| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of mild to moderate essential hypertension (MSDBP > or = 95 mmHg and < 110 mmHg) |
| Tratamiento de hipertensión esencial de leve a moderada (PADms > o = a 95 mmHg y < 110 mmHg) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with mild to moderate hypertension (increased blood pressure) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10015488 |
| E.1.2 | Term | Essential hypertension |
| E.1.2 | System Organ Class | 10047065 - Vascular 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 |
| To determine the dose-response of the various combinations of nifedipine GITS (gastrointestinal therapeutic system) and candesartan as compared to monotherapy and placebo based on the blood pressure (BP) lowering effects (mean seated diastolic blood pressure [MSDBP]) of a once daily regimen in subjects with World Health Organization (WHO) classification Grades 1 and 2 essential hypertension (MSDBP > or = 95 mmHg and < 110 mmHg). |
| El objetivo principal es determinar la relación dosis-respuesta de las distintas combinaciones de nifedipino GITS y candesartán comparadas con monoterapia y placebo sobre la base de los efectos de reducción de PA (PADms) de una pauta de dosis única diaria en sujetos con hipertensión esencial de Grados 1 y 2 según la clasificación de la Organización Mundial de la Salud (OMS) (PADms > ó = a 95 mmHg y < 110 mmHg |
|
| E.2.2 | Secondary objectives of the trial |
To confirm the best chosen dosage by tests for the responder rate, the control rate and the changes of MSDBP and mean seated systolic blood pressure (MSSBP) at week 8 from the baseline.
To assess safety and tolerability of the combination product. |
Confirmar la mejor dosificación elegida a través de pruebas para determinar la tasa de respuesta, la tasa de control y los cambios en PADms y presión arterial sistólica media en posición sedente (MSSBP) en la semana 8 a partir del período basal
Evaluar la seguridad y tolerabilidad del producto de combinación. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female subjects 18 years or older. Female subjects must be either post-menopausal for one year, surgically sterile, or using an effective contraceptive method. Hormonal contraceptive use is disallowed.
2. Subjects must have mild to moderate essential hypertension (Grade 1 and 2 WHO classifications) as measured by a calibrated electronic BP measuring device (as of Amd 1). (MSDBP of > or = 90 mmHg and < 110 mmHg at Visit 1 (placebo run-in), and MSDBP of > or = 95 mmHg and < 110 mmHg at Visit 2 (randomization)
3. Subjects must have an absolute difference in their MSDBP of less than 10 mmHg between Visit 1 (placebo run- in) and Visit 2 (randomization).
4. Written informed consent. |
1. Son elegibles hombres y mujeres de 18 años de edad o mayores. Las mujeres cumplirán alguno de los siguientes requisitos: haber transcurrido como mínimo un año desde el inicio del período menopáusico, ser quirúrgicamente estéril o utilizar un método anticonceptivo eficaz distinto del hormonal.
2. Sujetos con hipertensión esencial de leve a moderada (Grados 1 y 2 según clasificación de la OMS) medida con un esfigmomanómetro electrónico calibrado (según la Enmienda 1). Los sujetos deben tener una PADms de > ó = a 90 mmHg y < 110 mmHg en la visita 1 (semana -4 a -2) y una PADms de > ó = a 95 mmHg y < 110 mmHg en la visita 2 (semana 0).
3. Los sujetos deben tener una diferencia absoluta en su PADms de menos de 10 mmHg entre las visitas 1 y 2.
4. Consentimiento informado escrito |
|
| E.4 | Principal exclusion criteria |
- Severe hypertension (Grade 3 WHO classification; MSDBP ? 110 mmHg
and/or MSSBP ? 180 mmHg).
- Inability to washout of antihypertensive drugs (even if prescribed for
another indication) safely for a period of 14 weeks.
- History of hypertensive retinopathy ? known Keith Wagener Grade III
or IV.
- History of hypertensive encephalopathy.
- Cerebrovascular ischemic event (stroke, transient ischemic attack
[TIA])within the previous 12 months.
- History of intracerebral hemorrhage or subarachnoid hemorrhage.
- Evidence of secondary hypertension such as coarchation of the aorta,
pheochromocytoms, hypersaldosteronism, etc.
- Type I diabetes mellitus (DM) or poorly controlled DM Type II as
evidenced by a glycosylated hemoglobin [HbA1C] of greater than 9% on
visit 1.
- Allergies or known intolerance to one of the investigational drugs/drug
class or to one of their ingredients.
- Any history of heart failure, New York Heart Association (NYHA)
classification III or IV.
- Severe coronary heart disease as manifest by a history of myocardial
infarction or unstable angina in the last 6 months prior to visit 1.
- Clinically significant cardiac valvular disease.
- History of malignancy in the last 5 years, excluding basal or skin
cancer.
- Uncorrected hypokalemia or hyperkalemia: potassium outside 3.4-5.4
mmol/L (as of Amd 1).
- Surgical or medical conditions that might alter the metabolism,
excretion or distribution or absorption of any
drug:
- Gastrointestinal disease or surgery resulting in the potential for
malabsorption.
- Severe gastrointestinal tract narrowing; kock pouch (ileostomy after
proctocolectomy).
- Cholestasis or biliary obstruction or history of pancreatic injury or
clinical significant increase of lipase, amylase, or bilirubin.
- Liver disease or AST/ALT levels > 3 x upper limit of normal (ULN).
- Renal insufficiency, defined as eGFR of < 50 mL/min (computed using
the Cockroft-Gault formula, see Section 7.6.2) (as of Amd 1), or on
hemodialysis.
- Female subjects who are pregnant or lactating.
- Subjects who have night employment (night shift).
- Subjects with an aortic aneurysm that, in the opinion of the
investigator, will be unsuitable to be enrolled in the study.
- If differences greater than 20 mmHg for SBP and 10 mmHg for DBP are
present on 3 consecutive BP readings, the subject should be excluded
from the study. |
-Hipertensión severa (Grado 3 según clasificación de la OMS, PADms > ó = a 110 mmHg y/o PASms > ó = a 180 mmHg)
-Imposibilidad de realizar lavado de medicaciones antihipertensivas (incluso las prescritas para otra indicación) de forma segura durante un período de 14 semanas.
-Antecedentes de retinopatía hipertensiva (grado III o IV según clasificación de Keith-Wagener)
-Antecedentes de encefalopatía hipertensiva
-Accidente isquémico cerebrovascular (apoplejía, accidente isquémico transitorio [AIT]) en los 12 meses anteriores
-Antecedentes de hemorragia intracerebral o subaracnoidea
-Evidencia de hipertensión secundaria, como coartación aórtica, feocromocitomas, hiperaldosteronismo, etc.
-Diabetes mellitus (DM) de tipo I o DM de tipo II incorrectamente controlada demostrada por una hemoglobina glucosilada [HbA1C] superior al 9% en la visita 1.
-Alergias o intolerancia conocida a una de las medicaciones/clases de medicaciones del estudio o a cualquiera de sus componentes
-Antecedentes de fallo cardíaco de tipo III o IV según clasificación de la New York Heart Association (NYHA)
-Enfermedad cardíaca coronaria severa evidenciada por antecedentes de infarto de miocardio o angina inestable en los 6 meses anteriores a la visita 1.
-Enfermedad valvular cardíaca de trascendencia clínica
-Antecedentes de neoplasia maligna en los últimos 5 años, sin incluir carcinoma basal o cáncer de piel
-Hiperkalemia o hipokalemia no corregida: potasio fuera de los niveles 3,4-5,4 mmol/l (según la Enmienda 1)
-Estados quirúrgicos o médicos que pudieran alterar la absorción, la distribución, el metabolismo o la excreción de alguna de las medicaciones
- Enfermedad o cirugía gastrointestinal que pudiera provocar una malabsorción
- Estrechamiento severo del tracto gastrointestinal; bolsa de Kock (ileostomía posterior a proctocolectomía)
- Colestasis u obstrucción biliar o antecedentes de lesión pancreática o aumento de la lipasa, la amilasa o la bilirrubina de trascendencia clínica.
- Enfermedad hepática o niveles de AST/ALT >3 x LSN
- Insuficiencia renal, definida como eGFR de < 50 ml/min. (calculado utilizando la fórmula de Cockroft-Gault, véase la Sección 7.5.2) (según la Enmienda 1) o en hemodiálisis
- Sujetos mujeres embarazadas o en período de lactancia.
- Sujetos que desempeñen un empleo nocturno (turno de noche).
- Sujetos con aneurisma aórtico que, en opinión del investigador, no resulten elegibles para su inclusión en el estudio.
- Si existen diferencias mayores que 20 mmHg para PAS y 10 mmHg para PAD en tres lecturas de PA consecutivas, el sujeto debe ser excluido del estudio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy variable is the change from baseline in mean seated
diastolic blood pressure (MSDBP) at Week 8. |
| El criterio principal de valoración de la eficacia es la variación media en la PADms en la semana 8. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Visit 7, week 8 |
| Visita 7, semana 8 |
|
| E.5.2 | Secondary end point(s) |
| Change in MSSBP at Week 8, Control rate at Week 8, Response rate at week 8, Peripheral Edema |
| Variación de PASms en la semana 8, tasa de control en la semana 8. tasa de respuesta en la semana 8, edema periférico |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Visit 7, week 8 |
| Visita 7, semana 8 |
|
| 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 | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 16 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| 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 |
| Italy |
| Korea, Republic of |
| Lithuania |
| Russian Federation |
| South Africa |
| Spain |
| Ukraine |
| United Kingdom |
| 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
|
| According to protocol: 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 | 1 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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