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 systolic blood pressure (SBP) (average of last 2 measurements calculated by the device): 140-179 mmHg on 0 BP-lowering drugs, or 130-170 mmHg on 1 BP-lowering drug, 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: in the week before randomization, at least 6 measures (e.g. ≥2 sets of triplicate measures, ≥3 sets of duplicate measures) including at least 1 morning and 1 evening each with ≥2 measures. Morning is defined as any measure in the am and evening as any measure in the pm. Morning and evening do not have to be same day. 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. heart failure 3. Pregnant or had a positive pregnancy test or unwilling to undertake a pregnancy test during the trial and up to 30 days after the discontinuation of the trial medication or breastfeeding or of childbearing age and not using an acceptable method of contraception. Acceptable methods of birth control include hormonal prescription oral contraceptives, 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 at least 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 or regulatory requirements related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). 5. Contraindication, including hypersensitivity (e.g. anaphylaxis or angioedema), to the active run-in treatment or to any of the trial medication options in the four randomized 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 fibrillation are 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 not eligible. 9. Current/history of New York Heart Association class III and IV congestive heart failure. 10. Current/history of a known secondary cause of hypertension, such as primary aldosteronism, renal artery stenosis, pheochromocytoma, or Cushing's syndrome. 11. Current/history of substantially uncontrolled diabetes (HbA1c \> 11.0%) within last three months. 12. Current/history of end-stage renal disease or anuria or estimated glomerular filtration rate (eGFR) \<60 ml/min/1.73m2. 13. Electrolyte levels that would be regarded as contraindications for any of the potential 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 the judgment of the investigator could interfere with the effective conduct of the trial or constitutes a significant risk to the participants' well-being. 16. Arm circumference that is too large (\>55 cm) or too small (\<15-24 cm) to allow accurate measurement of BP. 17. Currently taking or might need during the trial, a concomitant treatment which is known 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: other antihypertensive drugs, endothelin receptor antagonists, neprilysin inhibitors, or other drugs that may affect BP. 19. Current surgical or medical condition that might significantly alter the absorption, distribution, metabolism, or excretion of trial drugs such as prior major gastrointestinal tract surgery (e.g. gastrectomy, lap band, or bowel resection) or acute 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 1. Unable to adhere to the trial procedures during the run-in treatment period. 2. Any of the following which in the investigator's judgment may compromise the safety of the participant if randomized to the trial medications: 1. High or low clinic BP levels even in the light of the values for home BP that are available for that participant. The exact levels of BP are not specified, since there is clinical uncertainty as to the relevance of BP levels which are high or low in clinic only; for example, the clinical relevance of 'whitecoat hypertension' is uncertain. 2. High or low home diastolic BP (DBP) levels. The exact levels of DBP is not specified, reflecting clinical uncertainty of the implications of isolated diastolic hypertension. However, home DBP values of \>99 mmHg may typically be considered as requiring treatment intensification, and such participants would not be suitable for randomization. 3. Any abnormal laboratory value which in the judgment of the investigator could interfere with the effective conduct of the trial or constitutes a significant risk to the participants' well-being. 4. Fulfilling any of the exclusion criteria mentioned for the screening visit, when verified again at randomization visit.