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Divalproex extended-release versus the original divalproex tablet: results of a randomized, crossover study of well-controlled epileptic patients with primary generalized seizures
Epilepsy Research 50 (2002) 243 /249 www.elsevier.com/locate/epilepsyres
Divalproex extended-release versus the original divalproex tablet: results of a randomized, crossover study of wellcontrolled epileptic patients with primary generalized seizures Manon Thibault a,*, Warren T. Blume b, Jean-Marc Saint-Hilaire c, Rafik Zakhari d, Kenneth W. Sommerville e a
Centre Hospitalier Affilie´ Enfant Je´sus, 1401 18th Street, Quebec, Quebec, Canada G1J 1Z4 b London Health Sciences Centre, London, Ont., Canada c CHUM, Campus Notre-Dame, Montreal, Quebec, Canada d Abbott Canada, St. Laurent, Quebec, Canada e Abbott Laboratories, Abbott Park, IL, USA
Received 10 September 2001; received in revised form 21 February 2002; accepted 28 February 2002
Abstract Purpose: To compare the safety and efficacy of two formulations of divalproex, extended-release divalproex versus the original divalproex tablet, in adolescent and adult patients with epilepsy. Methods: Eligible patients were between the ages of 12 and 65 years with primary generalized epilepsy, which was controlled over the month prior to study enrollment with divalproex or valproic acid 1000 mg to 2000 mg/day. The patients were well-controlled; 39 of 43 (91%) had no seizures in the previous year. Patients were randomized to receive 84 days of either divalproex two times a day (b.i.d.)/three times a day (t.i.d.) or extended-release divalproex qd and then (crossed over to) 84 days of the comparator formulation. During the two treatment periods, patients received the same daily dose equivalent of divalproex as was taken during the month prior to study entry. The clinical status of patients was evaluated at a screening visit and at four subsequent visits conducted every 42 days. Results: There was no statistically significant difference between the formulation groups for seizure control rate (95% [41/43] for divalproex and 93% [40/43] for extended-release divalproex). Likewise, the formulation groups were similar based on the incidence of treatment-related adverse events. The most frequently reported ( 5/11.4% for either formulation) treatment-related adverse events were asthenia, tremor, nausea, and dizziness. Conclusions: Extended-release divalproex was similar to divalproex for the treatment of wellcontrolled, primary generalized epilepsy in terms of overall safety and efficacy parameters. # 2002 Elsevier Science B.V. All rights reserved. Keywords: Divalproex; Extended-release; Epilepsy; Generalized seizures
These data were presented as a poster at the following meeting: Focus on epilepsy VI, treatment of epileptic syndromes: from molecular targets to quality of life, 7 /10 July 2001, Mont-Tremblant, QC, Canada. * Corresponding author. Tel.: /1-418-649-0252; fax: /1-418-649-5915
0920-1211/02/$ - see front matter # 2002 Elsevier Science B.V. All rights reserved. PII: S 0 9 2 0 - 1 2 1 1 ( 0 2 ) 0 0 0 4 8 - 7
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1. Introduction Divalproex sodium, a compound containing an equal proportion (on a molar basis) of sodium valproate and valproic acid, dissociates to the valproate ion in the gastrointestinal tract. Divalproex sodium is available in several formulations, including the original tablet (enteric-coated, delayed-release tablet), sprinkle capsule, and a recently approved, extended-release tablet. The original (hereafter called divalproex) tablet formulation of divalproex is indicated for use worldwide, either alone or an adjunct to other agents, in the treatment of a variety of seizure disorders (Beydoun et al., 1997; Davis et al., 1994). Divalproex is also indicated in the United States for acute mania associated with bipolar disorder and for prophylaxis of migraine headaches and it has become widely used to treat behavioral disturbances associated with dementia. The new extended-release divalproex formulation was recently approved in the United States for migraine headache prophylaxis. Divalproex requires administration on a twotimes a day (b.i.d.) to three-times a day (t.i.d) basis. Decreasing the frequency of daily drug administration, as can be achieved with extended-release formulations, increases compliance and can improve outcomes. (Foster and Plosker, 2000; Mulleners et al., 1998; Halpern et al., 1993; Prisant et al., 1992). Since some of the adverse events associated with valproic acid and divalproex have been reported to be concentrationdependent (e.g. thrombocytopenia, increase in liver function tests, tremors, somnolence) (McEvoy et al., 1990; Pugh and Garnett, 1991; Coulter and Allen, 1981), the new extended-release formulation would have the added advantage of decreasing peak plasma concentrations, thereby potentially minimizing the occurrence of concentration-dependent adverse events and sub-therapeutic concentrations. The pharmacokinetic profile of the extendedrelease divalproex formulation was compared with the original tablet formulation in three crossover studies (Collins et al., 1998; data on file, Abbott Laboratories). Bioequivalence between the formulations was established in two of these studies, but
was not confirmed in the third study. Although bioequivalence may suggest interchangeability of different formulations, clinical equivalence may only be established in clinical trials. This was a randomized, multicenter, open-label, two-period, crossover study of adolescent and adult epilepsy patients with generalized seizures. The objective of the clinical trial was to compare the seizure control rate obtained by the two formulations of divalproex, the new extendedrelease tablet and the original enteric-coated tablet in adolescent and adult patients diagnosed with primary generalized epilepsy.
2. Patients and methods The protocol was approved by the institutional review board of each participating study site. Written informed consent was obtained from each patient or parent/legal guardian of minor patients before enrollment into the study. 2.1. Patients Outpatients between the ages of 12 and 65 years with primary generalized epilepsy*/either convulsive, non-convulsive, or both */and treated for at least 6 months with divalproex or valproic acid were eligible for enrollment. Patients must have been controlled over the month prior to study enrollment with a stable dose of divalproex or valproic acid (1000 /2000 mg/day taken in two or three divided doses). According to an inclusion criterion for the study eligible patients had controlled generalized epilepsy, which was defined as less than six major convulsive seizures per year. Patients with absence who had received optimal treatment to control their seizures were appropriate candidates for the study, even if they had experienced regular non-convulsive seizures. Excluded from the study were patients with a history of hypersensitivity to divalproex or valproic acid and pregnant or lactating females. Patients with hepatic or renal impairment, with a medical or neurological disorder other than epilepsy, requiring frequent changes in medication, or with a coagulation disorder and/or platelet count
M. Thibault et al. / Epilepsy Research 50 (2002) 243 /249
of B/100 /109 per l were also excluded. The use of other antiepileptic medication (other than divalproex or valproic acid) was not allowed during the 6 months preceding study entry. Similarly, the use of aspirin, an anticoagulant, cimetidine, erythromycin, or a phenothiazine was not allowed within 7 days prior to enrollment and their concomitant use with study drug during patients’ participation in the study was discouraged. 2.2. Study drugs Eligible patients were randomly assigned in a 1:1 ratio to receive the original divalproex tablet (Epival† , Abbott Canada, equivalent to valproic acid 250 or 500 mg [trademarked as Depakote† in the United States]) twice or three times daily or divalproex extended-release tablets (Epival† ER, Abbott Canada, equivalent to valproic acid 500 mg [trademarked as Depakote† ER in the United States]) once daily for 84 days. Afterwards, the patients were immediately crossed over to take the comparative formulation (i.e. those originally taking divalproex tablets then took extendedrelease tablets and vice versa) for 84 days. During the two treatment periods, all patients received the same daily dose equivalent of valproic acid as they had taken during the month prior to study entry. 2.3. Clinical evaluation and outcome measures The clinical status of patients was evaluated at five office visits conducted throughout the study: at a screening visit (Visit 1, within 5 days prior to treatment start on day 0), at the middle and end of the first treatment period (day 429/5 [Visit 2] and day 849/5 [Visit 3]), and at the middle and end of the second treatment period (day 1269/5 [Visit 4] and day 1689/5 [Visit 5]). A neurological examination was conducted and a seizure history was taken at each study visit. A physical examination (i.e. review of site/systems, weight, and vital signs) was conducted at the first, third, and last visits. Compliance was assessed by tablet count at Visits 2 /5. Throughout their participation in the study, patients were asked to record information on seizures, adverse events, and usage of medications
245
other than study drug in a diary, which the investigators reviewed at each study visit. Efficacy was assessed by several endpoints, including seizure count, seizure control, triggering factors of seizures, and accompanying symptoms. Seizure count was the total number of seizures, regardless of seizure type, suffered by patients during each treatment period. Seizure control rate was the percentage of patients who were totally seizure-free throughout a treatment period. 2.4. Safety assessment All study patients who received at least one dose of study medication and had at least one postbaseline safety evaluation were included in the safety analysis. Patients were closely monitored for clinical adverse events as well as clinically significant changes from baseline in laboratory indices, physical and neurological examination findings, and vital signs. Adverse events were recorded using the COSTART V dictionary. The severity of clinical adverse events was categorized by the investigators as mild, moderate, or severe. The investigators also classified the relationship of adverse events to study drug as either probable, possible, probably not, or not related. Blood samples were collected from patients at the screening visit and at the end of each treatment period to measure selected hematology and clinical chemistry values as well as total plasma valproate levels. 2.5. Data analysis Sample size was determined based on the ability to detect a relevant change in the seizure rate (defined as the number of seizures per patient during the 12-week treatment period) between the two study drug formulations. A sample size of at least 43 evaluable patients would enable a 37.5% difference in seizure rates between the formulations to be detected with 80% power, using a twosided test of significance at the 0.05 level. Efficacy was evaluated in an intent-to-treat patient population. All randomized patients who received at least one dose of study drug and had at least one post-baseline efficacy evaluation within each treatment period were included in the intent-
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to-treat population. Statistical analysis of seizure control rate was performed using the McNemar test in which the data were dichotomized into absence or presence of seizures with each formulation. Compliance (based on pill counts) with the formulations was compared by paired t-test and the Wilcoxon test. McNemar’s test was used to compare the formulations with regard to incidence of treatment-related (probably-or possibly-related) adverse events. Adverse events with onset within the particular formulation period were counted. Vital sign and laboratory values (including valproate levels) were compared between the formulations using Student’s paired t -test, the Wilcoxon test, and analysis of variance (ANOVA).
3. Results A total of 44 patients were enrolled and randomized, and 43 completed the study. One patient attended a screening visit and took study drug (divalproex tablets) for 6 weeks, but never returned for any further study visits. The study population was exclusively Caucasian and had a fairly equal distribution by gender (57% male); the mean (S.D.) age was 35.8 (9/9.7) years. With the exception of seizures, the medical history of the randomized patients was unremarkable. As required by the protocol, all patients enrolled in this study, which began in 1998, were diagnosed with primary generalized epilepsy.The majority of enrolled patients (68%) had epilepsy between 11 and 30 years; 18 and 14%, had up to 10 years and over 30 years, respectively. EEG confirmed the diagnosis in the majority of patients (27, 61%). Over half of the randomized patients reported a family history of epilepsy (24, 56%) and idiopathic causes for their epilepsy (25, 57%). Less commonly reported etiologies (5/5% of patients) were anteor peri-natal injury, trauma, infection, alcohol abuse, congenital abnormality, and febrile seizures as an infant. The majority of randomized patients (41, 93%) had experienced tonic /clonic seizures (Table 1). The next most commonly reported seizure types experienced by the randomized patients was absence with impairment of con-
sciousness only (17, 39%), and myoclonic seizures (16, 36%). Four patients (9%) had experienced seizures of any type in the year prior to their enrollment in this study. All patients were taking divalproex as the only antiepileptic medication for at least 1 month prior to study enrollment. The majority were taking 500 mg twice daily (28, 64%). Others took 500 mg t.i.d. (8, 18%) or 250 mg (2, 5% [in violation of the protocol]), 750 mg (3, 7%), or 1000 mg (3, 7%) twice daily. During their participation in the study, patients were generally compliant with the prescribed study drug regimens. There was no statistically significant difference between the study drug formulations in the compliance percentage based on pill counts (96.4% for divalproex and 97.7% for extended-release divalproex). Mean plasma valproate levels were significantly higher while patients were taking divalproex tablets (769/38 vs. 679/26 mg/ml with extended-release divalproex tablets, P /0.0464). Blood levels were taken to determine patient compliance. There was no control for the time blood samples were collected in relation to the time the study drug was taken, therefore, the valproate blood levels were not necessarily trough levels. Thirty-nine of the 43 patients who completed the study (91%) were seizure-free throughout their participation in the study, and four patients (9%) had at least one seizure (Table 2). This reflects the estimated general seizure control rate during the year before the start of the study, when 40/44 (90.9%) patients reported being seizure free. There was no statistically significant difference between formulation groups for seizure control rate (95% Table 1 Distribution of seizures from seizure history for the 44 randomized patients Seizure type Tonic /clonic Absence with Myoclonic Absence with Tonic Absence with Absence with
impairment of consciousness only atonic components clonic components automatisms
n
%
41 17 16 5 3 2 1
93.2 38.6 36.4 11.4 6.8 4.5 2.3
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Table 2 Seizure control rate by formulation group in the intent-to-treat population Extended-release tablets
No seizures Seizures Total original tablets
Original tablets
Total extended-release tablets
No seizures
Seizures
39 2 41 (95.3%)
1 1 2 (4.7%)
40 (93.0%) 3 (7.0%) 43 (100%)
P /0.5637 (McNemar test).
[41/43] for divalproex tablets and 93% [40/43] for extended-release divalproex tablets). Two of the four patients who had suffered seizures in the year prior to enrollment in the study also had seizure(s) during the study (#140 experienced an estimated ten absences with impairment of consciousness only in the year prior to the study and an estimated four seizures of this type during the study and #103 had one seizure) (Table 3). The other two patients who experienced a seizure during the study (#120 and #130) had been seizure-free during the previous year. Three patients who had suffered seizures in the previous year to the study were seizure free throughout the study. One patient (#103 [absence with impairment of consciousness only]) experienced seizures only while receiving divalproex and two patients (#120 [tonic /clonic] and #140 [absence with impairment of consciousness only]) experienced seizures only while receiving extended-release divalproex. The fourth patient (#130) reported three episodes of tonic /clonic seizures, one during treatment with divalproex and two during treatment with extended-release divalproex. The patient had juvenile-onset diabetes and hypothyroidism, and at least two of the seizures (one with each formulation) occurred simultaneously with hypoglycemic periods (one with hypoglycemic coma). There was no statistically significant difference between the formulation groups in incidence of treatment-related adverse events (18 and 27% for divalproex and extended-release divalproex, respectively). The majority of treatment-related adverse events with each formulation were classified as mild in severity (]/67% of reported events),
and none were classified as severe. Across the formulation groups, the most frequently reported treatment-related adverse events were asthenia, tremor, nausea, and dizziness. No statistically significant differences between the formulations were observed for mean vital sign or laboratory values. Likewise, no clinically significant changes from baseline were observed at any evaluation time point for physical or neurological examination findings.
4. Discussion This is the first study conducted to evaluate the efficacy and safety of extended-release divalproex in patients with generalized seizures who were previously controlled with the original divalproex tablet formulation. The results of this randomized, crossover study show the extended-release and original tablet formulations of divalproex are similar to one another based not only on control of generalized seizures but also on safety. The seizure control rate was high and did not differ significantly between the two formulations (95% for patients when they were taking divalproex tablets and 93% when they were taking extendedrelease divalproex). These seizure control rates were consistent with the patients’ reported general seizure control rate over the year prior to their enrollment in the study (91%). A triggering factor was identified for most of the seizures reported in the study. Both formulations were well tolerated, with no subject requiring premature discontinuation from the study due to a treatment-related adverse event. The formulations were similar based on low incidences of treatment-related
248
Patient number
Period
103 120 130
ER [/TAB TAB[/ER TAB[/ER
140
TAB[/ER
Number of seizures in past year
Number of seizures during study 1 0 0
10 (estimated)
Study period when seizures occurred
Time of occurrence (between visits)
VPA level at final visit of period (mg/ml)a
Type of seizure
Triggering factor
1 1 1
TAB ER TAB
V3 /V4 V3 /V4 V2 /V3
71 188 60
AIC Tonic /clonic Tonic /clonic
1
ER
V3 /V4
111
Tonic /clonic
1 4 (estimated)
ER ER
V4 /V5 V4 /V5
111 74
Tonic /clonic AIC
Working on computer None Coma secondary to hypoglycemia Hypoglycemia and overworking None Menstruation and possibly 1 missed dose
VPA, valproic acid; TAB, original divalproex tablets; ER, extended-release; V, visit; AIC, absence with impairment of consciousness only. a The time of blood sample collection was not temporally associated with the occurrence of seizure.
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Table 3 Summary of patients who experienced seizures during the study
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adverse events, and no clinically significant changes from baseline were observed in physical or neurological examination findings. We recognize the potential limitations of our study. The small sample size and very few seizures reported for either formulation precluded analyses of treatment differences based on seizure rate. It should be acknowledged that a population with this degree of seizure control may not have difficulty switching to a new formulation. It is also possible that some patients were in remission and may no longer have required an antiepileptic drug. This population may not have all had primary generalized epilepsy. Although most reported a family history of idiopathic etiologies, some (5/5%) had etiologies suggestive of localization-related epilepsy such as trauma. This group was, however, small and unlikely to change the findings of this study. Furthermore, there was no control for the time blood samples were collected in relation to the time study drug was taken, therefore, the valproate blood levels measured were not necessarily trough. However, the significant difference found between the formulations suggests divalproex extended-release tablet is not bioequivalent to the original divalproex tablet. Valproic acid plasma levels should be used to guide dosing for patients being started on extended-release divalproex. The goal for dosing is a plasma concentration of 50 /100 mg/ml of total valproate (Depakote† Product Information, 2000). The probability of seizure control is maximized when plasma concentrations are maintained within this therapeutic range, although seizure control is occasionally achieved with plasma concentrations outside the range. For those being switched from the original tablet to extended-release tablet formulation, valproate plasma levels should be monitored and, if necessary, dosage adjustments made accordingly. Based on the results of a recently conducted bioequivalence study, the extended-release formulation may require doses of 8 /20% higher than the original divalproex tablet to attain similar blood levels (Dutta et al., 2002). In summary, divalproex extended-release was found to produce control of
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seizures and tolerability similar to that of divalproex in patients with largely well-controlled primary, generalized epilepsy.
Acknowledgements This study was supported by a grant from Abbott Canada, St. Laurent, Que´bec.
References Beydoun, A., Sackellares, J.C., Shu, V., 1997. Safety and efficacy of divalproex sodium monotherapy in partial epilepsy: a double-blind, concentration-response design clinical trial. Depakote monotherapy for partial seizures study group. Neurology 48, 182 /188. Collins, S.D., Cavanaugh, J., Elisseou, M., Lamm, J., Sommerville, K.W., 1998. Depakote CR: biopharmaceutical and pharmacokinetic studies of a new formulation for once daily dosing. Neurology 50 (Suppl. 4), A426. Coulter, D.L., Allen, R.J., 1981. Hyperammonemia associated with valproic acid therapy. Ann. Neurol. 10, 307. Davis, R., Peters, D.H., McTavish, D., 1994. Valproic acid: a reappraisal of its pharmacological properties and clinical efficacy in epilepsy. Drugs 47, 332 /372. Depakote† [Package insert]. North Chicago, IL, 2000. Dutta, S., Zhang, Y., Selness, D.S., Lee, L.L., Williams, L.A., Sommerville, K.W., 2002. Comparison of the bioavailability of unequal doses of divalproex sodium extended-release formulation relative to the delayed-release formulation in healthy volunteers. Epilepsy Res. 49, 1 /10. Foster, R.H., Plosker, G.L., 2000. Glipizide. A review of the pharmacoeconomic implications of the extended-release formulation in type 2 diabetes mellitus. Pharmacoeconomics 18, 289 /306. Halpern, M.T., Irwin, D.E., Brown, R.E., Clouse, J., Hatziandreu, E.J., 1993. Patient adherence to prescribed potassium supplement therapy. Clin. Therap. 15, 1133 /1145. McEvoy, G.K., Litvak, K., Welsh, O.H. (Eds.), AHFS Drug Information. American Society of Health Systems Pharmacists, Bethesda, MD 1990, pp. 1147 /1149. Mulleners, W.M., Whitmarsh, T.E., Steiner, T.J., 1998. Noncompliance may render migraine prophylaxis useless but once-daily regimens are better. Cephalalgia 18, 52 /56. Prisant, L.M., Bottini, B., DiPiro, J.T., Carr, A.A., 1992. Novel drug delivery systems for hypertension. Am. J. Med. 31 (suppl. 2A), 45S /55. Pugh, C.B., Garnett, W.R., 1991. Current issues in the treatment of epilepsy. Clin. Pharm. 10, 355 /358.
Divalproex extended-release versus the original divalproex tablet: results of a randomized, crossover study of wellcontrolled epileptic patients with primary generalized seizures Manon Thibault a,*, Warren T. Blume b, Jean-Marc Saint-Hilaire c, Rafik Zakhari d, Kenneth W. Sommerville e a
Centre Hospitalier Affilie´ Enfant Je´sus, 1401 18th Street, Quebec, Quebec, Canada G1J 1Z4 b London Health Sciences Centre, London, Ont., Canada c CHUM, Campus Notre-Dame, Montreal, Quebec, Canada d Abbott Canada, St. Laurent, Quebec, Canada e Abbott Laboratories, Abbott Park, IL, USA
Received 10 September 2001; received in revised form 21 February 2002; accepted 28 February 2002
Abstract Purpose: To compare the safety and efficacy of two formulations of divalproex, extended-release divalproex versus the original divalproex tablet, in adolescent and adult patients with epilepsy. Methods: Eligible patients were between the ages of 12 and 65 years with primary generalized epilepsy, which was controlled over the month prior to study enrollment with divalproex or valproic acid 1000 mg to 2000 mg/day. The patients were well-controlled; 39 of 43 (91%) had no seizures in the previous year. Patients were randomized to receive 84 days of either divalproex two times a day (b.i.d.)/three times a day (t.i.d.) or extended-release divalproex qd and then (crossed over to) 84 days of the comparator formulation. During the two treatment periods, patients received the same daily dose equivalent of divalproex as was taken during the month prior to study entry. The clinical status of patients was evaluated at a screening visit and at four subsequent visits conducted every 42 days. Results: There was no statistically significant difference between the formulation groups for seizure control rate (95% [41/43] for divalproex and 93% [40/43] for extended-release divalproex). Likewise, the formulation groups were similar based on the incidence of treatment-related adverse events. The most frequently reported ( 5/11.4% for either formulation) treatment-related adverse events were asthenia, tremor, nausea, and dizziness. Conclusions: Extended-release divalproex was similar to divalproex for the treatment of wellcontrolled, primary generalized epilepsy in terms of overall safety and efficacy parameters. # 2002 Elsevier Science B.V. All rights reserved. Keywords: Divalproex; Extended-release; Epilepsy; Generalized seizures
These data were presented as a poster at the following meeting: Focus on epilepsy VI, treatment of epileptic syndromes: from molecular targets to quality of life, 7 /10 July 2001, Mont-Tremblant, QC, Canada. * Corresponding author. Tel.: /1-418-649-0252; fax: /1-418-649-5915
0920-1211/02/$ - see front matter # 2002 Elsevier Science B.V. All rights reserved. PII: S 0 9 2 0 - 1 2 1 1 ( 0 2 ) 0 0 0 4 8 - 7
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1. Introduction Divalproex sodium, a compound containing an equal proportion (on a molar basis) of sodium valproate and valproic acid, dissociates to the valproate ion in the gastrointestinal tract. Divalproex sodium is available in several formulations, including the original tablet (enteric-coated, delayed-release tablet), sprinkle capsule, and a recently approved, extended-release tablet. The original (hereafter called divalproex) tablet formulation of divalproex is indicated for use worldwide, either alone or an adjunct to other agents, in the treatment of a variety of seizure disorders (Beydoun et al., 1997; Davis et al., 1994). Divalproex is also indicated in the United States for acute mania associated with bipolar disorder and for prophylaxis of migraine headaches and it has become widely used to treat behavioral disturbances associated with dementia. The new extended-release divalproex formulation was recently approved in the United States for migraine headache prophylaxis. Divalproex requires administration on a twotimes a day (b.i.d.) to three-times a day (t.i.d) basis. Decreasing the frequency of daily drug administration, as can be achieved with extended-release formulations, increases compliance and can improve outcomes. (Foster and Plosker, 2000; Mulleners et al., 1998; Halpern et al., 1993; Prisant et al., 1992). Since some of the adverse events associated with valproic acid and divalproex have been reported to be concentrationdependent (e.g. thrombocytopenia, increase in liver function tests, tremors, somnolence) (McEvoy et al., 1990; Pugh and Garnett, 1991; Coulter and Allen, 1981), the new extended-release formulation would have the added advantage of decreasing peak plasma concentrations, thereby potentially minimizing the occurrence of concentration-dependent adverse events and sub-therapeutic concentrations. The pharmacokinetic profile of the extendedrelease divalproex formulation was compared with the original tablet formulation in three crossover studies (Collins et al., 1998; data on file, Abbott Laboratories). Bioequivalence between the formulations was established in two of these studies, but
was not confirmed in the third study. Although bioequivalence may suggest interchangeability of different formulations, clinical equivalence may only be established in clinical trials. This was a randomized, multicenter, open-label, two-period, crossover study of adolescent and adult epilepsy patients with generalized seizures. The objective of the clinical trial was to compare the seizure control rate obtained by the two formulations of divalproex, the new extendedrelease tablet and the original enteric-coated tablet in adolescent and adult patients diagnosed with primary generalized epilepsy.
2. Patients and methods The protocol was approved by the institutional review board of each participating study site. Written informed consent was obtained from each patient or parent/legal guardian of minor patients before enrollment into the study. 2.1. Patients Outpatients between the ages of 12 and 65 years with primary generalized epilepsy*/either convulsive, non-convulsive, or both */and treated for at least 6 months with divalproex or valproic acid were eligible for enrollment. Patients must have been controlled over the month prior to study enrollment with a stable dose of divalproex or valproic acid (1000 /2000 mg/day taken in two or three divided doses). According to an inclusion criterion for the study eligible patients had controlled generalized epilepsy, which was defined as less than six major convulsive seizures per year. Patients with absence who had received optimal treatment to control their seizures were appropriate candidates for the study, even if they had experienced regular non-convulsive seizures. Excluded from the study were patients with a history of hypersensitivity to divalproex or valproic acid and pregnant or lactating females. Patients with hepatic or renal impairment, with a medical or neurological disorder other than epilepsy, requiring frequent changes in medication, or with a coagulation disorder and/or platelet count
M. Thibault et al. / Epilepsy Research 50 (2002) 243 /249
of B/100 /109 per l were also excluded. The use of other antiepileptic medication (other than divalproex or valproic acid) was not allowed during the 6 months preceding study entry. Similarly, the use of aspirin, an anticoagulant, cimetidine, erythromycin, or a phenothiazine was not allowed within 7 days prior to enrollment and their concomitant use with study drug during patients’ participation in the study was discouraged. 2.2. Study drugs Eligible patients were randomly assigned in a 1:1 ratio to receive the original divalproex tablet (Epival† , Abbott Canada, equivalent to valproic acid 250 or 500 mg [trademarked as Depakote† in the United States]) twice or three times daily or divalproex extended-release tablets (Epival† ER, Abbott Canada, equivalent to valproic acid 500 mg [trademarked as Depakote† ER in the United States]) once daily for 84 days. Afterwards, the patients were immediately crossed over to take the comparative formulation (i.e. those originally taking divalproex tablets then took extendedrelease tablets and vice versa) for 84 days. During the two treatment periods, all patients received the same daily dose equivalent of valproic acid as they had taken during the month prior to study entry. 2.3. Clinical evaluation and outcome measures The clinical status of patients was evaluated at five office visits conducted throughout the study: at a screening visit (Visit 1, within 5 days prior to treatment start on day 0), at the middle and end of the first treatment period (day 429/5 [Visit 2] and day 849/5 [Visit 3]), and at the middle and end of the second treatment period (day 1269/5 [Visit 4] and day 1689/5 [Visit 5]). A neurological examination was conducted and a seizure history was taken at each study visit. A physical examination (i.e. review of site/systems, weight, and vital signs) was conducted at the first, third, and last visits. Compliance was assessed by tablet count at Visits 2 /5. Throughout their participation in the study, patients were asked to record information on seizures, adverse events, and usage of medications
245
other than study drug in a diary, which the investigators reviewed at each study visit. Efficacy was assessed by several endpoints, including seizure count, seizure control, triggering factors of seizures, and accompanying symptoms. Seizure count was the total number of seizures, regardless of seizure type, suffered by patients during each treatment period. Seizure control rate was the percentage of patients who were totally seizure-free throughout a treatment period. 2.4. Safety assessment All study patients who received at least one dose of study medication and had at least one postbaseline safety evaluation were included in the safety analysis. Patients were closely monitored for clinical adverse events as well as clinically significant changes from baseline in laboratory indices, physical and neurological examination findings, and vital signs. Adverse events were recorded using the COSTART V dictionary. The severity of clinical adverse events was categorized by the investigators as mild, moderate, or severe. The investigators also classified the relationship of adverse events to study drug as either probable, possible, probably not, or not related. Blood samples were collected from patients at the screening visit and at the end of each treatment period to measure selected hematology and clinical chemistry values as well as total plasma valproate levels. 2.5. Data analysis Sample size was determined based on the ability to detect a relevant change in the seizure rate (defined as the number of seizures per patient during the 12-week treatment period) between the two study drug formulations. A sample size of at least 43 evaluable patients would enable a 37.5% difference in seizure rates between the formulations to be detected with 80% power, using a twosided test of significance at the 0.05 level. Efficacy was evaluated in an intent-to-treat patient population. All randomized patients who received at least one dose of study drug and had at least one post-baseline efficacy evaluation within each treatment period were included in the intent-
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M. Thibault et al. / Epilepsy Research 50 (2002) 243 /249
to-treat population. Statistical analysis of seizure control rate was performed using the McNemar test in which the data were dichotomized into absence or presence of seizures with each formulation. Compliance (based on pill counts) with the formulations was compared by paired t-test and the Wilcoxon test. McNemar’s test was used to compare the formulations with regard to incidence of treatment-related (probably-or possibly-related) adverse events. Adverse events with onset within the particular formulation period were counted. Vital sign and laboratory values (including valproate levels) were compared between the formulations using Student’s paired t -test, the Wilcoxon test, and analysis of variance (ANOVA).
3. Results A total of 44 patients were enrolled and randomized, and 43 completed the study. One patient attended a screening visit and took study drug (divalproex tablets) for 6 weeks, but never returned for any further study visits. The study population was exclusively Caucasian and had a fairly equal distribution by gender (57% male); the mean (S.D.) age was 35.8 (9/9.7) years. With the exception of seizures, the medical history of the randomized patients was unremarkable. As required by the protocol, all patients enrolled in this study, which began in 1998, were diagnosed with primary generalized epilepsy.The majority of enrolled patients (68%) had epilepsy between 11 and 30 years; 18 and 14%, had up to 10 years and over 30 years, respectively. EEG confirmed the diagnosis in the majority of patients (27, 61%). Over half of the randomized patients reported a family history of epilepsy (24, 56%) and idiopathic causes for their epilepsy (25, 57%). Less commonly reported etiologies (5/5% of patients) were anteor peri-natal injury, trauma, infection, alcohol abuse, congenital abnormality, and febrile seizures as an infant. The majority of randomized patients (41, 93%) had experienced tonic /clonic seizures (Table 1). The next most commonly reported seizure types experienced by the randomized patients was absence with impairment of con-
sciousness only (17, 39%), and myoclonic seizures (16, 36%). Four patients (9%) had experienced seizures of any type in the year prior to their enrollment in this study. All patients were taking divalproex as the only antiepileptic medication for at least 1 month prior to study enrollment. The majority were taking 500 mg twice daily (28, 64%). Others took 500 mg t.i.d. (8, 18%) or 250 mg (2, 5% [in violation of the protocol]), 750 mg (3, 7%), or 1000 mg (3, 7%) twice daily. During their participation in the study, patients were generally compliant with the prescribed study drug regimens. There was no statistically significant difference between the study drug formulations in the compliance percentage based on pill counts (96.4% for divalproex and 97.7% for extended-release divalproex). Mean plasma valproate levels were significantly higher while patients were taking divalproex tablets (769/38 vs. 679/26 mg/ml with extended-release divalproex tablets, P /0.0464). Blood levels were taken to determine patient compliance. There was no control for the time blood samples were collected in relation to the time the study drug was taken, therefore, the valproate blood levels were not necessarily trough levels. Thirty-nine of the 43 patients who completed the study (91%) were seizure-free throughout their participation in the study, and four patients (9%) had at least one seizure (Table 2). This reflects the estimated general seizure control rate during the year before the start of the study, when 40/44 (90.9%) patients reported being seizure free. There was no statistically significant difference between formulation groups for seizure control rate (95% Table 1 Distribution of seizures from seizure history for the 44 randomized patients Seizure type Tonic /clonic Absence with Myoclonic Absence with Tonic Absence with Absence with
impairment of consciousness only atonic components clonic components automatisms
n
%
41 17 16 5 3 2 1
93.2 38.6 36.4 11.4 6.8 4.5 2.3
M. Thibault et al. / Epilepsy Research 50 (2002) 243 /249
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Table 2 Seizure control rate by formulation group in the intent-to-treat population Extended-release tablets
No seizures Seizures Total original tablets
Original tablets
Total extended-release tablets
No seizures
Seizures
39 2 41 (95.3%)
1 1 2 (4.7%)
40 (93.0%) 3 (7.0%) 43 (100%)
P /0.5637 (McNemar test).
[41/43] for divalproex tablets and 93% [40/43] for extended-release divalproex tablets). Two of the four patients who had suffered seizures in the year prior to enrollment in the study also had seizure(s) during the study (#140 experienced an estimated ten absences with impairment of consciousness only in the year prior to the study and an estimated four seizures of this type during the study and #103 had one seizure) (Table 3). The other two patients who experienced a seizure during the study (#120 and #130) had been seizure-free during the previous year. Three patients who had suffered seizures in the previous year to the study were seizure free throughout the study. One patient (#103 [absence with impairment of consciousness only]) experienced seizures only while receiving divalproex and two patients (#120 [tonic /clonic] and #140 [absence with impairment of consciousness only]) experienced seizures only while receiving extended-release divalproex. The fourth patient (#130) reported three episodes of tonic /clonic seizures, one during treatment with divalproex and two during treatment with extended-release divalproex. The patient had juvenile-onset diabetes and hypothyroidism, and at least two of the seizures (one with each formulation) occurred simultaneously with hypoglycemic periods (one with hypoglycemic coma). There was no statistically significant difference between the formulation groups in incidence of treatment-related adverse events (18 and 27% for divalproex and extended-release divalproex, respectively). The majority of treatment-related adverse events with each formulation were classified as mild in severity (]/67% of reported events),
and none were classified as severe. Across the formulation groups, the most frequently reported treatment-related adverse events were asthenia, tremor, nausea, and dizziness. No statistically significant differences between the formulations were observed for mean vital sign or laboratory values. Likewise, no clinically significant changes from baseline were observed at any evaluation time point for physical or neurological examination findings.
4. Discussion This is the first study conducted to evaluate the efficacy and safety of extended-release divalproex in patients with generalized seizures who were previously controlled with the original divalproex tablet formulation. The results of this randomized, crossover study show the extended-release and original tablet formulations of divalproex are similar to one another based not only on control of generalized seizures but also on safety. The seizure control rate was high and did not differ significantly between the two formulations (95% for patients when they were taking divalproex tablets and 93% when they were taking extendedrelease divalproex). These seizure control rates were consistent with the patients’ reported general seizure control rate over the year prior to their enrollment in the study (91%). A triggering factor was identified for most of the seizures reported in the study. Both formulations were well tolerated, with no subject requiring premature discontinuation from the study due to a treatment-related adverse event. The formulations were similar based on low incidences of treatment-related
248
Patient number
Period
103 120 130
ER [/TAB TAB[/ER TAB[/ER
140
TAB[/ER
Number of seizures in past year
Number of seizures during study 1 0 0
10 (estimated)
Study period when seizures occurred
Time of occurrence (between visits)
VPA level at final visit of period (mg/ml)a
Type of seizure
Triggering factor
1 1 1
TAB ER TAB
V3 /V4 V3 /V4 V2 /V3
71 188 60
AIC Tonic /clonic Tonic /clonic
1
ER
V3 /V4
111
Tonic /clonic
1 4 (estimated)
ER ER
V4 /V5 V4 /V5
111 74
Tonic /clonic AIC
Working on computer None Coma secondary to hypoglycemia Hypoglycemia and overworking None Menstruation and possibly 1 missed dose
VPA, valproic acid; TAB, original divalproex tablets; ER, extended-release; V, visit; AIC, absence with impairment of consciousness only. a The time of blood sample collection was not temporally associated with the occurrence of seizure.
M. Thibault et al. / Epilepsy Research 50 (2002) 243 /249
Table 3 Summary of patients who experienced seizures during the study
M. Thibault et al. / Epilepsy Research 50 (2002) 243 /249
adverse events, and no clinically significant changes from baseline were observed in physical or neurological examination findings. We recognize the potential limitations of our study. The small sample size and very few seizures reported for either formulation precluded analyses of treatment differences based on seizure rate. It should be acknowledged that a population with this degree of seizure control may not have difficulty switching to a new formulation. It is also possible that some patients were in remission and may no longer have required an antiepileptic drug. This population may not have all had primary generalized epilepsy. Although most reported a family history of idiopathic etiologies, some (5/5%) had etiologies suggestive of localization-related epilepsy such as trauma. This group was, however, small and unlikely to change the findings of this study. Furthermore, there was no control for the time blood samples were collected in relation to the time study drug was taken, therefore, the valproate blood levels measured were not necessarily trough. However, the significant difference found between the formulations suggests divalproex extended-release tablet is not bioequivalent to the original divalproex tablet. Valproic acid plasma levels should be used to guide dosing for patients being started on extended-release divalproex. The goal for dosing is a plasma concentration of 50 /100 mg/ml of total valproate (Depakote† Product Information, 2000). The probability of seizure control is maximized when plasma concentrations are maintained within this therapeutic range, although seizure control is occasionally achieved with plasma concentrations outside the range. For those being switched from the original tablet to extended-release tablet formulation, valproate plasma levels should be monitored and, if necessary, dosage adjustments made accordingly. Based on the results of a recently conducted bioequivalence study, the extended-release formulation may require doses of 8 /20% higher than the original divalproex tablet to attain similar blood levels (Dutta et al., 2002). In summary, divalproex extended-release was found to produce control of
249
seizures and tolerability similar to that of divalproex in patients with largely well-controlled primary, generalized epilepsy.
Acknowledgements This study was supported by a grant from Abbott Canada, St. Laurent, Que´bec.
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