Ignite Creation Date:
2024-05-05 @ 4:57 PM
Last Modification Date:
2024-10-26 @ 9:26 AM
Study NCT ID:
NCT00356018
Status:
COMPLETED
Last Update Posted:
2020-03-04
First Post:
2006-07-21
Brief Title:
Compliance With Once-Daily Divalproex Extended-Release Tablets Depakote-ER Versus Multiple-Daily Dose Valproic Acid Capsules Depakene in Epilepsy
Sponsor:
Orlando Health Inc
Organization:
Orlando Health Inc
Study Overview
Official Title:
Compliance With Once-Daily Divalproex Extended-Release Tablets Depakote-ER Versus Multiple-Daily Dose Valproic Acid Capsules Depakene in Epilepsy A Randomized Parallel Prospectively-Controlled Outpatient Comparison
Status:
COMPLETED
Status Verified Date:
2020-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
To determine in a randomized parallel open-label fashion compliance rates between once-daily extended-release divalproex sodium tablets Depakote-ER Abbott Labs versus multiple-daily dose valproic acid capsules Depakene Abbott Labs in an epilepsy population
Detailed Description:
x_ Prospective x__ Single-center __ Multicenter x__ Open-label __ Double-blind __ Single-blind x_ Randomized please provide randomization ratio 11 This population includes both patients whose seizures are relatively well- controlled on their present conventional enteric-coated twice-daily or three-times daily Divalproex sodium Depakote DR regimen Patients on DR monotherapy are preferred but not required Partial onset seizures and primarily generalized seizures will both be represented in this study Patients will be randomized in 11 fashion
Group 1 10 patients will be randomized to IR-VPA to be taken 3 to 4 times a day in a total daily dose equivalent to DR The dosing regimen will likely be taken at meal times for those receiving IR-VPA tid not q 8 h and additionally at bedtime for those on a QID not q 6 h regimen The choice of TID vs QID regimen will be dictated by the patients total daily dose requirements with the attempt to keep the number of 250 mg capsules identical for each dose throughout the day
Group 2 10 patients will be randomized to ER to be taken once-daily in the AM or PM at the investigators discretion and patients choice since dosing ER in the AM or PM does not substantially differ as to plasma VPA concentrations 17 Once AM or PM once-daily ER dosing is chosen for a patient it will not be changed ER once-daily dosing will incorporate the recommended dose-proportional increase of 8-20 in total daily dose over that of DR for patients with epilepsy 18 However only one tablet strength 500 mg ER will be utilized so total daily dose will be rounded to the nearest 500 mg increment
A total of 20 patients should provide sufficient power 80 to adequately detect a statistically p 005 and clinically meaningful change in compliance rate between the groups if one exists
Compliance and precision will both be measure in this short-term study Compliance defined as the number of times the multiple-daily IR-VPA dose or ER dose was actually taken vs that prescribed daily will be tallied with a computer-chip recording device MEMS unit 13 and via the patients daily diary calendar Precision defined as the actual time the daily dose for ER was actually taken or multiple-daily doses for IR-VPA were actually taken compared to the prescribed times 15 min as documented by the MEMS unit
------------------------------------------------------------------------------
It will take 3 months to recruit 20 patients according to our protocol The total protocol can last from 49 to 70 days There will be up to a 21-day screening period per patient followed by a 7-day period for the patient to practice the MEMS unit and gain familiarity and demonstrate competency with the device After randomization at Day 0 there will be 42 consecutive days of prospective evaluation
From the end of study the time to first abstract manuscript submitted 2 months x__Abstractmanuscript poster assistance is anticipated
Washout period NA Screening Period 0 to 21 days prior to baseline observation Baseline observation period 7 days prior to randomization This period allows the patient to practice with the MEMS unit gaining familiarity with it and demonstrating competency with the device
Treatment period The treatment period is forty-two 42 days after Randomization
A rapid immediate conversion from multiple-daily dosed DR to once-daily divalproex-ER has been recommended for adults with epilepsy since it is a simple maneuver to understand with a low predicted chance for side effects 19 Likewise patients randomized to the IR-VPA group will be immediately converted from DR to multiple-daily dose IR-VPA without tapering the DR or gradual titration upward of IR-VPA
Taper period NA
Age adults 16 and older Gender malefemale Disease under study Patients with a chronic yet relatively stable partial and or generalized seizure disorder will be included in this study
Twenty patients currently currently undergoing treatment with enteric-coated divalproex DR for whom the treating physician elects to change to once-daily divalproex-ER will be candidates for this study Ten patients will be assigned to each group randomly which should yield sufficient power to make a definite statement regarding the best conversion strategy to use in this patient population
XX__ Depakote Tablets for Lead-in XX__ Depakote ER
No Drug Required __ Depakote Sprinkle
Depacon XX_Depakene Capsules Lead-in Patients with epilepsy who are already being treated with conventional enteric-coated delayed-release Depakote DR Patients on DR monotherapy are preferred but patients may be taking additional AEDs
ACTIVE Depakote-ER For those randomized to this group an 8-20 mg dose increase will be utilized in DR to ER conversion as recommended by the Divalproex-ER package insert Abbott and based upon published evidence for the need to compensate for the lesser bioavailability of ER Only 500 mg ER tablets will be used such that total daily dose will be rounded to the nearest 500 mg
ACTIVE COMPARATOR Depakene Capsules Depakene is a liquid-filled capsule containing 250 mg IR-VPA The same total daily dose of IR-VPA as DR will be utilized IR-VPA will be given TID not q 8 h or QID not q 6 h depending upon which regimen allows for an identical number of capsules to be given for each dose
Note Compliance and precision will only be recorded for either ER or IR-VPA not for other AEDS in those patients who happen to be taking concomitant AEDs
1 Patients age 16 and above currently taking Divalproex-DR for any seizure disorder 2 Other AEDs are permitted concurrently although compliance with these will not be recorded Other medications for co-morbid disease are permitted provided no plans for changes in medications used for the treatment of the concomitant disorder are expected
3 Patients must demonstrate a 75 or greater compliance rate with DR via calendar during the week of familiarity with the MEMs unit The threshold value of 75 has been chosen since research shows that people take approximately 75 of their AEDs as prescribed 1314 and the same numerical value is frequently used in determining whether or not to retain a patient in clinical Phase 2a-3b industry-sponsored study
1 patients with a recent history of status epilepticus
2 patients who have refractory or unstable epilepsy
3 patients with acute illnesses requiring changes in concurrent drugs
4 patients unwilling to change from their present DR regimen to divalproex-ER or IR-VPA
5 Patients unwilling or unable to utilize the MEMs monitoring unit
6 Pregnant or lactating women
IRB approval will be sought After the appropriate IRB approval written informed consent will be obtained for all patients participating
Patients in either Group will be instructed to take their ER or IR-VPA according to the PIs usual practice without different or special coaching or prompting techniques to enhance compliance throughout the study
Patients will be observed closely by physicians and allied health personnel on a weekly basis by actual visit to the study center Days 0 14 28 42 and via phone on Days 7 21 35 Blood work including CBC platelet counts LFTs serum chemistry panel and total valproate will be measured prior to and at the end of the study on Day 42 post-randomization
Criteria for premature discontinuation for safety reasons
1 Patients who pass screening but who do not demonstrate proficiency or competence with the MEMs monitoring unit for the 7-day period prior to randomization
2 Patients with a 50 increase in seizure frequency compared to their historic baseline or the development of seizures requiring hospitalization at any time during the study
3 Patients with a clinically significant increase in the number or severity of AEs as determined by the investigator
4 Patients with a MEMs if data is immediately accessible and available or calendar-documented compliance rate of 35 at any time during the study
5 Patients with a MEMs if data is immediately accessible and available or calendar-documented compliance rate between 35 and 75 on three separate occasions or two consecutive occasions during the study
Primary Measures
The primary efficacy parameter will be the difference in mean compliance rate defined as the does taken divided by the doses prescribed for the ER vs IR-VPA group at Day 42
Secondary Measures
1 The change in compliance rate from Day 0 to Day 42 will be compared for both groups 2 The precision of dose administration determined by the number of doses administered within 15 min of their assigned times will be compared for all dose times over the course of the study between the two groups 3 Drop out rates for both groups due to lack of seizure control adverse effects or noncompliance will be compared between groups
x_Statistical analysis assistance may be required
None foreseen Patients selected for this study will only be those who upon recommendations or orders from their physician will be switched from multiple-daily dose of divalproex-DR to the divalproex extended-release formulation administered once-daily or to IR-VPA
This project is considered research by virtue of the randomization of epilepsy patients to two different groups utilizing dosage formulations and regimens commonly encountered in clinical practice
Group 1 10 patients will be randomized to IR-VPA to be taken 3 to 4 times a day in a total daily dose equivalent to DR The dosing regimen will likely be taken at meal times for those receiving IR-VPA tid not q 8 h and additionally at bedtime for those on a QID not q 6 h regimen The choice of TID vs QID regimen will be dictated by the patients total daily dose requirements with the attempt to keep the number of 250 mg capsules identical for each dose throughout the day
Group 2 10 patients will be randomized to ER to be taken once-daily in the AM or PM at the investigators discretion and patients choice since dosing ER in the AM or PM does not substantially differ as to plasma VPA concentrations 17 Once AM or PM once-daily ER dosing is chosen for a patient it will not be changed ER once-daily dosing will incorporate the recommended dose-proportional increase of 8-20 in total daily dose over that of DR for patients with epilepsy 18 However only one tablet strength 500 mg ER will be utilized so total daily dose will be rounded to the nearest 500 mg increment
A total of 20 patients should provide sufficient power 80 to adequately detect a statistically p 005 and clinically meaningful change in compliance rate between the groups if one exists
Compliance and precision will both be measure in this short-term study Compliance defined as the number of times the multiple-daily IR-VPA dose or ER dose was actually taken vs that prescribed daily will be tallied with a computer-chip recording device MEMS unit 13 and via the patients daily diary calendar Precision defined as the actual time the daily dose for ER was actually taken or multiple-daily doses for IR-VPA were actually taken compared to the prescribed times 15 min as documented by the MEMS unit
------------------------------------------------------------------------------
It will take 3 months to recruit 20 patients according to our protocol The total protocol can last from 49 to 70 days There will be up to a 21-day screening period per patient followed by a 7-day period for the patient to practice the MEMS unit and gain familiarity and demonstrate competency with the device After randomization at Day 0 there will be 42 consecutive days of prospective evaluation
From the end of study the time to first abstract manuscript submitted 2 months x__Abstractmanuscript poster assistance is anticipated
Washout period NA Screening Period 0 to 21 days prior to baseline observation Baseline observation period 7 days prior to randomization This period allows the patient to practice with the MEMS unit gaining familiarity with it and demonstrating competency with the device
Treatment period The treatment period is forty-two 42 days after Randomization
A rapid immediate conversion from multiple-daily dosed DR to once-daily divalproex-ER has been recommended for adults with epilepsy since it is a simple maneuver to understand with a low predicted chance for side effects 19 Likewise patients randomized to the IR-VPA group will be immediately converted from DR to multiple-daily dose IR-VPA without tapering the DR or gradual titration upward of IR-VPA
Taper period NA
Age adults 16 and older Gender malefemale Disease under study Patients with a chronic yet relatively stable partial and or generalized seizure disorder will be included in this study
Twenty patients currently currently undergoing treatment with enteric-coated divalproex DR for whom the treating physician elects to change to once-daily divalproex-ER will be candidates for this study Ten patients will be assigned to each group randomly which should yield sufficient power to make a definite statement regarding the best conversion strategy to use in this patient population
XX__ Depakote Tablets for Lead-in XX__ Depakote ER
No Drug Required __ Depakote Sprinkle
Depacon XX_Depakene Capsules Lead-in Patients with epilepsy who are already being treated with conventional enteric-coated delayed-release Depakote DR Patients on DR monotherapy are preferred but patients may be taking additional AEDs
ACTIVE Depakote-ER For those randomized to this group an 8-20 mg dose increase will be utilized in DR to ER conversion as recommended by the Divalproex-ER package insert Abbott and based upon published evidence for the need to compensate for the lesser bioavailability of ER Only 500 mg ER tablets will be used such that total daily dose will be rounded to the nearest 500 mg
ACTIVE COMPARATOR Depakene Capsules Depakene is a liquid-filled capsule containing 250 mg IR-VPA The same total daily dose of IR-VPA as DR will be utilized IR-VPA will be given TID not q 8 h or QID not q 6 h depending upon which regimen allows for an identical number of capsules to be given for each dose
Note Compliance and precision will only be recorded for either ER or IR-VPA not for other AEDS in those patients who happen to be taking concomitant AEDs
1 Patients age 16 and above currently taking Divalproex-DR for any seizure disorder 2 Other AEDs are permitted concurrently although compliance with these will not be recorded Other medications for co-morbid disease are permitted provided no plans for changes in medications used for the treatment of the concomitant disorder are expected
3 Patients must demonstrate a 75 or greater compliance rate with DR via calendar during the week of familiarity with the MEMs unit The threshold value of 75 has been chosen since research shows that people take approximately 75 of their AEDs as prescribed 1314 and the same numerical value is frequently used in determining whether or not to retain a patient in clinical Phase 2a-3b industry-sponsored study
1 patients with a recent history of status epilepticus
2 patients who have refractory or unstable epilepsy
3 patients with acute illnesses requiring changes in concurrent drugs
4 patients unwilling to change from their present DR regimen to divalproex-ER or IR-VPA
5 Patients unwilling or unable to utilize the MEMs monitoring unit
6 Pregnant or lactating women
IRB approval will be sought After the appropriate IRB approval written informed consent will be obtained for all patients participating
Patients in either Group will be instructed to take their ER or IR-VPA according to the PIs usual practice without different or special coaching or prompting techniques to enhance compliance throughout the study
Patients will be observed closely by physicians and allied health personnel on a weekly basis by actual visit to the study center Days 0 14 28 42 and via phone on Days 7 21 35 Blood work including CBC platelet counts LFTs serum chemistry panel and total valproate will be measured prior to and at the end of the study on Day 42 post-randomization
Criteria for premature discontinuation for safety reasons
1 Patients who pass screening but who do not demonstrate proficiency or competence with the MEMs monitoring unit for the 7-day period prior to randomization
2 Patients with a 50 increase in seizure frequency compared to their historic baseline or the development of seizures requiring hospitalization at any time during the study
3 Patients with a clinically significant increase in the number or severity of AEs as determined by the investigator
4 Patients with a MEMs if data is immediately accessible and available or calendar-documented compliance rate of 35 at any time during the study
5 Patients with a MEMs if data is immediately accessible and available or calendar-documented compliance rate between 35 and 75 on three separate occasions or two consecutive occasions during the study
Primary Measures
The primary efficacy parameter will be the difference in mean compliance rate defined as the does taken divided by the doses prescribed for the ER vs IR-VPA group at Day 42
Secondary Measures
1 The change in compliance rate from Day 0 to Day 42 will be compared for both groups 2 The precision of dose administration determined by the number of doses administered within 15 min of their assigned times will be compared for all dose times over the course of the study between the two groups 3 Drop out rates for both groups due to lack of seizure control adverse effects or noncompliance will be compared between groups
x_Statistical analysis assistance may be required
None foreseen Patients selected for this study will only be those who upon recommendations or orders from their physician will be switched from multiple-daily dose of divalproex-DR to the divalproex extended-release formulation administered once-daily or to IR-VPA
This project is considered research by virtue of the randomization of epilepsy patients to two different groups utilizing dosage formulations and regimens commonly encountered in clinical practice
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None