Efficacy and Safety of GMRx2 Compared to Placebo for the Treatment of Hypertension

Inclusion Criteria At screening visit:

1. Provided signed consent to participate in the trial.
2. Adult aged ≥18 years.
3. Low calculated CV risk according to local guidelines such that pharmacologicalBP-lowering treatment is not mandatory: e.g. Pooled Cohorts Equation 10-years ASCVDrisk <10% in the USA.
4. Likely diagnosis of hypertension, defined as one or more of:

• automated SBP at this clinic visit according to trial methods (see Appendix 2) of ≥130mmHg on no BP lowering medicines or ≥120mmHg on 1 BP lowering medicine thatwill be stopped at this visit, OR
• documentation in last 6 months of office SBP ≥ 140 mmHg and/or DBP ≥ 90mmHg on noBP lowering medicines or SBP ≥ 130 mmHg and/or DBP ≥ 85mmHg on 1 BP loweringmedicine that will be stopped at this visit, OR
• documentation in last 6 months of home SBP ≥ 130 mmHg and/or DBP ≥ 80mmHg on noBP lowering medicines or SBP ≥ 120 mmHg and/or DBP ≥ 75mmHg on 1 BP loweringmedicine that will be stopped at this visit, OR
• documentation in last 6 months of ambulatory daytime SBP ≥ 130 mmHg and/or DBP ≥ 80mmHg on no BP lowering medicines or SBP ≥ 120 mmHg and/or DBP ≥ 75mmHg on 1 BPlowering medicine that will be stopped at this visit

5. No contraindication to trial medications, including 2-weeks placebo run-in and 4-weeksrandomized treatment period with GMRx2 (dose version 1 or 2) or placebo. At randomization visit:
6. Home seated mean SBP 130-154 mmHg in the week before the randomization visit.
7. Adherence of 80-120% to placebo run-in.
8. Tolerated placebo run-in.
9. Adherence to home BP monitoring schedule: in the week before randomization, at least 6measures (e.g. ≥2 sets of triplicate measures) including at least 1 morning and 1evening each with ≥2 measures. Morning is defined as any measure in the am and eveningas any measure in the pm. Morning and evening do not have to be same day.

Exclusion Criteria: At screening visit:

1. Receiving 2 or more BP-lowering drugs.
2. Clinic seated mean SBP ≥160 mmHg and/or DBP ≥100 mmHg.
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 anyof the 3 trial medications.
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/history of New York Heart Association class III and IV congestive heartfailure.
9. Current/history of a known secondary cause of hypertension, such as primaryaldosteronism, renal artery stenosis, pheochromocytoma, or Cushing's syndrome.
10. Current/history of substantially uncontrolled diabetes (HbA1c > 11.0%) within lastthree months.
11. Current/history of end-stage renal disease or anuria or estimated glomerularfiltration rate (eGFR) <60 ml/min/1.73m2.
12. Current/history of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times the upper limit of normal range within 6 months.
13. 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.
14. Arm circumference that is too large (>55 cm) or too small (<20 cm) to allow accuratemeasurement of BP.
15. Currently taking or might need during the trial, a concomitant treatment which isknown to interact significantly with the trial medication: digoxin, lithium, diabeticsreceiving aliskiren, moderate and strong CYP3A4 inhibitors [e.g. ritonavir,ketoconazole, diltiazem], simvastatin >20 mg/day, immunosuppressants.
16. 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 Error! Reference source not found.).
17. 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.
18. Individuals working >2-night shifts per week.
19. Participated in any investigational drug or device trial within the previous 30 days.
20. History of alcohol or drug abuse within 12 months. At randomization visit:
21. Unable to adhere to the trial procedures during the run-in period.
22. Any of the following which in the investigator's judgment may compromise the safety ofthe participant if randomized to the trial medications:
23. 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/lowin clinic only; for example the clinical relevance of 'whitecoat hypertension' isuncertain.
24. High or low home DBP levels. The exact levels of DBP are not specified,reflecting clinical uncertainty of for example isolated diastolic hypertension.However, home DBP values of >99 mmHg may typically be considered as requiringtreatment intensification, and such participants would not be suitable forrandomization.
25. 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.
26. Fulfilling any of the exclusion criteria mentioned for the screening visit, whenverified again at randomization visit.