Date

2022-05-11

Protocol

Protocol changed

Item Changed

Exclusion criteria

Previous Version

At screening visit 1. Receiving 4 or more BP-lowering drugs. 2. 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. 3. 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). 4. 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. 5. Current/history of transient ischemic attack, stroke, or hypertensive encephalopathy. 6. Current/history of acute coronary syndrome, unstable angina, myocardial infarction, percutaneous transluminal coronary revascularization, or coronary artery bypass graft. 7. Current/history of New York Heart Association class III and IV congestive heart failure. 8. Current/history of a known secondary cause of hypertension, such as primary aldosteronism, renal artery stenosis, pheochromocytoma, or Cushing's syndrome. 9. Current/history of substantially uncontrolled diabetes (HbA1c > 11.0%) within last three months. 10. Current/history of end-stage renal disease or anuria or estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2. 11. Current/history of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times the upper limit of normal range within 6 months. 12. 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. 13. Arm circumference that is too large (>55 cm) or too small (<20 cm) to allow accurate measurement of BP. 14. 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. 15. 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 (see Appendix 5). 16. 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. 17. Individuals working >2 nightshifts per week. 18. Participated in any investigative drug or device trial within the previous 30 days. 19. 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: a. 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. b. 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.

Next Version

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 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. Meets any criteria of local ethical or regulatory requirements related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that would deem participation in a clinical trial unsuitable. 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 patients 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 cardiomyopathy or any other cardiovascular condition of sufficient severity to contraindicate the trial medications or require a contraindicated medication. 11. Current/history of a known secondary cause of hypertension, such as primary aldosteronism, renal artery stenosis, pheochromocytoma, or Cushing's syndrome. 12. Current/history of severe uncontrolled diabetes (HbA1c > 11.0% (> 97 mmol/mol)) within last three months. 13. Current/history of end-stage renal disease or anuria; or current estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2 14. Current electrolyte levels that would be regarded as contraindications for any of the potential treatment arms e.g. serum sodium <132mmol/l or >148 mmol/l or serum potassium <3.1 mmol/l or >5.6mmol/l. 15. Current/history of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times the upper limit of normal range within 6 months. 16. 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 constitute a significant risk to the participants’ safety or well-being. Arm circumference that is too large or too small for available cuffs to allow accurate measurement of BP. Upper limit is 55cm in all countries, while lower limit is 15cm or 24cm in different countries, depending on available cuff sizes. 18. 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. 19. 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 (see Appendix 5). 20. 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. 21. Individuals working >2 nightshifts per week. 22. Participated in any investigational drug or device trial within the previous 30 days. This does not include participants in the extended safety follow-up portion of a trial. 23. 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: 3. 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. 4. 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. 5. 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. 6. Fulfilling any of the exclusion criteria mentioned for the screening visit, when verified again at randomization visit. At week 12 (for optional open-label extension) 1. Contraindication to open-label GMRx2-based BP-lowering treatment.