| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Partial onset seizures and Primary Generalised Tonic Clonic Seizures |
| Tratamiento adyuvante de sujetos pediátricos y adultos con crisis tónico-clónicas primarias generalizadas |
|
| E.1.1.1 | Medical condition in easily understood language |
| Seizures or epilepsy |
| Crisis o Epilepsia |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10034089 |
| E.1.2 | Term | Partial seizures NOS |
| E.1.2 | System Organ Class | 100000004852 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the long term safety and tolerability of pregabalin in pediatric subjects 1 month through 16 years of age with partial onset seizures and pediatric and adult subjects 5 to 65 years of age with (PGTC) seizures. |
| Evaluar la seguridad y la tolerabilidad a largo plazo de la pregabalina en sujetos pediátricos de 1 mes a 16 años con crisis de inicio parcial, y en sujetos pediátricos y adultos de 5 a 65 años con crisis TCPG. |
|
| E.2.2 | Secondary objectives of the trial |
| There are no Secondary Objectives in this study |
| No hay objetivos secundarios en este estudio. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria for Subjects who have Participated in Studies A0081041, A0081042, or A0081105-Subject eligibility should be reviewed and documented by an appropriately qualified member of investigators study team before subjects are included in study. Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:1.Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of Study A0081106.When there are 2 parents or 2 legally acceptable representatives,consent should be obtained from both of the childs parents/legal representatives if present at the meeting where the informed consent document is signed.Subject to local regulations whenever the minor is able to give assent, the minors assent must be obtained.2.Subjects and/or parents/legally acceptable representative who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.3.Male and female subjects who have participated in and completed, or participated in Studies A0081041, A0081042, or A0081105.For subjects who have participated in, but did not complete Studies A0081041, A0081042, or A0081105, eligibility for Study A0081106 will be reviewed with a member of the Pfizer study team to determine further eligibility.Subjects are required to have completed a minimum of 4 weeks of double blind treatment in Studies A0081041 or A0081105 to be considered potentially eligible for Study A0081106.4.Male and female epilepsy subjects who have participated in either Study A0081041 or Study A0081042, 1 month to 16 years of age inclusive on the date of the Screening Visit with diagnosis of epilepsy with seizures classified as simple partial, complex partial or partial becoming secondarily generalized, according to the ILAE 2010.The diagnosis must be established by:Subjects history family history and neurological exam;Subjects must have had a contrast enhanced CT or MRI scan of the brain and EEG testing prior to Study A0081041 or Study A0081042.Results must have been consistent with the diagnosis of focal onset epilepsy and must have demonstrated that no abnormality was likely to be progressive.
5.Male and female subjects 5-65 years of age who have participated in Study A0081105 with a diagnosis of epilepsy with PGTC seizures and who continue to satisfy seizure related inclusion criteria for that study.
6.Currently receiving 1 to 3 antiepileptic drugs at Visit 1. Benzodiazepine medication used on a regular basis will be considered 1 of the concurrent antiepileptic treatments.The vagus nerve stimulator is allowed and considered 1 of the 3 antiepileptic treatments.
7.A 12 lead ECG at without significant abnormal findings.
Inclusion Criteria for Directly Enrolling Subjects
1.Evidence of a personally signed and dated informed consent document indicating that the parent/legally acceptable representative has been informed of all pertinent aspects
of the study.When there are 2 parents or 2 legally acceptable representatives,consent should be obtained from both of the child?s parents/legal representatives if present at the meeting where the informed consent document is signed. Subject to
local regulations whenever the minor is able to give assent, the minor?s assent must be obtained.
2.Subjects and/or parents/legally acceptable representative who are willing and able to comply with scheduled visits, treatment plan, laboratory tests,and other study procedures.
3.Subjects and/or parent/legally acceptable representative must be considered willing and able to complete daily seizure diaries and monitor seizure frequency.
4.Male and female epilepsy subjects,1 month to 16 years of age inclusive on the date of the Screening Visit with diagnosis of epilepsy with seizures classified as simple partial,complex partial or partial becoming secondarily
generalized,according to the ILAE 20103.The diagnosis must be established by:-Subject?s history,family history and neurological exam.
-Subjects must have had a contrast enhanced CT or MRI scan of the brain within 60 months of the Screening Visit and an EEG within 24 months of the screening visit.
Imaging results must be consistent with the diagnosis of focal-onset epilepsy and must demonstrate that no abnormality is likely to be progressive.
-Subjects must have had an average of at least 3 seizures per month in the 3 months prior to screening.
5.Currently receiving a stable regimen of 1 to 3 antiepileptic treatments.Benzodiazepine medication used on a regular basis at a
stable dosage will be considered 1 of the concurrent antiepileptic treatments.The VNS is allowed and considered 1 of the 3 antiepileptic treatments.
6.A 12-lead ECG at screening without clinically significant abnormal findings as determined by the investigator. |
Criterios de inclusión para los sujetos que hayan participado en los estudios A0081041, A0081042 o A0081105- Antes de incluir a cada sujeto en el estudio, un miembro debidamente cualificado del equipo de investigación deberá revisar los criterios de participación y documentar que el sujeto los cumple. Para poder participar en el estudio, los sujetos deberán cumplir todos los criterios de inclusión que se indican a continuación:1.-Existencia de un documento de consentimiento informado firmado y fechado personalmente por el sujeto (o un representante legalmente aceptable), que indique que este ha sido informado de todos los aspectos importantes relacionados con el estudio A0081106. Cuando un menor tenga dos padres o dos representantes legalmente aceptables, y los dos estén presentes en la entrevista en la que se firme el documento de consentimiento informado, deberá obtenerse el consentimiento de ambos. Sin menoscabo de la normativa local, deberá obtenerse el consentimiento de un menor siempre que sea capaz de otorgarlo.
2.- Sujetos y/o padres/representante legalmente aceptable que estén dispuestos a acudir a las visitas programadas y cumplir el plan de tratamiento, los análisis clínicos y los demás procedimientos del estudio, y que sean capaces de hacerlo.
3.- Sujetos de ambos sexos que hayan participado en los estudios A0081041, A0081042 o A0081105, y los hayan completado. En el caso de los sujetos que hayan participado en los estudios A0081041, A0081042 o A0081105 pero no los hayan completado, se deberá revisar el caso con un miembro del equipo del estudio de Pfizer a fin de determinar si cumplen los criterios de participación. Para que se considere su posible participación en el estudio A0081106,los sujetos deberán haber completado al menos 4 semanas de tratamiento doble ciego en los estudios A0081041 o A0081105.
Sujetos de ambos sexos que hayan participado en los estudios A0081041 o A0081042, que el día de la visita de selección tengan de 1 mes a 16 años de edad, inclusive, con diagnóstico de epilepsia y que presenten crisis convulsivas parciales simples, parciales complejas o parciales secundariamente generalizadas según la clasificación de la Liga internacional contra la epilepsia (International League Against Epilepsy, ILAE 2010)3 (véanse otros tipos de crisis en el Apéndice 1). El diagnóstico deberá confirmarse mediante:
- La historia clínica del sujeto (p. ej., la descripción de las crisis, con exclusión de trastornos que se presten a confusión, como pseudocrisis, síncopes, etc.), los antecedentes familiares y la exploración neurológica.
- Antes de los estudios A0081041 o A0081042 se deberá haber realizado una tomografía computarizada con contraste o una resonancia magnética cerebral, así como un electroencefalograma a los sujetos. Los resultados de estos estudios deberán ser coherentes con el diagnóstico de epilepsia focal y constatar la improbabilidad de que las anomalías sean progresivas.
5. Sujetos de ambos sexos de 5 a 65 años que hayan participado en el estudio A0081105, tengan diagnóstico de epilepsia (ILAE 20103) con crisis TCPG y sigan cumpliendo los criterios de inclusión de dicho estudio relativos a las crisis (véase el protocolo A0081105).
6. Sujetos que estén tomando de 1 a 3 antiepilépticos en el momento de la visita 1. Las benzodiacepinas empleadas con regularidad se considerarán uno de los tratamientos antiepilépticos concomitantes. Se permite el uso del estimulador vagal, que se considerará uno de los 3 tratamientos antiepilépticos.
7. En la última visita de los estudios A0081041, A0081042 o A0081105 se deberá haber obtenido un electrocardiograma de 12 derivaciones sin anomalías destacables.
Para Criterios de Inclusión para los sujetos incluidos directamente por favor diríjase a la página 25 y 26 del protocolo del estudio en español. |
|
| E.4 | Principal exclusion criteria |
1. Lennox-Gastaut syndrome, Infantile Spasms, Absence seizures, BECT (Benign epilepsy with centrotemporal spikes) 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.
2. Status epilepticus within 1 year prior to Visit 1 of this study.
3. Seizures related to drugs, alcohol, or acute medical illness.
4. Progressive structural CNS lesion or a progressive encephalopathy. Progressive inborn errors of metabolism.
Known or suspected chronic hematologic, hepatic or renal disease (AST and ALT above 3 times the upper limit of normal; or bilirubin, BUN, or creatinine above 2 times the upper limit of normal within the previous 6 months for infants, children and adolescents aged 6 months or more, or at any postnatal period for infants younger
than 6 months). Estimated creatinine clearance (CLcr) <60 mL/min for subjects >=17 yr and <80 mL/min/1.73m2 (using age appropriate equations) for subjects <17 years of age. For subjects who previously participated in A0081041, A0081042
or A0081105, it is assumed the subjects have already met entry criteria, therefore, the creatinine clearance exclusion is based upon results collected at the Screening Visit laboratory of A0081041, A0081042 or A0081105. The laboratory exclusion criteria
noted above will be based upon data collected at the Last visit (Visit 9, Early Termination, or Unscheduled Visit) of the A0081041, A0081042 or A0081105.
5. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
6. Pregnant or nursing females (females who are menarchal must have a negative urine pregnancy test); menarchal females of childbearing potential who are unwilling or unable to use an acceptable method of contraception, as outlined in the protocol, until completion of follow-up procedures.
7. Taking any non-antiepileptic (non-AED) medication that could alter the effectiveness of the subject's medication, response, seizure frequency or characteristics.
Medications for Attention Deficit/Hyperactivity Disorder will be permitted if medication doses are stable and remain so throughout the duration of the study. A ketogenic diet will also be allowed given that the diet is adhered to for the duration of
the study.
8. Taking or have taken any other investigational drug (aside from participation in Studies A0081041, A0081042 or A0081105) within the last 30 days prior to screening.
9. The concomitant use of gabapentin is prohibited.
10. Use of cocaine, phencyclidine (PCP), or other illegal or illicit drugs is prohibited.
Use of amphetamines, barbiturates, opiates, or benzodiazepines without a valid current prescription is prohibited.
11. Unwilling or unable to comply with the Life Style Guidelines.
12. Subjects not reasonably expected to complete the study.
13. Any subjects considered at risk of suicide based on the MINI-KID and C-SSRS Lifetime (subjects >=6 years of age) or CBCL (subjects <6 years of age) or likely to self harm based on clinical judgment. Based on the judgment of the investigator, a subject should be excluded or a risk assessment should be done by a qualified mental health professional based on responses to assessment of suicidal ideation and behavior and if the subject has had suicidal ideation in the last 6 months prior to screening, suicidal behaviors or attempts in the past year, or current major psychiatric disorders that are not explicitly permitted in the inclusion/exclusion criteria. A risk assessment should also be performed in any child <6 years of age who has ever exhibited any potentially self-injurious or high-risk behaviors such as hurting himself or herself, or unusual behaviors such as running into traffic or using items as weapons (eg, knife, bat).
14. For subjects who have not participated in Studies A0081041, A0081042, or A0081105 and enrolling directly into Study A0081106, treatment with pregabalin for any reason within 60 days prior to screening, or prior participation in a pregabalin
clinical study is prohibited.
15. Known allergy or intolerance to pregabalin or its excipients, including lactose, or other alpha 2 delta ligands (eg, gabapentin).
16. Subjects, or subjects whose parents/legally acceptable representatives are investigational site staff members; and subjects, or subjects whose parents/legally acceptable representative are Pfizer employees directly involved in the conduct of the study. |
1.Síndrome de Lennox-Gastaut, espasmos del lactante, ausencias, epilepsia benigna con paroxismos centrotemporales y síndrome de Dravet. Diagnóstico actual de convulsiones febriles o convulsiones relacionadas con la existencia de un padecimiento médico agudo en curso. Sujetos que hayan tenido algún episodio de convulsiones febriles en el año anterior a la visita de selección.
2.Sujetos que en el año anterior a la visita 1 de este estudio hayan presentado estado epiléptico.
3. Convulsiones relacionadas con drogas, alcohol o padecimientos médicos agudos.
4. Lesión estructural progresiva del SNC o encefalopatía progresiva. Metabolopatías congénitas progresivas.
Certeza o sospecha de enfermedades crónicas de tipo hematológico, hepático o renal. CLcr inferior a 60 ml/min para los sujetos de 17 años o más, o inferior a 80 ml/min/1,73 m2 para los sujetos menores de 17 años. En el caso de los sujetos que hayan participado en los estudios A0081041, A0081042 o A0081105, se presupone que ya han cumplido los criterios de inclusión y, por lo tanto, la exclusión por el aclaramiento de la creatinina se basará en los resultados obtenidos en el análisis clínico correspondiente a la visita de selección del estudio A0081041, A0081042 o A0081105. Los criterios de exclusión relativos a los análisis clínicos indicados anteriormente se basarán en los datos obtenidos en la última visita de los estudios A0081041, A0081042 o A0081105.
5. Otras afecciones médicas o psiquiátricas graves de carácter agudo o crónico que puedan aumentar el riesgo asociado a la participación en el estudio o a la administración del producto en investigación, o que puedan interferir con la interpretación de los resultados y que, a juicio del investigador, hagan que el sujeto no sea apto para participar en este estudio.
6.Mujeres embarazadas o en periodo de lactancia; mujeres posmenárquicas capaces de concebir que no deseen o no puedan usar un método anticonceptivo aceptable hasta la finalización de los procedimientos de seguimiento.
7. Sujetos tratados con cualquier fármaco no antiepiléptico que pueda alterar la eficacia de la medicación del sujeto, la respuesta del sujeto, o la frecuencia o las características de las crisis. Se permitirá el uso de medicamentos para el trastorno por déficit de atención con hiperactividad si se utilizan en dosis estables y se mantienen así durante todo el estudio. También se permitirán las dietas cetógenas, siempre que se sigan durante todo el estudio.
8. Sujetos que tomen o hayan tomado cualquier otro medicamento en investigación (aparte de la participación en los estudios A0081041, A0081042 o A0081105) en los 30 días anteriores a la visita de selección.
9.Se prohíbe el uso concomitante de gabapentina.
10.Se prohíbe el consumo de cocaína, fenciclidina, u otras drogas ilegales o ilícitas. Se prohíbe el uso de anfetaminas, barbitúricos, opiáceos o benzodiacepinas si no es con receta válida vigente.
11.Sujetos que no estén dispuestos a cumplir las pautas sobre el estilo de vida o no sean capaces de hacerlo.
12.Sujetos con motivos razonables para suponer que no finalizarán el estudio.
13.Sujetos que se considere que tienen riesgo de suicidio según el MINI-KID y la C-SSRS de «toda la vida» (sujetos mayores de 6 años) o el CBCL (sujetos menores de 6 años), o que a juicio del médico tengan probabilidad de autolesionarse. A criterio del investigador, deberá excluirse a los sujetos (o deberá hacerse una evaluación de riesgos por parte de un profesional de salud mental cualificado) si lo justifican las respuestas dadas en la evaluación de las ideas y conductas suicidas, y si han presentado ideas suicidas en los 6 meses anteriores a la visita de selección, conductas o intentos suicidas durante el año anterior, o trastornos psiquiátricos actuales importantes que no estén expresamente permitidos en los criterios de inclusión/exclusión. También deberá hacerse una evaluación de riesgos para cualquier niño menor de 6 años que haya presentado alguna vez conductas potencialmente autolesivas o de alto riesgo, como por ejemplo autolesionarse, o conductas insólitas como abalanzarse contra vehículos en movimiento o usar objetos como armas (p. ej., un cuchillo o un palo grande).
14.En el caso de los sujetos que no hayan participado en los estudios A0081041, A0081042 o A0081105 y se incorporen directamente al estudio A0081106, está prohibido el tratamiento con pregabalina (cualquiera que sea el motivo) en los 60 días anteriores a la visita de selección, así como la participación anterior en un estudio clínico con pregabalina.
15.Alergia o intolerancia conocidas a la pregabalina o a sus excipientes, entre ellos la lactosa, o a otros ligandos de la subunidad alfa 2 delta.16. Sujetos integrantes del personal del centro de investigación o cuyos padres/representantes legales lo sean; o sujetos que sean empleados de Pfizer directamente implicados en la realización del estudio o cuyos padres/representantes legalmente aceptables lo sean. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Adverse event (AE) data (occurrence, nature, intensity, and relationship to study drug).
- Physical and neurological examinations.
- Vital signs.
- Growth and development parameters (height, weight, Tanner stage).
- Clinical laboratory data (hematology, chemistry, urinalysis).
- Electrocardiograms (ECGs).
- 28 day seizure rate (number of seizures per 28 day period).
- Suicidality assessments.
- Cognitive assessment battery (POS pediatric subjects 4 16 years of age only). |
-Datos de acontecimientos adversos (AA): fecha de aparición, naturaleza, intensidad y relación con el medicamento del estudio.
-Exploración física y neurológica.
-Constantes vitales.
-Parámetros de crecimiento y desarrollo (estatura y peso), incluido el estadio de Tanner.
-Datos de análisis clínicos (hematología, bioquímica, análisis de orina).
-Electrocardiograma (ECG).
-Frecuencia de crisis en 28 días (número de crisis sufridas en un periodo de 28 días).
-Evaluación de las ideas y conductas suicidas.
-Pruebas cognitivas. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Various endpoints throughout the study |
| Varios criterios de valoración a lo largo del estudio. |
|
| E.5.2 | Secondary end point(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability |
| Tolerabilidad |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 47 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Belgium |
| Bulgaria |
| Czech Republic |
| Estonia |
| Finland |
| France |
| Greece |
| Guatemala |
| Hungary |
| Italy |
| Korea, Republic of |
| Lithuania |
| Netherlands |
| Panama |
| Philippines |
| Poland |
| Romania |
| Russian Federation |
| Singapore |
| Slovakia |
| Spain |
| Sweden |
| Turkey |
| United Kingdom |
| Croatia |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last subject last visit |
| Ultima Visita del Último Paciente. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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