| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Cushing?s disease is a rare disease that is caused by an adrenocorticotropic hormone (ACTH) secreting pituitary adenoma. The elevated ACTH secreted by these tumors stimulates the adrenal glands to produce excess cortisol, leading to the subsequent development of the clinical signs and symptoms of hypercortisolism. Cushing?s disease is a rare disease associated with severe morbidity and premature mortality and most commonly affects adults aged 20-50, primarily females. |
| La enfermedad de Cushing es una enfermedad rara causada por un adenoma hipofisario secretor de ACTH. La elevada cantidad de ACTH secretada por estos tumores estimula las glándulas suprarrenales para producir un exceso de cortisol, lo que conduce al posterior desarrollo de los signos y síntomas clínicos de hipercortisolismo. La enfermedad de Cushing está asociada con una morbididad grave y una mortalidad prematura, y suele afectar a adultos de 20-50 años de edad, principalmente mujeres. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cushing´s disease is caused by an excesive grown of hipofisis, a brain gland, which increase the cortsiol levels. Without treatment, it could even cause death. |
| La enfermedad de Cushing se debe a un crecimiento excesivo de la hipófisis, una glándula del cerebro, que hace aumentar los niveles de cortisol. Sin tratamiento puede provocar incluso la muerte. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10011651 |
| E.1.2 | Term | Cushing's disease |
| E.1.2 | System Organ Class | 100000004860 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| ?To assess the efficacy in terms of response to pasireotide 600 ?g s.c. b.i.d. and 900 ?g s.c. b.i.d. independently in patients with Cushing?s disease as measured by mean UFC ? 1.0 X ULN after 6 months of treatment |
| Evaluar la eficacia en términos de respuesta de pasireotide 600 ?g y 900 ?g s.c. dos veces al día, de forma independiente, en pacientes con enfermedad de Cushing, mediante los niveles de UFC ? 1,0 x LSN con respecto a la situación basal tras 6 meses de tratamiento. |
|
| E.2.2 | Secondary objectives of the trial |
? reduction of mean UFC to ? 1.0XULN at months 3 and 12
?time to first response
?the effect of pasireotide s.c. on plasma ACTH and serum cortisol.
? median UFC response
? improvement in clinical signs.
? improvement in clinical symptoms of Cushing?s disease.
?the effect of pasireotide s.c. on tumor volume
?To assess censor-adjusted response, pooled dose response. the response by dose group at intermediate visits, the effect of pasireotide s.c. on Quality of Life
?To determine the pharmacokinetics of pasireotide
?To identify any patient-related factors that may affect the pharmacokinetics or pharmacodynamics
?To explore potential relationships between pharmacokinetics and pharmacodynamics
?To evaluate the safety and tolerability of pasireotide s.c.
Exploratory
?To evaluate pasireotide 600 ?g s.c. b.i.d. and 900 ?g s.c. b.i.d. dose response
?To evaluate midnight salivary cortisol level relationship with mean UFC and serum cortisol |
EVALUAR
?REDUCCION DE UFC A ? 1,0 x LSN A LOS 3 Y 12 MESES
?TIEMPO HASTA LA PRIMERA RESPUESTA
?Efecto sobre ACTH en plasma y cortisol en suero
?Mediana de la respuesta de UFC
?Mejora de los signos clinicos
?Mejora en los sintomas clinicos
?Efecto sobre EL VOLUMEN DEL TUMOR, mediante RM
?Respuesta ajustada por censura
?Respuesta por dosis agrupada
?Respuesta por grupo de dosis
?Efecto sobre la calidad de vida
?Farmacocinética (FC)
?Identificar los factores relacionados que puedan afectar a la FC y farmacodinamia (FD)
?Explorar las posibles relaciones entre la FC y la FD
?seguridad y la tolerabilidad del pasireotide s.c.
OBJETIVOS EXPLORATORIOS:
?EVALUAR la respuesta a las dosis de 600 ?g s.c y 900 ?g s.c. b.i.d. de pasireotide LONGITUDINALMENTE
?EVALUAR LOS NIVELES DE CORTISOL EN SALIVA |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
?Male or female patients aged 18 years or greater
?Patients with confirmed diagnosis of ACTH-dependent Cushing?s disease, as evidenced by
1.mean UFC from four 24-hour urinary collections at least 1.5 times the upper limit of the laboratory normal range collected within 2 weeks;
2.morning plasma ACTH within the normal or above normal range;
3.either MRI confirmation of pituitary macroadenoma (greater than or equal to 1 cm) or inferior petrosal sinus gradient >3 after corticotrophin-releasing hormone (CRH) for those patients with a microadenoma (tumor less than 1 cm)*, or for patients who have had prior pituitary surgery, documentation confirming an ACTH staining adenoma.
* if IPSS had previously been performed without CRH (e.g.with DDAVP), then a central to peripheral pre-stimulation gradient > 2 is required. If IPSS had not previously been performed, IPSS with CRH stimulation is required.
?Patients with de novo Cushing?s disease can be included only if they are not considered candidates for pituitary surgery (poor surgery candidates, surgically unapproachable tumors, patients who refuse to have surgical treatment)
?Confirmatory testing prior to IPSS (low-dose dexamethasone suppression testing or dexamethasone-CRH testing) has to be performed for patients with UFC ? 3.0 X ULN and a pituitary microadenoma in order to exclude possible pseudo-Cushing?s syndrome.
?[(France only) confirmatory testing with a dexamethasone suppression test is required for all patients with UFC ? 3.0 x ULN for whom IPSS has not been done and for whom no histological proof of an ACTH-staining adenoma is available]
?Karnofsky performance status ? 60 (i.e. requires occasional assistance, but is able to care for most of this personal needs)
?For patients on medical treatment for Cushing?s disease the following washout periods must be completed before baseline efficacy assessments are performed
?Inhibitors of steroidogenesis ? ketoconazole, metyrapone, rosiglitazone: 1 week
?Dopamine agonists - bromocriptine, cabergoline: 4 weeks
?Octreotide LAR and Lanreotide autogel: 8 weeks
?Lanreotide SR: 4 weeks
?Octreotide - immediate release formulation: 1 week
?Patients with a known history of impaired fasting glucose or Diabetes Mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary |
?Pacientes varones o mujeres con más de 18 años de edad
?Pacientes con diagnóstico confirmado de enfermedad de Cushing dependiente de ACTH, demostrado por:
-Nivel medio de cortisol libre en orina obtenido en 4 muestras de orina de 24 horas recogidas en un periodo de 2 semanas, de al menos dos veces el límite superior de normalidad
-Niveles de ACTH en plasma por la mañana dentro de su valor normal o por encima de éste
-Confirmación por RM de la presencia de un macroadenoma hipofisario (igual o superior a 1 cm) o gradiente del seno petroso inferior > 3 tras la estimulación con CRH para pacientes con UN MICROADENOMA (tumores menores de 1 cm), o para pacientes que han sido sometidos a una cirugía hipofisaria previa, histopatología que confirme la presencia de un adenoma productor de ACTH marcable.
?Los pacientes con enfermedad de Cushing de novo sólo se pueden incluir si no se consideran candidatos para la cirugía hipofisaria.
?Estado funcional de Karnofsky ? 60% (es decir, requiere ayuda ocasional, pero puede atender a la mayoría de sus necesidades personales).
?Para los pacientes en tratamiento médico para la enfermedad de Cushing, antes de realizar las evaluaciones de eficacia basales se deberán completar los siguientes periodos de lavado:
-Inhibidores de la estereoidogénesis (ketoconazol, metirapona, rosiglitazona): 1 semana.
-Agonistas dopaminérgicos (bromocriptina, cabergolina): 4 semanas.
-Octreótida LAR y Lanreótida Autogel: 8 semanas.
-Lanreótida SR: 4 semanas.
-Octreótida (formulación de liberación inmediata): 1 semana.
?Se pueden incluir pacientes con antecedentes conocidos de alteración del metabolismo de la glucosa en ayunas o DM, aunque la glucemia y el tratamiento antidiabético deberán ser vigilados estrechamente durante todo el estudio, y ajustarse en caso necesario.
.A los pacientes con UFC MENOR O IGUAL A 3,0 X LSN y un microadenoma hipofisiario se les realizará una prueba confirmatoria (prueba de supresion con dexametasona a dosis bajas o prueba dexametasona-CRH) para excluir un posible síndrome de pseudo-Cushing. |
|
| E.4 | Principal exclusion criteria |
?Patients who have received pituitary irradiation within the last ten years prior to visit 1, as the onset time of the radiation effects cannot be determined
?Patients who have been treated with mitotane during the last 6 months
?Patients with compression of the optic chiasm causing any visual field defect, in order to exclude patients with a tumor causing chiasma compression requiring surgery
?Patients with Cushing?s syndrome due to ectopic ACTH secretion
?Patients with hypercortisolism secondary to adrenal tumors or Nodular (primary) bilateral adrenal hyperplasia
?Patients who have a known inherited syndrome as the cause for hormone over secretion (i.e. Carney Complex, McCune-Albright syndrome, MEN-1)
?Patients with a diagnosis of glucocorticoid-remedial aldosteronism (GRA)
?Patients who are hypothyroid and not on adequate replacement therapy
?Patients who have undergone major surgery within 1 month
?Patients with symptomatic cholelithiasis
?Diabetic patients on antidiabetic medications whose fasting blood glucose is poorly controlled as evidenced by HbA1C >8%
?Patients with abnormal coagulation (PT or PTT elevated by 30% above normal limits)
?Patients receiving anticoagulants that affect PT or PTT
?Patients who have congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, symptomatic bradycardia, advanced heart block, history of acute MI less than one year prior to study entry or clinically significant impairment in cardiovascular function.
?Patients with risk factors for torsade de pointes, i.e. patients with a baseline QTc >480 ms, hypokalemia, family history of long QT syndrome, and concomitant medications known to prolong QT interval
?Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis, or patients with ALT/AST more than 2 X ULN, serum creatinine >2.0 X ULN, serum bilirubin >2.0 X ULN, serum albumin < 0.67 X LLN
?Patients with WBC <3 X 109/L; Hgb < LLN ; PLT <100 X 109/L
?Patients who have any current or prior medical condition that can interfere with the conduct of the study or the evaluation of its results in the opinion of the investigator or the sponsor?s medical monitor
?Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a medically acceptable method for birth control. Female patients must use barrier contraception with condoms. If oral contraception is used, the patient must have been practicing this method for at least two months prior to enrollment and must agree to continue the oral contraceptive throughout the course of the study and for one month after the last dose of study drug. Male patients who are sexually active are required to use condoms during the study and for 1 month afterwards
?History of immunocompromise, including a positive HIV test result (Elisa and Western blot). A HIV test will not be required, however, previous medical history will be reviewed
?Patients who have a history of alcohol or drug abuse in the 6 month period prior to receiving pasireotide
?Patients who have given a blood donation (of 400 ml or more) within 2 months before receiving pasireotide
?Patients who have participated in any clinical investigation with an investigational drug within 1 month prior to dosing and patients who have previously been treated with pasireotide
?Known hypersensitivity to somatostatin analogues
?Patients with active malignant disease within the last five years (with the exception of basal cell carcinoma or carcinoma in situ of the cervix)
?Patients with the presence of active or suspected acute or chronic uncontrolled infection
?Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will be unable to complete the entire study |
?Pacientes que hayan recibido irradiación hipofisaria, durante los DIEZ últimos años previos a la Visita 1, ya que no puede determinarse el momento en el que empiezan a aparecer los efectos de la radiación.
?Pacientes que han sido tratados con mitotano durante los últimos 6 meses antes de la visita basal.
?Pacientes con compresión del quiasma óptico que les produce algún defecto del campo visual, con el fin de poder excluir a los pacientes con un tumor causante de compresión del quiasma que requiera cirugía.
?Pacientes con síndrome de Cushing por secreción ectópica de ACTH.
?Pacientes con hipercortisolismo secundario a tumores suprarrenales o a hiperplasia nodular suprarrenal bilateral (primaria).
?Pacientes con un síndrome hereditario conocido como la causa de hipersecreción hormonal (es decir, Complejo de Carney, síndrome de McCune-Albright, MEN-1).
?Pacientes con diagnóstico de aldosteronismo sensible a glucocorticoides (GRA).
?Pacientes HIPOTIROIDEOS.
?Pacientes sometidos a una cirugía mayor en el plazo de 1 mes antes del inicio del estudio.
?Pacientes con colelitiasis sintomática.
?Pacientes diabéticos tratados con antidiabéticos cuya glucemia en ayunas no está bien controlada, demostrado por una HbA1c > 8%.
?Pacientes con coagulación anómala (TP o TTP un 30% por encima de los límites normales).
?Pacientes en tratamiento con anticoagulantes que afectan al TP o al TTP.
?Pacientes con insuficiencia cardiaca congestiva (clase III o IV de la NYHA), angina inestable, taquicardia ventricular sostenida, bradicardia clínicamente significativa, bloqueo cardíaco en estado avanzado, antecedentes de IM agudo en menos de un año antes de la entrada en el estudio o alteraciones clínicamente significativas en la función cardiovascular.
?Pacientes con hepatopatía, como cirrosis, hepatitis crónica activa o hepatitis crónica persistente, o pacientes con niveles de ALT/AST > 2 x LSN, de creatinina sérica > 2,0 x LSN, de bilirrubina sérica > 2,0 x LSN y de albumina sérica< 0,67 x LIN.
?Pacientes con un recuento de leucocitos < 3 x 109/l; Hb < LLN; plaquetas <100 x 109/l.
?Pacientes con algún trastorno médico presente o pasado que, en opinión del investigador o del monitor médico del promotor, pudiera interferir con la realización del estudio o la evaluación de sus resultados.
?Pacientes embarazadas o en periodo de lactancia, o en edad fértil que no utilizan ningún método anticonceptivo médicamente aceptable. Las pacientes deberán usar anticoncepción de barrera con preservativo. Si se utiliza anticoncepción oral, la paciente debe haber estado usando este método durante al menos dos meses antes de la inclusión en este estudio y deberán acceder a continuar con la anticoncepción oral durante todo el estudio y hasta un mes después de la última dosis del fármaco del mismo. Los pacientes varones sexualmente activos deberán usar preservativos durante todo el estudio y hasta 1 mes tras su finalización.
?Antecedentes de inmunosupresión, incluido un resultado de positividad del VIH (Elisa y Western blot). No se exigirá una prueba de detección de VIH, aunque se revisará la historia médica previa.
?Pacientes con antecedentes de alcoholismo o toxicomanía durante un periodo de 6 meses anterior a la administración de pasireotide.
?Pacientes que han donado sangre (400 ml o más) en los 2 meses anteriores a la administración de pasireotide.
?Pacientes que han participado en alguna investigación clínica con un fármaco experimental en el mes anterior a la primera dosis Y PACIENTES TRATADOS PREVIAMENTE CON PASIREOTIDE.
?Hipersensibilidad conocida a los análogos de somatostatina.
?Pacientes con otras neoplasias malignas activas en los cinco años anteriores (con la excepción del carcinoma de células basales o del carcinoma cervical in situ).
?Pacientes que presenten infección aguda o crónica activa o sospechada no controlada.
?Pacientes con antecedentes de falta de cumplimiento terapéutico o que se considera que son potencialmente no fiables o que serán incapaces de completar todo el estudio.
. Pacientes con factores de riesgo de Torsade de Pointes, es decir, pacientes con un QTC basal > 480 MS, hipocalcemia, antecedentes familiares de Síndrome QT prolongado y medicaciones concomitantes que se conozca que prolongan el intervalo QT. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy parameter will be the proportion of patients in each independent treatment arm with mean UFC concentrations ? 1.0 X ULN at month 6 of pasireotide treatment. Patients required to be unblinded and to increase the dose at month 3 will be classified as non-responders for the month 6 primary analysis . |
| El parámetro principal de eficacia se basará en la proporción de pacientes en cada rama de tratamiento independiente con UNA MEDIA DE UFC ? 1,0 x LSN a los 6 meses de tratamiento. PACIENTES UNBLINDED A LOS 3 MESES SE CONSIDERARAN COMO NO RESPONDEDORES. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After 6 months of treatment. |
| A los 6 meses de tratamiento. |
|
| E.5.2 | Secondary end point(s) |
UFC response according to the primary efficacy criteria will be calculated at month 6 regardless of their mean UFC level at month 3.
Secondary efficacy parameters
Reduction of UFC to ? 1.0xULN at month 3 and 12: percent of patients whose mean UFC is ? 1xULN.
Time to first response: time to first mean UFC ? 1.0xULN
Serum cortisol: A predose blood draw for serum cortisol sampling will be taken at every visit (at baseline and every 15 days for the first 3 months, every month thereafter, and at study completion). Procedures for sample drawing, handling, storage and transportation will be provided by the central laboratory.
Plasma ACTH: A predose blood draw for plasma ACTH sampling will be taken at every visit (at baseline and every 15 days for the first 3 months, every month thereafter, and at study completion). Procedures for sample drawing, handling, storage and transportation will be provided by the central laboratory.
Median UFC response: The efficacy variable will be defined as the proportion of patients in each independent treatment arm with ? 1.0 X ULN median UFC at month 6.
The clinical signs and symptoms related to Cushing?s disease will be evaluated at baseline, 3, 6 and 12 months (except body composition and bone mineral density which will be assessed at baseline, 6 and 12 months; [Germany Only -for patients in Germany body composition and bone mineral density will not be determined]
Tumor volume: an MRI scan will be performed at baseline, at 6 and at 12 months.
Censor-adjusted response: Patients discontinuing at or before month 6 for reasons unrelated to efficacy will be considered unobserved and non-responders at all subsequent visits
Pooled UFC response: the pooled percentage of patients in both the pasireotide 600 ?g sc bid and 900 ?g treatment arms meeting the primary efficacy criteria month 6 will be provided.
Response by dose group at intermediate visits
Quality of Life: a quality of life assessment will be performed at baseline, 3, 6 and 12 months. |
| Los criterios secundarios para la evaluación de la eficacia incluirán la respuesta ajustada por censura, la respuesta agrupada de UFC, la mediana de la respuesta UFC, el nivel de cortisol en suero, ACTH, los signos y síntomas clínicos de la enfermedad de Cushing, la calidad de vida y el tamaño del tumor hipofisario como se ha descrito anteriormente |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After 6 months of treatment. |
| A los 6 meses de tratamiento. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| randomizacion a diferentes dosis de pasireotide |
| Randomization to different doses of pasireotide |
|
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| randomizacion a diferentes dosis de pasireotide |
| randomization to different doses of pasireotide |
|
| 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 | 26 |
| 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 |
| Argentina |
| Belgium |
| Brazil |
| Canada |
| China |
| Denmark |
| Finland |
| France |
| Germany |
| Greece |
| Israel |
| Italy |
| Mexico |
| Poland |
| Portugal |
| Spain |
| Turkey |
| United States |
|
| 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
|
| Patients could have the option of reciving treatment while they go on demostrating benefit and they don't experienced unnacceptable toxicity. |
| Los pacientes tendrán la opción de recibir terapia mientras continuen demostrando beneficio y no experimenten toxicidad inaceptable. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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