A Safety, Efficacy, and Tolerability Trial of Pregabalin as Add-On Treatment in Pediatric Subjects <4 Years of Age With Partial Onset Seizures.

• ClinicalTrials.gov Identifier: NCT02072824
• Recruitment Status: Completed
• First Posted: February 27, 2014
• Results First Posted: October 9, 2018
• 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: February 25, 2014
• First Posted Date: February 27, 2014
• Results First Submitted Date: September 10, 2018
• Results First Posted Date: October 9, 2018
• Last Update Posted Date: January 20, 2021
• Actual Study Start Date: September 16, 2014
• Actual Primary Completion Date: March 13, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 10, 2018)

Log Transformed 24-Hour Seizure Rate for All Partial Onset Seizures During the Double-Blind Treatment Phase [ Time Frame: Day 1 up to Day 14 ]

All partial onset seizures experienced during treatment phase were recorded by central reader during the 48 to 72 hour video-electroencephalogram (EEG). Double Blind 24 hour EEG seizure rate for all partial onset seizures = ([Number of seizures in double blind 48 to 72 hour EEG assessment] divided by [number of hours of video-EEG monitoring])*24. The EEG assessment was done at the end of the fixed dose treatment. For log-transformation, the quantity 1 was added to the double blind 24 hour EEG seizure rate for all participants to account for any possible "0" seizure incidence. This resulted in final calculation as: log transformed (double-blind 24-hour EEG seizure rate + 1).

Original Primary Outcome Measures (submitted: February 25, 2014)

Percent reduction of 24 hour seizure rate for all partial onset seizures relative to placebo during the double-blind assesment phase. [ Time Frame: Video-EEG recordings for a target minimum of 48 hours ]

Percent reduction of partial onset seizures during the double-blind assesment phase, collected by video-EEG recording.

Current Secondary Outcome Measures (submitted: September 10, 2018)

Responder Rate: Percentage of Participants With at Least 50 Percent (%) or Greater Reduction From Baseline in 24-Hour Seizure Rate for All Partial Onset Seizures During the Double-Blind Treatment Phase [ Time Frame: Day 1 up to Day 14 ]

Responder Rate was defined as percentage of participants who had a 50% or greater reduction from baseline in 24-hour seizure rate during the double-blind treatment phase. Double Blind 24 hour EEG seizure rate for all partial onset seizures = ([Number of seizures in double blind 48 to 72 hour EEG assessment] divided by [number of hours of video-EEG monitoring])*24. The EEG assessment was done at the end of the fixed dose treatment.

Original Secondary Outcome Measures (submitted: February 25, 2014)

Responder rate, defined as the proportion of subjects who had at least a 50% reduction in 24 hour partial onset seizure rate. [ Time Frame: calculated from 48 hour basline through the 2 week double-blind treatment phase ]

The proportion of subjects who have at least a 50% reduction in 24 hour partial onset seizure rate during the double-blind assesment phase, as measured from baseline (data collected during the 48 hour baseline video-EEG phase).

Current Other Pre-specified Outcome Measures (submitted: September 10, 2018)

• Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Day 1 up to End of study (EOS) (maximum Day 25) ]
  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 AEs were events which occurred between first dose of study drug and up to end of study (up to Day 25) 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-Related Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Day 1 up to EOS (maximum Day 25) ]
  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 AEs were events which occurred between first dose of study drug and up to end of study (up to Day 25) 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 EOS (maximum Day 25) ]
  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 With Laboratory Test Abnormalities [ Time Frame: From Baseline up to EOS (maximum Day 25) ]
  Abnormality Criteria: hemoglobin,hematocrit,red blood cells(RBC)count:<0.8*lower limit of normal[LLN],platelets:<0.5*LLN/>1.75*upper limit of normal[ULN]; leukocytes:<0.6*LLN/>1.5*ULN; lymphocytes,neutrophils, total protein,albumin, tetraiodothyronine,thyroid stimulating hormone:<0.8*LLN/>1.2*ULN; basophils,eosinophils,monocytes:>1.2*ULN; prothrombin [PT],PT international ratio:>1.1*ULN; aspartate aminotransferase,alanine aminotransferase,alkaline phosphatase,gamma glutamyl transferase:>0.3*ULN; bilirubin:>1.5*ULN; blood urea nitrogen,creatinine, cholesterol,triglycerides:>1.3*ULN; sodium: <0.95*LLN/>1.05*ULN; potassium,chloride,calcium,bicarbonate:<0.9*LLN/>1.1*ULN; glucose fasting:<0.6*LLN/>1.5*ULN; creatine kinase:>2*ULN;urine glucose,ketone,protein:>=1;urine WBC,RBC:>= 20/High Power Field[HPF]; urine casts,hyaline casts:>1/Low Power Field; urine bacteria:>20/HPF.
• Number of Participants With Vital Signs Abnormalities [ Time Frame: From Baseline (BL) up to EOS (maximum Day 25) ]
  Criteria for abnormalities in vital signs included: sitting/supine systolic blood pressure (SBP) values: maximum increase and decrease of greater than or equal to (>=) 30 millimeter of mercury (mmHg) from baseline; sitting/supine diastolic blood pressure (DBP) value: maximum increase and decrease of >=20 mmHg from baseline.
• Percentage of Participants With Abnormal Physical Examination Findings at Screening and End of Study [ Time Frame: Screening and EOS (maximum Day 25) ]
  Physical examinations evaluated the following body systems/organs: abdomen; ears; extremities; eyes; general appearance; head; heart; lungs; lymph nodes; mouth; musculoskeletal; nose; skin and throat. Abnormalities in physical examination were based on investigator's discretion.
• Percentage of Participants With Abnormal Neurological Examination Findings at Baseline and End of Study [ Time Frame: Baseline (BL) and EOS (maximum Day 25) ]
  Neurological examinations included: coordination; cranial nerve function (CNF); gait and station; level of consciousness (LOC); lower and upper extremity sensation; muscle strength; muscle tone; nystagmus; reflexes and speech. Abnormalities in neurological examination were based on investigator's discretion and also, some components of the neurological examination were not done for certain participants due to participant age or significant developmental impairment. Only those categories of neurological examination in which at least 10% of participants had an abnormality in any treatment group at any time point were reported in this outcome measure.
• Number of Participants With Electrocardiogram (ECG) Abnormalities [ Time Frame: From screening up to EOS (maximum Day 25) ]
  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 (maximum QTCB interval 450-<480 msec), were reported in this outcome measure.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Safety, Efficacy, and Tolerability Trial of Pregabalin as Add-On Treatment in Pediatric Subjects <4 Years of Age With Partial Onset Seizures.
• Official Title: A Double-blind, Placebo-controlled, Parallel-group, Multicenter Study Of The Efficacy And Safety Of Pregabalin As Adjunctive Therapy In Children 1 Month Through <4 Years Of Age With Partial Onset Seizures
• Brief Summary: This study is designed to evaluate the effectiveness of 2 doses of pregabalin to reduce seizure frequency as an add on therapy in pediatric subjects 1 month to <4 years of age with refractory partial onset seizures. It is hypothesized that both doses of pregabalin will demonstrate superior efficacy when compared to placebo by reducing the partial onset seizure frequency and that pregabalin will be safe and well tolerated.
• 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: Partial Onset Seizures

Intervention

• Drug: Pregabalin Dose Level 1
  Pregabalin liquid dosed daily three times a day in equally divided doses escalated to 7.0 mg/kg/day beginning at Randomization through Taper Phase then tapered to 3.5 mg/kg/day during 1 week Taper Phase
• Drug: Pregabalin Dose Level 2
  Pregabalin liquid dosed daily three times a day in equally divided doses escalated to 14.0 mg/kg/day beginning at Randomization through Taper Phase then tapered to 3.5 mg/kg/day during 1 week Taper Phase
• Drug: Placebo
  Placebo Liquid dosed three times daily beginning at Randomization through Taper Phase

Study Arms

• Experimental: Study Drug Level 1
  Intervention: Drug: Pregabalin Dose Level 1
• Experimental: Study Drug Level 2
  Intervention: Drug: Pregabalin Dose Level 2
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

• Publications *: Mann D, Antinew J, Knapp L, Almas M, Liu J, Scavone J, Yang R, Modequillo M, Makedonska I, Ortiz M, Kyrychenko A, Nordli D, Farkas V, Farkas MK; A0081042 study group. Pregabalin adjunctive therapy for focal onset seizures in children 1 month to <4 years of age: A double-blind, placebo-controlled, video-electroencephalographic trial. Epilepsia. 2020 Apr;61(4):617-626. doi: 10.1111/epi.16466. Epub 2020 Mar 18.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 16, 2018): 175
• Original Estimated Enrollment (submitted: February 25, 2014): 123
• Actual Study Completion Date: March 13, 2018
• Actual Primary Completion Date: March 13, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Subject must have 3 partial onset seizures in the month prior to screening.
• Subject must have 2 partial onset seizures during the 48 hour baseline phase.
• Signed Informed Consent.
• On 1-3 stable anti-epileptic drugs at screening.

Exclusion Criteria:

• Primary generalized seizures including clonic, tonic, clonic-tonic, absence, febrile seizures, and infantile spasms.
• Lennox-Gasteau, BECTS, and Dravet's syndrome.
• Status epliepticus within 1 year of screening.
• Any change in AED regimen with 7 days of screening.
• Progressive structural central nervous system (CNS) lesion or a progressive encephalopathy.
• Progressive errors of metabolism.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 1 Month to 3 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belarus, Belgium, Bosnia and Herzegovina, Bulgaria, China, France, Germany, Greece, Hungary, Israel, Korea, Republic of, Lebanon, Malaysia, Philippines, Romania, Russian Federation, Serbia, Spain, Taiwan, Thailand, Turkey, Ukraine, United States
• Removed Location Countries: Argentina, Netherlands, Poland, Singapore, Slovakia, South Africa

Administrative Information

• NCT Number: NCT02072824
• Other Study ID Numbers: A0081042; 2013-003420-37 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• 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: September 2018