FULL-LENGTH ORIGINAL RESEARCH
`
`Epilepsia, 51(6):968-978, 2010
`doi: 10.1111/j.1528-1167.2010.02532.x
`
`Long-term add-on pregabalin treatment in patients
`with partial-onset epilepsy: Pooled analysis of open-label
`clinical trials
`*Basim M. Uthman, 1-Carl W. Bazil, fAhmad Beydoun, §Andreas Schulze-Bonhage,
`41[Reina Benabou, ¶Ed Whalen, ¶Birol Emir, ¶Teresa Griesing, and ¶Teresa Leon
`
`*Weill Cornell Medical College in Qatar, Doha, Qatar; tCollege of Physicians & Surgeons, Columbia University, New York, New York,
`U.S.A; $American University of Beirut, Beirut, Lebanon; §Epilepsy Centre, University Hospital, Freiburg, Germany; and
`¶Pfizer Global Pharmaceuticals, New York, New York, U.S.A.
`
`SUMMARY
`
`Purpose: To evaluate the safety, tolerability, and efficacy
`of long-term pregabalin as add-on therapy for patients
`with poorly controlled partial seizures.
`Methods: Analysis of data from six long-term clinical trials
`involving 2,061 patients receiving open-label pregabalin
`75-600 mg/day adjunctive therapy for partial onset epi-
`lepsy refractory to multiple antiepileptic drugs.
`Results: Total pregabalin exposure was 3,877 person-
`years. The mean duration of pregabalin treatment was
`534 days (range 0.3-8 years) and 59% completed I year.
`One-third of patients discontinued for lack of efficacy. The
`most common dose was .?_300 mg/day; over half took
`450 mg/day. There was a mean reduction in the 28-day
`seizure rate of 25-40%, and more than 40% of all patients
`had a>_50% reduction in seizures from baseline during the
`last 3 months of treatment. Twelve percent of all patients
`
`had a 6-month period continuously free of seizures. In the
`last year, 6% were seizure-free for the entire year. Pregab-
`alin was generally well-tolerated and the safety profile
`favorable in patients treated for up to several years, with
`an adverse event (AE) profile similar to short-term pla-
`cebo-controlled trials. Common AEs included CNS symp-
`toms (dizziness, somnolence, headache, and asthenia),
`accidental injury, and weight gain. CNS AEs tended to be
`mild and transient. Rates of sudden unexpected death in
`epilepsy (SUDEP), mortality, cancer, and status epilepti-
`cus were within the expected range for this population.
`Conclusions: Adjunctive pregabalin was effective, gener-
`ally well tolerated, and safe in the long-term treatment of
`partial seizures, and provided clinically meaningful seizure
`reduction and freedom without evidence of tolerance
`over 2 years of follow-up.
`KEY WORDS: Pregabalin, Epilepsy, Antiepileptic drugs,
`Long-term therapy, Clinical trials, Open-label.
`
`Pregabalin is a novel anticonvulsant, which has also dem-
`onstrated analgesic and anxiolytic effects in preclinical ani-
`mal models (Ben-Menachem, 2004) and in randomized
`controlled clinical trials (Brodie, 2004). These actions may
`be due to potent binding of pregabalin to the auxiliary
`alpha2-delta subunit of voltage-gated calcium channels
`(Taylor et al., 1993; Dooley et al., 2002; Fink et al., 2002;
`Ben-Menachem, 2004) in the peripheral and central nervous
`system (CNS). A series of four well-designed, 12-week clin-
`ical trials have already demonstrated that pregabalin (150-
`600 mg/day) is effective, safe, and well-tolerated when
`administered as adjunctive therapy in patients with treat-
`
`ment-refractory partial-onset epilepsy (French et al., 2003;
`Arroyo et al., 2004; Beydoun et al., 2005; Elger et al.,
`2005). Furthermore, a dose—response effect was observed,
`which has also been confirmed by an exposure—response
`analysis of the data (Miller et al., 2003). Moreover, pregaba-
`lin has a low potential for drug interactions, as indicated by
`the absence of metabolism by the cytochrome P450 system,
`its lack of protein binding (Ben-Menachem, 2004), and its
`lack of pharmacokinetic interaction with concomitantly
`administered antiepileptic drugs (AEDs) (Bockbrader et al.,
`2001; Ben-Menachem, 2004; Brodie et al., 2005).
`Epilepsy is largely a chronic, debilitating condition
`(Baker, 2002), and approximately one-third of patients
`with partial epilepsy will continue to experience seizures
`despite ongoing use of AED treatment (Brodie & Kwan,
`2002). Such treatment-refractory patients are often treated
`with AED polytherapy (Landmark et al., 2007). There is a
`continuing need for well-tolerated and safe treatments that
`ARGENTUM Exhibit 1074
` Argentum Pharmaceuticals LLC v. Research Corporation Technologies, Inc.
`968
`IPR2016-00204
`
`Accepted January 27, 2010; Early View publication March 19, 2010.
`Address correspondence to Basim M. Uthman, M.D. WCMC-Q, Educa-
`tion City, P.O. Box 24144, Doha, Qatar. E-mail: bmu2001@qatar-med.
`cornell.edu
`
`Wiley Periodicals, Inc.
`© 2010 International League
`
`EXHIBIT
`
`vo--/0,_/6-7/,)/
`
`Page 00001
`
`(cid:9)
`

`
`Long-Term Pregabalin in Epilepsy
`
`969
`
`may provide additional seizure control. Most patients with
`epilepsy take AEDs for several years, if not for life. Such
`long-term exposure will require the management of drug
`interactions, tolerability issues, and safety concerns that
`can affect patient adherence to long-term treatment. In
`addition, rare potential adverse events (AEs) will not
`always be apparent in short-term clinical trials required
`for marketing approval. It is vital that prescribing clini-
`cians are aware of potential long-term AEs, particularly
`those that could have serious consequences for affected
`patients.
`It is commonplace in the clinical development of drugs
`for chronic illnesses such as epilepsy to offer patients
`who take part in randomized, placebo-controlled, double-
`blind trials the opportunity to receive treatment with the
`experimental agent in extension studies, which are usually
`open-label. Such studies tend to run until the agent being
`studied receives a license and is brought to market. There-
`fore, some patients might be treated with a new agent
`under such circumstances for several years during which
`time data on efficacy, tolerability, and safety are routinely
`collected. Such data provide useful insight into the behav-
`ior of a new drug when it is used long-term under condi-
`tions that are more akin to clinical practice than
`controlled trials.
`To determine what physicians might expect during long-
`term treatment with pregabalin, six open-label extension
`studies evaluated the long-term efficacy, safety, and tolera-
`bility of pregabalin (dose range 75-600 mg/day) adminis-
`tered two or three times daily as adjunctive therapy in
`partial epilepsy. This report examines the long-term effects
`of pregabalin on seizure control, as well as tolerability and
`safety, by evaluating data pooled from the six studies that
`have very similar designs.
`
`METHODS
`
`This report includes data from six open-label studies, all
`of which allowed pregabalin adjunctive therapy with mar-
`keted AEDs. Investigators at 252 centers throughout 19
`countries worldwide conducted these studies between
`November 1997 and February 2006. The studies ranged in
`duration from 3.5 years to almost 8 years (Table 1). Each
`study was approved by institutional review boards and eth-
`ics committees and was conducted in accordance with the
`International Conference on Harmonisation Guidelines for
`Good Clinical Practice and the Declaration of Helsinki.
`Patients or their authorized representatives gave written
`informed consent.
`
`Studies
`These were six long-term, open-label, adjunctive therapy
`studies conducted in patients with partial-onset seizures
`refractory to AED treatment. Patients who had taken part in
`six preceding randomized, double-blind clinical trials
`(French et al., 2003; Arroyo et al., 2004; Beydoun et al.,
`2005; Elger et al., 2005; Data on file, Pfizer Inc., New York,
`NY, U.S.A.) had the option to enter the open-label extension
`studies (Table 1). All but one of the preceding double-blind
`clinical trials evaluated adjunctive treatment. The other was
`a small 1-week study of monotherapy in inpatients who
`were hospitalized for seizure monitoring and had existing
`AED treatment discontinued as a standard procedure in
`seizure presurgical workup (Abou-Khalil et al., 1999).
`Patients voluntarily extended their hospitalization beyond
`the presurgical workup requirements without resuming
`existing AEDs prior to randomization to pregabalin
`600 mg/day or gabapentin 300 mg/day (n = 93) (Data on
`file, Pfizer Inc., New York, NY, U.S.A.). In addition, three
`
`Table I . Summary of six open-label extension studies
`
`Study no. (cid:9)
`
`008 (cid:9)
`010 (cid:9)
`
`012 (cid:9)
`
`035 (cid:9)
`
`114 (cid:9)
`
`164 (cid:9)
`
`Pregabalin (cid:9)
`dose (mg/day) (cid:9)
`
`150-600 (cid:9)
`225-600 (cid:9)
`
`Dosing (cid:9)
`frequency (cid:9)
`
`TID (cid:9)
`TID or BID (cid:9)
`
`75-600 (cid:9)
`
`TID or BID (cid:9)
`
`100-600 (cid:9)
`
`150-600 (cid:9)
`
`BID (cid:9)
`
`BID (cid:9)
`
`150-600 (cid:9)
`
`BID (cid:9)
`
`Target dose° (cid:9)
`(mg/day) (cid:9)
`
`Study duration (cid:9)
`(months) (cid:9)
`
`Total
`N (ITT) (cid:9)
`
`De novo entered (cid:9)
`
`Location
`
`450 (cid:9)
`450 (cid:9)
`
`450 (cid:9)
`
`400 (cid:9)
`
`300 (cid:9)
`
`300 (cid:9)
`
`95 (cid:9)
`86 (cid:9)
`
`85 (cid:9)
`
`70 (cid:9)
`
`44 (cid:9)
`
`53 (cid:9)
`
`82 (cid:9)
`454 (cid:9)
`
`321 (cid:9)
`
`623 (cid:9)
`
`333 (cid:9)
`
`No (cid:9)
`Yes (n = 195) (cid:9)
`
`Yes (n = 89) (cid:9)
`
`Yes (n = 228) (cid:9)
`
`No (cid:9)
`
`248 (cid:9)
`
`No (cid:9)
`
`U.S.A.
`Canada
`U.S.A.
`Australia
`Europe
`South Africa
`Canada
`U.S.A.
`Australia
`Canada
`Europe
`Canada
`Europe
`
`ITT, intent to treat; TID, three times daily dosing; BID, twice daily dosing.
`°In each of the studies patients received a target dose in the initial phase of the study irrespective of previous double-blind treatment assignment, which was
`unknown by the investigator at the time of entry to the open-label study. Target doses were attained either within 1-7 days of entry, depending on the study.
`Dosing was fully flexible from 75-600 mg/day after the target dose had been reached (or an attempt had been made to reach).
`
`Epilepsia, 51(6):968-978, 2010
`doi: 10.1111/j.1528-1167.2010.02532.x
`
`Page 00002
`
`

`
`970
`
`B. M. Uthman et al.
`
`of the studies allowed the entry of de novo patients. The dos-
`ing regimens, duration of the studies, and numbers of
`patients in each of the studies are summarized in Table 1.
`
`Patients
`Patients were male or female (pregnant or lactating
`women excluded), with a diagnosis of epilepsy with partial-
`onset seizures with or without secondary generalization, as
`defined in the International League Against Epilepsy
`(ILEA) Classification of Seizures (Commission on Classifi-
`cation and Terminology of the International League against
`Epilepsy, 1981). In most studies the minimum age was
`18 years, except for two studies with U.S. sites in which a
`few patients aged 12-18 were allowed to enter. Patients in
`the five adjunctive double-blind pregabalin studies that pre-
`ceded open-label treatment were on one to three other
`AEDs; had no longer than a 4-week period free of seizures
`during the pretreatment, baseline assessment phase; and had
`at least six partial seizures during the 8-week pretreatment,
`baseline period (French et al., 2003; Arroyo et al., 2004;
`Beydoun et al., 2005) or at least four in the 6-week prestudy,
`baseline period (Elger et al., 2005; Data on file, Pfizer Inc.,
`New York, NY, U.S.A.). De novo patients with partial
`seizures who had not taken part in the preceding double-
`blind trials and entered the long-term open-label study had
`at least four seizures in the preceding 2 months based on ret-
`rospective assessment, were not adequately controlled on
`current AED treatment, and investigators thought they
`could possibly benefit from adjunctive pregabalin treat-
`ment.
`At the request of the U.S. Food and Drug Administration
`(FDA) in March 2001, approximately 2 to 3.5 years after
`the studies started, the 431 U.S. patients remaining in the
`studies at that time were required to meet requalification cri-
`teria to continue, at both an initial requalification visit and at
`every subsequent study visit. Only those U.S. patients who
`were refractory to other AEDs (defined as failing three
`AEDs from two different mechanistic AED classes in the
`past and with an epilepsy diagnosis years), and who were
`responding to pregabalin (defined as 30% reduction in all-
`type seizure frequency compared to baseline) were allowed
`to continue in these studies. It is worth noting that under
`these response criteria a patient presenting at any follow-up
`visit with an average of five simple partial seizures per
`28 days during the most recent 12 weeks compared to a
`28-day average baseline frequency of one simple partial
`seizure, four complex partial seizures, and two secondarily
`generalized seizures would not requalify by protocol and
`would be discontinued from the study despite having a
`marked reduction in the actual severity of seizures.
`
`Assessments
`Patients maintained a daily seizure diary. The clinic visit
`schedule varied across studies but was generally monthly
`for the first 4 months and then 3-monthly thereafter. In addi-
`
`Epilepsia,51(6):968-978,2010
`doi: 10.1111/j.1528-1167.2010.02532.x
`
`tion to the collecting of seizure diaries, AEs were recorded
`at each clinic visit. All treatment-emergent, spontaneously
`reported, or observed AEs were recorded by the investigator
`or designee and classified using the COSTART IV dictio-
`nary (Department of Health and Human Services, 1996).
`For the open-label extension studies, treatment emergent
`was defined as any AE that was not evident during double-
`blind treatment, or that was previously observed but
`increased in intensity or frequency, or changed in character
`during open-label treatment. Prolongations of seizure dura-
`tion, or increase in seizure intensity or frequency, were con-
`sidered to indicate lack of efficacy and were not recorded as
`AEs. Status epilepticus was classified separately from AEs
`and lack of efficacy. A central laboratory performed clinical
`laboratory tests on blood and urine samples collected at each
`study visit, and upon discontinuation. Physical and neuro-
`logic examinations were conducted at each visit, and elec-
`trocardiography(ECG) was conducted at study entry, after
`1-2 months, and at 6-month intervals thereafter.
`
`Data analyses
`Two populations were analyzed for efficacy: all patients
`enrolled in the extension studies who took at least one dose
`of pregabalin treatment, and the cohort of patients who com-
`pleted 2 years of treatment. No inferential testing was
`undertaken. The baseline 28-day seizure rate was that
`derived from diaries before patients were exposed to active
`study treatment, that is, before entry to double-blind studies
`for patients originally randomized to active AED treatment,
`and the last month of the double-blind phase for patients
`who had been on placebo before entering the open-label
`extension. Prospective assessments of baseline seizure rates
`were not available for de novo patients or those who had
`originally taken part in the small monotherapy study. The
`mean percentage reduction in seizures from baseline was
`calculated for each 3-month treatment interval. The percent-
`age of patients with _50% reduction from baseline in sei-
`zures was calculated. For the 2-year cohort the percentages
`with ..?..25% and 75% reductions were also determined. The
`percentages of patients free of seizures for specified inter-
`vals were calculated. The cumulative frequency of discon-
`tinuation by month for any reason was calculated.
`The time to pregabalin discontinuation was evaluated
`using Kaplan-Meier survival analysis. The most common
`pregabalin dose was determined for each patient, and aver-
`ages were calculated. The mean pregabalin dose was also
`determined by month for the cohorts who remained on treat-
`ment for 1, 2, and 3 years.
`All patients who received at least one dose of study medi-
`cation were included in the evaluation of safety data. The
`frequency of AEs and discontinuations due to AEs were cal-
`culated. The median times to onset and duration of the most
`common treatment-emergent AEs were also determined.
`For patients who had received placebo, fixed-dose
`pregabalin 600 mg/day, and semiflexible pregabalin
`
`Page 00003
`
`

`
`150-600 mg/day in preceding 12-week double-blind trials,
`the frequency of treatment-emergent AEs during double-
`blind treatment and the first 12 weeks of open-label pregab-
`alin treatment were compared.
`The number of concomitant AEDs taken during open-
`label pregabalin treatment was also recorded and com-
`pared with the number of concomitant AEDs at baseline.
`In this analysis, any patients from the double-blind,
`adjunctive studies who switched between different con-
`comitant AED medications were counted as an increase in
`the number of concomitant AEDs during open-label.
`Hence, only patients who did not switch or reduce/
`increase the number of concomitant AED medications
`were counted as "no change."
`An exploratory analysis of weight changes occurring
`during the first year of open-label-treatment with pregaba-
`lin was conducted using patients who were randomized to
`placebo in the double-blind trials, or who entered the
`open-label trials de novo (i.e., pregabalin-naive). In order
`to examine weight change over time in a homogeneous
`population exposed to pregabalin, patients previously ran-
`domized to double-blind pregabalin were not included in
`this analysis, since they had already received 12 weeks
`treatment before the start of open-label. Because each
`study had a different schedule for patient visits, weight
`change during open-label pregabalin treatment was ana-
`lyzed and reported as a continuum rather than at discrete
`time points. Estimates at selected time points were then
`derived from the fitted nonparametric weight-change-by-
`time curve. Similar estimates were also determined for
`pregabalin-naive patients who entered the open-label stud-
`ies and discontinued pregabalin prior to 1 year of open-
`label treatment.
`
`RESULTS
`
`Patients and disposition
`In total 2,061 patients were treated with open-label pre-
`gabalin (Fig. 1). On entry to the open-label studies 50% of
`patients were women and the mean age was 38.6 years
`(range 12-82 years). Concomitant AED use before entry
`was as follows: zero = 2.1%, one = 26.4%, two = 47.3%,
`three = 22.3%, and more than three = 1.9%. The median
`baseline seizure rate before patients were treated in the
`original double-blind adjunctive studies was 9.5/28 days
`(mean 21/28 days, range 0-356/28 days,). Before entering
`the open-label extension studies, 47% had previously been
`treated with pregabalin, 21% with placebo, and 7% had
`previously been randomized to other AEDs (45 patients on
`gabapentin, 103 on lamotrigine), whereas the remaining
`25% were de novo. The patients who had previously been
`exposed to pregabalin 2% had been taking <150 mg/day.
`Patient characteristics for the double-blind cohort were
`similar to those of the de novo cohort, and these combined
`patient characteristics were similar to those in each of the
`
`Long-Term Pregabalin in Epilepsy
`
`971
`
`6 randomized,
`double-blind trials
`N=1826
`
`Entered extension
`studies N=1549
`
`De novo patients
`N=5 I 2
`
`Total in 6 open-label extension studies
`N=2061 (100%)
`
`Completed
`N=575 (28%)
`
`Did not requalify
`N=I82 (9%)
`
`Discontinued N=I304 (63%)
`• Lack of efficacy N=683 (33%)
`• Adverse event N=262 (13%)
`• Status epilepticus N=4 (0.2%)
`• Non-adherence N=63 (3%)
`• Other N=292 (14%)
`
`Figure I.
`Disposition of patients who entered open-label extension stud-
`ies. Other includes lost to follow-up and administrative rea-
`sons. In March 2001 patients in the United States had to meet
`the following requalification criteria at each clinic visit to
`remain on pregabalin treatment Had history of failing A an-
`tiepileptic drugs (AEDs) from A different mechanistic classes
`and had ?..30% reduction from pretreatment baseline. Of the
`patients who entered from randomized, double-blind trials, 82
`were from the monotherapy trial; the remainder were from
`adjunctive trials. Patients were classified as completed if they
`remained in the study until it ended (i.e., when pregabalin was
`approved and made available on prescription).
`Epilepsia (4) I LAE
`
`six open-label studies (Table S1, supplemental material
`appendix). The proportions of patients who were classified
`as double-blind responders (>-5O% seizure reduction from
`baseline) were similar among those who did (29%) and
`did not (30%) choose to enter the open-label extension
`studies.
`Of the 1,979 patients who had not been in the preceding
`monotherapy study, 57% did not change concomitant AEDs
`during open-label treatment and 43% changed concomitant
`AEDs. Of the 82 patients who entered from the monothera-
`py study, 71 added concomitant AEDs during open-label
`treatment. In general, the most frequently used concomitant
`AEDs in each of the six trials were similar. Overall, the most
`commonly used AEDS (>10% of all patients) were carba-
`mazepine (56.7%), topiramate (26.7%), phenytoin (25.9%),
`lamotrigine (25.8%), levetiracetam (20.1%), lorazepam
`(10.2%), and clobazam (10.2%).
`
`Epilepsia, 51(6):968-978, 2010
`doi: 10.1111/j.1528-1167.2010.02532.x
`
`Page 00004
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`
`972
`
`B. M. Uthman et al.
`
`Pregabalin exposure and dosing
`A total of 575 patients [28% of the total intent-to-
`treat (ITT) population] completed one of the six open-
`label studies (i.e., remained on treatment until the study
`ended; Fig. 1). Overall, at the completion date, 79% of
`patients had been exposed to pregabalin for (cid:9)
`months,
`year, 34% for (cid:9)
`years, and 14% for
`61% for (cid:9)
`years. The total exposure to pregabalin was 3,877
`person-years. The percentage of patients completing at
`least 1 year was similar in each of the six open-label
`studies. Of the 795 patients who were on treatment
`for <1 year, 779 discontinued, one failed to requalify,
`and for 15 patients the study they were in ended before
`they had the opportunity to complete 1 year of
`treatment. Of the 1,364 patients who were on treatment
`for <2 years, 1,195 discontinued, one failed to requalify,
`and for 168 patients the study ended before they could
`complete 2 years of treatment. Therefore, of the patients
`who had the opportunity to complete 1 and 2 years of
`treatment, 38.1% and 63.1% discontinued, respectively.
`In the Kaplan-Meier analysis of time to pregabalin
`discontinuation, the probability of remaining on pregaba-
`lin treatment was 59% at 1 year and 37% at 2 years.
`The mean duration of open-label pregabalin treatment
`was 534 days and the median was 450 days (range 1-
`1,764 days). The distribution of patients according to
`their most common pregabalin dose is shown in Fig.
`2A. In the analysis of pregabalin dosing in cohorts who
`were on pregabalin treatment for at least 1, 2, and
`3 years, the dose tended to stabilize at approximately
`500 mg/day by 6 months of treatment (Fig. 2B). The
`mean dose among patients who discontinued pregabalin
`in the first year, when the majority of discontinuations
`occurred, tended to be lower than in those who stayed
`on treatment and across quarters ranged from 311-
`315 mg/day.
`
`Efficacy
`The mean percentage reductions in seizures from baseline
`in those patients who had taken part in the preceding dou-
`ble-blind trials, for all patients, and for the 2-year cohort are
`shown in Fig. 3. In the analysis of responder rates in all
`patients, overall 43% had a _50% reduction in the 28-day
`seizure frequency from baseline during their last 3 months
`of pregabalin treatment. The percentage of patients who
`were 50% responders in the first 3 months of pregabalin
`treatment and in their last 3 months of treatment, irrespec-
`tive of the duration between these periods, was 24%. In the
`analysis of the 2-year cohort in which different levels of
`response were evaluated, response rates were consistent
`over time (Fig. 4).
`The percentages of patients who achieved seizure free-
`dom continuously at any time on treatment and during the
`last period on treatment are shown in Table 2. In the all
`patient group, 27.3% reached seizure freedom for any
`3 months and 6.2% for any year. Rates of seizure freedom
`in the 2-year cohort were greater than in the all patient group
`in the analysis of seizure freedom continuously. The rates of
`seizure freedom in the last periods on treatment were similar
`in the all patient analysis, the 2-year cohort (Table 2), and in
`de novo patients alone (data not shown).
`
`Tolerability and safety
`Of the 2,061 patients in total who received open-label
`pregabalin, 1,891 (91.7%) experienced at least one AE and
`262 patients (12.7%) discontinued because of AEs. Most
`AEs were mild or moderate in intensity; only 386 patients
`(18.7%) experienced AEs that were rated as severe in inten-
`sity. The most common AEs generally affected the CNS
`(Table 3). The AE coded as "thinking abnormal" was
`reported in 9.8% of patients, but this was not deemed to be
`suggestive of psychosis or other psychiatric AEs. Peripheral
`edema was observed in 7.6% of patients. There was only a
`
`A 60-
`
`45
`
`30
`0
`
`15
`
`26
`
`21
`
`0 (cid:9) .
`
`3
`
`<150
`
`6
`
`2
`awn
`150
`
`450 -
`300 -
`<I50-
`<600
`<450
`<300
`Pregabalin dose (mg/day)
`
`g 600
`sz
`a (cid:9)
`
`soo 4
`
`0
`
`40
`
`•
`300-1
`
`200-4
`
`100
`
`— 3 year cohort (n=270)
`— • 2-year cohort (n=647)
` 1-year cohort (n=1218)
`
`600
`
`0 (cid:9)
`
`6 (cid:9)
`
`18 (cid:9)
`12 (cid:9)
`24 (cid:9)
`Months on pregabalin treatment
`
`30 (cid:9)
`
`36
`
`Figure 2.
`(A) Pregabalin most common dose distribution during open-label treatment and (B) mean pregabalin dose in patient cohorts treated
`for at least I , 2, and 3 years. The pregabalin dose range varied across the six open-label studies. Across all studies the dose range was
`75-600 mg/day. The target dose also varied across studies and ranged between 300 and 400 mg/day.
`Epilepsia © ILAE
`
`Epilepsia, 51(6):968-978, 2010
`doi: 10.1111/j.1528-1167.2010.02532.x
`
`Page 00005
`
`(cid:9)
`

`
`Long-Term Pregabalin in Epilepsy
`
`973
`
`100 -
`
`90 -
`
`80 -
`
`70 -
`
`2 60 -
`a
`a. 50 -
`
`• •
`
`40 -
`
`30 -
`
`20 -
`
`10 -
`
`0 (cid:9)
`
`
`
`— -Ar
`
`-,E- — (cid:9)
`
`—
`
`25% reduction
`500/0 reduction
`— • — 75cYcn reduction
`
`3 (cid:9)
`
`6 (cid:9)
`
`9 (cid:9)
`
`12 (cid:9)
`
`1 S (cid:9)
`
`18
`
`21 (cid:9)
`
`24
`
`Months on open-label pregabalin
`
`Figure 4.
`Percentages of patients with 25%, 50%, and 75% reductions
`in 28-day seizure frequency from baseline (assessment immedi-
`ately before initial pregabalin exposure) in the 2-year cohort.
`The 2-year efficacy analysis cohort includes 453 patients who
`were treated with pregabalin for at least 2 years and who had
`complete efficacy assessment data.
`Epilepsia Q ILAE
`
`Table 2. Percentages of patients free of seizures in
`the all-patient group and the 2-year efficacy cohort
`
`All patients (cid:9)
`(n = 2,061) (%) (cid:9)
`
`2-year cohort
`(n = 453) (%)
`
`Any 3 months continuously (cid:9)
`Any 6 months continuously (cid:9)
`Any 12 months continuously (cid:9)
`Last 3 months (cid:9)
`Last 6 months (cid:9)
`Last 12 months (cid:9)
`
`27.3
`11.6
`6.2
`19.3
`8.4
`5.2
`
`35.8
`15.7
`9.3
`18.1
`9.5
`6.0
`
`De novo patients were not included in the 2-year efficacy cohort.
`
`All patients
`Months on pregabalin treatment
`
`1-3 4-6 7-9 10-12 13-15 16-18 19-21 22-24
`(n=1465) (n=1291) (n=1125) (n=988) (n=882) (n=774) (n=700) (n=594)
`
`2-year cohort (n=453)
`Months on pregabalin treatment
`1-3 4-6 7-9 10-12 13-15 16-18 19-21 22-24
`
`0
`
`-10-
`
`-20 -
`
`-30 -
`
`-40 -
`
`-50 -
`
`-60 -
`
`Mean % change in seizure frequency
`
`0
`
`z -10 -4
`cr
`
`1,2 -20
`N
`N a
`•c -30
`a
`00 5 -40 -4
`_c
`
`-S01
`
`X
`
`-60
`
`Figure 3.
`Mean percentage reduction in 28-day seizure frequency from
`baseline in all patients and the 2-year efficacy cohort. Mean %
`change from back-transformed Response ratio (RRatio). Only
`patients with prospective baseline diary data collected before
`entry into double-blind studies could be included in this
`analysis. The baseline 28-day seizure rate was that preceding
`exposure to active study treatment.
`Epilepsia Q ILAE
`
`low incidence of AEs that have been associated with certain
`other AEDs (Wong & Lhatoo, 2000), such as hyponatremia
`(29 patients, 1.41%.), and glaucoma (one patient). Only in 4
`of the 29 patients was hyponatremia considered a serious
`adverse event, and in none of these four cases was the AE
`related to pregabalin; two patients were on carbamazepine
`or oxcarbazepine at the time. Examination of the median
`onset and duration of the most common AEs (Table 3) indi-
`cates that they were mainly observed within the first few
`weeks of open-label pregabalin treatment and that they
`tended to be transient in nature. Additional data on AEs are
`provided in Table S2 of supplemental material appendix.
`In patients who had taken part in the preceding double-
`blind trials, the frequency of some common AEs occurring
`during the 12 weeks of double-blind treatment was
`compared with the first 12 weeks of open-label treatment
`
`(Table 4). The frequency of these AEs increased when
`patients switched from double-blind placebo to open-label
`pregabalin, and decreased when patients switched from dou-
`ble-blind, high-dose pregabalin (600 mg) to open-label
`flexible pregabalin, when target pregabalin doses were
`lower. A lower frequency of these AEs was also observed
`when patients were switched from the semiflexible pregaba-
`lin 150-600 mg/day dosing to the truly flexible dosing of
`the open-label study.
`Serious AEs were reported in 309 patients (15.0%); how-
`ever, in only 21 patients (1.0%) were these considered to be
`related to treatment with study drug. The most frequent seri-
`ous AEs experienced were accidental injury (68 patients,
`3.3%), pneumonia (21 patients, 1.02%), overdose (14
`patients, 0.68%), depression (12 patients, 0.58%), psychosis
`(10 patients, 0.48%), and cancer (11 patients, 0.53%). Most
`(20) of the 21 patients experiencing treatment-related
`
`Epilepsia, 51(6):968-978, 2010
`doi: 10.1111/j.1528-1167.2010.02532.x
`
`Page 00006
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`

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`974
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`B. M. Uthm n et al.
`
`Table 3. Summary of incidence, time to onset, and duration of most common treatment-emergent adverse
`events (AEs)° (experienced by ?_ 10% of patients) for all patientsb in the open-label studies (n = 2,06 I ) and their
`contributions to discontinuation of treatment
`
`AE (cid:9)
`
`Frequency of AE (%) (cid:9)
`
`Discontinuation due to AE (%) (cid:9)
`
`Median time to onset (days)
`
`Median duration (days)
`
`Dizziness (cid:9)
`Accidental injury (cid:9)
`Somnolence (cid:9)
`Weight gain (cid:9)
`Infection (cid:9)
`Headache (cid:9)
`Asthenia (cid:9)
`Pain (cid:9)
`Ataxia (cid:9)
`Amblyopia (cid:9)
`Diplopia (cid:9)
`
`30.0 (cid:9)
`25.3 (cid:9)
`22.8 (cid:9)
`20.8 (cid:9)
`20.2 (cid:9)
`18.2 (cid:9)
`17.6 (cid:9)
`14.6 (cid:9)
`12.1 (cid:9)
`11.0 (cid:9)
`10.0 (cid:9)
`
`1.6 (cid:9)
`0.3 (cid:9)
`2.0 (cid:9)
`1.6 (cid:9)
`0 (cid:9)
`0.5 (cid:9)
`1.3 (cid:9)
`0.1 (cid:9)
`0.9 (cid:9)
`0.5 (cid:9)
`0.3 (cid:9)
`
`19 (9, 28)
`215 (174,251)
`26 (16,32)
`69 (60, 92)
`243 (212, 293)
`159 (122, 192)
`52 (32, 78)
`214 (177,257)
`42 (28, 69)
`53 (29, 81)
`79 (63, 98)
`
`19 (15, 27)
`20 (16, 28)
`57 (44, 67)
`564 (472, 652)
`10(8,11)
`30 (15, 43)
`93 (79, 119)
`42 (30, 62)
`39 (31, 55)
`41 (30, 58)
`24 (15, 40)
`
`°All-causality adverse events under treatment with study drug.
`b53% of patients were pregabalin naive before entering the open-label studies.
`The five most common adverse events as listed in the U.S.A. prescribing information for pregabalin are highlighted in bold text.
`
`Table 4. Comparison of treatment-emergent adverse events observed during the previous 12-week double-blind
`treatment period and during the first 12 weeks of open-label pregabalin treatment
`. (cid:9)
`,
`
`DB placebo to OL flexible (cid:9)
`pregabalin (n = 427) (cid:9)
`
`DB pregabalin 600 mg to OL (cid:9)
`flexible pregabalin (n = 402) (cid:9)
`
`DB semiflexible pregabalin
`(150-600 mg)° to OL flexible
`pregabalin (n = 103)
`
`Adverse event (cid:9)
`
`DB (%) (cid:9)
`
`OL (%) (cid:9)
`
`DB (%) (cid:9)
`
`OL (%) (cid:9)
`
`DB (%) (cid:9)
`
`OL (%)
`
`Dizziness (cid:9)
`Somnolence (cid:9)
`Ataxia (cid:9)
`Weight gain (cid:9)
`Amblyopia (cid:9)
`
`9.6 (cid:9)
`9.1 (cid:9)
`3.0 (cid:9)
`1.9 (cid:9)
`3.5 (cid:9)
`
`23.9 (cid:9)
`15.0 (cid:9)
`10.3 (cid:9)
`10.5 (cid:9)
`6.6 (cid:9)
`
`38.8 (cid:9)
`24.6 (cid:9)
`18.9 (cid:9)
`17.4 (cid:9)
`12.2 (cid:9)
`
`9.2 (cid:9)
`8.2 (cid:9)
`2.5 (cid:9)
`6.7 (cid:9)
`2.0 (cid:9)
`
`22.3 (cid:9)
`18.4 (cid:9)
`9.7 (cid:9)
`21.4 (cid:9)
`1.9 (cid:9)
`
`15.5
`3.9
`0.9
`4.9
`1.9
`
`Data are given for the five most common adverse events as listed in the U.S. prescribing information for pregabalin. DB, double-blind; OL, open-label.
`°The average daily dose of flexible-dose pregabalin was 588 m