| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
The intended indication is:
Chronic severe non malignant pain, chronic severe malignant pain, requiring opioids. |
La indicación que se pretende es:
Dolor intenso no oncológico/oncológico, que requiere opiáceos |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic severe non cancer pain, chronic severe cancer pain, requiring opioids. |
| Dolor intenso no oncológico/oncológico, que requiere opiáceos |
|
| E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033371 |
| E.1.2 | Term | Pain |
| E.1.2 | System Organ Class | 10018065 - General disorders and administration site conditions |
|
| 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 |
Primary objective:
To demonstrate equivalence between multiple lower strength OXN PR tablets and a single higher strength OXN PR tablet taken at the same overall total daily dose as shown by:
? Analgesic efficacy based on the mean of subjects? ?Average Pain over the last 24 hours? at the last 2 visits of each Cross-over Period, as assessed by the Pain Intensity Scale.
Co-primary objective:
? Equivalent bowel function as assessed by the Bowel Function Index (BFI). |
Objetivo principal:
Demostrar la equivalencia entre varios comprimidos de OXN PR de menor concentración y un solo comprimido de OXN PR de mayor concentración tomados en la misma dosis diaria total, como se demuestra por medio de lo siguiente:
?Eficacia analgésica, basada en la media del dolor promedio de los pacientes durante las 24 horas anteriores en las 2 últimas visitas de cada período cruzado, evaluada mediante la Escala de intensidad del dolor. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives:
? To assess analgesic efficacy (each visit) and rescue medication use.
? To assess bowel function (each visit) and laxative use.
? To assess quality of life based on the EuroQol EQ-5D.
? To assess safety profile. |
Objetivos secundarios:
?Evaluar la eficacia analgésica (en cada visita) y el uso de medicamentos de rescate.
?Evaluar la función intestinal (en cada visita) y el uso de laxantes.
?Evaluar la calidad de vida basada en el EuroQol EQ-5D.
?Evaluar el perfil de seguridad. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects to be included in the study are those who meet all of the following criteria:
1. Male or female subjects at least 18 years (females less than one year post-menopausal must have a negative serum or urine pregnancy test prior to the first dose of study treatment, be non-lactating, and willing to use adequate and highly effective methods of contraception throughout the study. A highly effective method of birth control is defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as sterilisation, implants, injectables, combined oral contraceptives, some IUDs (Intrauterine Device, hormonal), sexual abstinence or vasoectomised partner).
2. Subjects receiving WHO step III opioid analgesic medication for the treatment of severe non-malignant or malignant pain in the oxycodone equivalent range of 100 ? 160 mg per day, who could benefit from improved analgesic efficacy, improved tolerability or optimised treatment regimen (e.g. reduction of number of different drugs, less different formulation usage/route of applications).
3. Documented history of severe non-malignant or malignant pain that will require around-the-clock opioid therapy for a minimum of 6 weeks (OXN60/30 mg PR or OXN80/40 mg PR twice daily).
4. Subjects must be willing to change/adapt their current opioid analgesic treatment/regimen.
5. Subjects must be willing and able (e.g. mental and physical condition) to participate in all aspects of the study, including use of medication, completion of subjective evaluations, attending scheduled clinic visits, completing telephone contacts, and compliance with protocol requirements as evidenced by providing written, informed consent.
6. In the Investigator?s opinion the subject?s non-analgesic concomitant medications, including those medications for the treatment of depression are thought to be stable, and will remain stable throughout the Double-blind Phase of the study.
7. In the Investigator?s opinion the non-opioid analgesic medication dose will remain stable during the Double-blind Phase. |
Los pacientes que se incluirán en el estudio son los que cumplan todos los criterios siguientes:
1.Pacientes de ambos sexos de al menos 18 años de edad (Las mujeres con menos de un año de menopausia deben tener una prueba de embarazo en suero u orina negativa antes de recibir la primera dosis del tratamiento del estudio, no estar en período de lactancia, y estar dispuestas a utilizar métodos anticonceptivos adecuados y altamente efectivos durante todo el estudio. Un método anticonceptivo muy eficaz se define como aquel que se asocia a una tasa baja de fracasos (es decir, menos del 1 % anual) cuando se utiliza de forma continuada y correcta, como esterilización, implantes, inyectables, anticonceptivos orales combinados, algunos DIU (dispositivos intrauterinos, hormonales), abstinencia sexual o vasectomía de la pareja).
2.Pacientes que reciben analgésicos en el tercer escalón de la OMS para el tratamiento del dolor intenso no oncológico o oncológico en un intervalo equivalente a oxicodona 100 ? 160 mg al día, que podrían beneficiarse de la mejora de la eficacia analgésica, la mejora de la tolerabilidad o del régimen de tratamiento optimizado (p. ej., reducción del número de fármacos diferentes, menos uso de distintas formulaciones y vías de administración).
3.Antecedentes documentados de dolores intensos no oncológicos o oncológicos que requerirán tratamiento con opiáceos a lo largo de todo el día durante al menos 6 semanas (OXN60/30 mg PR u OXN80/40 mg PR dos veces al día).
4.Pacientes dispuestos a cambiar o adaptar su tratamiento/régimen analgésico opioide actual.
5.Pacientes dispuestos y capaces (mental y físicamente) de participar en todos los aspectos del estudio, incluido el uso del medicamento, la realización de evaluaciones subjetivas, la asistencia a las visitas programadas al centro clínico, la respuesta a los contactos telefónicos y el cumplimiento de los requisitos del protocolo, como se prueba proporcionando por escrito el consentimiento informado.
6.En opinión del investigador, los medicamentos concomitantes no analgésicos del paciente, incluidos los utilizados para el tratamiento de la depresión, son estables y se mantendrán estables a lo largo de la fase doble ciego del estudio.
7.En opinión del investigador, la dosis del analgésico no opioide se mantendrá estable durante la fase doble ciego. |
|
| E.4 | Principal exclusion criteria |
Subjects to be excluded from the study are those who meet any of the following criteria:
1. Any history of hypersensitivity to oxycodone, naloxone, related products or other ingredients of the study treatment.
2. Any contraindication to oxycodone, naloxone and other ingredients of the study treatment.
3. Subjects with any situation in which opioids are contraindicated (e.g. severe respiratory depression with hypoxia and/or hypercapnia, severe chronic obstructive lung disease, paralytic ileus).
4. Subjects already receiving OXN PR plus additional opioid and being dissatisfied due to unacceptable tolerability of OXN PR.
5. Active alcohol or drug abuse and/or history of opioid abuse.
6. Subjects with a positive urine drug test at screening visit 1, which indicates unreported illicit drug use or unreported use of a concomitant medication not required to treat the subjects? medical condition(s).
7. Evidence of clinically significant cardiovascular, renal, hepatic, gastrointestinal (e.g. paralytic ileus), or psychiatric disease, as determined by medical history, clinical laboratory tests, ECG results, and physical examination, that would place the subject at risk upon exposure to the study treatment or that may confound the analysis and/or interpretation of the study results.
8. Chronic or intermittent pain that results from Fibromyalgia or Rheumatoid Arthritis.
9. Subjects with hypothyroidism (non-compensated), Addison`s disease or increase of intracranial pressure.
10. Subjects receiving hypnotics or other central nervous system (CNS) depressants that, in the Investigator?s opinion, may pose a risk of additional CNS depression with opioid study treatment.
11. Subjects with uncontrolled seizures or convulsive disorder.
12. Surgery within 2 months prior to the start of the Screening Period, or planned surgery during the Run-in Period and 6-week Double-blind Phase that may affect GI motility or pain.
13. Subjects presently taking, or who have taken peripheral antagonists (methylnaltrexone, Almivopan) ? 30 days prior to the start of the Screening Period.
14. Subjects suffering from diarrhoea.
15. Abnormal aspartate aminotransferase (AST; SGOT), alanine aminotransferase (ALT; SGPT), or alkaline phosphatase levels (> 3 times the upper limit of normal) or an abnormal total bilirubin and/or creatinine level(s) (> 1.5 times the upper limit of normal), gamma glutamyl transpeptidase (GGT or GGTP) ? 3 times the upper limit of normal.
16. Subjects presently taking or who have taken monoamine oxidase inhibitors (MAOI) ? 2 weeks prior to the start of the Screening Period.
17. Subjects who have experienced persistent drug withdrawal symptoms during a previous treatment with OXN PR.
Additional exclusion criterion for subjects suffering from non-malignant pain:
18. Subjects who participated in a clinical research study involving a new chemical entity or an experimental drug within 30 days of study entry (defined as the start of the Screening Period).
Additional exclusion criteria for subjects suffering from cancer pain:
19. Subjects with known or suspected unstable brain metastases or spinal cord compression that may require changes in steroid treatment throughout the duration of the study.
20. Cyclic chemotherapy in the 2 weeks before the screening visit or planned during the study that has shown in the past to significantly influence bowel function. If subjects are having their first cycle of chemotherapy during the 2 weeks before the screening visit or during the study they should be excluded.
21. Radiotherapy that, in the Investigators opinion, would influence bowel function or pain during the study.
22. Subjects who have received a new chemical entity or an experimental drug within 30 days of study entry (defined as the start of the Screening Period). Concurrent participation in another clinical trial is not permitted unless long-term survival data will be assessed in an epidemiological study only.
23. Subjects with an expected life expectancy of less than 3 months and a Karnofsky Performance Scale Index < 40. |
Se excluirá del estudio a los pacientes si cumplen alguno de los siguientes criterios:
1.Antecedentes de hipersensibilidad a la oxicodona, a la naloxona, a productos relacionados o a otros ingredientes del tratamiento del estudio.
2.Contraindicaciones a la oxicodona, a la naloxona y a otros ingredientes del tratamiento del estudio.
3.Cualquier situación en la que los opiáceos estén contraindicados (p. ej., depresión respiratoria grave con hipoxia y/o hipercapnia, neumopatía obstructiva crónica grave o íleo paralítico).
4.Pacientes que ya están recibiendo OXN PR más un opioide adicional y que no estén satisfechos debido a la tolerabilidad inaceptable de OXN PR.
5.Alcoholismo o toxicomanía activos y/o antecedentes de abuso de opiáceos.
6.Pacientes con resultado positivo en la prueba de drogas en orina en la visita 1 de selección, que indica una drogadicción ilícita no declarada o el uso no declarado de un medicamento concomitante que no se requiera para el tratamiento de su afección.
7.Indicios de enfermedad cardiovascular, renal, hepática, digestiva (p. ej., íleo paralítico) o psiquiátrica clínicamente significativa, según lo determinado por la historia clínica, los análisis clínicos, los resultados del ECG y la exploración física, que supusiera un riesgo para el paciente al exponerse al tratamiento del estudio o que pudiera confundir el análisis y/o la interpretación de los resultados del estudio.
8.Dolor crónico o intermitente debido a fibromialgia o artritis reumatoide.
9.Pacientes con hipotiroidismo (no compensado), enfermedad de Addison o aumento de la presión intracraneal.
10.Pacientes que reciben hipnóticos u otros depresores del sistema nervioso central (SNC) que, en opinión del investigador, puedan representar un riesgo de depresión adicional del SNC por el tratamiento con opiáceos del estudio.
11.Pacientes con convulsiones o trastorno convulsivo no controlados.
12.Cirugía en los 2 meses anteriores al inicio del período de selección, o cirugía programada durante el período de pre-inclusión y la fase doble ciego de 6 semanas de duración, que pudiera afectar a la motilidad digestiva o provocar dolor.
13.Uso actual o anterior de antagonistas periféricos (metilnaltrexona, almivopán) <= 30 días antes del inicio del período de selección.
14.Pacientes que presentan diarrea
15.Concentraciones anómalas de aspartato-aminotransferasa (AST, SGOT), alanina-aminotransferasa (ALT, SGPT), fosfatasa alcalina (> 3 veces el límite superior de la normalidad), bilirrubina total y/o creatinina (>1,5 veces el límite superior de la normalidad) o ?-glutamiltransferasa (GGT o GGTP)? 3 veces el límite superior de la normalidad.
16.Uso actual o anterior de inhibidores de la monoaminooxidasa (IMAO)?2 semanas antes del inicio del período de selección.
17.Pacientes que han experimentado síntomas persistentes de abstinencia de drogas durante un tratamiento anterior con OXN PR. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint:
Analgesic efficacy based on the mean of subjects? ?Average Pain over the last 24 hours? at the last 2 visits of each cross-over Period, as assessed by the Pain Intensity Scale.
Co-primary Endpoint:
Equivalent bowel function as assessed by the Bowel Function Index (BFI). |
Variable principal:
Eficacia analgésica, basada en la media del dolor promedio de los pacientes durante las 24 horas anteriores en las 2 últimas visitas de cada período cruzado, evaluada mediante la Escala de intensidad del dolor.
Variable co-principal:
Función intestinal equivalente, evaluada mediante el Índice de función intestinal (Bowel Function Index, BFI). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint 'Average Pain over the last 24 hours' and the co-primary endpoint 'BFI? will be derived as the arithmetic mean value of the observed values at Visits 5 and 6 with cross-over period 1, and the arithmetic mean value of the observed values at Visits 8 and 9 with cross-over period 2, respectively |
| Variable principal de eficacia:Escala de intensidad del dolor (Escala de valoración numérica, EVN, 0 ? 10) ? «Media del dolor en las últimas 24 horas», según la evaluación en las visitas 5 y 6 y en las visitas 8 y 9. |
|
| E.5.2 | Secondary end point(s) |
To assess analgesic efficacy (each visit) and rescue medication use.
To assess bowel function (each visit) and laxative use.
To assess quality of life based on the EuroQol EQ-5D.
To assess safety profile. |
Evaluar la eficacia analgésica (en cada visita) y el uso de medicamentos de rescate.
Evaluar la función intestinal (en cada visita) y el uso de laxantes.
Evaluar la calidad de vida basada en el EuroQol EQ-5D.
Evaluar el perfil de seguridad. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Each cross over visit |
| Cada visita cruzada |
|
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Open label extension phase |
|
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 9 |
| 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 | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 10 |
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