For each subject, the study will include a Screening Visit, a Run-in Period, an Inclusion Visit (Visit 2A, Day 0, and Visit 2B, Day 1), and up to 3 study treatment periods with clinic visits and safety phone calls.
Screening assessments will be performed at Visit 1, Day -28. Eligible subjects will then enter the Run-in Period, during which medication adherence will be assessed via a medication diary. The duration of the Run in Period will be no less than 28 days and no more than 33 days; this time period allows for 2 repeat ambulatory BP monitoring (ABPM) recordings at Visit 2A, if required.
Subjects who meet the inclusion/exclusion criteria at the end of the Run in Period will be randomly assigned to either Group A or Group B. A total of 200 subjects (100 in Group A and 100 in Group B) will be randomized to continue treatment with firibastat (QGC001) during Period 3. Subjects will receive either double-blind firibastat (QGC001) or placebo for the first 12-week study treatment period (Period 1), followed by open label treatment with firibastat for 24 weeks (Period 2), or 36-weeks (Period 2 plus an additional 12-weeks of open-label treatment in Period 3).
At Visit 2A, Day 0, an ABPM device will be installed for each subject who has successfully completed the Run-in Period with a medication adherence ≥80%, and remains eligible to participate in the study. The ABPM device will be set to record for at least 24 hours, with the measurement frequency set at 30-minute intervals during the day (8:00 am to 10:00 pm \[theoretically 28 readings, 2 per hour\]) and 60-minute intervals at night (10:00 pm to 8:00 am \[theoretically 10 readings, 1 per hour\]). Subjects must have a successful ABPM measurement prior to being randomized and starting treatment with investigational product (IP) at Visit 2B, Day 1. An ABPM recording is considered successful if at least 21 daytime readings and 6 nighttime readings have been successfully recorded. A duration of less than 24 hours (e.g., 23 hours and 30 minutes) would be acceptable for a successful ABPM recording providing it successfully confirms 21 daytime readings and 6 nighttime readings. If the ABPM recording is not successful, 2 further attempts are permitted.
Following a successful ABPM recording (assessed at Visit 2B, Day 1), subjects who still meet the inclusion/exclusion criteria and who have a mean daytime systolic ambulatory blood pressure (ABP) \>135 mmHg, will undergo visit-specific assessments and will be randomized to Group A or Group B, and receive either firibastat (QGC001) or placebo for the 12-week double-blind treatment period (Period 1), followed by open label firibastat for 24 weeks (Period 2), or 36 weeks (Period 2 plus Period 3 \[200 subjects\]), in addition to their current chronic antihypertensive treatments.
During Period 1, the investigator (or designee) will call subjects by telephone on Day 14 (±3 d) to collect any potential adverse events (AEs), check IP compliance, and record any concomitant medications. Subjects will receive a second safety phone call during Period 2, at Day 98 (±3 d).
Subjects will attend the study site for the following study visits:
Period 1: Visit 2A, Day 0; Visit 2B, Day 1; Visit 3, Day 42 (±3 d); Visit 4A, Day 84 (±3 d); and Visit 4B, Day 85 (±3 d).
Period 2: Visit 5, Day 126 (±3 d); Visit 6, Day 168 (±3 d); Visit 7, Day 252 (±3 d); and Visit 8, Day 280 (±3 d).
Period 3:Visit 9, Day 336 (±3 d), and Visit 10, Day 364 (±3 d). On completion of their final study treatment period, subjects will attend an End of Treatment (EOT) Visit. A safety follow-up will be performed at the End of Study (EOS) Visit.
For subjects who stop study treatment at the end of Period 2, the EOT Visit will be at Visit 7, Day 252 (±3 d), and the EOS Visit will be Visit 8, Day 280 (±3 d).
Subjects who continue study treatment into Period 3 will not attend Visit 8, Day 280 (±3 d). Subjects who stop treatment with firibastat (QGC001) after Period 3 will attend an EOT Visit at Visit 9, Day 336 (±3 d), and an EOS Visit at Visit 10, Day 364 (±3 d).
Subjects who discontinue the study early should undergo an Early Termination Visit, and an EOS visit 28 days (±3 d) after the last dose of IP (except in the case of consent withdrawal).
Each subject will be assigned to one of 5 pharmacokinetic (PK) subgroups; 50 subjects (at selected sites) will undergo an enhanced PK sampling schedule (6 PK samples will be collected according to the PK subgroup sampling schedule), and 700 subjects will be assigned to the standard PK sampling schedule (2 PK samples will be collected according to the PK subgroup sampling schedule).
At each study visit, AOBP, orthostatic BP, and heart rate (HR) will be measured, and other visit-specific procedures will be performed, including electrocardiograms (ECGs), clinical laboratory evaluations, clinical examinations, collection of blood for PK samples and the biomarker N terminal pro-B-type natriuretic peptide (NT-ProBNP), and monitoring of AEs and concomitant medications. At the EOS Visit (safety follow-up) assessments will include clinical examination, AOBP, orthostatic BP, ECG, HR, and clinical laboratory assessments, AE monitoring, and concomitant medications.
Allergic skin reactions and/or diabetes insipidus (DI) are considered adverse events of special interest (AESIs) with immediate notification during the study treatment period.
