E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Resistant hypertension |
hypertension résistante |
|
E.1.1.1 | Medical condition in easily understood language |
High blood pressure not controlled |
hypertension résistante |
|
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 | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10015491 |
E.1.2 | Term | Essential hypertension, unspecified |
E.1.2 | System Organ Class | 100000004866 |
|
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 whether LHW090 displays the clinical safety and efficacy profile to support further development in patients with resistant hypertension: i.e
- To assess the safety and tolerability of LHW090 for 4 weeks on a background of conventional anti-hypertensive medications in patients with resistant hypertension.
- To evaluate the effect of LHW090 on placebo-adjusted mean daytime systolic blood pressure (SBP) after 4 weeks in patients with resistant hypertension.
|
Évaluer la sécurité d’emploi et la tolérance du LHW090 pendant 4 semaines en association aux traitements antihypertenseurs conventionnels chez des patients présentant une hypertension résistante
Évaluer l'effet du LHW090 sur la pression artérielle systolique (PAS) moyenne diurne ajustée en fonction du placebo après 4 semaines chez des patients présentant une hypertension résistante. |
|
E.2.2 | Secondary objectives of the trial |
To evaluate the pharmacokinetics (PK) of LHW090 and its active metabolite LHV527 in patients with resistant hypertension. |
Évaluer la pharmacocinétique (PK) du LHW090 et de son métabolite actif LHV527 chez des patients présentant une hypertension résistante. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent must be obtained before any assessment is performed.
2. Male and female patients, age 40 to 85 years inclusive.
3. Demonstrating a ≥ 80% medication compliance rate during the single-blind run-in period.
4. Patients with uncontrolled hypertension (here defined as having a daytime BP ≥ 135/85 by ABPM) despite treatment with a stable (at least 2 months) regimen that includes an optimal dose of an ARB plus optimal doses of two or more of the following classes of anti-hypertensive medications: thiazide diuretics, loop diuretics, beta-blockers, and calcium channel blockers.
For the purposes of this trial, optimal doses of anti-hypertensive medications are defined as:
a) the highest dose listed in the clinical practice guideline from the American Society for Hypertension and the International Society for Hypertension [Weber, et al. 2014] or
b) the highest allowable prescribed dose per the manufacturer's label or
c) the highest dose tolerated by an individual patient or
d) the highest dose appropriate for an individual patient in the judgment of the Investigator
5. Subjects must weigh at least 45 kg to participate in the study and must have a body mass index
(BMI) within the range of 18-36 kg/m2.
6. Able to communicate well with the investigator, to understand and comply with the requirements of
the study.
Other protocol defined inclusion criteria may apply |
Obtention du consentement éclairé signé avant toute évaluation.
Hommes et femmes âgés de 40 à 85 ans (inclus)
Taux d'observance du traitement ≥ 80 % pendant la période de d’initiation en simple aveugle.
Hypertension non contrôlée (définie ici comme une PA moyenne diurne ≥ 135/85 mesurée par MAPA) malgré un schéma thérapeutique stable (au moins 2 mois) comprenant une dose optimale d'un ARA plus des doses optimales d'un diurétique plus un médicament anti-hypertenseur appartenant à l'une des classes de médicaments suivantes : bêta-bloquants ou inhibiteurs calciques.
Aux fins de cet essai, les doses optimales de médicaments anti-hypertenseurs sont définies comme suit :
la plus forte dose énoncée dans les recommandations de pratique clinique de l'American Society for Hypertension and the International Society for Hypertension (Weber et al 2014) ou
la plus forte dose prescrite autorisée conformément au résumé des caractéristiques produit (RCP) du fabricant ou
la plus forte dose tolérée par un patient individuel ou
la plus forte dose appropriée pour un patient individuel selon l'avis de l'investigateur.
Remarque : les valeurs MAPA documentées dans les 3 mois précédant la sélection sont acceptables.
Les sujets doivent peser au moins 45 kg pour participer à l'étude et doivent avoir un indice de masse corporelle (IMC) dans la plage de 18 à 36 kg/m2.
Être en mesure de bien communiquer avec l'investigateur, de comprendre et respecter les exigences de l'étude. |
|
E.4 | Principal exclusion criteria |
Use of other investigational drugs at the time of enrollment, or within 30 days or 5 halflives
of enrollment, whichever is longer; or longer if required by local regulations, and for
any other limitation of participation in an investigational trial based on local regulations.
2. History of hypersensitivity to any of the study drugs or to drugs of similar chemical
classes.
3. Patients with an estimated GFR <60 ml/min/1.73m2 at screening using the MDRD
equation.
4. Use of angiotensin converting enzyme inhibitors (ACE-inhibitors).
Note: Patients who discontinue their ACE-inhibitor and substitute with an angiotensin
receptor blocker may be eligible to be re-screened provided their anti-hypertensive
regimen has been stable for at least 2 months. Any substitutions or changes to a patient's
anti-hypertensive regimen should be done under the guidance of the patient's treating
physician.
5. Clinically significant ECG abnormalities at screening as determined by the Investigator.
6. Severe hypertension as defined by systolic blood pressure ≥180 mmHg or diastolic blood
pressure ≥110 mmHg at screening.
7. A history of secondary hypertension of any etiology including but not limited to unilateral
or bilateral renal artery stenosis, polycystic kidney disease, coarctation of the aorta,
primary hyperaldosteronism, Cushing's disease, pheochromocytoma, and drug-induced
hypertension.
8. Known current significant left ventricular outflow obstruction, such as obstructive
hypertrophic cardiomyopathy or significant severe valvular disease on prior or current
echocardiogram).
9. A history of known moderate or malignant retinopathy defined as moderate (retinal signs
of hemorrhage), microaneurysms, cotton-wool spots, hard exudates, or a combination
thereof) or malignant (signs of moderate retinopathy plus swelling of the optic disk).
10. To facilitate ABPM assessment of daytime readings, an upper arm circumference greater
than 42 cm or third shift or overnight workers.
11. History within the previous 6 months of myocardial infarction, coronary artery bypass
graft (CABG), percutaneous coronary intervention (PCI), hypertensive encephalopathy,
stroke, or transient ischemic attack (TIA).
12. Hemoglobin levels below 9.0 g/dL at screening.
13. History of malignancy of any organ system (other than localized basal cell carcinoma of
the skin or in-situ cervical cancer), treated or untreated, within the past 1 year, regardless
of whether there is evidence of local recurrence or metastases.
14. Donation or loss of 400 mL or more of blood within 8 weeks prior to initial dosing, or
longer if required by local regulation.
15. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female
after conception and until the termination of gestation, confirmed by a positive hCG
laboratory test.
16. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during dosing and for 1 week after stopping study medication.
17. Sexually active males must use a condom during intercourse while taking drug and for
1 week after stopping study medication and should not father a child in this period.
A condom is required to be used also by vasectomized men in order to prevent delivery of
the drug via seminal fluid.
18. Any surgical or medical condition, which in the opinion of the investigator, may place the
patient at higher risk from his/her participation in the study, or is likely to prevent the
patient from complying with the requirements of the study or completing the study.
19. Vulnerable subjects, e.g. subjects kept in detention, soldiers and employees of the sponsor
or a clinical research organization, involved in this study.
Other protocol defined exclusion criteria may apply |
d'exclusion
Débit de filtration glomérulaire (DFG) estimé < 60 ml/min/1,73m2.
Utilisation d'inhibiteurs de l’enzyme de conversion de l'angiotensine II (IEC).
Remarque : Les patients qui arrêtent leur traitement par un IEC et le remplace par un ARAII peuvent être éligibles et faire l'objet d'une nouvelle sélection à condition que leur traitement anti-hypertenseur ait été stable pendant au moins 2 mois. Toutes les substitutions ou modifications d'un traitement anti-hypertenseur doivent être effectuées sous la direction du médecin traitant du patient.
Hypertension artérielle sévère telle que définie par une PAS ≥180 mmHg ou une PAD ≥ 110 mmHg à la sélection.
Antécédents d'hypertension secondaire de toute étiologie, incluant notamment une sténose unilatérale ou bilatérale de l'artère rénale, une polykystose rénale, une coarctation de l'aorte, un hyperaldostéronisme primaire, une maladie de Cushing, un phéochromocytome et une hypertension d'origine médicamenteuse.
Obstruction de l'éjection ventriculaire gauche significative connue, telle qu'une cardiomyopathie hypertrophique obstructive ou une valvulopathie sévère significative visible sur une échocardiographie antérieure ou actuelle).
Antécédents de rétinopathie connue, modérée ou maligne, définie comme modérée (signes d'hémorragie rétinienne, microanévrismes, nodules cotonneux, exsudats durs, ou une combinaison de ceux-ci), ou comme maligne (signes de rétinopathie modérée plus oedème papillaire).
Pour faciliter l'évaluation MAPA, circonférence du bras supérieure à 42 cm ou travailleurs en 3x8 ou travailleurs de nuit.
Antécédents au cours des 6 derniers mois d'infarctus du myocarde, de pontage aorto-coronarien, d'angioplastie coronarienne percutanée, d'encéphalopathie hypertensive, d'accident vasculaire cérébral (AVC) ou d'accident ischémique transitoire (AIT). |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Safety endpoints (adverse events, serious adverse events) will be measured up to and including end of study assessments
The primary efficacy variable will be the change in the 12 hour average of systolic blood pressure
measured by ambulatory blood pressure monitoring (ABPM) 28 days following the start of treatment
|
Les évlauations de la sécurité d’emploi (évènements indésirables, évènements indésirables graves) seront réalisées jusqu’à la fin de l’analyse des données de l’étude.
La variable d'efficacité primaire sera la variation de la moyenne sur 12 heures de la pression artérielle systolique mesurée la MAPA 28 jours après le début du traitement.
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
-Efficacy and Safety parameters will be routinely evaluated over the 4 weeks of treatment as defined in the protocol
-ABPM measured at baseline and at the end of the treatment at day 28 |
- Les paramètres de sécurité d’emploi et d’efficacité seront évalués systématiquement pendant les 4 semaines de traitement comme défini dans le protocole.
- La mesure ambulatoire de la pression artérielle (MAPA) sera réalisée au début et à la fin du traitement au jour 28
|
|
E.5.2 | Secondary end point(s) |
Pharmacokinetics (PK) parameters of LHW090 and its active metabolite LHV527 in patients with resistant hypertension.
|
Évaluer la pharmacocinétique (PK) du LHW090 et de son métabolite actif LHV527 chez des patients présentant une hypertension résistante. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
As defined in the protocol : PK parameters will be measured on Day 28 (Cmax, Tmax, AUClast, AUC0-t) |
Comme défini dans le protocole, le recueil des évaluations la pharmacocinétique (PK) se fera au jour 28. |
|
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) | 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 | Yes |
E.8.1.7.1 | Other trial design description |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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 |
France |
Germany |
Switzerland |
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
|
LVLS |
dernier patient dernière visite |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 13 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 12 |
E.8.9.2 | In all countries concerned by the trial days | 19 |