A Study of the Efficacy and Safety of Pregabalin as Add-On Therapy for Partial Onset Seizures in Children Ages 4-16 Years (PERIWINKLE)

• ClinicalTrials.gov Identifier: NCT01389596
• Recruitment Status: Completed
• First Posted: July 8, 2011
• Results First Posted: March 21, 2017
• Last Update Posted: January 20, 2021
• Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
• Information provided by (Responsible Party): Pfizer ( Pfizer's Upjohn has merged with Mylan to form Viatris Inc. )

Tracking Information

• First Submitted Date: July 6, 2011
• First Posted Date: July 8, 2011
• Results First Submitted Date: January 31, 2017
• Results First Posted Date: March 21, 2017
• Last Update Posted Date: January 20, 2021
• Actual Study Start Date: September 27, 2011
• Actual Primary Completion Date: August 10, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 31, 2017)

• Log-Transformed 28-Day Seizure Rate For All Partial Onset Seizures During Baseline Phase [ Time Frame: Baseline phase (up to 8 weeks prior to treatment phase [Day 1]) ]
  All partial onset seizures experienced during baseline phase were recorded by the participants or their parents/legal guardian, in a daily seizure diary. 28-day seizure rate for all partial onset seizures = ([number of seizures in the baseline phase] divided by [number of days in baseline phase minus {-} number of missing diary days in baseline phase])*28. For log-transformation, the quantity 1 was added to the 28-day seizure rate for all participants to account for any possible "0" seizure incidence. This resulted in final calculation as: log transformed (28-day seizure rate +1).
• Log-Transformed 28-Day Seizure Rate For All Partial Onset Seizures During 12-Week Treatment Phase [ Time Frame: Day 1 up to Week 12 ]
  All partial onset seizures experienced during treatment phase were recorded by the participants or their parents/legal guardian in a daily seizure diary. 28-day seizure rate for all partial onset seizures = ([number of seizures in the treatment phase] divided by [number of days in treatment phase minus {-} number of missing diary days in treatment phase])*28. For log-transformation, the quantity 1 was added to the 28-day seizure rate for all participants to account for any possible "0" seizure incidence. This resulted in final calculation as: log transformed (28-day seizure rate +1).

• Original Primary Outcome Measures (submitted: July 6, 2011): Log transformed (loge) 28 day seizure rate for all partial onset seizures collected during the 12 week double-blind treatment phase, reported as "percent reduction in seizures" relative to placebo. [ Time Frame: 12 weeks ]

Current Secondary Outcome Measures (submitted: January 31, 2017)

Percentage of Participants With at Least 50 Percent (%) or Greater Reduction From Baseline in 28-day Seizure Rate During the 12 Week Treatment Phase [ Time Frame: Day 1 up to Week 12 ]

Percentage of participants with 50 percent (%) or greater reduction from baseline in 28-day seizure rate during the 12 week treatment phase were reported. 28-day seizure rate for all partial onset seizures = ([number of seizures in the treatment phase] divided by [number of days in treatment phase minus {-} number of missing diary days in treatment phase])*28.

• Original Secondary Outcome Measures (submitted: July 6, 2011): Responder Rate, defined as subjects who have a 50% or greater reduction in partial seizure rate from baseline during the double-blind treatment phase. [ Time Frame: 12 weeks ]

Current Other Pre-specified Outcome Measures (submitted: January 31, 2017)

• Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Day 1 up to 7 days after last dose of study drug (up to 13 weeks) ]
  An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 7 days after last dose of study drug (up to 13 weeks) that were absent before treatment or that worsened relative to pre- treatment state. AEs included both serious and non-serious adverse events.
• Number of Participants With Treatment Emergent Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Day 1 up to 7 days after last dose of study drug (up to 13 weeks) ]
  Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 7 days after last dose of study drug (up to 13 weeks) that were absent before treatment or that worsened relative to pre-treatment state. Relatedness to drug was assessed by the investigator. AEs included both serious and non-serious adverse events.
• Number of Adverse Events by Severity [ Time Frame: Day 1 up to 7 days after last dose of study drug (up to 13 weeks) ]
  An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. AEs were classified according to the severity in 3 categories a) mild: AEs does not interfere with participant's usual function b) moderate: AEs interferes to some extent with participant's usual function c) severe: AEs interferes significantly with participant's usual function.
• Number of Participants (6-16 Years of Age) With Positive Response to Columbia Suicide-Severity Rating Scale (C-SSRS) According to the Columbia Classification Algorithm of Suicide Assessment (C-CASA) Categories At Baseline [ Time Frame: Baseline (4 week prior to Day 1 of treatment) ]
  The C-SSRS (mapped to C-CASA) is a participant-rated questionnaire to assess suicidal ideation and suicidal behavior. For suicidal ideation and behaviour, data from C-SSRS was mapped to C-CASA codes 1, 2, 3, 4 and 7. C-SSRS assessed whether participant experienced the following: completed suicide (C-CASA code 1); suicide attempt (response of "Yes" on "actual attempt") (C-CASA code 2); preparatory acts toward imminent suicidal behavior (ISB) ("Yes" on "preparatory acts or behavior")(C-CASA code 3); suicidal ideation ("Yes" on "wish to be dead", "non-specific active suicidal thoughts", "active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent) (C-CASA code 4); any self-injurious behavior with no suicidal intent (C-CASA code 7). In this outcome, number of participants with positive response (response of "yes") to C-SSRS (mapped to C-CASA categories 2, 3, 4 and 7) at baseline were reported.
• Number of Participants (6-16 Years of Age) With Positive Response to Columbia Suicide-Severity Rating Scale (C-SSRS) According to the Columbia Classification Algorithm of Suicide Assessment (C-CASA) Categories During Post Baseline Time Period [ Time Frame: Day 1 up to Week 13 ]
  C-SSRS (mapped to C-CASA):participant-rated questionnaire to assess suicidal ideation and suicidal behavior. For suicidal ideation and behaviour, data from C-SSRS was mapped to C-CASA codes 1, 2, 3, 4 and 7. C-SSRS assessed whether participant experienced the following: completed suicide (C-CASA code 1); suicide attempt (response of "Yes" on "actual attempt") (C-CASA code 2); preparatory acts toward imminent suicidal behavior (ISB) ("Yes" on "preparatory acts or behavior")(C-CASA code 3); suicidal ideation ("Yes" on "wish to be dead", "non-specific active suicidal thoughts", "active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent) (C-CASA code 4); any self-injurious behavior with no suicidal intent (C-CASA code 7). Number of participants with positive response (response of "yes") to C-SSRS (mapped to C-CASA categories 1, 2, 3, 4 and 7) during post baseline time period (Day 1 up to Week 13) were reported
• Child Behaviour Checklist (CBCL): Internalizing Subscale Score in Participants Less Than 6 Years of Age [ Time Frame: Week -8 (8 weeks prior to Day 1 of treatment), Week -4 (4 weeks prior to Day 1 of treatment), Day 1 (Week 0), Week 1, 2, 3, 6, 9, 12, end of study visit (Week 13) ]
  CBCL assessed suicidal behavior in children below 6 years. It is 100-item questionnaire completed by parent/legal guardian, based on participant's behavior in past 2 months. All 100 items rated on 3-point scale: 0=not true for that child; 1=sometimes true; 2=very/often true. Total CBCL score ranges from 0 (not true) to 200 (very/often true). Higher scores=higher levels of problematic behaviors or dysfunction. Scores from all items were used to calculate 3 subscale scores: Withdrawn subscale scores, Internalizing problems subscale scores and total problem subscale scores. All subscale scores reported scaled to T Scores. Higher scores for each CBCL subscales indicated higher levels of problematic behaviors or dysfunction. In this study, a cut-off of >=68 on the T-scores was used for all 3 subscales. If a participant T Score was >=68 in any of the sub-scales, the participant was referred for Mental Health Risk Assessment that included assessment of participant continuation to the study.
• Child Behaviour Checklist (CBCL): Withdrawn Subscale Score in Participants Less Than 6 Years of Age [ Time Frame: Week -8 (8 weeks prior to Day 1 of treatment), Week -4 (4 weeks prior to Day 1 of treatment), Day 1 (Week 0), Week 1, 2, 3, 6, 9, 12, end of study visit (Week 13) ]
  CBCL assessed suicidal behavior in children below 6 years. It is 100-item questionnaire completed by parent/legal guardian, based on participant's behavior in past 2 months. All 100 items rated on 3-point scale: 0=not true for that child; 1=sometimes true; 2=very/often true. Total CBCL score ranges from 0 (not true) to 200 (very/often true). Higher scores=higher levels of problematic behaviors or dysfunction. Scores from all items were used to calculate 3 subscale scores: Withdrawn subscale scores, Internalizing problems subscale scores and total problem subscale scores. All subscale scores reported scaled to T Scores. Higher scores for each CBCL subscales indicated higher levels of problematic behaviors or dysfunction. In this study, a cut-off of >=68 on the T-scores was used for all 3 subscales. If a participant T Score was >=68 in any of the sub-scales, the participant was referred for Mental Health Risk Assessment that included assessment of participant continuation to the study
• Child Behaviour Checklist (CBCL): Total Problem Subscale Score in Participants Less Than 6 Years of Age [ Time Frame: Week -8 (8 weeks prior to Day 1 of treatment), Week -4 (4 weeks prior to Day 1 of treatment), Day 1 (Week 0), Week 1, 2, 3, 6, 9, 12, end of study visit (Week 13) ]
  CBCL assessed suicidal behavior in children below 6 years. It is 100-item questionnaire completed by parent/legal guardian, based on participant's behavior in past 2 months. All 100 items rated on 3-point scale: 0=not true for that child; 1=sometimes true; 2=very/often true. Total CBCL score ranges from 0 (not true) to 200 (very/often true). Higher scores=higher levels of problematic behaviors or dysfunction. Scores from all items were used to calculate 3 subscale scores: Withdrawn subscale scores, Internalizing problems subscale scores and total problem subscale scores. All subscale scores reported scaled to T Scores. Higher scores for each CBCL subscales indicated higher levels of problematic behaviors or dysfunction. In this study, a cut-off of >=68 on the T-scores was used for all 3 subscales. If a participant T Score was >=68 in any of the sub-scales, the participant was referred for Mental Health Risk Assessment that included assessment of participant continuation to the study
• Change From Baseline in Cognitive Test Battery (CogState Battery) Scores at Week 12: Detection Task [ Time Frame: Baseline (pre-dose at Day 1), Week 12 ]
  CogState battery:computerized test battery used to assess cognitive domains through cognition tests/tasks. The test battery was presented on computer with external response buttons. In this study, Cogstate battery consisted of 2 tasks which measured psychomotor function (detection task) and attention (paediatric identification task). Detection task was a measure of simple reaction time and provided a valid assessment of psychomotor function in participants. In this task, a playing card turning face up was presented in the center of the computer screen. As soon as this happened, the participant was to press the 'Yes' response key. There was no minimum or maximum scores since it was a time-based assessment. The software measured the speed of accurate responses to each event. In this outcome measure, speed of performance of participants (calculated as mean of the logarithmic base 10 transformed reaction times) for correct responses was reported. Lower scores indicated better performance.
• Change From Baseline in Cognitive Test Battery (CogState Battery) Score at Week 12: Paediatric Identification (Go-No Go: Attention) Tasks [ Time Frame: Baseline (pre-dose at Day 1), Week 12 ]
  CogState battery: computerized test battery used to assess cognitive domains through cognition tests/tasks. The test battery was presented on computer with external response buttons. Paediatric identification task: a measure of choice reaction time and valid assessment of visual attention. In this task, a playing card turning face up was presented in center of the computer screen. As soon as this happened, participant had to decide whether color of card was black or not. If color was black, participants was to press "Yes" response key, otherwise "no". There was no minimum/maximum scores since it was a time-based assessment. The software measured speed of accurate responses (correct identification of color) to each event. In this outcome measure, speed of performance of participants to correctly identify the color (calculated as mean of the logarithmic base 10 transformed reaction times) for correct responses was reported. Lower scores indicated better performance.
• Number of Participants With Clinically Significant Laboratory Abnormalities [ Time Frame: Baseline (from 8 weeks prior to Day 1 of treatment) up to Week 13 ]
  Criteria for abnormality: hematology (hemoglobin, hematocrit, red blood cells count:<]0.8*lower limit of normal [LLN],platelets:<0.5*LLN/greater than [>]1.75*upper limit of normal [ULN],leukocytes:<0.6*LLN or>1.5*ULN, lymphocytes, total neutrophils:<0.8*LLN or >1.2*ULN, basophils, eosinophil, monocytes:>1.2*ULN); Liver Function(aspartate aminotransferase ,alanine aminotransferase, alkaline phosphatase, Gamma glutamyl transferase:>0.3*ULN, total protein, albumin:<0.8*LLN or >1.2*ULN); bilirubin:>1.5*ULN; renal function(blood urea nitrogen, creatinine:>1.3*ULN); Electrolytes(sodium:<0.95*LLN or>1.05*ULN, potassium, chloride, calcium, bicarbonate:<0.9*LLN or >1.1*ULN); Lipids(cholesterol, triglycerides >1.3*ULN); creatine kinase:>2.0*ULN; glucose fasting:<0.6*LLN or >1.5*ULN, urine white blood corpuscles and RBC:>= 20/High Power Field [HPF];urine casts: >1/Low Power Field(LPF);urine bacteria:>20/HPF. Hormones (tetraiodothyronine and thyroid stimulating hormone:<0.8*LLN or >1.2*ULN).
• Number of Participants With Vital Signs Abnormalities [ Time Frame: Baseline (from 8 weeks prior to Day 1 of treatment) up to Week 13 ]
  Criteria for abnormalities in vital signs included: sitting systolic blood pressure (SBP) values: maximum increase and decrease of >=30 millimeter of mercury (mmHg) from baseline; sitting diastolic blood pressure (DBP) value: maximum increase and decrease of >=20 mmHg from baseline.
• Number of Participants With Clinically Significant Change From Baseline in Neurological Examinations [ Time Frame: Baseline (from 8 weeks prior to Day 1 of treatment) up to Week 13 ]
  Neurological examinations included: level of consciousness, mental status, cranial nerve assessment, muscle strength and tone, reflexes, pin prick and vibratory sensation (the latter using a 128-Hertz tuning fork), coordination and gait. Clinical significance was based on investigator's discretion.
• Number of Participants With Electrocardiogram (ECG) Abnormalities [ Time Frame: Baseline (from 8 weeks prior to Day 1 of treatment) up to Week 13 ]
  Criteria for abnormalities in ECG findings: 1) Time from ECG Q wave to the end of the S wave corresponding to ventricle depolarization (QRS complex): >=140 milliseconds (msec); 2) The interval between the start of the P wave and the start of the QRS complex, corresponding to the time between the onset of the atrial depolarization and onset of ventricular depolarization (PR interval): >=200 msec; 3) Time from ECG Q wave to the end of the T wave corresponding to electrical systole corrected for heart rate using Fridericia's formula (QTCF interval): absolute value 450 to <480 msec, 480 to <500 msec, >=500 msec; 4) Maximum QT interval: >=500 msec; 5) Maximum QTCB interval (Bazett's correction): 450 to< 480 msec, 480 to <500 msec, >=500 msec. Only those categories of ECG abnormalities in which participants were found abnormal, were reported in this outcome measure.
• Number of Participants With Clinically Significant Change From Baseline in Physical Examinations at Week 13 [ Time Frame: Baseline (from 8 weeks prior to Day 1 of treatment) up to Week 13 ]
  Physical examinations evaluated the following body systems/organs: general appearance; dermatological; head and eyes; ears, nose, mouth, and throat; pulmonary; cardiovascular; abdominal; genitourinary (optional); lymphatic; musculoskeletal/extremities; and neurological. Clinical significance was determined by the investigator.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of the Efficacy and Safety of Pregabalin as Add-On Therapy for Partial Onset Seizures in Children Ages 4-16 Years
• Official Title: A DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, MULTICENTER STUDY OF THE EFFICACY AND SAFETY OF PREGABALIN AS ADJUNCTIVE THERAPY IN CHILDREN 4 -16 YEARS OF AGE WITH PARTIAL ONSET SEIZURES
• Brief Summary: Study A0081041 is a double blind, placebo controlled, randomized, parallel group, multicenter study to evaluate the safety and efficacy of two dose levels of pregabalin administered in equally divided daily doses, in either capsule or oral liquid formulation, as adjunctive therapy in pediatric subjects 4 to 16 years of age with partial onset seizures.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Epilepsy, Partial Seizures

Intervention

Drug: Pregabalin add-on therapy

Subjects will be randomized to receive a fixed dose of either placebo, pregabalin Level 1 (maximum 150 mg/day) or pregabalin Level 2 (maximum 600 mg/day) in a 1:1:1 ratio, in addition to the subjects current AED medication regimen. Either capsules or oral liquid form will be administered, depending on subjects preference and ability to swallow capsules, in two equally divided daily doses. The study will have an 8 week baseline period; a 2 week dose escalation period; a 9 week dose maintenance period; and a 1 week dose taper period.

Study Arms

• Placebo Comparator: Placebo
  Intervention: Drug: Pregabalin add-on therapy
• Experimental: Pregabalin Level 1 (max 150 mg/day)
  Intervention: Drug: Pregabalin add-on therapy
• Experimental: Pregabalin Level 2 (max 600 mg day)
  Intervention: Drug: Pregabalin add-on therapy

• Publications *: Antinew J, Pitrosky B, Knapp L, Almas M, Pitman V, Liu J, Craiu D, Modequillo M, Nordli D, Farkas V, Farkas MK. Pregabalin as Adjunctive Treatment for Focal Onset Seizures in Pediatric Patients: A Randomized Controlled Trial. J Child Neurol. 2019 Apr;34(5):248-255. doi: 10.1177/0883073818821035. Epub 2019 Jan 27.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 23, 2017): 295
• Original Estimated Enrollment (submitted: July 6, 2011): 153
• Actual Study Completion Date: August 10, 2016
• Actual Primary Completion Date: August 10, 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Subjects and/or parent(s)/legally acceptable representative must be considered willing and able to sign consent, and complete daily seizure diaries and monitor seizure frequency.
• Male and female epilepsy subjects, 4 to 16 years of age inclusive on the date of the Screening Visit.
• Diagnosis of epilepsy with partial onset seizures classified as simple partial, complex partial or partial becoming secondarily generalized, according to the International League Against Epilepsy (ILAE) Diagnosis criteria.
• Must have a partial onset seizure frequency of at least 3 seizures per 28 day period prior to screening. Must have a partial onset seizure frequency of at least 6 seizures and no continuous 4 week seizure free period during the 8 week baseline phase prior to randomization.
• Currently receiving a stable dose of 1 to 3 antiepileptic drugs (stable within 28 days prior to screening).

Exclusion Criteria:

• Primary generalized seizures (including in the setting of co-existing partial onset seizures) which include, for example: Clonic, tonic and clonic-tonic seizures (note that partial onset seizures that become secondarily generalized are not exclusionary); Absence seizures; Infantile spasms; Myoclonic, myoclonic atonic, myoclonic tonic seizures.
• Lennox Gastaut syndrome, Benign Epilepsy with Centrotemporal Spikes (BECTS) and Dravet syndrome.
• A current diagnosis of febrile seizures, or seizures related to an ongoing acute medical illness. Any febrile seizures within 1 year of screening.
• Status epilepticus within 1 year prior to screening.
• Seizures related to drugs, alcohol, or acute medical illness.
• Any change in AED regimen (type of medication or dose) within 28 days of the Screening Visit or during the Baseline Phase.
• Progressive structural CNS lesion or a progressive encephalopathy.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 4 Years to 16 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Bulgaria, Czechia, France, Greece, Hungary, Israel, Italy, Korea, Republic of, Malaysia, Philippines, Poland, Romania, Serbia, Singapore, Turkey, Ukraine, United States
• Removed Location Countries: Austria, Czech Republic, Estonia, Finland, India, Lithuania, Netherlands, Sweden

Administrative Information

• NCT Number: NCT01389596
• Other Study ID Numbers: A0081041; 2010-020852-79 ( EudraCT Number ); XALCORY 1014 ( Other Identifier: Alias Study Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
• URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

• Responsible Party: Pfizer ( Pfizer's Upjohn has merged with Mylan to form Viatris Inc. )
• Study Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: January 2019