Efficacy and Safety of GMRx2 Compared to Dual Combinations for the Treatment of Hypertension

Inclusion Criteria: At screening visit

1. Provided signed consent to participate in the trial.
2. Adult of age ≥18 years.
3. Attended automated clinic seated mean SBP (average of last 2 measurements calculatedby the device):

140-179 mmHg on 0 blood pressure (BP)-lowering drugs, or 130-170 mmHg on 1 BP-loweringdrug, or 120-160 mmHg on 2 BP-lowering drugs, or 110-150 mmHg on 3 BP-lowering drugs. At randomization visit

1. Home seated mean SBP 110-154 mmHg in the week prior to the randomization visit .
2. Adherence of 80-120% to run-in medication.
3. Tolerated run-in medication.
4. Adherence to home BP monitoring schedule: ≥3 days in the week before the randomizationvisit and ≥1 day per week during the preceding weeks, , with ≥2 measures in thespecified morning and evening time periods on each day (i.e. accepting measuresoutside of the recommended 0600-1000 and 1800-2200 periods as long as they are in theam or pm, respectively). At week 12 (for optional open-label extension)
5. Provided signed informed consent.
6. completed randomized treatment and willing to continue GMRx2-based regimen for up to 12 months.

Exclusion Criteria: At screening visit

1. Receiving 4 or more BP-lowering drugs.
2. receiving any BP lowering drugs for indications other than hypertension e.g. heartfailure
3. Pregnant or had a positive pregnancy test or unwilling to undertake a pregnancy testduring the trial and up to 30 days after the discontinuation of the trial medicationor breastfeeding or of childbearing age and not using an acceptable method ofcontraception. Acceptable methods of birth control include hormonal prescription oralcontraceptives, contraceptive injections, contraceptive patch, intrauterine device,double-barrier method (e.g. condoms, diaphragm, or cervical cap with spermicidal foam,cream, or gel), or male partner sterilization. Contraception should be used for atleast 1 month before the screening visit and until the end of trial participation.
4. Not suitable for participation in a clinical trial according to local ethical orregulatory requirements related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).
5. Contraindication, including hypersensitivity (e.g. anaphylaxis or angioedema), to theactive run-in treatment or to any of the trial medication options in the fourrandomized groups.
6. Current/history of transient ischemic attack, stroke, or hypertensive encephalopathy.
7. Current/history of acute coronary syndrome, unstable angina, myocardial infarction,percutaneous transluminal coronary revascularization, or coronary artery bypass graft.
8. Current atrial fibrillation. Patients with a history of paroxysmal atrial fibrillationare potentially eligible as long as there has been no episode in the last 3 months,while patient with a history of persistent or permanent atrial fibrillation are noteligible.
9. Current/history of New York Heart Association class III and IV congestive heartfailure.
10. Current/history of a known secondary cause of hypertension, such as primaryaldosteronism, renal artery stenosis, pheochromocytoma, or Cushing's syndrome.
11. Current/history of substantially uncontrolled diabetes (HbA1c > 11.0%) within lastthree months.
12. Current/history of end-stage renal disease or anuria or estimated glomerularfiltration rate (eGFR) <60 ml/min/1.73m2.
13. Electrolyte levels that would be regarded as contraindications for any of thepotential treatment arms e.g. serum sodium <132mmol/l or >148mmol/l serum potassium <3.1 mmol/l or >5.6 mmol/l.
14. Current/history of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times the upper limit of normal range within 6 months.
15. Current concomitant illness or physical impairment or mental condition that in thejudgment of the investigator could interfere with the effective conduct of the trialor constitutes a significant risk to the participants' well-being.
16. Arm circumference that is too large (>55 cm) or too small (<20 cm) to allow accuratemeasurement of BP.
17. Currently taking or might need during the trial, a concomitant treatment which isknown to interact with one or more of the trial medications: digoxin, lithium,diabetics receiving aliskiren, moderate and strong CYP3A4 inhibitors (e.g. ritonavir,ketoconazole, diltiazem], simvastatin >20 mg/day, immunosuppressants.
18. Might need treatment with drugs that are prohibited during the trial: otherantihypertensive drugs, endothelin receptor antagonists, neprilysin inhibitors, orother drugs that may affect BP (see Appendix 5).
19. Current surgical or medical condition that might significantly alter the absorption,distribution, metabolism, or excretion of trial drugs such as prior majorgastrointestinal tract surgery (e.g. gastrectomy, lap band, or bowel resection) oracute flare of inflammatory bowel disease within one year.
20. Individuals working >2 nightshifts per week.
21. Participated in any investigative drug or device trial within the previous 30 days.
22. History of alcohol or drug abuse within 12 months. At randomization visit
23. Unable to adhere to the trial procedures during the run-in treatment period.
24. Any of the following which in the investigator's judgment may compromise the safety ofthe participant if randomized to the trial medications:
25. High or low clinic BP levels even in the light of the values for home BP that areavailable for that participant. The exact levels of BP are not specified, sincethere is clinical uncertainty as to the relevance of BP levels which are high orlow in clinic only; for example, the clinical relevance of 'whitecoathypertension' is uncertain.
26. High or low home diastolic BP (DBP) levels. The exact levels of DBP is notspecified, reflecting clinical uncertainty of the implications of isolateddiastolic hypertension. However, home DBP values of >99 mmHg may typically beconsidered as requiring treatment intensification, and such participants wouldnot be suitable for randomization.
27. Any abnormal laboratory value which in the judgment of the investigator couldinterfere with the effective conduct of the trial or constitutes a significant risk tothe participants' well-being.
28. Fulfilling any of the exclusion criteria mentioned for the screening visit, whenverified again at randomization visit.