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

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

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.

Study Overview

• Status: Completed
• Conditions: Partial Onset Seizures
• Intervention / Treatment: Drug: Pregabalin Dose Level 1; Drug: Pregabalin Dose Level 2; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 175
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belarus
  • Minsk, Belarus, 220053
    • GU Republican Scientific and Practical Center Mother and Child
• Belgium
  • Bruxelles Capitale
    • Brussels, Bruxelles Capitale, Belgium, 1090
      • UZ Brussel
• Bosnia and Herzegovina
  • Banja Luka, Bosnia and Herzegovina, 78000
    • University Clinical Centre of the Republic of Srpska
• Bulgaria
  • Pleven, Bulgaria, 5800
    • UMHAT Dr. Georgi Stranski Ltd.
  • Plovdiv, Bulgaria, 4002
    • UMHAT "Sveti Georgi" Ltd.
• China
  • Beijing, China, 100045
    • Beijing Children's Hospital
  • Jilin
    • Changchun, Jilin, China, 130021
      • The First Bethune Hospital of Jilin University
  • Shanghai
    • Shanghai, Shanghai, China, 201102
      • Children's Hospital of Fudan University
• France
  • Garches, France, 92380
    • Hôpital Raymond Poincaré
• Germany
  • Thueringen
    • Jena, Thueringen, Germany, 07747
      • Universitaetsklinikum Jena
• Greece
  • Athens, Greece, 12462
    • University General Hospital Attikon
  • Thessaloniki, Greece, 54642
    • General Hospital of Thessaloniki Ippokratio
• Hungary
  • Balassagyarmat, Hungary, H-2660
    • Dr. Kenessey Albert Korhaz es Rendelointezet
  • Budapest, Hungary, H-1032
    • Szent Margit Kórház
  • Budapest, Hungary, H-1146
    • Magyarorszagi Reformatus Egyhaz Bethesda Gyermekkorhaz, Gyermekneurologia
  • Budapest, Hungary, H-1083
    • Semmelweis Egyetem, I. Sz. Gyermekgyogyaszati Klinika
  • Budapest, Hungary, H-1023
    • Szent Janos Korhaz es Eszak Budai Egyesitett Korhazak
  • Debrecen, Hungary, H-4032
    • Debreceni Egyetem Klinikai Központ
• Israel
  • Holon, Israel, 5810001
    • Pharmacy of The E. Wolfson Medical Center
  • Holon, Israel, 5810001
    • The E. Wolfson Medical Center
  • Tel Aviv, Israel, 6423906
    • Tel Aviv Sourasky Medical Center
  • Tel Aviv, Israel, 6423906
    • Pharmacy of Tel Aviv Sourasky Medical Center
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center
• Lebanon
  • Beirut, Lebanon
    • American University of Beirut Medical Center
  • Beirut, Lebanon
    • Saint George Hospital - University Medical Center
• Malaysia
  • Kelantan
    • Kota Bharu, Kelantan, Malaysia, 15586
      • Hospital Raja Perempuan Zainab II
• Philippines
  • Manila, Philippines, 1003
    • Metropolitan Medical Center
  • Manila, Philippines, 1008
    • University of Santo Tomas Hospital
  • Manila, Philippines, 1000
    • Manila Doctors Hospital
  • Quezon City, Philippines, 1102
    • St. Luke's Medical Center
  • Quezon City, Philippines, 1105
    • Philippine Children's Medical Center
  • Cebu
    • Cebu City, Cebu, Philippines, 6000
      • Cebu Doctors' University Hospital
    • Cebu City, Cebu, Philippines, 6000
      • Perpetual Succour Hospital
• Romania
  • Bucuresti, Romania, 013766
    • Centrul Medical Unirea
  • Iasi, Romania, 700309
    • Spitalul Clinic de Urgente pentru Copii "Sf. Maria"
• Russian Federation
  • Moscow, Russian Federation, 117997
    • FSFEI HE N.I. Pirogov RNRMU of Minzdrav of Russia
  • Moscow, Russian Federation, 125412
    • FSFEI HE N.I. Pirogov RNRMU of Minzdrav of Russia
  • Perm, Russian Federation, 614990
    • Perm State Medical University n. a. acad. E.A. Vagner
  • Saint Petersburg, Russian Federation, 194100
    • St. Petersburg State Pediatric Medical University
  • Saint Petersburg, Russian Federation, 194356
    • "Baltiyskaya Medicyna" LLC
  • Saint-Petersburg, Russian Federation, 191025
    • LLC Medical Technologies
  • Saint-Petersburg, Russian Federation, 192148
    • LLC Medical Technologies
  • Smolensk, Russian Federation, 214018
    • RSBHI Smolensk Regional Clinical Hospital
  • Ulyanovsk, Russian Federation, 432011
    • SHI Ulyanovsk Regional Children's Clinical Hospital n. a. Y.F.Goryachev
  • Ulyanovsk, Russian Federation, 432026
    • SHI Central Clinical Medical Unit
  • Ulyanovsk, Russian Federation, 432045
    • SHI Central Clinical Medical Unit
  • Yekaterinburg, Russian Federation, 620134
    • MAI Children's City Clinical Hospital 9
  • Nizhegorodskaya Oblast
    • Nizhniy Novgorod, Nizhegorodskaya Oblast, Russian Federation, 603159
      • Nizhmedklinika
  • Permskiy KRAY
    • Perm, Permskiy KRAY, Russian Federation, 614000
      • Perm State Medical University n. a. acad. E.A. Vagner
• Serbia
  • Belgrade, Serbia, 11000
    • Mother and Child Healthcare Institute Dr Vukan Cupic
  • Belgrade, Serbia, 11000
    • University Children's Hospital Belgrade
  • Vojvodina
    • Novi Sad, Vojvodina, Serbia, 21000
      • Institute for Child and Youth Healthcare of Vojvodina
• Spain
  • Zaragoza, Spain, 50009
    • Hospital Universitario Miguel Servet
• Taiwan
  • Kaohsiung, Taiwan, 833
    • Chang Gung Memorial Hospital- Kaohsiung branch
  • Taichung, Taiwan, 40447
    • China Medical University Hospital
  • Taipei, Taiwan, 100
    • National Taiwan University Hospital
• Thailand
  • Bangkok
    • Bangkoknoi, Bangkok, Thailand, 10700
      • Siriraj Hospital, Faculty of Medicine, Mahidol university
    • Ratchathevee, Bangkok, Thailand, 10400
      • Phramongkutklao Hospital
• Turkey
  • Eskisehir, Turkey, 26480
    • Eskisehir Osmangazi Universitesi Tip Fakultesi
  • Trabzon, Turkey, 61080
    • Karadeniz Teknik Universitesi Tip Fakultesi Farabi Hastanesi
  • Konak
    • Izmir, Konak, Turkey, 35120
      • Izmir Tepecik Training and Research Hospital
• Ukraine
  • Dnipro, Ukraine, 49027
    • Komunalnyi zaklad "Dnipropetrovska dytiacha miska klinichna likarnia #5"
  • Dnipro, Ukraine, 49100
    • Komunalnyi zaklad "Dnipropetrovska oblasna dytiacha klinichna likarnia"
  • Ivano-Frankivsk, Ukraine, 76018
    • Ivano-Frankivska oblasna dytiacha klinichna likarnia
  • Kyiv, Ukraine, 04209
    • DZ "Ukrainskyi medychnyi tsentr reabilitatsii ditei z orhanichnym urazhenniam
  • Uzhgorod, Ukraine, 88018
    • Oblasnyi klinichnyi tsentr neirokhirurhii ta nevrolohii,viddilennia neirokhirurhii #2
• United States
  • Florida
    • Orlando, Florida, United States, 32819
      • Pediatric Neurology, PA
    • Orlando, Florida, United States, 32819
      • Pediatric Epilepsy Center of Central Florida
    • Tampa, Florida, United States, 33609
      • Pediatric Epilepsy & Neurology Specialists, PA
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas Health Science Center at Houston
    • San Antonio, Texas, United States, 78249
      • Road Runner Research, Ltd.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 3 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo	Drug: Placebo; Placebo Liquid dosed three times daily beginning at Randomization through Taper Phase
EXPERIMENTAL: Study Drug Level 1	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
EXPERIMENTAL: Study Drug Level 2	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Log Transformed 24-Hour Seizure Rate for All Partial Onset Seizures During the Double-Blind Treatment Phase	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).	Day 1 up to Day 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	Day 1 up to Day 14

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	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.	Day 1 up to End of study (EOS) (maximum Day 25)
Number of Participants With Treatment-Related Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	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.	Day 1 up to EOS (maximum Day 25)
Number of Adverse Events by Severity	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.	Day 1 up to EOS (maximum Day 25)
Number of Participants With Laboratory Test Abnormalities	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.	From Baseline up to EOS (maximum Day 25)
Number of Participants With Vital Signs Abnormalities	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.	From Baseline (BL) up to EOS (maximum Day 25)
Percentage of Participants With Abnormal Physical Examination Findings at Screening and End of Study	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.	Screening and EOS (maximum Day 25)
Percentage of Participants With Abnormal Neurological Examination Findings at Baseline and End of Study	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.	Baseline (BL) and EOS (maximum Day 25)
Number of Participants With Electrocardiogram (ECG) Abnormalities	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.	From screening up to EOS (maximum Day 25)

Collaborators and Investigators

• Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.

Publications and helpful links

General 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.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 16, 2014
• Primary Completion (ACTUAL): March 13, 2018
• Study Completion (ACTUAL): March 13, 2018

Study Registration Dates

• First Submitted: February 25, 2014
• First Submitted That Met QC Criteria: February 25, 2014
• First Posted (ESTIMATE): February 27, 2014

Study Record Updates

• Last Update Posted (ACTUAL): January 20, 2021
• Last Update Submitted That Met QC Criteria: January 15, 2021
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Keywords: Epilepsy; Safety; Efficacy; Tolerability; Pregabalin; blinded; Partial Onset Seizures; Placebo controlled; Lyrica; Adjunctive treatment; Eligibility Criteria
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Seizures; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; Anti-Anxiety Agents; Anticonvulsants; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Pregabalin
• Other Study ID Numbers: A0081042; 2013-003420-37 (EUDRACT_NUMBER)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No