| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10081349 |
| E.1.2 | Term | Resistant hypertension |
| E.1.2 | System Organ Class | 100000004866 |
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| 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 evaluate the efficacy and dose-response relationship of different doses of XXB750 SC compared to placebo in reducing the mean 24hr ambulatory systolic blood pressure (mean 24hr SBP) from baseline at Week 12. |
Evaluer l'efficacité et la relation dose-réponse du XXB750 30 mg SC q4w, 60 mg SC q4w, 120 mg SC q4w et 240 mg SC q4w par rapport
au placebo dans la réduction de la pression artérielle systolique ambulatoire moyenne sur 24 heures (PAS moyenne sur 24 heures) de la baseline à la semaine 12. |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the treatment effect of the highest XXB750 dose versus placebo in reducing the mean 24hr SBP from baseline to Week 12.
To characterize the dose-response relationship of XXB750 compared to placebo in the nocturnal systolic blood pressure (SBP) dipping at Week 12.
To evaluate the proportions of participants achieving ambulatory BP control (i.e., mean 24hr SBP < 130 mmHg and mean 24hr DBP < 80 mmHg) with respect to the dose-response relationship of the four XXB750 dose level groups compared to placebo at week 12.
To evaluate the safety and tolerability of the XXB750 regimens over 12 weeks of treatment and over the 20-week study period.
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Evaluer l'effet du traitement en utilisant la dose la plus élevée de XXB750 par rapport au placebo dans la réduction de la PAS moyenne sur 24 heures entre la baseline et la semaine 12.
Evaluer la relation dose-réponse du XXB750 30 mg SC q4w, 60 mg SC q4w, 120 mg SC q4w et 240 mg SC q4w par rapport au placebo dans la baisse de la PAS nocturne à la semaine 12.
Evaluer les proportions de patients obtenant le contrôle de la PA (pression artérielle) par le monitorage ambulatoire de la pression artérielle - MAPA (c.-à-d., PAS moyenne sur 24 heures < 130 mmHg et pression artérielle diastolique ambulatoire moyenne sur 24 heures (PAD moyenne sur 24 heures)
<80 mmHg) et relation dose-réponse dans les quatre groupes de niveaux de dose de XXB750 par rapport au placebo à la semaine 12.
Evaluer la sécurité d'emploi et la tolérance des schémas thérapeutiques XXB750 sur 12 semaines de traitement et sur les 20 semaines globales de la durée de l'étude, y compris le suivi de la sécurité d'emploi |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female participants who are ≥ 18 years old.
2. Signed informed consent prior to participation in the study.
3. Apparent rHTN at screening (Visit 1) defined as uncontrolled BP with an office msSBP ≥ 145 mmHg despite treatment with stable (i.e., unchanged for ≥4 weeks), maximally tolerated doses of three antihypertensive drugs of different classes, specifically an ACEI/ARB, a long-acting dihydropyridine CCB, and a thiazide or thiazide-like diuretic. Refer to Section 10.8 for minimum required doses of some commonly prescribed drugs in those classes.
4. Mean 24hr SBP ≥135 mmHg (measured by ABPM) at the end-of Run-in-Visit (Visit 30) on treatment with maximally tolerated doses of an ACEI/ARB, a long-acting dihydropyridine CCB, and a thiazide or thiazide-like diuretic.
Additional inclusion criteria are described in the clinical study protocol. |
1.Patients masculins et féminins âgés de 18 ans ou plus.
2. Recueil du formulaire de consentement éclairé signé avant la participation à l’étude
3.HTAr apparente à la visite de sélection (visite 1) définie comme une PA non contrôlée avec une PAS moyenne assise en consultation ≥ 145 mmHg malgré un traitement par doses maximales tolérées stables (c.-à-d. inchangées pendant ≥ 4 semaines) de trois médicaments antihypertenseurs de différentes classes, en particulier un iECA/ARA, un ICC dihydropyridine à action prolongée et un diurétique thiazidique ou de type thiazidique. Reportez-vous à la section 10.8 pour connaître les doses minimales requises de certains médicaments couramment prescrits dans ces classes.
4. PAS moyenne sur 24 heures ≥ 135 mmHg (mesurée par MAPA) à la fin de la visite de run-in (visite 30) sous traitement par les doses maximales tolérées d'un iECA/ARA, d'un ICC dihydropyridine à action prolongée et d'un diurétique thiazidique ou de type thiazidique.
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| E.4 | Principal exclusion criteria |
1. Office msSBP <140 mmHg (at Visit 20 or Visit 30) OR or office msSBP ≥180 mmHg or office msDBP ≥110 mmHg at the end-of-run-in visit (Visit 30) OR 24h mean SBP ≥170 mmHg or 24h mean DBP ≥105 mmHg measured by ABPM at the end of the run the Run-in (Visit 30)
2. Known history of secondary hypertension (moderate-to-severe obstructive sleep apnea without receiving CPAP therapy (either face mask or nasal device), renovascular hypertension, primary aldosteronism, pheochromocytoma, Cushing syndrome, aortic coarctation or other cause of secondary hypertension).
3. Estimated GFR <30 mL/min/1.73m2 using CKD-Epi equation at screening (Visit 1) or at end-of-run-in visit (Visit 30).
4. Serum potassium >5.0 mmol/L (or equivalent plasma potassium value) at screening or end-of-run-in visit (Visit 30).
5. Current therapy with a mineralocorticoid receptor antagonist (MRA) or received an MRA within the 4 weeks prior to screening.
6. Type I diabetes mellitus or uncontrolled Type II diabetes (defined as a plasma HbA1c ≥9%)
7. Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), high-grade AV block (e.g., Mobitz type II and third-degree AV block in absence of a pacemaker) within 6 months of screening according to investigator's judgement.
8. Chronic non-paroxysmal atrial fibrillation
9. Acute myocardial infarction (AMI) or unstable angina, or any history of ischemic or hemorrhagic stroke within 12 months of screening; or any percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) within 12 months of screening
10. History of a renal denervation procedure.
11. Mid-arm circumference ≥42 cm.
12. Hospitalization for hypertensive emergency / crisis within the 12 months prior to screening.
13. Received any antihypertensive medication other than the CCB, ACEI/ARB, and thiazide/thiazide-like diuretic components of the triple background antihypertensive therapy, including sacubitril/valsartan within the 4 weeks before screening (Visit 1). Participants receiving beta blockers and prostate-specific alpha blockers (e.g., tamsulosin) are allowed in the study only if those medications are being used for non-hypertension indications and benign prostatic hypertrophy, respectively.
14. Night shift workers.
15. History of presence of any other disease where the life expectancy is less than 3 years.
16. History of malignancy of any organ system (other than localized basal or squamous cell carcinoma of the skin or localized prostate cancer), treated or untreated, within the past 3 years, regardless of whether there is evidence of local recurrence or metastases.
17. Evidence of hepatic disease as determined by any one of the following: SGOT (AST) or SGPT (ALT) values exceeding 3x the upper limit of normal (ULN), or bilirubin >1.5 mg/dl at Visit 1.
18. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer.
19. History of drug abuse or alcohol dependency.
20. Lacking the ability to comprehend or follow instructions, or for any reason in the opinion of the investigator, a participant that would be unlikely or unable to comply with study protocol.
21. Concurrent enrollment in any other investigational drug or device trial (participation in non-interventional registries is acceptable).
22. Requiring prolonged/regular use of NSAIDs or other prohibited medications during of the study (i.e., required use for longer than 1 week).
23. Pregnant, nursing or planning to become pregnant (documented negative pregnancy test required within a maximum of 7 days prior to enrollment of all women of childbearing potential). Documentation of highly effective contraception is also required for women of childbearing potential (see below).
Additional exclusion criteria are described in the clinical study protocol.
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1.PAS moyenne assise en consultation <140 mmHg à la visite 20 ou à la visite 30 OU PAS moyenne assise en consultation ≥180 mmHg ou PAD moyenne assise en consultation ≥110 mmHg à la visite de fin de run-in (visite 30) OU PAS moyenne sur 24 heures ≥170 mmHg ou PAD moyenne sur 24 heures ≥105 mmHg mesurée par MAPA à la visite de fin de run-in (visite 30).
2.Antécédents connus d'hypertension secondaire (apnée obstructive du sommeil modérée à sévère sans traitement CPAP (masque facial ou dispositif nasal), hypertension rénovasculaire, hyperaldostéronisme primaire, phéochromocytome, syndrome de Cushing, coarctation aortique ou autre cause d'hypertension secondaire).
3.DFG estimé < 30 mL/min/1,73 m2 calculé à l'aide de l'équation CKD-Epi à la visite de sélection (visite 1) ou à la visite de fin de run-in (visite 30).
4.Potassium sérique > 5,0 mmol/L (ou valeur équivalente de potassium plasmatique) lors de la visite de sélection ou de la visite de fin de run-in (visite 30).
5.Traitement actuel par un antagoniste des récepteurs minéralocorticoïdes (ARM) ou sous ARM dans les 4 semaines précédant la sélection.
6.Arythmies cardiaques cliniquement significatives selon l'investigateur (par ex. tachycardie ventriculaire), bloc AV de haut degré (par ex. Mobitz de type II et bloc AV du troisième degré en l'absence de stimulateur cardiaque) dans les 6 mois suivant la sélection.
7. Prise de traitement antihypertenseur autre que ICC, iECA/ARA, et diurétiques thiazidiques ou de type
thiazidique dans le cadre de la trithérapie antihypertensive de fond, y compris sacubitril/valsartan, et
ce dans les 4 semaines précédant la visite de sélection (visite 1). Les patients traités avec des βbloquants et des α-bloquants spécifiques de la prostate (par exemple, tamsulosine) sont autorisés dans l’étude seulement si ces traitements sont utilisés dans des indications non-hypertensives et
d’hypertrophie bénine de la prostate.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in mean 24hr SBP at Week 12 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Change from baseline in mean 24hr SBP at Week 12
Nocturnal SBP dipping expressed as (nighttime mean SBP/daytime mean SBP) at Week 12
The proportions of participants achieving blood pressure control defined as mean 24hr SBP <130 mmHg and mean 24hr DBP <80 mmHg at Week 12
Adverse events, safety laboratory parameters, and vital signs through end of treatment/study (EOT/EOS)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 56 |
| 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 |
| Australia |
| China |
| Japan |
| South Africa |
| Taiwan |
| United States |
| Austria |
| France |
| Poland |
| Bulgaria |
| Netherlands |
| Spain |
| Czechia |
| Germany |
| Italy |
| Hungary |
| Monaco |
| Slovakia |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
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| 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 | 5 |
| E.8.9.1 | In the Member State concerned days | 8 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 12 |
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