| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of patients with difficult-to-treat and/or treatment-resistant hypertension (HTN). |
| Trattamento di pazienti con ipertensione difficile da trattare o resistente. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Treatment of patients with difficult-to-treat and/or treatment-resistant high blood pressure. |
| Trattamento di pazienti con pressione sanguigna elevata difficile da trattare/resistente. |
|
| 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 | 10036695 |
| E.1.2 | Term | Primary hypertension |
| 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 assess the effects of firibastat (QGC001) administered at 1000 mg orally (po) once daily (QD) on blood pressure (BP) over 12 weeks. |
| Valutare gli effetti di firibastat (QGC001) somministrato a una dose di 1.000 mg per via orale (po) una volta al giorno (QD) sulla pressione arteriosa (PA) nell’arco di 12 settimane. |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the safety of firibastat (QGC001) administered at 1000 mg po QD over 24 weeks and 48 weeks.
• To assess change in BP over time in subjects with uncontrolled primary HTN who have been treated with at least 2 classes of antihypertensive therapies at the maximum tolerated doses (MTDs) (ie, difficult-to-treat or treatment resistant patients). |
• valutare la sicurezza di firibastat (QGC001) somministrato a una dose di 1.000 mg po QD nell’arco di un periodo di 24 settimane e 48 settimane.
• Valutare la variazione della PA nel tempo in soggetti con HTN primaria non controllata che sono stati trattati con almeno 2 classi di terapie antipertensive alle dosi massime tollerate (MTD) (ovvero, pazienti difficili da trattare o resistenti al trattamento). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Able to understand and willing to provide written informed consent, and able to comply with the study procedures and restrictions.
2. Adult men and women (at Screening).
3. Diagnosis of primary HTN for at least 6 months prior to Screening and:
• Currently treated with 2 antihypertensive classes of drug (difficult-totreat subjects), or currently treated with at least 3 antihypertensive
classes of drug including a diuretic (treatment resistant subjects), at the MTDs of those medications (ie, the subject can tolerate the current dose of each medication but higher doses have caused or may worsen side effects), with no change in their antihypertensive regimen (drug, dose, or schedule) for at least 6 weeks, and with medication adherence >or=80% during the Run in Period.
• Have a systolic AOBP between 140 mmHg and 179 mmHg (inclusive) at Screening while on their current chronic antihypertensive treatments.
• Have a successful ABPM measurement with a mean systolic daytime ABP >135 mmHg after the Run-in Period while on their current chronic antihypertensive treatments. An ABPM is successful if at least 21 daytime readings and 6 nighttime readings have been successfully recorded.
4. Women of childbearing potential and nonsurgically sterile male subjects who are sexually active must agree to use an approved highly
effective form of contraception from the time of informed consent until 30 days post dose. Approved forms of contraception include hormonal intrauterine devices, hormonal contraceptives (oral birth control pills, depo, patch, or injectable) together with supplementary barrier methods such as condoms or diaphragms with spermicidal gel or foam.
5. Women of childbearing potential must have a negative serum pregnancy test result at Screening and a negative urine pregnancy test
result at the Inclusion Visit (Visit 2B, Day 1). |
1. In grado di comprendere e disposti a fornire il consenso informato scritto e in grado di conformarsi a tutte le procedure e le restrizioni dello studio.
2. Uomini e donne adulti (allo screening).
3. Diagnosi di HTN primaria per almeno 6 mesi prima dello screening e:
• attualmente trattati con 2 classi di farmaci antipertensivi (soggetti difficili da trattare), o attualmente trattati con almeno 3 classi di farmaci antipertensivi, compreso un diuretico (soggetti resistenti al trattamento), alle MTD di tali farmaci (ovvero, il soggetto è in grado di tollerare la dose attuale di ciascun farmaco, ma dosi più elevate hanno causato o potrebbero peggiorare gli effetti collaterali); senza alcuna variazione nel regime antipertensivo (farmaco, dose, o programma) per almeno 6 settimane, e con aderenza al farmaco >o=80% durante il Periodo di run-in.
• Presentano un’AOBP sistolica compresa tra 140 mmHg e 179 mmHg (inclusi) allo screening durante i loro attuali trattamenti antipertensivi cronici.
• Presentano una misurazione andata a buon fine dell’ABPM con un’ABP sistolica diurna media >135 mmHg dopo il periodo di run-in durante i loro attuali trattamenti antipertensivi cronici. Un’ABPM va a buon fine se sono state registrate almeno 21 letture diurne e 6 letture notturne.
4. Le donne in età fertile e i soggetti di sesso maschile non chirurgicamente sterili che sono sessualmente attivi devono accettare di utilizzare un metodo contraccettivo altamente efficace approvato dal momento del consenso informato fino a 30 giorni post-dose. Le forme di contraccezione approvate includono dispositivi intrauterini ormonali, contraccettivi ormonali (pillole contraccettive orali, formulazioni a lento rilascio, cerotto o iniettabili) insieme a metodi barriera supplementari come preservativi o diaframmi con gel o schiuma spermicida.
5. Le donne in età fertile devono presentare un risultato negativo al test di gravidanza sul siero allo screening e un risultato negativo al test di gravidanza sulle urine alla Visita di inclusione (Visita 2B, Giorno 1). |
|
| E.4 | Principal exclusion criteria |
1. Known or suspected secondary HTN (eg, hyperaldosteronism, renovascular HTN, pheochromocytoma, Cushing's disease).
2. Systolic AOBP >or=180 mmHg or DBP >or=110 mmHg at the Screening or Inclusion Visit (Visit 2B, Day 1) and confirmed by a second measurement within 30 minutes to 1 hour.
3. Known hypertensive retinopathy (Keith-Wagener Grade 3 or Grade 4) and/or hypertensive encephalopathy.
4. Upper arm circumference that is outside the limits of the studyprovided BP cuff associated with either the ABPM and/or AOBP
measurement device.
5. History of spontaneous or drug-induced angioedema.
6. History of any drug-related allergy or hypersensitivity to any components of the IP (firibastat [QGC001] or placebo).
7. Known severe aortic stenosis (symptomatic or asymptomatic with valvular indexed surface <0.5 cm²/m²).
8. Subjects with severe symptomatic heart failure (New York Heart Association [NYHA] Class III or Class IV).
9. History of acute coronary syndrome (non-ST elevation myocardial infarction [MI], ST elevation MI, and unstable angina pectoris), stroke,
or transient ischemic attack within 6 months prior to Visit 2A, Day 0.
10. Known history of malabsorption syndrome, or has undergone gastrointestinal surgery, including bariatric procedures that induce
chronic malabsorption, within 2 years of Screening.
11. Treatment with anti-obesity drugs or procedures 3 months prior to Screening (ie, surgery, aggressive diet regimen, etc.), leading to
unstable body weight.
12. Female who is breastfeeding, pregnant, or planning to become pregnant during the study period.
13. Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 3 years.
14. Shift workers who routinely sleep during the daytime and/or whose work hours include midnight.
15. Subjects with moderate to severe hepatic impairment (Child-Pugh A, B, or C); alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) >3×upper limit of normal (ULN), or
a total bilirubin >or=1.5×ULN (unless secondary to Gilbert's syndrome), or direct bilirubin >ULN in subjects with Gilbert's syndrome at Screening.
16. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, as calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (Levey AS, et al. 2009) at Screening.
17. History of any blood disorder, other than sickle cell trait, causing hemolysis or unstable red blood cells (eg, malaria, babesiosis, hemolytic anemia, thalassemia, sickle cell anemia).
18. Subjects with documented DI.
19. Subjects with Type 1 diabetes mellitus.
20. Subjects with Type 2 diabetes mellitus who:
• Are poorly controlled, defined as glycosylated hemoglobin A1c (HbA1c) >9% at Screening; OR
• Are taking short-acting insulin. Use of a stable dose [>or=12 weeks prior to Screening] of the following medications, (or any combination of the following medications) is permitted: glucagon like peptide 1 analog, metformin, sulfonylurea, dipeptidyl peptidase-4 inhibitor, and single basal insulin, sodium glucose co-transporter 2 (SGLT2) inhibitors and pioglitazone.
21. Routine or anticipated treatment with any systemic corticosteroid. Use of topical, inhaled, intra articular or nasal corticosteroids is
permitted.
22. Clinical evidence of thyroid disease, thyroid hormone therapy that is not stable or=4 weeks prior to Screening, or a thyroid-stimulating
hormone (TSH) level <0.75×lower limit of normal or >1.5×ULN at Screening.
23. History of alcohol or drug abuse (including opioid overuse/misuse) within the 3 months prior to Screening that would interfere with study participation or lead to decreased compliance to study procedures or IP intake in the investigator's opinion.
[Please refer to the protocol as regards the other exclusion criteria] |
1. HTN secondaria nota o sospetta (ad es. iperaldosteronismo, HTN renovascolare, feocromocitoma, malattia di Cushing).
2. AOBP sistolica >or=180 mmHg o DBP >or=110 mmHg alla Visita di screening o di inclusione (Visita 2B, Giorno 1) e confermata da una seconda misurazione entro 30 minuti fino a 1 ora.
3. Retinopatia ipertensiva nota (di grado 3 o 4 di Keith-Wagener) e/o encefalopatia ipertensiva.
4. Circonferenza della parte superiore del braccio al di fuori dei limiti del manicotto per la PA fornito dallo studio associato al dispositivo di misurazione dell’ABPM e/o AOBP.
5. Anamnesi di angioedema spontaneo o farmaco-indotto.
6. Anamnesi di qualsiasi allergia o ipersensibilità correlata al farmaco a qualsiasi componente dell’IP (firibastat [QGC001] o del placebo).
7. Stenosi aortica grave nota (sintomatica o asintomatica con superficie valvolare indicizzata <0,5 cm²/m²).
8. Soggetti con grave insufficienza cardiaca sintomatica (classe III o IV secondo la New York Heart Association [NYHA]).
9. Anamnesi di sindrome coronarica acuta (infarto miocardico [IM] con elevazione non ST, IM con elevazione ST e angina pectoris instabile), ictus o attacco ischemico transitorio nei 6 mesi precedenti la Visita 2A, Giorno 0.
10. Anamnesi nota di sindrome da malassorbimento o intervento chirurgico gastrointestinale, comprese le procedure bariatriche che inducono malassorbimento cronico, entro 2 anni dallo screening.
11. Trattamento con farmaci o procedure anti-obesità 3 mesi prima dello screening (ovvero, intervento chirurgico, regime dietetico aggressivo, ecc.), con conseguente instabilità del peso corporeo.
12. Donne che allattano al seno o in gravidanza o che prevedono di avviare una gravidanza durante il periodo dello studio.
13. Anamnesi medica di tumore (ad eccezione del carcinoma basocellulare) e/o trattamento oncologico negli ultimi 3 anni.
14. Lavoratori a turni che dormono regolarmente durante il giorno e/o le cui ore di lavoro includono la mezzanotte.
15. Soggetti con insufficienza epatica da moderata a grave (classificazione di Child-Pugh A, B o C); alanina aminotransferasi (ALT), aspartato aminotransferasi (AST) o fosfatasi alcalina (ALP) >3× limite superiore della norma (Upper Limit of Normal, ULN) o bilirubina totale >or=1,5× ULN (a meno che non sia secondaria alla sindrome di Gilbert) o bilirubina diretta >ULN in soggetti con sindrome di Gilbert allo screening.
16. Velocità di filtrazione glomerulare stimata (eGFR) <30 ml/min/1,73 m2, calcolata utilizzando la Formula di collaborazione epidemiologica per la malattia renale cronica (CKD-EPI) (Levey AS, et al. 2009) allo screening.
17. Anamnesi di qualsiasi disturbo del sangue, diverso dal tratto a cellule falciformi, che causa emolisi o globuli rossi instabili (ad es., malaria, babesiosi, anemia emolitica, talassemia, anemia a cellule falciformi).
18. Soggetti con DI documentato.
19. Soggetti con diabete mellito di tipo 1.
20. Soggetti con diabete mellito di tipo 2 che:
• sono scarsamente controllati, definito come livelli di emoglobina glicosilata A1c (HbA1c) >9% allo screening; OPPURE
• stanno assumendo insulina a breve durata d’azione. È consentito l’uso di una dose stabile [>or=12 settimane prima dello screening] dei seguenti farmaci (o di una qualsiasi combinazione dei seguenti farmaci): analoghi del peptide glucagone-simile 1, metformina, sulfonilurea, inibitori della dipeptidil peptidasi-4 e insulina basale singola, inibitori del co-trasportatore sodio-glucosio 2 (Sodium-Glucose co-Transporter 2, SGLT2) e pioglitazone.
21. Trattamento di routine o previsto con qualsiasi corticosteroide sistemico. È consentito l’uso di corticosteroidi topici, inalatori, intra-articolari o nasali.
[Si prega di fare riferimento alla sinossi del protocollo in italiano per i restanti criteri di esclusione]. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the change from baseline in systolic AOBP at Week 12. |
| L’endpoint primario di efficacia è la variazione rispetto al basale della AOBP sistolica alla Settimana 12. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- AOBP at every visit.
- 24-hour ambulatory BP monitoring (ABPM) assessed at baseline and after 12 weeks (end of double-blind period [Period 1]).
- Biomarker N-terminal pro-B-type natriuretic peptide (NT-ProBNP) - change from baseline to Visit 4B, Day 85 (±3 d).
- Proportion of subjects requiring an increase in the dose of current antihypertensive drugs or addition of another hypertensive drug during the open-label treatment periods (Periods 2 and 3) of the study. |
- AOBP ad ogni visita.
- PA monitorata in modo continuo nelle 24 ore dopo 12 settimane (fine del periodo in doppio cieco [Periodo 1]).
- Biomarcatore NT-ProBNP alla Visita 2B, Giorno 1 e Visita 4B, Giorno 85 (±3 gg) rispetto al basale.
- Percentuale di soggetti che richiede un aumento della dose di farmaci antipertensivi attuali o l’aggiunta di un altro farmaco antipertensivo durante i periodi di trattamento in aperto (Periodo 2 e 3) dello studio. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- AOBP at every visit.
- 24-hour ambulatory BP at baseline and after 12 weeks.
- Biomarker NT-ProBNP at Visit 2B, Day 1, and Visit 4B, Day 85 (±3 d). |
- AOBP ad ogni visita.
- PA monitorata per 24 ore in ambulatorio al basale e dopo 12 settimane.
- Biomarcatore NT-ProBNP alla Visita 2B, Giorno 1, e Visita 4B, Giorno 85 (±3 d). |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Studio di efficacia in aperto e di sicurezza a lungo termine. |
| Open-label Efficacy and Long-term Safety Study. |
|
| 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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 | Information not present in EudraCT |
| 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 |
| Canada |
| Korea, Republic of |
| Russian Federation |
| Taiwan |
| United States |
| Belgium |
| France |
| Hungary |
| Italy |
| Poland |
| Slovakia |
| Spain |
| Czechia |
|
| 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. |
| Ultima visita dell'ultimo soggetto. |
|
| 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 | 25 |
| 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 | 25 |
Print
