Randomized Study of Extended Treatment With Firibastat in Treatment-Resistant Hypertension (REFRESH)

Inclusion Criteria:

• Able to understand and willing to provide written informed consent, and able to complywith the study procedures and restrictions.
• Adult men and women (at Screening).
• Diagnosis of primary HTN for at least 6 months prior to Screening and:
• Currently treated with 2 antihypertensive classes of drug (difficult-to-treatsubjects), or currently treated with at least 3 antihypertensive classes of drugincluding a diuretic (treatment resistant subjects), at the MTDs of thosemedications (ie, the subject can tolerate the current dose of each medication buthigher doses have caused or may worsen side effects), with no change in theirantihypertensive regimen (drug, dose, or schedule) for at least 6 weeks, and withmedication adherence ≥80% during the Run in Period.
• Have a systolic AOBP between 140 mmHg and 179 mmHg (inclusive) at Screening whileon their current chronic antihypertensive treatments.
• Have a successful ABPM measurement with a mean systolic daytime ABP >135 mmHgafter the Run-in Period while on their current chronic antihypertensivetreatments. An ABPM is successful if at least 21 daytime readings and 6 nighttimereadings have been successfully recorded.
• Women of childbearing potential and nonsurgically sterile male subjects who aresexually active must agree to use an approved highly effective form of contraceptionfrom the time of informed consent until 30 days post dose. Approved forms ofcontraception include hormonal intrauterine devices, hormonal contraceptives (oralbirth control pills, depo, patch, or injectable) together with supplementary barriermethods such as condoms or diaphragms with spermicidal gel or foam.
• Women of childbearing potential must have a negative serum pregnancy test result atScreening and a negative urine pregnancy test result at the Inclusion Visit (Visit 2B,Day 1)

Exclusion Criteria:

• Target population: Subjects with uncontrolled primary HTN despite being treated with at least 2 classes ofantihypertensive therapies, at the MTDs (difficult-to-treat or treatment-resistantpatients). Inclusion criteria: Subjects who meet all of the following criteria will be eligible to participate in thestudy:

1. Able to understand and willing to provide written informed consent, and able to complywith 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-to-treatsubjects), or currently treated with at least 3 antihypertensive classes of drugincluding a diuretic (treatment resistant subjects), at the MTDs of thosemedications (ie, the subject can tolerate the current dose of each medication buthigher doses have caused or may worsen side effects), with no change in theirantihypertensive regimen (drug, dose, or schedule) for at least 6 weeks, and withmedication adherence ≥80% during the Run in Period.
• Have a systolic AOBP between 140 mmHg and 179 mmHg (inclusive) at Screening whileon their current chronic antihypertensive treatments.
• Have a successful ABPM measurement with a mean systolic daytime ABP >135 mmHgafter the Run-in Period while on their current chronic antihypertensivetreatments. An ABPM is successful if at least 21 daytime readings and 6 nighttimereadings have been successfully recorded.

4. Women of childbearing potential and nonsurgically sterile male subjects who aresexually active must agree to use an approved highly effective form of contraceptionfrom the time of informed consent until 30 days post dose. Approved forms ofcontraception include hormonal intrauterine devices, hormonal contraceptives (oralbirth control pills, depo, patch, or injectable) together with supplementary barriermethods such as condoms or diaphragms with spermicidal gel or foam.
5. Women of childbearing potential must have a negative serum pregnancy test result atScreening and a negative urine pregnancy test result at the Inclusion Visit (Visit 2B,Day 1). Exclusion criteria: Subjects who meet any of the following criteria will be excluded from participation in thestudy:
6. Known or suspected secondary HTN (eg, hyperaldosteronism, renovascular HTN,pheochromocytoma, Cushing's disease).
7. Systolic AOBP ≥180 mmHg or DBP ≥110 mmHg at the Screening or Inclusion Visit (Visit 2B, Day 1) and confirmed by a second measurement within 30 minutes to 1 hour.
8. Known hypertensive retinopathy (Keith-Wagener Grade 3 or Grade 4) and/or hypertensiveencephalopathy.
9. Upper arm circumference that is outside the limits of the study-provided BP cuffassociated with either the ABPM and/or AOBP measurement device.
10. History of spontaneous or drug-induced angioedema.
11. History of any drug-related allergy or hypersensitivity to any components of the IP (firibastat [QGC001] or placebo).
12. Known severe aortic stenosis (symptomatic or asymptomatic with valvular indexedsurface <0.5 cm²/m²).
13. Subjects with severe symptomatic heart failure (New York Heart Association [NYHA]Class III or Class IV).
14. History of acute coronary syndrome (non-ST elevation myocardial infarction [MI], STelevation MI, and unstable angina pectoris), stroke, or transient ischemic attackwithin 6 months prior to Visit 2A, Day 0.
15. Known history of malabsorption syndrome, or has undergone gastrointestinal surgery,including bariatric procedures that induce chronic malabsorption, within 2 years ofScreening.
16. Treatment with anti-obesity drugs or procedures 3 months prior to Screening (ie,surgery, aggressive diet regimen, etc.), leading to unstable body weight.
17. Female who is breastfeeding, pregnant, or planning to become pregnant during the studyperiod.
18. Medical history of cancer (except for basal cell carcinoma) and/or treatment forcancer within the last 3 years.
19. Shift workers who routinely sleep during the daytime and/or whose work hours includemidnight.
20. Subjects with moderate to severe hepatic impairment (Child-Pugh A, B, or C); alanineaminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) >3×upper limit of normal (ULN), or a total bilirubin ≥1.5×ULN (unless secondaryto Gilbert's syndrome), or direct bilirubin >ULN in subjects with Gilbert's syndromeat Screening.
21. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, as calculated usingthe Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (Levey AS, etal. 2009) at Screening.
22. History of any blood disorder, other than sickle cell trait, causing hemolysis orunstable red blood cells (eg, malaria, babesiosis, hemolytic anemia, thalassemia,sickle cell anemia).
23. Subjects with documented DI.
24. Subjects with Type 1 diabetes mellitus.
25. Subjects with Type 2 diabetes mellitus who:

• Are poorly controlled, defined as glycosylated hemoglobin A1c (HbA1c) >9% atScreening; OR
• Are taking short-acting insulin. Use of a stable dose [≥12 weeks prior toScreening] of the following medications, (or any combination of the followingmedications) is permitted: glucagon like peptide 1 analog, metformin,sulfonylurea, dipeptidyl peptidase-4 inhibitor, and single basal insulin, sodiumglucose 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 ≥4weeks prior to Screening, or a thyroid-stimulating hormone (TSH) level <0.75×lowerlimit of normal or >1.5×ULN at Screening.
23. History of alcohol or drug abuse (including opioid overuse/misuse) within the 3 monthsprior to Screening that would interfere with study participation or lead to decreasedcompliance to study procedures or IP intake in the investigator's opinion.
24. Participation in another clinical study involving an investigational drug within 30days prior to Screening or plans to participate in another clinical study within 30days of discontinuation of IP.
25. Any other condition that precludes adequate understanding, cooperation, and compliancewith 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 any clinical study with firibastat (QGC001).
29. Subjects with any history of documented allergic reactions or allergic diseases, withthe exception of documented seasonal allergies (per the investigator's decision).