| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Neuralgia post herpética y dolor por polineuropatía diabética. |
|
| E.1.1.1 | Medical condition in easily understood language |
| postherpetic neuralgia and diabetic polyneuropathic pain |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Biological Phenomena [G16] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10054095 |
| E.1.2 | Term | Neuropathic pain |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| 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 |
| The primary objective of this trial is to evaluate the safety and efficacy of lidocaine 5% medicated plaster versus pregabalin after 4 weeks of treatment in subjects with postherpetic neuralgia and diabetic polyneuropathic pain |
| El objetivo principal de este estudio es evaluar la seguridad y eficacia de un parche de lidocaína al 5% comparado con pregabalina en pacientes con neuralgia post-herpética y dolor por polineuropatía diabética al cabo de 4 semanas. |
|
| E.2.2 | Secondary objectives of the trial |
? Estimate the suitability of lidocaine 5% medicated plaster as stand-alone medication, as an alternative to and in combination with pregabalin.
? Evaluate the safety and efficacy of lidocaine 5% medicated plaster in combination with pregabalin.
? Evaluate the pregabalin-sparing effect of lidocaine 5% medicated plaster by down-titrating pregabalin (sub-study). |
? Evaluar la viabilidad del parche de lidocaína al 5% como tratamiento único, como tratamiento alternativo, o en tratamiento combinado con pregabalina.
? Evaluar la seguridad y la eficacia del parche de lidocaína al 5% en combinación con pregabalina.
? Evaluar el efecto ahorrador de pregabalina del parche de lidocaína al 5% durante la fase de retirada progresiva de pregabalina (sub-estudio). |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Not applicable. It is included in the same protocol |
|
| E.3 | Principal inclusion criteria |
? Male or female subjects with ? 18 years of age.
? Written informed consent given.
? For women of childbearing potential, a negative urine pregnancy test.
? Negative urine test for drugs of abuse with the exception of short and medium acting benzodiazepine users for insomnia.
? Intact skin in the area of topical treatment.
Subjects with painful DPN
? Controlled, treated type 1 or 2 diabetes mellitus with glycosylated hemoglobin (HbA1c) ? 11%.
? Painful, distal, symmetrical, sensomotor polyneuropathy of the lower extremities for ? 3 months (below the knees on both extremities) with at least 2 of the following symptoms present: burning sensation, tingling or prickling, paresthesias, painful heat or cold sensation (e.g. warm or cold water).
? The most painful area is coverable by up to 4 plasters.
Subjects with PHN
? Subjects with PHN and neuropathic pain present for ? 3 months after healing of the herpes zoster skin rash.
? Without neurolytic neurosurgical therapy for their condition. |
? Pacientes de sexo masculino o femenino de al menos 18 años de edad..
? Consentimiento informado por escrito.
? En caso de mujeres fértiles, prueba de embarazo en orina negativa..
? Prueba de abuso de sustancias en orina con resultado negativo, a excepción de benzodiazepinas de acción corta e intermedia para insomnio
? Piel sana en la zona de tratamiento tópico.
? NRS-3 > 4 (intensidad de dolor promedio evocada durante los últimos 3 días)
? Aclaramiento de creatinina (CLCR) > > 30mL/min
Pacientes con DPD
? Diabetes mellitus controlada tipos 1 ó 2 con hemoglobina glicosilada (HbA1c) ? 11%..
? Polineuropatía dolorosa sensorimotora, distal, simétrica de las extremidades inferiores durante 3 o más meses (bajo las rodillas en ambas extremidades) con la presencia de al menos dos de los síntomas siguientes: sensación de escozor, hormigueo o pinchazos, pesadez ocasional, parestesias, sensación dolorosa de quemazón o de congelamiento (similar a la de sumergir las extremidades en agua muy caliente o muy fría).
? La mayor parte del área dolorosa puede cubrirse a lo sumo con 4 parches.
Pacientes con NPH
? Pacientes con NPH y dolor neuropático presente durante 3 o más meses tras la curación de la erupción cutánea asociada al herpes zoster.
? Sin posibilidad de terapia neuroquirúrgica de neurólisis para su dolencia. |
|
| E.4 | Principal exclusion criteria |
General
? Evidence or history of alcohol, medication or drug abuse and/or dependency in the past 2 years, unstable psychological personality requiring intermittent or permanent treatment.
? Psychiatric illness (subjects with well-controlled depression or anxiety disorder may participate if they are not taking any of the prohibited medications defined below), epilepsy or suicide risk.
? Pregnant or breastfeeding women.
? Women of childbearing potential who are sexually active without satisfactory contraception, i.e. with a Pearl Index < 1 (e.g. most oral contraceptives, intra-uterine device (IUD) method with hormonal supplement, or male or female condom with diaphragm and a spermicidal agent [foam, jelly, or cream]) for at least 28 days prior to enrollment, during the trial, and until 28 days after the follow-up visit. Women of childbearing age must be counseled about the use of adequate contraception.
? Subjects with severe cardiac impairment e.g. NYHA class > 3, myocardial infarction less than 6 months prior to enrollment, and/or unstable angina pectoris.
? Subjects with severe hepatic disorder and/or AST or ALT ? 3x the upper limit of normal.
? Subjects with known or suspected severe renal failure (CLCR < 30 mL/min).
? Anticipated need for surgery during the trial, requiring at least regional or general anesthesia.
? Subjects who are undergoing active treatment for cancer, are known to be infected with HIV, or being acutely and intensively immunosuppressed following transplantation.
? Participation in another trial of investigational medicinal products or devices parallel to or less than 1 month before entry into the trial, or previous participation in this trial.
? Known to or suspected of not being able to comply with the trial protocol.
? Not able to communicate meaningfully with the Investigator and staff.
? Any dependency of the subject to the Investigator or the trial site, e.g. employees with direct involvement in the proposed trial or in other trials under the direction of this Investigator or trial site, as well as family members of the employees or the Investigator.
? The investigator may exclude any potential subject for any safety concern or any other reason that according to the investigator?s assessment makes the patient not suitable for this trial.
Trial-specific
? Any former treatment with topical lidocaine for treatment of neuropathic pain, pregabalin, or gabapentin (during the last 6 months).
? Any concomitant use of drugs for the treatment of neuropathic pain or commonly used for the treatment of neuropathic pain e.g.:
? Non-SSRI antidepressant drugs (i.e. tricylcic antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRIs), e.g. venlafaxine, duloxetine).
? Non-steroidal anti-inflammatory drugs (NSAIDs, including COX-2 inhibitors) if not specifically allowed per protocol.
? Monoamine oxidase inhibitors (MAO-inhibitors),
? antieleptic drugs (e.g. carbamazepine, clonzepam, phenytoin, valproic acid, lamotrigine, topiramate, gabapentin) besides the IMPs.
? Benzodiazepines (except for short or medium acting benzodiazepines for insomnia).
? Skeletal muscle relaxants.
? Opioids (including dextromethorphan and tramadol), memantine, retinotoxins (e.g. hydroxychloroquine, deferoxamine, thioridazine, vigabatrin).
? Known contraindications or hypersensitivity to local anesthetics of the amide type, pregabalin or paracetamol or to any of the excipients.
? Administration of Class I anti-arrhythmic drugs (e.g. tocainide, mexiletine).
? Intake of other local anesthetics (besides the IMPs).
? Use of capsaicin in the last month prior to Visit 2.
? Galactose intolerance.
? Lapp lactase deficiency.
? Glucose-galactose malabsorption.
? Evidence of another cause for pain in the area of neuropathic pain such as lumbar radiculopathy, surgery trauma, restless legs syndrome, if this could confound the assessment or self-evaluation of the neuropathic pain.
? Presence of other severe pain that could confound the assessment or self-evaluation of the neuropathic pain.
? History of malignancy within the past 5 years (with the exception of basal cell carcinoma).
Subjects with PHN
? Active herpes zoster lesion or dermatitis of any origin at the affected site.
? Subjects who had neurological ablation by block or neurosurgical intervention for control of pain.
Subjects with painful DPN
? No palpable pulse of the arteria dorsalis pedis in one foot or both feet.
? Clinical signs for venous insufficiency and/or postthrombotic syndrome Stage III/IV (i.e. extensive varicosis)
? Ulcers on the lower extremities |
Generales
? Evidencia o antecedentes de adicción y/o dependencia de alcohol, fármacos o sustancias durante los dos años anteriores, personalidad inestable psicológicamente que requiera tratamiento intermitente o permanente.
? Trastornos psiquiátricos (los pacientes con depresión o trastorno de ansiedad bien controlados podrán participar siempre que no estén utilizando ninguno de los fármacos prohibidos que se indican más adelante), con epilepsia o riesgo de suicidio.
? Mujeres embarazadas o en período de lactancia.
? Mujeres fértiles con vida sexual activa que no utilicen un método anticonceptivo eficaz, es decir con un índice de Pearl < 1 (como la mayor parte de los anticonceptivos orales, dispositivo intra-uterino (DIU) con suplemento hormonal o preservativo masculino o femenino con diafragma y un agente espermicida [en espuma, gel o crema]) durante un periodo mínimo de 28 días antes del reclutamiento, durante el estudio y hasta que no transcurran 28 días tras la visita de seguimiento. Se deberá orientar a las mujeres en edad fértil sobre de los métodos anticonceptivos eficaces
? Pacientes con insuficiencia cardiaca severa, de clase NYHA > 3, infarto de miocardio en los seis meses anteriores al reclutamiento, y/o angina inestable.
? Pacientes con trastorno hepático severo y/o AST o ALT ? 3 veces el límite superior de la normalidad.
? Pacientes con presencia o sospecha de fallo renal severo (CLCR < 30 ml/min).
? Cirugía programada en una fecha dentro del estudio que requiera anestesia local o general
? Pacientes que estén recibiendo tratamiento activo para el cáncer, presenten infección por VIH confirmada, o se encuentren sometidos a inmunodepresión aguda o intensiva tras un trasplante.
? Participación en otro estudio con fármacos o dispositivos experimentales de forma simultánea o en el mes anterior a su inclusión en este estudio o participación previa en este estudio.
? Sospecha o evidencia de incapacidad para el cumplimiento del protocolo del estudio.
? Dificultades para comunicarse con el Investigador o su equipo.
? Cualquier dependencia del paciente con el Investigador o con el centro del estudio, como por ejemplo: empleados con relación directa con el estudio propuesto o con otros estudios bajo la dirección del mismo Investigador o centro del estudio, así como familiares de los empleados o del Investigador.
? El investigador podría excluir a cualquier paciente basándose en razones de seguridad o en cualquier otra razón que, de acuerdo con su criterio, haga que el paciente no sea adecuado para este estudio.
Específicos del estudio
? Cualquier tratamiento anterior con lidocaína tópica, pregabalina o gabapentina (durante los últimos 6 meses) para el tratamiento de dolor neuropático.
? Cualquier uso concomitante de fármacos para el tratamiento de dolor neuropático o de fármacos que se utilicen normalmente para el tratamiento del dolor neuropático como:
- Fármacos antidepresivos no ISRS (es decir, antidepresivos tricíclicos, inhibidores de la recaptación de serotonina-noradrenalina (IRSN) como venlafaxina, duloxetina)
- Antiinflamatorios no esteroideos (AINEs, inhibidores de la COX-2 incluídos) si no están permitidos específicamente en el protocolo.
- Inhibidores de la monoamino oxidasa (inhibidores de la MAO)
- Fármacos antiepilépticos (ej: carbamazepina, clonazepam, fenitoína, ácido valproico, lamotriguina, topiramato, gabapentina) excepto los PMEs
- Benzodiazepinas (excepto benzodiazepinas de acción corta y media para el insomnio)
- Relajantes músculo-esqueléticos
- Opioides (incluídos dextrometorfano y tramadol), nemantina, retinotoxinas (como hidroxicloroquina, deferoxamina, tioridazina, vigabatrina).
? Contraindicación o hipersensibilidad conocidas a anestésicos locales de tipo amida, pregabalina o paracetamol o a cualquiera de los excipientes
? Administration of Class I anti-arrhythmic drugs (e.g. tocainide, mexiletine).
? Uso de otros analgésicos locales (además del Producto Medicinal en Investigación). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ? Decrease of NRS-3 (recalled average pain intensity during the last 3 days) after 4 weeks of treatment with lidocaine 5% medicated plaster or pregabalin as stand alone medication, i.e. between Week 4 (Visit 4) and Baseline (Visit 2), expressed as a response rate. Response is defined as a reduction of at least 2 points or a value of 4 or less on the NRS-3 scale after 4 weeks of treatment. All drop-outs will be defined as non-responders |
| PEl parámetro principal de valoración de este protocolo es el descenso de la puntuación NRS-3 (intensidad de dolor promedio evocado durante los últimos 3 días) tras 4 semanas de tratamiento con el parche de lidocaína al 5% o pregabalina en monoterapia; es decir, entre la Semana 4 (Visita 4) y el momento basal (Visita 2), expresado como proporción de respondedores. Se define respuesta como la reducción de al menos 2 puntos o la consecución de una puntuación de 4 o menos en la escala NRS-3 tras 4 semanas de tratamiento. Los pacientes que abandonen se considerarán como no respondedores. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After 4 weeks of treatment |
| Tras 4 semanas de tratamiento |
|
| E.5.2 | Secondary end point(s) |
? Clinical Global Impression of Change (CGIC) at Visits 4, 6, 7, and 8, and the Switch Visit.
? Patient Global Impression of Change (PIGC) at Visits 4, 6, 7, and 8, and the Switch Visit.
? Subject satisfaction with the treatment at Visits 1, 4, 6, 7, and 8 and the Switch Visit.
? Recalled average pain intensity over the last 3 days at each visit (NRS-3) and changes from Baseline.
? Percentage of subjects with 30% and 50% reduction in pain score based on the NRS-3 compared to Baseline at Visit 4 and Visit 7.
? Daily pain assessment from Visit 2 to Visit 4: average pain intensity during the last 24 hours (recorded in the evening; A NRS) and worst pain intensity during the last 24 hours (recorded in the evening; W-NRS) and changes from Baseline
? Time to onset of response: Time between Baseline and the first day of a 3-day period with an A-NRS decreased by at least 2 points or an A-NRS ? 4 on all 3 days.
? Time to onset of pain relief on Day 0 (only for subjects treated with lidocaine 5% medicated plaster).
? Neuropathic Pain Symptom Inventory (NPSI) at Visits 1, 2, 4, 6, 7, 8, and the Switch Visit, and changes from Baseline.
? SF-MPQ (Short Form McGill Pain Questionnaire) at Visits 1, 2, 4, 6, 7, 8, and the Switch Visit, and changes from Baseline.
? SF-36 at Visits 1, 2, 4, 6, 7, 8, and the Switch Visit, and changes from Baseline.
? EuroQol-5 Dimension (EQ-5D; quality of life index) at Visits 1, 2, 4, 6, 7, 8, and the Switch Visit, and changes from Baseline.
? Chronic Pain Sleep Inventory (CPSI) at Visits 1, 2, 4, 6, 7, 8, and the Switch Visit, and changes from Baseline.
? Allodynia severity rating at Visits 1, 2, 4, 6, 7, 8 and the Switch Visit, and changes from Baseline.
? Number of plasters used to cover the most painful areas
? Use of rescue medication
Secondary safety endpoint criteria:
? Safety laboratory.
? Vital signs.
? Physical examination.
? Adverse events.
? Concomitant medication.
? Time to withdrawal due to adverse event and adverse drug reaction (ADR).
Sub-study endpoint criterion:
? Pregabalin-sparing effect of lidocaine 5% medicated plaster (decrease of pregabalin dose while maintaining an NRS-3 ?4). For each subject, whose pregabalin-dose can be reduced during the down-titration phase without resulting in an NRS-3>4, a pregabalin-sparing effect is achieved |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| 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 | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| adaptado en dos etapas, estratificado por indicación |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 | Information not present in EudraCT |
| 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 |
| Croatia |
| Czech Republic |
| Germany |
| Italy |
| Poland |
| Portugal |
| Russian Federation |
| Slovenia |
| Spain |
| Sweden |
| United Kingdom |
|
| 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
|
La finalización del ensayo viene definida como la última visita del último sujeto en el ensayo.
Dependiendo de los resultados del análisis intermedio, el estudio puede ser finalizado prematuramente. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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