The primary objective of this study is to assess the overall effectiveness of LCM (optimizedwithin the range of 200mg/day to 600mg/day) when added to a stable dose of LEV (in thelabel range of 1000mg/day to 3000mg/day) with withdrawal of the…
ID
Source
Brief title
Condition
- Seizures (incl subtypes)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
There are 2 analysis sets defined for this study; the safety set (SS) is all
subjects who received at least 1 dose of LCM; and the full analysis set (FAS)
is all subjects in the SS who have at least 1 seizure diary data assessment
during LCM treatment.
The primary efficacy variable to support the objective of evaluating overall
effectiveness is the retention rate at the end the 21-week Treatment Period
Secondary outcome
Percent change in partial-onset seizure frequency per 28 days from Baseline to
the 12-week Maintenance Period
Percent change in partial-onset seizure frequency per 28 days from Baseline to
the 21-week Treatment Period
50% response where a responder is a subject experiencing >=50% reduction in
partial-onset seizure frequency per 28 days from Baseline to the 12-week
Maintenance Period
50% response where a responder is a subject experiencing >=50% reduction in
partial-onset seizure frequency per 28 days from Baseline to the 21-week
Treatment Period
75% response where a responder is a subject experiencing >=75% reduction in
partial-onset seizure frequency per 28 days from Baseline to the 12-week
Maintenance Period
75% response where a responder is a subject experiencing >=75% reduction in
partial-onset seizure frequency per 28 days from Baseline to the 21-week
Treatment Period
Seizure-free status (yes/no) during the 12-week Maintenance Period in subjects
who completed the entire Maintenance Period
Quality of Life Inventory in Epilepsy-31-P (QOLIE-31-P)
Clinical Global Impression of Change (CGIC) at the end of the Maintenance Period
Patient Global Impression of Change (PGIC) at the end of the Maintenance Period
Background summary
In the past decade, several new options for the medical treatment of epilepsy
have been
introduced, including novel AEDs and vagus nerve stimulation (VNS). The newer
AEDs
differ from older agents in several important ways, including mechanism of
action (MOA),
spectrum of activity, and pharmacokinetic (PK) characteristics (Herman and
Pedley, 1998).
Despite this increase in treatment options, more than 30% of patients have
inadequate seizure
control on currently-available AEDs or experience significant adverse drug
effects (Beghi
and Sander, 2008), and less than 50% of newly diagnosed patients become seizure
free after
initial monotherapy treatment with an AED (Kwan and Brodie, 2000; Mohanraj and
Brodie, 2006).
Antiepileptic drug polytherapy typically is recommended for those patients not
achieving
adequate seizure control following 2 AED monotherapy treatments (Kwan and
Brodie, 2006);
however, evidence-based guidelines for optimal AED combinations are not
available. When
selecting an adjunctive AED, a number of factors may be used to identify the
optimal
combination treatment, including rational criteria for a lack of PK
interactions, minimized
toxicity, or a consideration of MOA. A common assumption is that adding an AED
with a
different MOA would provide a better potential for additive or even synergistic
efficacy
and/or a more favorable tolerability profile than combining 2 AEDs that share
the same MOA
(Deckers et al, 2000; St. Louis, 2009), yet clinical experience with
nonoverlapping
mechanisms has not shown a consistent improvement in efficacy or tolerability
in patients
(Deckers et al, 2000; Brodie and Mumford, 1999; Stafstrom, 2010).
Lacosamide belongs to a novel class of functionalized amino acids and is
approved for the
adjunctive treatment of partial-onset seizures in adults. Lacosamide*s mode of
action is
proposed to be mediated by a selective enhancement of slow inactivation of
voltage-gated
sodium channels which may explain the anticonvulsant effects of LCM
(Errington et al, 2008).
Previous analyses of pooled double blind, placebo-controlled, Phase 2/3 studies
(Ben Menachem et al, 2007; Halasz et al, 2009; Chung and Sperling, 2010; Chung
and Ben Menachem, 2010) have demonstrated that LCM provides additional efficacy
when added to a broad range of AEDs. In addition, recent posthoc analyses (Sake
et al, 2010) suggest improved tolerability and efficacy when LCM is combined
with non-sodium channel blocking antiepileptic drugs (NSCB-AEDs). This excludes
*traditional* SCB-AEDs, which are defined as carbamazepine, oxcarbazepine,
lamotrigine, and phenytoin.
Based on the results of the posthoc analyses for LCM, future prospective
studies evaluating single AED combinations (eg, LCM plus 1 other drug) are
needed to better evaluate the potential for additive or synergistic effects of
LCM in combination with AEDs not considered *traditional* sodium channel
blockers (ie, NSCB-AEDs). Lacosamide and LEV have the potential to be an
optimal treatment combination since the MOA are not overlapping (ie,
enhancement of sodium channel slow inactivation and binding to synaptic vesicle
protein 2A, respectively), and both drugs have favorable efficacy and
tolerability profiles. Thus, the goal of the current study is to prospectively
evaluate the therapeutic potential of LCM added to a stable dose of LEV in
subjects with partial-onset seizures not adequately controlled by a dual LEV
and SCB-AED regimen.
In the double-blind, placebo-controlled Phase 2/3 studies conducted for the
development of LCM, LCM was administered in fixed titration schedules and added
to stable concomitant AEDs. In contrast, the dose of LCM and concomitant AEDs
is adjusted in routine clinical practice based on the patient*s individual
clinical response. Since recent independent published case reports have
suggested that a stepwise progressive reduction of concomitant SCB-AEDs when
titrating LCM may improve tolerability and clinical outcome (Griffiths et al,
2010; Novy et al, 2011), the titration scheme in the current study was designed
to optimize AED treatment conversion from a SCB-AED to LCM, and is a truer
replication of clinical practice. This study will allow the dose of LCM to be
titrated to an optimally effective dose as the dose of the SCB-AED is
progressively withdrawn.
Further information on LCM PK, efficacy, and safety profiles, as well as
nonclinical results, can be obtained from the current version of the LCM
Investigator*s Brochure.
Study objective
The primary objective of this study is to assess the overall effectiveness of
LCM (optimized
within the range of 200mg/day to 600mg/day) when added to a stable dose of LEV
(in the
label range of 1000mg/day to 3000mg/day) with withdrawal of the concomitant
SCB-AED in
subjects with partial-onset seizures not adequately controlled on their dual
LEV and
SCB-AED regimen.
Other objectives of this study are to evaluate seizure reduction during the
study versus
Baseline and to evaluate the safety of LCM when LCM (optimized within the range
of
200mg/day to 600mg/day) is added to LEV (in the label range of 1000mg/day to
3000mg/day) with withdrawal of the concomitant SCB-AED in subjects with
partial-onset
seizures not adequately controlled on their dual SCB-AED and LEV regimen.
Study design
SP0980 is a Phase 3b, prospective, multinational, open-label, single-arm,
explorative study in
subjects with uncontrolled partial-onset seizures. The objective of this study
is to assess the
overall effectiveness of LCM (optimized within the range of 200mg/day to
600mg/day) when
added to a stable dose of LEV (in the label range of 1000mg/day to 3000mg/day)
with
withdrawal of the concomitant SCB-AED in subjects with partial-onset seizures
not
adequately controlled on their dual LEV and SCB-AED regimen (defined as
subjects who
have experienced on average at least 2 seizures per 28 days during the 8-week
period prior to
the Screening Visit [8-week Retrospective Seizure Baseline]).
The study consists of a 4-week Screening Period, a 21-week Treatment Period
(comprised of
a 9-week Dose Adjustment Period, and a 12-week Maintenance Period), and an up
to a
4-week Taper/Safety Follow-Up Period.
Intervention
The objective of this study is to assess the overall effectiveness of LCM
(optimized within the range of 200mg/day to 600mg/day) when added to a stable
dose of LEV (in the label range of 1000mg/day to 3000mg/day) with withdrawal of
the concomitant SCB-AED in subjects with partial-onset seizures not adequately
controlled on their dual LEV and SCB-AED regimen (defined as subjects who have
experienced on average at least 2 seizures per 28 days during the 8-week period
prior to the Screening Visit [8-week Retrospective Seizure Baseline]).
The study consists of a 4-week Screening Period, a 21-week Treatment Period
(comprised of a 9 week Dose Adjustment Period, and a 12 week Maintenance
Period), and an up to a 4 week Taper/Safety Follow-Up Period.
Study burden and risks
during the study the patient will have several times an ECG, will have to
answer questions, will undergo physical and neurological tests and blood
sampling and will complete a diary. However, some of these procedures are also
routinely done as part of these patients' usual epilepsy treatment.
The patients are also informed about the tests and procedures that will be done
at each visit.
8010 Arco Corporate Drive
NC 27617 Raleigh
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8010 Arco Corporate Drive
NC 27617 Raleigh
US
Listed location countries
Age
Inclusion criteria
1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved
written Informed Consent form is signed and dated by the subject or legal representative.
2. Subject/legal representative is considered reliable and capable of adhering to the protocol
(eg, able to understand and complete diaries), visit schedule, and medication intake
according to the judgment of the investigator.
3. Subject is male or female, at least 18 years of age.
4. Subject has a diagnosis of epilepsy with partial-onset seizures according to the
International Classification of Epileptic Seizures (1981).
5. Subject is taking LEV in combination with 1 SCB-AED (defined as carbamazepine,
lamotrigine, oxcarbazepine, phenytoin, or eslicarbazepine) as adjunctive treatment for
epilepsy.
6. The minimum required seizure frequency during the 8-week Retrospective Seizure
Baseline is on average >=2 partial-onset seizures (IA, IB, or IC) per 28 days (based on
investigator assessment of subject report) with at least 1 seizure per 4-week period within
the 8-week Retrospective Seizure Baseline. Additionally, subjects must experience at
least 1 seizure during the 4-week Prospective Seizure Baseline. In the case of simple
partial seizures, only those with motor signs (IA1) will be counted towards meeting this
inclusion criterion.
7. Subject has been maintained on a stable dose of LEV and a SCB-AED for at least
4-weeks prior to the Screening Visit (Visit 1) and during the 4-week Prospective Seizure
Baseline, with or without additional concurrent stable VNS. The VNS must have been in
place for at least 6 months prior to the Screening Visit (Visit 1) with constant settings for
at least 4-weeks prior to the Screening Visit (Visit 1) and throughout the duration of the
study.
Exclusion criteria
1. Subject has previously participated in this study or subject has previously been exposed to
LCM.
2. Subject has participated in another study of an investigational medicinal product (IMP) or
an experimental medical device within the last 2 months or is currently participating in
another study of an IMP or a medical device.
3. Female subject who is pregnant or nursing, and/or a woman of childbearing potential who
is not surgically sterile, 2 years postmenopausal or does not practice 2 combined methods
of contraception, unless sexually abstinent, for the duration of the study. Male subject
who does not agree to practice 2 combined methods of contraception (eg, condom,
spermicide), unless sexually abstinent, for the duration of the study.
4. Subject has a history of chronic alcohol or drug abuse within the last 2 years.
5. Subject has a seizure disorder characterized primarily by isolated auras (ie, simple partial
seizures without observable motor signs).
6. Subject has a history of primary generalized seizures.
7. Subject has a history of status epilepticus within the 12-month period prior to Visit 1.
8. Subject has seizures that are uncountable due to clustering (ie, an episode lasting less than
30 minutes in which several seizures occur with such frequency that the initiation and
completion of each individual seizure cannot be distinguished) during the 8-week
Retrospective Seizure Baseline and during the 4-week Prospective Seizure Baseline.
9. Subject has a current or previous diagnosis of pseudoseizures, conversion disorders, or
other nonepileptic ictal events which could be confused with seizures.
10. Subject has any medical or psychiatric condition that, in the opinion of the investigator,
could jeopardize the subject*s health or would compromise the subject*s ability to
participate in this study.
11. Subject has a lifetime history of suicide attempt (including an active attempt, interrupted
attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by
a positive response (*Yes*) to either Question 4 or Question 5 of the Columbia-Suicide
Severity Rating Scale (C-SSRS) at Screening.
12. Subject has a known hypersensitivity to any components of LCM tablets.
13. Subject has taken an AED other than the current SCB-AED and LEV during the 4-weeks
prior to the Screening Visit (Visit 1), excepting 1-time use of benzodiazepines as rescue
medication (less than or equal to 3 doses within 24 hours).
14. Subject has a medical condition that could reasonably be expected to interfere with drug
absorption, distribution, metabolism, or excretion.
15. Subject has an acute or sub-acute progressive central nervous system disease.
16. Subject has a known history of severe anaphylactic reaction or serious blood dyscrasias.
17. Subject has alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total
bilirubin levels >=2x the upper limit of normal (ULN) or has alkaline phosphatase levels
>=3xULN at Visit 1.
18. Subject has impaired renal function (ie, creatinine clearance [CLcr] is lower than
30mL/min) at Visit 1. Creatinine clearance will be estimated as follows:
Adult males: CLcr = (140-age) x weight in kg/(72 x serum creatinine in mg/dL)
Adult females: CLcr = [(140-age) x weight in kg/(72 x serum creatinine in mg/dL)] x 0.85
19. Subject has sick sinus syndrome without a pacemaker, or atrioventricular (AV) block, or
subject has any other clinically significant ECG abnormalities.
20. Subject has a known sodium channelopathy, such as Brugada syndrome.
21. Subject has experienced a myocardial infarction in the last 3 months.
22. Subject has New York Heart Association Class III or Class IV heart failure.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-002461-37-NL |
| ClinicalTrials.gov | NCT01484977 |
| CCMO | NL38748.091.12 |