to 35.1)

 
Table 4. Neuropsychological tests used

StudyTest

Dodrill 1997Stroop test

Rey auditory verbal learning test

Controlled oral word association test

Lafayette grooved pegboard

Benton visual retention test

Symbol digit modalities test

Wonderlic personnel test

Digit cancellation

Fritz 2005Edinburgh inventory

Mehrfachwahl-Wortschatz-Intelligenztest (MWT-B)

Kurztest zur cerebralen Insuffizienz (c.I. test)

Trailmaking test

Weiner test system

HAWIE-R (verbal memory)

Corsi block test

Verbal learning and memory test (VLMT)

Diagnosticum fur cerebralschaden (DSC-R) (visual memory)

Boston naming test

Word fluency test (LPS)

Token test

Kalviainen 1996Stroop test

Rey auditory verbal learning test

Controlled oral word association test

Modified finger tapping test

Binary choice reaction

Full-scale I.Q. (WAIS)

Logical prose, story A from the Wechsler memory scale

Forward digit span

Corsi block span

Alternating S-task

Letter cancellation task

The WMS visual reproduction subtest

Auditory and visual reaction times

Sveinbjornsdottir 1994Stroop test

Rey auditory verbal learning test

Binary choice reaction

Modified finger tapping

Semantic processing

Information processing speed

Bimanual hand movements

Simple reaction time

Tapping rate

Verbal memory

 
Table 5. Neuropsychological tests with statistically significant differences

TestStudyResult (P)Treatment favoured

Benton visual retention test, form FDodrill 19970.049Placebo

Benton visual retention test, form GDodrill 19970.051Placebo

Symbol digit modalities testDodrill 19970.051Placebo

 
Table 6. Tests of mood and adjustment

StudyTestDomain

Dodrill 1997Profile of Mood States (POMS)Tension-anxiety

Depression-dejection

Anger-hostility

Vigour-activity

Fatigue-inertia

Confusion-bewilderment

Total mood disturbance

Washington Psychosocial Seizure Inventory (WPSI)Family background

Emotional adjustment

Interpersonal adjustment

Vocational adjustment

Financial status

Adjustment to seizures

Medicine and medical management

Overall functioning

Mood Rating ScaleAverage score

Fritz 2005Befindlichkeits-Skala (BFS)Dysphoria

Beck Depression InventoryDepression

Self-rating Anxiety Scale (SAS)Anxiety

QOLIE-31Health-related quality of life

Sveinbjornsdottir 1994The Mood Adjective Check List (MACL)Depression

Anxiety

Fatigue

Activity

Aggression

Rating Scale Adapted from Brooks and McKinlayIndividual's behaviour