Lacosamide, tablets, 50 mg, 100 mg, 150 mg and 200 mg, Vimpat® - November 2011
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Public Summary Document
Product: Lacosamide, tablets, 50 mg, 100 mg, 150
mg and 200 mg, Vimpat®
Sponsor: UCB Australia Pty Ltd
Date of PBAC Consideration: November 2011
1. Purpose of Application
To request an Authority Required (STREAMLINED) listing and to
extend the current PBS listing to include the treatment, in
combination with a non-sodium channel target anti-epileptic drug,
of a patient with partial epileptic seizures which are not
controlled satisfactorily by other anti-epileptic drugs.
2. Background
At the November 2009 meeting, the PBAC recommended listing
lacosamide tablets as an Authority Required benefit for intractable
epilepsy, as add-on treatment initiated by a neurologist in a
patient who has failed previous therapy, on a cost-effectiveness
basis compared with placebo plus standard background therapy. A
Streamlined Authority was not considered suitable for use in this
last-line setting. Listing was effective from 1 May 2010.
3. Registration Status
Lacosamide was registered by the TGA on 20 July 2009 for the indication:
Add-on therapy, in the treatment of partial seizures with or without secondary generalisation in patients with epilepsy aged 16 years and older.
4. Listing Requested and PBAC’s View
Authority Required (STREAMLINED)
Treatment, initiated by a neurologist, of patients with partial
epileptic seizures which are not controlled satisfactorily by other
antiepileptic drugs in a patient aged 16 years or older, in
combination with a non-sodium channel target antiepileptic
drug.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Epilepsy is a common neurological condition, characterised by
recurrent, unprovoked seizures, and produces significant morbidity
in the general community.
In partial (focal) epilepsy, carbamazepine is generally considered
first-line drug therapy. If seizures are still not controlled, a
second drug is added to the first. Clobazam, gabapentin,
lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenytoin,
pregabalin, sodium valproate, tiagabine, topiramate or zonisamide
may be used. If a patient’s seizures are not controlled after
trying two or three different drug options, referral to a
specialist epilepsy centre should be considered. Patients’
refractory to drugs may be suitable for surgery.
The submission proposed that the place in therapy of lacosamide is
as a second line anti-epileptic drug that must be given in
combination with a non-sodium channel target anti-epileptic
drug.
6. Comparator
The submission presented two “Stages” for which
separate comparators are nominated.
Stage 1: Lamotrigine was nominated as the comparator, where the
comparison of lacosamide + any AED versus lamotrigine + any AED was
presented.
Stage 2: As the submission requested first-line add-on use for
lacosamide to non-sodium AEDs, the nominated comparator for this
sub-group was lacosamide + sodium AED to be used as a proxy for any
first-line add-on AED (including lamotrigine) + any AED.
The PBAC did not accept that this, see Recommendation and
Reasons.
7. Clinical Trials
The submission presented three randomised controlled trials (Trials
SP667, SP754 and SP755) which compared lacosamide (200-600 mg/day)
versus placebo and 12 lamotrigine trials, which compared
lamotrigine (75-500 mg/day) versus placebo in patients with partial
epilepsy.
The submission conducted meta-analyses of the three lacosamide and
12 lamotrigine trials and performed an indirect comparison using
placebo as the common comparator.
The PBAC considered that the trials recruited subjects who were not
entirely representative of those for whom PBS listing was
requested, as only 20% of patients in the trial would have been
representative of the requested population.
These trials had been published at the time of submission as
follows:
| Trial ID/First author | Protocol title/Publication title | Publication citation | |
|---|---|---|---|
| Common reference - Placebo | |||
| Lacosamide | |||
| Lamotrigine | |||
| SP667 | |||
| Ben-Menachem E et al. | Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. | Epilepsia (2007); 48(7): 1308-17. | |
| SP754 | |||
| Chung S et al. | Lacosamide as adjunctive therapy for partial-onset seizures: A randomized controlled trial. | Epilepsia (2010); 51(6): 958-967. | |
| SP755 | |||
| Halasz P et al | Adjunctive lacosamide for partial-onset seizures: Efficacy and safety results from a randomized controlled trial. | Epilepsia (2009); 50 (3):443-453. | |
| Baulac M et al. | Randomised, double-blind parallel group study of add-on therapy in adults with partial seizures. A comparison of pregabalin, lamotrigine, and placebo as adjunctive therapy in patients with refractory partial-onset seizures. | Epilepsy Res (2010); 91(1):10-19. | |
| Binnie C et al | Randomised, double-blind crossover study of add-on therapy in adults with partial seizures. Double-blind crossover trial of lamotrigine as add-on therapy in intractable epilepsy. | Epilepsy Res (1989); 4: 222-9. | |
| Boas J et al | Randomised, double-blind crossover study of add-on therapy in adults with partial seizures. Controlled trial of lamotrigine for treatment-resistant partial seizures. | Acta Neurol Scand (1996); 94:247-52. | |
| Jawad S et al | Randomised, double-blind crossover study of add-on therapy in adults with partial seizures. Controlled trial of lamotrigine for refractory partial seizures. | Epilepsia (1989); 30: 356-63. | |
| Loiseau P et al | Randomised, double-blind crossover study of add-on therapy in adults with partial seizures. A randomised double-blind placebo-controlled crossover add-on trial of lamotrigine in patients with treatment-resistant partial seizures. | Epilepsy Res; (1990) 7(2): 136-145. | |
| Matsuo F et al | Randomised, double-blind parallel group study of add-on therapy in adults with partial seizures. Placebo-controlled study of the efficacy and safety of lamotrigine in patients with partial seizures. U.S. Lamotrigine Protocol 0.5 Clinical Trial Group. | Neurology (1993); 43(11): 2284-2291. | |
| Messen-heimer J et al | Randomised, double-blind crossover study of add-on therapy in adults with partial seizures. Lamotrigine therapy for partial seizures: a multicenter placebo-controlled, double-blind, crossover trial. | Epilepsia (1994); 35: 113-21. | |
| Naritoku D et al | Randomised, double-blind parallel group study of add-on therapy in adults with partial seizures. Lamotrigine extended-release as adjunctive therapy for partial seizures. | Neurology (2007); 69(16): 1610-1618. | |
| Schachter S et al | Randomised, double-blind parallel group study of add-on therapy in adults with partial seizures (safety assessments only). Lamotrigine: A six-month, placebo-controlled, safety and tolerance study. | Journal of Epilepsy(1995); 8(3): 201-209. | |
| Schapel G et al | Randomised, double-blind crossover study of add-on therapy in adults with partial seizures. Double-blind, placebo controlled, crossover study of lamotrigine in treatment resistant partial seizures. | J Neurol Neurosurg Psychiatry (1993); 56(5): 448-453. | |
| Schmidt D et al | Randomised, double-blind crossover study of add-on therapy in adults with partial seizures. Add-on treatment with lamotrigine for intractable partial epilepsy: a placebo-controlled, cross-over trial. | Epilepsia (1993); 34 Suppl(2): 66. | |
| Smith D et al | Randomised, double-blind crossover study of add-on therapy in adults with partial seizures. Outcomes of add-on treatment with lamotrigine in partial epilepsy. | Epilepsia (1993); 34(2): 312-322. | |
8. Results of Trials
The submission presented two outcomes to compare lacosamide and lamotrigine in Stage 1 – 50% responder rate and proportion of patients who are seizure-free. The results of the comparison are presented in the table below.
50% responder rate and proportion of patients who are seizure-free for the lacosamide 200/400mg combined group versus placebo, lamotrigine versus placebo and lacosamide versus lamotrigine
| Lacosamide v placebo Meta-analysis of 3 trials | Lamotrigine v placebo Meta-analysis of 12 trials | Indirect: Lacosamide v lamotrigine | ||||
|---|---|---|---|---|---|---|
| RD (95% CI) | RR (95% CI) | RD (95% CI) | RR (95% CI | RD (95% CI) | RR (95% CI) | |
| 50% repsonder rate | 0.15 (0.10, 0.21) | 1.65 (1.33, 2.04) | 0.09 (0.05, 0.14) | 1.58 (1.24, 2.01) | 0.06 (-0.01, 0.13) | 1.04 (0.76, 1.44) |
| Propotion of patients seizure-free | 0.02 (0.00, 0.03) | 1.99 (0.66, 6.01) | -0.00 (-0.02,0.02) | 0.87 (0.25, 3.08) | 2.29 (0.43, 12.26) | 0.06 (-0.01, 0.13) |
50% responder rate
The lacosamide 200 mg and 400 mg treatment arms (pooled) were compared with the lamotrigine
treatment arms in an indirect comparison.
The results of the meta-analyses of the lacosamide and lamotrigine trials demonstrated
that treatment with both therapies results in a statistically significantly greater
proportion of patients achieving a 50% reduction in seizure frequency compared with
placebo. The results of the indirect comparison indicate that there is no statistically
significant difference between lacosamide and lamotrigine, when both are used in combination
with ‘any AED’.
Proportion of patients seizure-free
The meta-analysis did not show a statistical difference compared to placebo for either
the lacosamide or the lamotrigine combined estimates of treatment effect.
Patients in both the lacosamide and lamotrigine trials were refractory. In the lamotrigine
meta-analysis, there were significant missing data, and the lack of difference observed
for lamotrigine versus placebo may be as a result of the limited data available to
inform the comparison, in addition to this not being a specified outcome in any of
the lamotrigine trials.
For Stage 2, the submission presented a post-hoc analysis of the sub-group in the
lacosamide trials that were consistent with the patient population for whom listing
was sought (ie, those treated with lacosamide + non-sodium AED) versus lacosamide
+ sodium AED (which is used as a proxy for “any other first-line add-on AED + any
AED). The results are presented in the table below.
50% responder rate for the lacosamide 200/400mg combined group versus placebo. For
the sub-group, complement and total trial populations of the lacosamide and lamotrigine
trials
| Outcome: 50% responder rate | ||||
|---|---|---|---|---|
| LCM 200/400 combined group n/N, (%) | Placebo n/N, (%) | Relative Risk (95% CI) | Risk Difference (95% CI) | |
| Sub-group: Lacosamide added to only non-sodium AED - (with non-Na) | ||||
| SP754 | 20/36 (55.6%) | 3/19 (15.8%) | 3.52 (1.20, 10.35) | 0.40 (0.17, 0.63) |
| Meta-analysis of sub-group using random effects model | 2.05 (1.30, 3.23) | 0.28 (0.15, 0.41) | ||
| Complement sub-group: Lacosamide added to at least one sodium AED | ||||
| SP754 | 57/165 (34.5%) | 16/85 (18.8%) | 1.84 (1.13, 2.99) | 0.16 (0.05, 0.27) |
| SP755 | 94/268 (35.1%) | 33/133 (34.8%) | 1.41 (1.01, 1.98) | 0.10 (0.01, 0.20) |
| Meta-analysis of complement using random effects model | 1.55 (1.22, 1.97) | 0.13 (0.06, 0.19) | ||
| Meta-analysis of total lacosamide RCT population | 1.65 (1.33, 2.04) | 0.16 (0.10, 0.23) | ||
| Comparison of sub-group to complement | 1.32 (0.79, 2.22) | 0.16 (0.01, 0.30) | ||
| Meta-analysis of total lamotrigine RCT population | 1.58 (1.24, 2.01) | 0.09 (0.05, 0.14) | ||
| Comparison of sub-group to total lamotrigine RCT population | 1.30 (0.78, 2.17) | 0.19 (0.05, 0.33) | ||
| SP667 | 22/47 (46.8%) | 5/22 (22.7%) | 2.06 (0.90, 4.72) | 0.24 (0.01, 0.47) |
| SP755 | 26/50 (52.0%) | 8/26 (30.8%) | 1.69 (0.90, 3.19) | 0.21 (-0.01, 0.44) |
| Pooled | 68/133 (51.1%) | 16/67 (23.9%) | - | - |
| Chi-square heterogeneity | P=0.51 | P=0.48 | ||
| I 2 statistic | 0% | 0% | ||
| SP667 | 57/167 (34.1%) | 16/74 (21.6%) | 1.58 (0.97. 2.56) | 0.13 (0.01, 0.24) |
| Pooled | 208/600 (34.7%) | 65/292 (22.3%) | - | - |
| Chi-square heterogeneity | P=0.69 | P=0.76 | ||
| I 2 statistic | 0% | 0% | ||
| Test for treatment effect variation | P=0.29 | P=0.03 | ||
| I 2 statistic | 11% | 78% | ||
| Comparison of complement to total lamotrigine RCT population | 0.98 (0.70, 1.38) | 0.04 (-0.04, 0.12) | ||
* The random effects model was analysed using RevMan
More patients in the non-sodium sub-group (proposed PBS listing) achieved a ≥50% reduction
in seizure frequency compared to the complement subgroup (lacosamide + sodium AED),
51.1% versus 34.7% respectively, however this was only statistically significantly
different when analysing the results by risk difference (0.16 (95% CI: 0.01, 0.30)).
For PBAC’s view of these results, see Recommendation and Reasons.
The comparison of adverse events in the lacosamide and lamotrigine trials demonstrated
that lacosamide and lamotrigine have comparable adverse event profiles, but there
may be an increase in the incidence of dizziness and a decrease in the incidence diplopia
for lacosamide compared with lamotrigine. The types of adverse reactions identified
in the extended assessment of comparative harms were generally consistent with those
identified in the shorter-term trials, including mainly CNS-related effects such as
dizziness, fatigue, somnolence and headache.
9. Clinical Claim
For Stage 1, in a comparison of lacosamide + any AED versus
lamotrigine + any AED, the submission described lacosamide as
non-inferior in terms of comparative effectiveness and non-inferior
in terms of comparative safety over lamotrigine.
For Stage 2, in a comparison of lacosamide + non-sodium AED versus
lacosamide + sodium AED (which is also used as a proxy for any
first-line add-on AED + AED), the submission described lacosamide +
non-sodium AED as superior in terms of comparative effectiveness
and equivalent in terms of comparative safety over lacosamide +
sodium AED.
The PBAC considered that the evidence presented did not support the
claim of superior clinical efficacy of lacosamide in combination
with a non-sodium AED over lamotrigine in combination with any
AED.
10. Economic Analysis
A stepped economic evaluation was presented.
The time horizon of the model was 120 days in the base case,
however the submission provided a sensitivity analysis in which the
time horizon was extended to 52 weeks.
The economic evaluation presented an incremental cost/extra
responder gained over 120 days analysis, which was less than
$10,000.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The net total financial cost to the PBS was estimated by the
submission to be less than $10 million in Year 5. The estimate was
considered uncertain given the likely use in combination with
sodium AEDs.
For PBAC’s view, see Recommendation and
Reasons.
12. Recommendation and Reasons
The PBAC considered that the requested restriction was
inappropriate. The PBAC noted that the requested restriction was
inconsistent with currently PBS listed first line add-on
antiepileptic drugs (AEDs) and with the way that AEDs are
prescribed in clinical practice. The PBAC considered that
clinicians do not make decisions about which AED to use in the
treatment of epilepsy based on distinguishing between sodium
channel blocking (sodium) and non-sodium channel blocking
(non-sodium) AEDs. Further, the PBAC considered there is ambiguity
about the definition of AEDs in relation to whether their mechanism
of action is based on blocking sodium channels or not, as some AEDs
may have multiple/various mechanisms of action, some of which may
be attributed to blocking sodium channels e.g. topiramate and
sodium valproate.
The PBAC noted that the submission first compared lacosamide in
combination with any AED to lamotrigine in combination with any
AED. The PBAC considered that this may have been an appropriate
comparator if the submission had been claiming non-inferiority to
lamotrigine as add-on to first line treatment of epilepsy. However,
the submission claimed superior clinical efficacy of the comparison
of lacosamide + non-sodium AED versus lacosamide + sodium AED. The
PBAC noted that this comparison is a proxy for any first line
add-on AED treatment (including lamotrigine) in combination with
any AED, but the PBAC did not accept this proxy comparator.
Firstly, the PBAC noted that the comparison of lacosamide in
combination with a sodium AED with any first-line add-on AED
(including lamotrigine) with any AED has not been specifically
established as cost effective. The comparison was also considered
inappropriate to inform the proposed cost effectiveness of
lacosamide in combination with a non-sodium AED. Further, if the
rationale for superior efficacy of lacosamide in combination with a
non-sodium AED is followed, based on a synergistic effect of the
combination of different mechanisms of action (sodium and
non-sodium), then a comparison of a sodium and non-sodium AED (such
as lamotrigine in combination with a non-sodium AED) would have
followed the submission’s rationale. However, as noted above,
the PBAC did not consider the classification of AEDs as sodium and
non-sodium channel blocking as appropriate for the intended use as
part of an unambiguous PBS restriction.
The PBAC noted that the submission presented an indirect comparison
of three lacosamide trials and twelve lamotrigine trials in
combination with other AEDs with placebo as the common reference.
The PBAC considered that the results of the meta-analysis expressed
as 50 % responder rate suggest non-inferiority of lacosamide to
lamotrigine in combination with any AED. However the PBAC noted
that the results for placebo show different 50 % responder rates
across the two sets of trials (15.7% for the lamotrigine trials and
22.6% for the lacosamide trials), which may reflect the fact that
the lamotrigine trials were published mainly in the 1990s and the
lacosamide trials were completed 2005-2007. In turn, this suggests
that management of patients might have improved over this period,
which would reduce the comparability of the trial populations and
affect the indirect comparison of the drugs. The PBAC also noted
that for the outcome, ‘proportion of patients
seizure-free’, results of the meta-analysis did not show a
statistical difference compared to placebo for either the
lacosamide or the lamotrigine combined estimates of treatment
effect.
In addition to these major issues with the requested restriction
and the comparison presented in the submission, the PBAC considered
that the results for the second stage of the comparison of the
subgroup of lacosamide in combination with non-sodium AEDs were
uncertain as the analysis was post hoc, consisted of subgroups
representing a small proportion of the pooled total trial
population (18 %) and was not supported by the statistical tests
for treatment effect variation across the proposed subgroup and its
complement from the trials.
The PBAC considered the problems with the requested restriction,
comparator and clinical data analysis flowed into the economic
evaluation. The PBAC noted that the economic evaluation presented a
cost per responder gained analysis (over 120 days). Presentation of
an incremental cost per QALY would be more informative considering
the less severe epileptic population for whom listing was sought
and the number of AEDs currently PBS listed for first line add-on
or second line treatment.
The PBAC considered that the utilisation estimates presented in the
submission are uncertain. In addition to the potential for
extensive use beyond the requested restriction, the PBAC considered
that both the extent to which lacosamide would substitute for other
AEDs currently PBS listed and the pattern of substitution were
uncertain.
The PBAC therefore rejected the submission on the basis that the
evidence presented did not support the claim of superior clinical
efficacy of lacosamide in combination with a non-sodium AED over
lamotrigine in combination with any AED, and on the basis of an
inappropriate requested restriction and therefore comparator.
Recommendation:
Reject
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
UCB will continue working with the PBAC in order to make Vimpat available to Australian patients who can benefit from this treatment.
