E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of hypertension (HTN) in difficult-to-treat and/or treatment resistant patients |
|
E.1.1.1 | Medical condition in easily understood language |
Treatment of high blood pressure in difficult-to-treat and/or treatment resistant patients |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
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 |
The primary objective is to assess the effects of administration of firibastat (QGC001) 500 mg oral (po) twice daily (bis in die [bid]) on blood pressure (BP) over 12 weeks in subjects with uncontrolled primary HTN despite being treated with 2 classes of antihypertensive therapies, at the maximum tolerated doses (MTDs). The secondary objective is to assess the safety of firibastat (QGC001). |
|
E.2.2 | Secondary objectives of the trial |
The secondary objective is to assess the safety of firibastat (QGC001). |
|
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. Men and women ≥18 years of age 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-to-treat 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 site effects), with no change in their antihypertensive regimen (drug dose or schedule) for at least 6 weeks and with medication adherence ≥80% during the Run-in Period. • Have a systolic AOBP between 140 mmHg and 180 mmHg (inclusive) at Screening while on their current chronic antihypertensive treatments. • Have a successful ABPM measurement according to the criteria in Section 6.2.2.1, with a mean systolic daytime ABP >135 mmHg after the Run-in Period while on their current chronic antihypertensive treatments. 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 postdose. Approved forms of contraception include hormonal intrauterine devices, hormonal contraceptives (oral birth control pills, depo, patch, or injectable) together with supplementary double barrier methods such as condoms or diaphragms with spermicidal gel or foam. Note: The following categories define women who are NOT considered to be of childbearing potential: • Premenopausal women with 1 of the following: o Documented hysterectomy o Documented bilateral salpingectomy o Documented bilateral oophorectomy OR • Postmenopausal women, defined as having amenorrhea for at least 12 months without an alternative medical cause. 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 2, Day 1). |
|
E.4 | Principal exclusion criteria |
1. Known or suspected secondary HTN (eg, hyperaldosteronism, renovascular HTN, pheochromocytoma, Cushing's disease). 2. Automated office SBP >170 mmHg or DBP >110 mmHg at the Screening or Inclusion Visit (Visit 2, 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 study provided BP cuff associated with either the ABPM and/or AOBP measurement device. 5. History of spontaneous or drug-induced angioedema. 6. History of 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 HF (NYHA Class III or Class IV). 9. History of acute coronary syndrome (non-ST elevation MI, ST elevation MI, and unstable angina pectoris), stroke, or transient ischemic attack within 6 months prior to Screening. 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 antiobesity 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 B or C); alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) >3×upper limit of normal (ULN), or a total bilirubin ≥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)41 formula at Screening. 17. History of any blood disorder, other than sickle cell trait, causing hemolysis or unstable red blood cells (eg, malaria, babesiosis, hemolytic 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(≥12 weeks prior to Screening) of medications listed in Section 7.7.1 is permitted. 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 ≥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. 24. Participation in another clinical study involving an investigational drug within 30 days prior to Screening or plans to participate in another clinical study within 30 days of discontinuation of IP. 25. Any other condition that precludes adequate understanding, cooperation, and compliance with study procedures or any condition that could pose a risk to the subject's safety, as per the investigator's judgment. 26. Subjects with a life expectancy of less than 1 year per investigator's discretion. 27. Legal incapacity or limited legal capacity. 28. Previous participation in this study. 29. Subjects with any history of documented allergic reactions or allergic diseases, with the exception of documented seasonal allergies (per the investigator's decision). |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the change in systolic AOBP. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline to Week 12 (Visit 5, Day 84). |
|
E.5.2 | Secondary end point(s) |
• Change in diastolic AOBP from baseline to Week 12 (Visit 5, Day 84) • Change in systolic and diastolic AOBP from baseline to Week 4 (Visit 3, Day 28) and Week 8 (Visit 4, Day 56) • Change in mean 24-hour ambulatory SBP and DBP from baseline to Week 12 (Visit 5, Day 84) • Percentage of controlled subjects (defined as subjects with normalized AOBP, ie, <140/90 mmHg at Week 12 [Visit 5, Day 84]) (as per European Society of Cardiology [ESC]/European Society of Hypertension [ESH] guidelines) • Percentage of controlled subjects (defined as subjects with normalized AOBP, ie, <130/80 mmHg at Week 12 [Visit 5, Day 84]) (as per 2017 American College of Cardiology [ACC]/American Heart Association [AHA] guidelines) • Predictive factors for controlled subjects at Week 12 (Visit 5, Day 84) • Change from baseline in plasma concentration of Biomarkers NT-ProBNP |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
From baseline to Week 12 (Visit 5, Day 84). |
|
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 | No |
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 | 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 | 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 | 50 |
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 |
Brazil |
Canada |
Mexico |
United States |
Bulgaria |
France |
Germany |
Hungary |
Poland |
Slovakia |
Spain |
Czechia |
|
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
|
|
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 | 8 |
E.8.9.1 | In the Member State concerned days | 15 |
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 | 8 |
E.8.9.2 | In all countries concerned by the trial days | 15 |